NEOFAX NOV 2024 - Epidemiologia (2024)

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Micromedex NeoFax NOV. 2024 I Table of Contents Micormedex NeoFax NOV. 2042 DRUGS Pg Acetaminophen 1 AcetaZOLAMIDE 7 Acetylcysteine 12 Acyclovir 20 Adenosine 27 Albumin 30 Albuterol 38 Alprostadil 47 Alteplase 52 Amikacin 48 Aminocaproic Acid 61 Aminophylline 66 Amiodarone 69 Amoxicillin 77 Amphotericin B Lipid Complex 82 Amphotericin B Liposome 86 Amphotericin B 91 Ampicillin 97 Anidulafungin 107 Arginine 113 Ascorbic Acid 116 Aspirin 119 Atropine 122 Azithromycin 127 Aztreonam 132 Beractant 135 Bevacizumab 139 Bumetanide 145 Bupivacaine 149 Buprenorphine 157 Caffeine Citrate 164 Calcium – Oral 170 Calcium chloride 172 II Calcium gluconate 177 Calfactant 182 Captopril 186 Carglumic Acid 189 Caspofungin 193 CeFAZolin 198 Cefepime 204 Cefotaxime 209 CefOXitin 216 CefTAZidime 219 CefTRIAXone 225 Chloral hydrate 233 Chloramphenicol 235 Chlorothiazide 238 Cimetidine 241 Clindamycin 245 CloNIDine 253 Clopidogrel 258 Colistin 262 Cosyntropin 268 Cyclopentolate (Ophthalmic) 271 Dexamethasone 273 Dextrose 279 Diazoxide 283 Didanosine 289 Digoxin Immune Fab (Ovine) 293 Digoxin 296 DOBUTamine 300 DOPamine 305 Dornase alfa 310 Doxycycline 312 Electrolytes/Minerals 318 Emtricitabine 319 Enalapril maleate 328 Enalaprilat 331 Enoxaparin 334 EPINEPHrine (Adrenaline) 340 Epoetin alfa 348 Erythromycin 353 III Esmolol 358 Factor IX (Recombinant), Fc Fusion Protein 361 Factor VIIa, recombinant 368 Factor X Human 372 Factor XIII Concentrate, Human 376 Famotidine 379 Fat Emulsion 383 FentaNYL 394 Ferrous sulfate 401 Flecainide 403 Fluconazole 406 Flucytosine 413 Flumazenil 416 Folic Acid 419 Fosphenytoin 424 Furosemide 432 Ganciclovir 437 Gentamicin 441 Glucagon 450 Heparin 453 Hepatitis B Immune Globulin (Human) 457 Hepatitis B Vaccine (Recombinant) 459 Hib Conjugate\Hepatitis B Combination Vaccine 462 Hyaluronidase 464 HydrALAZINE 468 HydroCHLOROthiazide 471 Hydrocortisone 473 Ibuprofen 482 Imipenem\Cilastatin 489 Immune Globulin (Human) 494 Indomethacin 504 INFUVITE® Pediatric 509 Insulin Human Regular 513 Ipratropium 517 Iron Dextran 519 Isoproterenol 521 LamiVUDine 524 Lansoprazole 537 LevETIRAcetam 541 IV Levothyroxine 546 Lidocaine – Antiarrhythmic 551 Lidocaine - CNS 555 Lidocaine/Prilocaine 559 Linezolid 562 Lopinavir\Ritonavir 568 LORazepam 578 Lucinactant 583 Magnesium sulfate 587 Mannitol 590 MCT Oil 594 Meropenem 596 Methadone 602 Metoclopramide 609 MetroNIDAZOLE 613 Micafungin 620 Microlipid® 627 Midazolam 629 Milrinone 634 Morphine 640 Moxifloxacin 649 Mupirocin 651 Nafcillin 653 Naloxone 658 Neostigmine 665 Netilmicin 668 Nevirapine 671 NiCARdipine 678 Nitric Oxide 682 Norepinephrine 689 Nystatin 694 Octreotide 697 Omeprazole 700 Oseltamivir 704 Oxacillin 708 Palivizumab 713 Pancuronium 717 Pantoprazole 720 Papaverine 727 V Penicillin G benzathine 729 Penicillin G procaine 733 Penicillin G 736 PENTobarbital 746 PHENobarbital 749 Phentolamine 758 Phenylephrine 760 Phenytoin 762 Piperacillin 769 Piperacillin \Tazobactam 772 Poractant alfa 780 Potassium chloride 784 Potassium Iodide 787 Procainamide 789 Propranolol 792 Protamine 798 Protein C Concentrate (Human) 801 Pyridoxine 804 Quinupristin\Dalfopristin 807 Ranibizumab 810 Ranitidine 815 Rifampin 819 Rocuronium 828 Sildenafil 832 Simethicone 837 Sodium Bicarbonate 839 Sodium Chloride (0.9%) 842 Sodium Glycerophosphate 844 Sodium Nitroprusside 847 Sodium phenylacetate\Sodium benzoate 851 Sotalol 855 Spironolactone 860 Succinylcholine 864 Sucrose 869 THAM acetate 871 Ticarcillin\Clavulanate 873 Tobramycin 876 Topiramate 884 Tropicamide (Ophthalmic) 889 VI Ursodiol 890 ValGANciclovir 893 Vancomycin 898 Varicella-zoster Immune Globulin 911 Vecuronium 914 Multivitamin Drops 917 Vitamin A. 919 Vitamin D 922 Vitamin E 925 Vitamin K1 927 Zidovudine 932 AcetaminophenNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseIntravenousFeverGestational age 32 weeks or more: 12.5 mg/kg/dose IV every 6 hours up to a MAX 50mg/kg/day of all routes of administration [1].Fever/PainOralPreterm infants less than 32 weeks Postmenstrual Age: 20 to 25 mg/kg orally; then12 to 15 mg/kg/dose every 12 hours as needed or around-the-clock.Preterm infants greater than or equal to 32 weeks Postmenstrual Age: 20 to 25mg/kg orally; then 12 to 15 mg/kg/dose every 8 hours as needed or around-the-clock.Term infants: 20 to 25 mg/kg orally; then 12 to 15 mg/kg/dose every 6 hours as needed oraround-the-clock.RectalPreterm infants less than 32 weeks Postmenstrual Age: 30 mg/kg rectally; then 12 to18 mg/kg/dose every 12 hours as needed or around-the-clock.Preterm infants greater than or equal to 32 weeks Postmenstrual Age: 30 mg/kgrectally; then 12 to 18 mg/kg/dose every 8 hours as needed or around-the-clock.Term infants: 30 mg/kg rectally; then 12 to 18 mg/kg/dose every 6 hours as needed oraround-the-clock.Closure of Patent Ductus ArteriosusOral or IVPreterm infants: 15 mg/kg/dose orally or IV every 6 hours for 3 days [2][3]; a secondcourse may be required [4].UsesClosure of patent ductus arteriosus (PDA): NSAIDs (indomethacin and ibuprofen) arethe standard drugs for closure of PDA. However, there are risks to NSAIDs and there is a highrate of spontaneous closure; therefore, treatment should be limited to select pretermnewborns with symptomatic PDA [8][9]. Acetaminophen may be a treatment option in thosehaving NSAID failure or contraindications to NSAIDs [10]. IV acetaminophen may be anoption in those who have a contraindication to feeding, or who have feeding intolerance[11][4]. Oral acetaminophen appears as effective as ibuprofen, but long-term safety trials areneeded [3].A systematic review and meta-analysis of studies of preterm (less than 37 weeks1postmenstrual age) or low birth weight (less than 2500 g at birth) infants reported nosignificant difference in the rate of failure of PDA closure after first course of treatment forthe following comparisons: Acetaminophen (oral or IV) vs ibuprofen (oral or IV; 18 studies,1535 patients), and acetaminophen (oral or IV) vs indomethacin (IV; 4 studies, 380patients). All cause mortality was not significantly different for either comparison, whileacetaminophen was associated with a significantly lower rate of necrotizing enterocolitiscompared with indomethacin (relative risk, 0.42; 95% CI 0.19 to 0.96). When comparingacetaminophen to placebo or no intervention, the rate of failure of PDA closure wassignificantly lower in the acetaminophen group (relative risk, 0.27; 95% CI 0.18 to 0.42; 3studies, 240 patients), though all cause mortality was not different between groups. Earlyacetaminophen treatment (postnatal age less than 14 days) was associated with asignificantly lower rate of failure of PDA closure compared with placebo or no intervention(relative risk, 0.35; 95% CI 0.23 to 0.53; 2 studies, 127 patients), while late acetaminophentreatment (postnatal age 14 days or older) was not associated with a lower rate of failure ofPDA closure [2].Adverse effects: Acetaminophen was associated with significantly lower rates of renalimpairment (odds ratio 0.27; 95% CI, 0.09 to 0.8; 1 study), oliguria (OR 0.51; 95% CI 0.27to 0.97; 3 studies), and hyperbilirubinemia (OR 0.46; 95% CI 0.23 to 0.94; 1 study)compared with ibuprofen in another meta-analysis. When comparing acetaminophen withindomethacin, there was no significant difference in rates of necrotizing enterocolitis (OR0.44; 95% CI, 0.18 to 1.06; 4 studies)10 mL/kg isotonic crystalloid orcolloid boluses up to 40 mL/kg untilimproved perfusion or unlesshepatomegaly.Begin prostaglandin infusion until ruleout ductal-dependent lesion.15minutesDOPamine less than 10 mcg/kg/min +/-DOBUTamine for fluid-refractory shockEPINEPHrine 0.05 to 0.3 mcg/kg/minfor fluid-refractory DOPamine-resistantshock60 minCold shock-Poor LVfunctionNormal bloodpressureScvO(2) less than70%*/Hgb greaterthan 12 g/dLSVC flow less than40 mL/kg/min or CIless than 3.3L/min/m(2)Addnitrovasodilatormilrinone orinamrinone withvolume loadingCold shock- PoorRV functionPPHNScvO(2) less thanInhaled nitric oxideInhaled iloprost orIV adenosineIV milrinone or3270%*SVC flow less than40 mL/kg/min or CIless than 3.3L/min/m(2)inamrinoneWarm shock- Lowblood pressureTitrate volumeAdd norepinephrineVasopressin orterlipressin orangiotensinRefractory shockHydrocortisone ifabsolute adrenalinsufficiency.Triiodothyronine ifhypothyroid.Begin pentoxifyllineif VLBW newborn.Consider closingPDA ifhemodynamicallysignificant.ECMOGoals•First Hour: restore and maintain heart ratethresholds, capillary refill of 2 seconds or less,and normal blood pressure.• NICU: normal MAP-CVP, preductal andpostductal oxygen saturation difference less than5%, *ScvO(2) greater than 70% (exceptcongenital heart patients with mixing lesions),SVC flow greater than 40 mL/kg/min, or cardiacindex greater than 3.3 L/min/m(2)KEY: CI = cardiac index, Hgb = hemoglobin, LVfunction = left ventricle function, MAP-CVP =mean arterial pressure-central venous pressure,PDA = patent ductus arteriosus, PPHN =persistent pulmonary hypertension of thenewborn, ScvO(2) = continuous central venousoxygen saturation, SVC = superior vena cava,VLBW = very low birth weightDavis et al: Crit Care Med 2017;45(6)Pediatric FDA Approved IndicationsAlbuRx®-25 and Flexbumin® 25%: Indicated for hemolytic disease of the newborn toattempt to bind and detoxify unconjugated bilirubin in infants with severe hemolytic diseaseprior to exchange transfusion [1][2].Kedbumin™: In patients 12 to 16 years of age, indicated for hypovolemia,hypoalbuminemia, burns (after 24 hours post burn in patients experiencing severe albumindepletion in order to favor edema reabsorption), ovarian hyperstimulation syndrome, andadult respiratory distress syndrome, and in cardiopulmonary bypass (as part of the primingfluids), hemodialysis, and to prevent central volume depletion after paracentesis due to33cirrhotic ascites [14].Safety of albumin solutions has been demonstrated in children provided the dose isappropriate for body weight; however, the safety of Flexbumin® 25% has not beenevaluated in sponsor conducted pediatric studies[1]. No clinical studies using Albuminar®-5have been conducted in pediatric patients. Safety and effectiveness in pediatric patients havenot been established. However, extensive experience in patients suggests that childrenrespond to Albuminar®-5 in the same manner as adults [8]Administration•Administer slow enough to avoid too-rapid plasma volume expansion. The 5% and 25%may be administered without dilution or diluted with normal saline or D5W [1][8].Adequately hydrate patients during or after infusion of albumin 25% solutions [9][10].•In patients with normal blood volume, avoid circulatory overload and pulmonary edema byadministering albumin no faster than 1 mL/min [1][11][12].•In the presence of hypertension, infuse at a slower rate [13][8].•Do not administer more than 4 hours after vial has been entered. Ensure substitution ofother blood constituents (coagulation factors, electrolytes, platelets, and erythrocytes) isadequate when replacing comparatively large volumes of albumin or if blood loss is severe[1][9][14][2].•Warm to room temperature if infusing large volumes. In plasma exchange, adjust infusionrate to the rate of removal [14].MEDICATION SAFETYContraindications/PrecautionsContraindicated :•Severe anemia or cardiac failure [14][38][9][10] with normal or increased intravascularvolume•History of hypersensitivity reaction to albumin preparations or to any component of theproduct (eg, N-acetyltryptophan, sodium caprylate) [11][1]PrecautionAdministration: Conditions where hypervolemia and/or hemodilution may occur mayrequire dose and infusion rate adjustment; increased risk with heart failure, hypertension,esophageal varices, pulmonary edema, hemorrhagic diathesis, severe anemia, and renalfailure; monitoring recommended [11][1]Administration: Circulatory overload or cardiac overload (eg, headache, dyspnea, jugularvenous distention, rales and abnormal elevations in systemic or central venous bloodpressure) may occur; monitoring recommended [11][1][39][40][41]; discontinue use at firstclinical signs of cardiovascular overload [11][1]Administration: Rapid rise in blood pressure may occur; monitoring recommended34[39][40][41]Administration: Do not dilute product with Sterile Water for Injection as there is risk ofhemolysis, including potentially fatal cases, and acute renal failure in recipients [11][1]Hematologic: Re-bleeding secondary to clot disruption can occur in trama andpostoperative surgery patients; monitoring recommended [11][1]Immunologic: Hypersensitivity reactions, including anaphylactic reactions, have beenobserved; discontinue use for suspected hypersensitivity reaction; implement standardtreatment for anaphylactic shock [11][1]Immunologic: Infectious agent transmission may occur, including a risk of exposure toviruses, Creutzfeldt-Jakob disease or variant Creutzfeldt-Jakob disease, and other pathogens[11][1][39][40][41].Adverse EffectsCommon: flushing, urticaria, fever, chills, nausea, vomiting, tachycardia, and hypotension.These reactions usually subside when the infusion rate is slowed or stopped [14].Lid edema occurred in 19.5% and 29.3% of newborns (at 30 weeks gestation) and infantsyounger than 24 months of age undergoing non-cardiac surgery receiving albumin 5% andhydroxyethyl starch 130/0.4, respectively [33].Solution CompatibilityD5W, D10W, D5LR, D5NS, D50.45%NaCl, NS, 0.45%NaCl.Solution IncompatibilityProtein hydrolysates, amino acid mixtures, or alcohol-containing solutions [2][14].Terminal Injection Site CompatibilityAlbumin, Human, 20%Lorazepam 0.33 mg/mL.Albumin, Human, 25%Diltiazem 5 mg/mL, ketamine 50 mg/mL.35Terminal Injection Site IncompatibilityFat emulsion, micafungin, midazolam, vancomycin, verapamil.MonitoringClosely monitor infusion rates and the patient's clinical state during infusion. Observe injuredpatients after restoration of blood pressure for bleeding points that may have failed to bleedat lower blood pressure [38][9][10].Closely monitor for circulatory overload during administration. Regularly monitorhemodynamic performance, including arterial blood pressure and pulse rate, central venouspressure, pulmonary artery occlusion pressure, urine output, electrolyte levels, and HCT/Hb[14].Closely monitor hemodynamic parameters after administering for evidence of cardiac orrespiratory failure, renal failure or increasing intracranial pressure [11][1]For a full-term newborn, the target heart rate and perfusion pressure (mean arterial pressureminus central venous pressure) are 110 to 160 beats/min and 55 mmHg, respectively [7].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAlbumin products of various concentration are an aqueous solution of albumin obtained fromlarge pools of human plasma. The colloid osmotic or oncotic properties of albumin areutilized for plasma or blood volume deficit and for oncotic deficit from hypoproteinemia[10][38][9][2].[14]. Albumin's ability to bind and transport various molecules allows for useto bind free albumin in infants having severe hemolytic disease of the newborn [2].The total exchangeable albumin pool is 4 to 5 g/kg (intravascular, 40% to 45%;extravascular, 55% to 60%)and the half-life of albumin is approximately 19 days.Metabolism is achieved by feedback regulation; elimination is primarily intracellular(lysosomal proteases). During the first 2 hours following albumin infusion in healthy subjects,less than 10% leaves the intravascular compartment [14].ABOUTSpecial Considerations/PreparationAlbuminar®-5: Preservative-free IV solution containing serum albumin 5% and supplied as362.5 g/50 mL, 12.5 g/250 mL, and 25 g/500 mL in single-dose vials. May be administeredundiluted [10].Albuminar®-20: Preservative-free IV solution containing serum albumin 20% and suppliedas 10 g/50 mL and 20 g/100 mL in single-dose vials [38].Albuminar®-25: Preservative-free IV solution containing serum albumin 25% and suppliedas 5 g/20 mL, 12.5 g/50 mL, and 25 g/100 mL in single-dose vials [9].AlbuRx®-25: Preservative-free IV solution containing serum albumin 25% and supplied as12.5 g/50 mL and 25 g/100 mL in single-dose vials. Do not store at temperatures above 30degrees C (86 degrees F) [2].Flexbumin® 5%: Preservative-free IV solution containing serum albumin 25% andsupplied as 12.5 g/250 mL in a single-dose plastic container. Do not store above 30 degreesC and protect from freezing [1]Flexbumin® 25%: Preservative-free IV solution containing serum albumin 25% andsupplied as 12.5 g/50 mL and 25 g/100 mL in single-dose plastic containers. Do not storeabove 30 degrees C and protect from freezing [1]Kedbumin™: Preservative-free IV solution containing serum albumin 25% (0.25 g/mL) andsupplied in 50-mL and 100-mL single-dose vials. Do not freeze or store above 30 degrees C.Protect from light [14].Albumin 25% solutions should only be diluted in suitable infusion solutions, such as D5W orNS. Dilution of albumin 25% with sterile water for injection produces a hypotonic solutionthat may result in life-threatening hemolysis and acute renal failure [1][9][14][2].© Merative US L.P. 1973, 202437AlbuterolNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseBronchodilation: 0.1 to 0.5 mg/kg/dose every 2 to 6 hours via nebulizer.1 Metered-dose inhaler (MDI) actuation per dose (approximately 0.1 mg or 100 mcg) every 2to 6 hours via MDI with spacer device placed in the inspiratory limb of the ventilator circuit.Simulated neonatal lung models suggest greater delivery when using a spacer with the MDI.Use chlorofluorocarbon free preparations when administering to neonates.For nebulizations, use preservative-free solutions; benzalkonium chloride in the 20-mLmultidose bottles may cause bronchoconstriction, particularly with frequent or continuousadministration [1].Oral: 0.1 to 0.3 mg/kg/dose orally every 6 to 8 hours.Treatment of hyperkalemiaPreterm neonates: 0.4 mg/dose every 2 hours via nebulization until serum potassiumdecreases to desired safe level (eg, less than 5 mmol/L) [2]. Consider alternative potassium-lowering therapies for potassium levels greater than 7.5 mmol/L.Neonates (AAP guidelines): 2.5 mg/dose via nebulization. If using intermittent nebulizertreatment with 0.5% mL solution, may administer every 20 mins for 1 to 2 doses [3]UsesBronchodilatorHyperkalemia in preterm neonates: Published data using the nebulized formulation ofalbuterol for the treatment of hyperkalemia in preterm neonates are limited to onerandomized, placebo-controlled trial (n=19). Following administration every 2 hours untilserum potassium dropped below 5 mmol/L (or a maximum of 12 doses), nebulized albuterol(n=8) was effective in lowering potassium levels at 4 and 8 hours when compared withplacebo (saline via nebulization; n=11) [2].Bronchiolitis: Albuterol is not recommended for the routine treatment of bronchiolitis ininfants and children. Consistent benefits have not been demonstrated. There are a lack ofdata in those with severe disease or with respiratory failure [13].AdministrationInhalation38ProAir® HFA, Proventil® HFA, Ventolin® HFAMetered-dose inhaler: Shake well before each spray; canister should be at roomtemperature before use. Prime before using for the first time, or if the inhaler has not beenused for more than 2 weeks, or when the inhaler has been dropped; prime the inhaler byspraying it 4 times for Proventil® HFA or Ventolin® HFA or 3 times for ProAir® HFA into theair, away from the face [4][5][6]. Use a spacer or a valve holding chamber in youngerpatients (less than 5 years of age) or patients with poor inhaler technique. A mask should beadded for children less than 4 years of age [7].Proair® Respiclick™, Proair® Digihaler™Metered-dose inhaler: Does not require priming [8][9]Do not use with spacer or volume holding chamber [8][9]Keep inhaler clean and dry by wiping with dry cloth or tissue as needed; never wash or putany part of inhaler in water [8][9]NebulizationSolution for inhalation: Use the entire contents of pre-diluted vials for inhalation vianebulizer immediately after opening [10]. The dose withdrawn from the 0.5% 20-mLmultidose bottle must be further diluted with sterile normal saline to a total volume of 3 mLprior to administration [11]. Preservative-free solutions are recommended, particularly withcontinuous nebulization; benzalkonium chloride in 20-mL multidose bottles may causebronchoconstriction [1]. There are no data in neonates, however, no significant differences inresponse were observed between albuterol solutions with and without benzalkonium chloridein a retrospective study of 128 hospitalized pediatric patients (4 to 17 years of age)administered continuous nebulized albuterol [12].Administer via nebulizer over 5 to 15 minutes at a gas flow of 6 to 8 L/minute [11][7][10]. Atight-fitting face mask should be used in patients who cannot use a mouthpiece [7].MEDICATION SAFETYContraindications/PrecautionsContraindicationsProair® Respiclick™ and Proair® Digihaler™ are contraindicated in patients with history ofhypersensitivity to albuterol and/or severe hypersensitivity to milk proteins [8][9].PrecautionsCardiovascular:Use sympathomimetic amines with caution in patients with preexistingcardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, andhypertension; possibility for cardiovascular events seen in heart rate, blood pressure and ECGchanges [8][9][6][14][15][16][17][18]. Discontinuation may be required [8][9]Cardiovascular: Avoid use for the treatment of hyperkalemia in patients with preexistingcardiac arrythmia (AAP guidelines) [3]Endocrine and metabolic: Use caution in patients with preexisting diabetes mellitus [8][9][6][15][14][16][17][18] as large doses of IV albuterol have been reported to aggravatecondition [8][9]Endocrine and metabolic: Use caution in patients with preexisting ketoacidosis [8][6]39[15][14] as large doses of IV albuterol have been reported to aggravate condition [8][9]Endocrine and metabolic: Use caution in patients with preexisting hyperthyroidism [8][9][6][14][15][16][17][18]Endocrine and metabolic: Hypokalemia has occurred but considered transient and notrequiring supplementation, but has potential to lead to other cardiovascular side effects[8][9][6][14][15][16][17][18]Higher doses: Fatalities have been reported upon exceeding recommended doses orexcessive use. The cause of death is unknown, but severe acute asthmatic crisis andsubsequent hypoxia suspected [8][9][6][15][14]Immunologic: Rare immediate hypersensitivity can occur and manifest as symptoms ofurticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema [8][9].Consider not reinitiating if immediate hypersensitivity occurs [8][6][15][14]Immunologic: Lactose, used as an inactive ingredient in some inhalers, could lead toimmediate hypersensitivity reactions to milk proteins, including anaphylaxis, angioedema,pruritus, and rash [8][9]Neurologic: Use caution in patients with preexisting convulsive disorders [8][9][6][15][14][16][17][18]Respiratory: Beta adrenergic agonist therapy alonemay be insufficient to control asthma inmany patients; consider adding anti-inflammatory agents (eg, corticosteroids) to therapeuticregimen [8]Respiratory: Benzalkonium chloride preservative, in the multi-dose bottle for nebulization,may induce bronchoconstriction; use only single-use preservative-free, albuterol, particularlywhen using continuous nebulized albuterol (off-label use) [1].Respiratory: Asthma deterioration may occur suddenly over a few hours or chronically overa few days; use of more albuterol than usual may indicate asthma deterioration [9], consideralternative therapy [6][15][14] and reevaluation of treatment regimen, giving specialconsideration to possible need for anti-inflammatory treatment [8]Respiratory: Potentially life-threatening paradoxical bronchospasm has been reported andoften occurs with first use of new canister. Discontinue immediately if this occurs andconsider alternative treatments [8][9][6][15][14]Adverse EffectsTachycardia, arrhythmias, tremor, hypokalemia, and irritable behavior.MonitoringTherapeutic Laboratory MonitoringAssess degree of bronchospasm and monitor serum potassium [2].Hyperkalemia: Monitor serum potassium. The expected decrease within an hour ofadministration of albuterol is 1 to 1.5 mEq/L [3]Toxic Laboratory MonitoringContinuous EKG monitoring. Consider not administering when heart rate is greaterthan 180 beats per minute. Serum potassium [2].40MECHANISM OF ACTION/PHARMACOKINETICSPharmacologySpecific β2-adrenergic agonist. Minimal cardiovascular effects unless used concurrently withaminophylline. Stimulates production of intracellular cyclic AMP, enhancing the binding ofintracellular calcium to the cell membrane and endoplasmic reticulum, resulting inbronchodilation. Enhances mucociliary clearance. Drives potassium intracellular. Studies invitro indicate that approximately 5% of a MDI dose administered using an in-line holdingchamber/spacer device, versus less than 1% of a nebulizer dose, is delivered to the lung.Optimal aerosol dose in neonates is uncertain due to differences in aerosol drug deliverytechniques. The therapeutic margin appears to be wide.Well absorbed when administered orally. Onset of action is 30 minutes; duration is 4 to 8hours. Serum half-life is approximately 6 hours (adults). Time to peak serum concentration is3 to 4 hours. Tolerance may develop.ABOUTSpecial Considerations/PreparationOral dosage form: Syrup, 2 mg/5 mL.Solution for inhalation: Pre-diluted 0.63 mg/3 mL (0.021%), 1.25 mg/3 mL (0.042%),and 2.5 mg/3 mL (0.083%) unit dosed vials. Albuterol 0.5% multidose 20-mL bottle containsbenzalkonium chloride 0.01%. After the dose is withdrawn from the concentrated 0.5%solution, dilute with sterile normal saline to a total volume of 3 mL per dose prior tonebulization [11].Store unit dose vial in protective foil pouch at all times to protect it from light; use within 1week once removed from the foil pouch. Do not use if the solution in the vial changes coloror becomes cloudy. Store at controlled room temperature between 20 to 25 degrees C[19][10].Stability and SterilityPreservative-free (PF) Albuterol Solution (0.67 mg/mL and 0.17 mg/mL): Albuterolsingle-use mini nebs (2.5 mg/0.5 mL, PF, Nephron Pharmaceuticals, West Colombia, SC)diluted with normal saline for irrigation to a concentration of 0.67 mg/mL and 0.17 mg/mLwas stable through 168 hours when stored at room temperature (20 to 25°C) and atrefrigeration (2 to 8°C). There was no bacterial growth detected throughout 10 days ofincubation. [20].Stability and SterilityBenzalkonium Chloride (BAC)-Albuterol Solution (0.67 mg/mL and 0.17 mg/mL):Albuterol BAC (5 mg/mL, Hi-Tech Pharmaceuticals, Amityville, NY) diluted with normal salinefor irrigation to a concentration of 0.67 mg/mL and 0.17 mg/mL was stable through 16841hours when stored at room temperature (20 to 25°C) and at refrigeration (2 to 8°C). Therewas no bacterial growth detected throughout 10 days of incubation. [20].Metered-Dose Inhaler: Pressurized hydrofluoroalkane metered dose inhaler (contains nochlorofluorocarbons (CFC)). Proventil® HFA and Ventolin® HFA 90 mcg albuterol base peractuation.© Merative US L.P. 1973, 202442AlprostadilNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseInitial dose: 0.05 to 0.1 mcg/kg per minute by continuous IV infusion.Titrate to infant's response--oxygenation versus adverse effects.Maintenance dose: May be as low as 0.01 mcg/kg per minute.Higher initial doses are usually no more effective and have a high incidence of adverseeffects.May also be given via UAC positioned near ductus arteriosus.UsesTo promote dilation of ductus arteriosus in infants with congenital heart diseasedependent on ductal shunting for oxygenation/perfusion.Pediatric FDA Approved IndicationsTo promote dilation of ductus arteriosus in infants with congenital heart disease (ie,pulmonary atresia, pulmonary stenosis, tricuspid atresia, tetralogy of Fallot, interruption ofthe aortic arch, coarctation of the aorta, or transposition of the great vessels with or withoutother defects) dependent on ductal shunting for oxygenation/perfusion [1][3][4][5]. Lowsuccess rates for prostaglandin E1 are usually due to an irreversibly closed ductus and severeacidemia and collapse. Functional closure of the ductus occurs within a few hours of birth,and anatomical closure occurs in 21 days (normal term infant) [4].AdministrationContinuous infusion via a large vein is the preferred route of administration. May also begiven via UAC positioned near the ductus arteriosus. For continuous infusion, dilute incompatible solution to a concentration of 2 to 20 mcg/mL [1]. The recommended standardconcentrations are 1, 2.5, 5, 10, and 20 mcg/mL for continuous infusions [2].MEDICATION SAFETYContraindications/Precautions43CONTRAINDICATIONS: NonePRECAUTIONS:Cardiovascular: Structural alterations (intimal lacerations, decreased medial muscularity,and disruption of the medial and internal elastic lamina) of the ductus and pulmonary arterieshave been observed [6].Gastrointestinal: Gastric outlet obstruction due to antral hyperplasia may occur; dose- andduration-related [6].Hematological: Use with caution in neonates with bleeding tendencies [6].Musculoskeletal: Cortical proliferation of the long bones has been observed with long-terminfusions; resolution with discontinuation of alprostadil [6].Respiratory: Do not use in neonates with respiratory distress syndrome [6].Adverse EffectsCommon (6% to 15%): Apnea (consider treating with aminophylline), hypotension, fever,leukocytosis, cutaneous flushing, and bradycardia. Hypokalemia reported with long-termtherapy (greater than 20 days), especially with doses greater than 0.05 mcg/kg/minute.Gastric outlet obstruction and reversible cortical proliferation of the long bones afterprolonged treatment (greater than 120 hours).Uncommon (1% to 5%): Seizures, hypoventilation, tachycardia, cardiac arrest, edema,sepsis, diarrhea, and disseminated intravascular coagulation.Rare (less than 1%): Urticaria, bronchospasm, hemorrhage, hypoglycemia, andhypocalcemia.Musculoskeletal changes: Widened fontanels, pretibial and soft tissue swelling, andswelling of the extremities may occur after 9 days of therapy. Cortical hyperostosis andperiostitis may occur with long-term (greater than 3 months) therapy. These changes resolveover weeks after discontinuation of therapy.Black Box WarningApnea has been reported in 10% to 12% of neonates with congenital heart defects treatedwith alprostadil. Apnea is seen most often in neonates weighing less than 2 kg at birth, andusually appears during the first hour of drug infusion. Monitor respiratory status throughouttreatment and be prepared to intubate/resuscitate.Solution CompatibilityD5W and NS.44Terminal Injection Site CompatibilityAminophylline, ampicillin, caffeine citrate, calcium chloride,cefazolin, cefotaxime, cimetidine,clindamycin, dobutamine, dopamine, fentanyl, furosemide, gentamicin, glycopyrrolate,metoclopramide, metronidazole, nitroglycerin, nitroprusside, potassium chloride, penicillin G,tobramycin, vancomycin, and vecuronium.MonitoringTherapeuticRestricted pulmonary blood flow: Improvement in blood oxygenation demonstrates efficacy[6]Restricted systemic blood flow: Improvement of systemic blood pressure and blood pHdemonstrates efficacy [6]ToxicCardiovascular: Measure arterial pressure intermittently by umbilical artery catheter,auscultation, or with a Doppler transducer [6].Gastrointestinal: Monitor for signs and symptoms of antral hyperplasia and gastric outletobstruction in neonates administered alprostadil for more than 120 hours [6].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAlprostadil causes vasodilation of all arterioles. Inhibition of platelet aggregation. Stimulationof uterine and intestinal smooth muscle. Maximal drug effect usually seen within 30 minutesin cyanotic lesion; may take several hours in acyanotic lesions.ABOUTSpecial Considerations/PreparationSupplied: 500 mcg in 1 mL of dehydrated alcohol ampules that must be refrigerated. Dilutebefore administration to a concentration of 20 mcg/mL or less. Prepare freshinfusion solutions every 24 hours.45Dilutions and StabilityAlprostadil 11 mcg/mL in 250 mL of 0.9% sodium chloride stored in polyvinyl chloride(Viaflex) containers at refrigerated temperature and protected from light was stable for 10days. Prostin VR Pediatric® was used for this stability study [7].Alprostadil 20 mcg/mL in 0.9% sodium chloride stored in glass ampules or plasticsyringes was stable (degrades to 90%) for 106.5 days at 4°C and 9.8 days at 25°C andstable (degrades to 95%) for 51.8 days at 4°C and 4.8 days at 25°C. Storage in plasticsyringes led to components leaching from the plastic and silicone piston head seals. ProstinVR Pediatric® was used for this stability study [8].When mixing in a volumetric infusion chamber, undiluted alprostadil should not come incontact with the walls of the chamber. Add the appropriate amount of IV solution to chamber,then add the undiluted alprostadil solution. Replace volumetric infusion chamber if theappearance of the chamber changes and the solution becomes hazy[6].Sample Dilution and Infusion Rate: Mix 1 ampule (500 mcg) in 50 mL of compatiblesolution (eg, D5W) yielding an approximate concentration of 10 mcg/mL. Infuse at a rate of0.01 mL/kg/min to provide a dose of 0.1 mcg/kg/minute [6]© Merative US L.P. 1973, 202446AlteplaseNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseRestoration of function to central venous catheter: Instill into dysfunctional catheterat a concentration of 1 mg/mL. Use 110% of the internal lumen volume of the catheter, notto exceed 2 mg in 2 mL. If catheter function is not restored in 120 minutes after 1 dose, asecond dose may be instilled.An alternative dosing regimen using a smaller dose (0.5 mg diluted in NS to volume requiredto fill the central venous catheter) was used in children 10 kg or less in 1 study (n=25;infants as young as 7 weeks included).Dissolution of intravascular thrombi: 200 mcg/kg per hour (0.2 mg/kg per hour).Duration of therapy is 6 to 48 hours. If administering directly into the thrombus, dose may beincreased after 6 hours to a maximum of 500 mcg/kg per hour. If localized bleeding occurs,stop infusion for 1 hour and restart using 100 mcg/kg per hour. Discontinue heparin severalhours prior to initiation of therapy.Note: Reports in the literature are a collection of cases gathered over several years. Someauthors used loading doses, others did not. Infused doses ranged from 20 to 500 mcg/kg perhour. Complications were most often linked with higher doses and longer duration of therapy.Call 1-800-NOCLOTS for case reporting and treatment guidance.UsesDissolution of intravascular thrombi of recent onset that are either intraarterial or life-threatening. Adjuvant treatment of infective endocarditis vegetations.Restoration of function to central venous access devices as assessed by the ability towithdraw blood.AdministrationRestoration of function to central venous catheter: Concentration of 1 mg/mL. Use110% of the internal lumen volume of the catheter, not to exceed 2 mg in 2 mL [1][2][3][4].Alternatively, use a smaller dose (0.5 mg diluted in NS to volume required to fill the centralvenous catheter) [5].Dissolution of intravascular thrombi: May be administered as reconstituted at 1 mg/mL47or further diluted in compatible diluent (in PVC bags or glass vials) to a concentration of 0.5mg/mL [6].Call 1-800-NOCLOTS for case reporting and treatment guidance.MEDICATION SAFETYContraindications/PrecautionsUse is contraindicated in patients with acute ischemic stroke under the following conditions[7]:◦ Active internal bleeding◦ Bleeding diathesis◦ Current intracranial hemorrhage◦ Hypertension that is current, severe, and uncontrolled◦ Intracranial or intraspinal surgery within the last 3 months◦ Intracranial conditions that may increase the risk of bleeding (ie, neoplasm, aneurysm,arteriovenous malformation)◦ Serious head trauma within the last 3 months◦ Subarachnoid hemorrhageUse is contraindicated for the treatment of acute myocardial infarction or pulmonaryembolism under the following conditions [7]:◦ Active internal bleeding◦ Bleeding diathesis◦ Hypertension that is current, severe, and uncontrolled◦ Intracranial or intraspinal surgery within the last 3 months◦ Intracranial conditions that may increase the risk of bleeding (ie, neoplasm, aneurysm,arteriovenous malformation)◦ Recent history of stroke◦ Serious head trauma within the last 3 monthsPrecautionsAdministration: Avoid noncompressible arterial, internal jugular, or subclavian punctures orIM injection [7]Angioedema: Angioedema has been reported during and up to 2 hours after administrationin patients with ischemic stroke or myocardial infarction; risk may have been increased withuse of concomitant ACE inhibitors. Discontinue and institute appropriate therapy if conditionoccurs [8]48Cardiovascular: Acute pericarditis or subacute bacterial endocarditis increase the risk ofadverse effects [7]Cardiovascular: Increased risk of thromboembolic events in patients with high likelihood ofleft-heart thrombus (eg, mitral stenosis or atrial fibrillation) [8]Cardiovascular: Hypertensive patients (systolic, 175 mmHg or greater; diastolic, 110mmHg or greater) are at an increased risk of adverse effects [7]Cardiovascular: Stroke risk may outweigh treatment benefit in myocardial infarctionpatients at low risk of cardiac death [7]Endocrine and metabolic: Cholesterol embolism has been reported with thrombolyticagents [7]Gastrointestinal: Recent gastrointestinal bleeding increases the risk of alteplase adverseeffects [7]Hematologic: Fatal hemorrhage associated with traumatic intubation has occurred [7]Hematologic: If treatment is initiated before coagulation test results are available,discontinue if baseline INR or aPTT elevations are seen [7]Hematologic: Bleeding may occur with concurrent anticoagulant therapy, especially atarterial puncture sites. If serious bleeding develops, discontinue and treat appropriately [8]Hematologic: Active internal bleeding or embolic complications may occur with venouscatheter occlusion [2]Hematologic: Significant or fatal internal (ie, intracranial, retroperitoneal, gastrointestinal,genitourinary, respiratory) or external bleeding have been reported; discontinue use if seriousbleeding occurs [9]Hematologic: Serious bleeding at critical location can occur; discontinue use [2]Hematologic: Septic thrombophlebitis increases the risk of adverse effects [7]Hematologic: An occluded AV cannula at a seriously infected site increases the risk ofadverse effects [7]Hematologic: Hemostatic defects,including defects secondary to severe renal or hepaticdisease, increase the risk of adverse effects [7]Hematologic: Underlying DVT may not be adequately treated in pulmonary embolismpatients [8]Hematologic: Increased risk of re-embolization due to lysis of underlying DVT in pulmonaryembolism patients [8]Hematologic: Minimize arterial and venous punctures due to an increased risk of bleeding;discontinue use if serious bleeding occurs [7]Hematologic: Thrombocytopenia [2]Hepatic: Significant hepatic dysfunction increases the risk of adverse effects [7]Immunologic: Hypersensitivity, including urticarial and anaphylactic reactions (eg, laryngealedema, rash, and shock) with rare fatal outcome, have been reported [8][10]; ifhypersensitivity occurs, discontinue use and institute appropriate therapy [8]Immunologic: Catheter infection may occur with venous catheter occlusion [2]Neurologic: Cerebrovascular disease increases the risk of adverse effects [7]Ophthalmic: Hemorrhagic ophthalmic conditions, including diabetic hemorrhagicretinopathy, increase the risk of adverse effects [7]Renal: Recent genitourinary bleeding increases the risk of adverse effects [7]Reproductive: Pregnancy may increase the risk of adverse effects [7]Reproductive: Recent genitourinary bleeding may increase the risk of adverse effects [7]Surgery: Recent major surgery increases the risk of adverse effects [7][2]Special populations: Recent trauma increases the risk of adverse effects [7]49Adverse EffectsIntracranial hemorrhage may occur, especially in premature infants treated for prolongedperiods. Bleeding from venipuncture sites occurs in approximately half of treated patients.The risk of complications increases at doses above 450 mcg/kg per hour.Solution CompatibilityNS and D5W.Terminal Injection Site CompatibilityLidocaine, morphine, nitroglycerin, and propranolol.Terminal Injection Site IncompatibilityDobutamine, dopamine, and heparin.MonitoringFollow coagulation studies (PT, aPTT, fibrinogen, fibrin split products) prior to therapy and atleast daily during treatment. Maintain fibrinogen levels greater than 100 mg/dL and plateletsgreater than 50,000/mm3. Echocardiography to assess clot lysis at least every 12 hours(every 6 hours optimal). Cranial ultrasound to assess for hemorrhage prior to therapy.MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAlteplase binds strongly and specifically to fibrin in a thrombus and converts the entrappedplasminogen to plasmin. This initiates local fibrinolysis with limited systemic proteolysis.Alteplase has a shorter half-life than streptokinase and does not cause anaphylacticreactions. It is cleared rapidly from the plasma, primarily via the liver.50ABOUTSpecial Considerations/PreparationActivase® is supplied as lyophilized powder in 50 mg and 100 mg vials. Reconstitute 50- or100-mg vial by adding 50 or 100 mL of sterile water for injection (do not use bacteriostaticwater for injection) respectively, for a concentration of 1 mg/mL. Can be further diluted withNS or D5W to a concentration of 0.5 mg/mL if necessary. Use reconstituted solution within 8hours of mixing when stored refrigerated or at room temperature.Cathflo® Activase® is supplied as lyophilized powder in 2-mg vials. Reconstitute by adding2.2 mL sterile water for injection to a final concentration of 1 mg/mL. Do not usebacteriostatic water for injection. Mix by gently swirling until the contents are completelydissolved. DO NOT SHAKE. Use reconstituted solution within 8 hours of mixing. Reconstitutedsolution may be stored refrigerated or at room temperature.© Merative US L.P. 1973, 202451AmikacinNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDosePostnatal Age - Weight DosingThese regimens were developed based on population pharmacokinetics, simulations, andsubsequent prospective validations. Target concentrations: peak (1 hour after completion of20 minute infusion)– greater than 24 mg/L, trough (just before dose) less than 3 mg/L[1][2][3].WeightPostnatal AgeYounger than 14days14 days or older800 g orless16 mg/kg/doseevery 48 hours20 mg/kg/doseevery 42 hours801 to1200 g16 mg/kg/doseevery 42 hours20 mg/kg/doseevery 36 hours1201 to2000 g15 mg/kg/doseevery 36 hours18 mg/kg/doseevery 30 hours2001 to2800 g15 mg/kg/doseevery 36 hours18 mg/kg/doseevery 24 hours2800 g orgreater15 mg/kg/doseevery 30 hours18 mg/kg/doseevery 20 hoursSmits et al, 2017; Rivera-Chaparro et al, 2017;Smits et al, 2015Postnatal Age - Postmenstrual Age DosingThese regimens were developed by a retrospective pharmacokinetic study (n=278). Targetpeak concentrations were attained in 84% of neonates (median (interquartile range):gestational age 36.9 weeks (30.1 to 38.9), postnatal age 1 day (0 to 2), and postmenstrualage 37 weeks (33 to 39)). Mean peak and trough concentrations were 28.5+/-5.8 mg/mLand 2+/-1.7 mg/L, respectively. Target concentrations: Peak of (30 minutes after completionof the infusion) 20 to 35 mg/L and trough (30 to 60 minutes before dose) less than 8 mg/L[4].Postmenstrual AgePostnatalAgeDosage29 weeks or less0 to 7 days14 mg/kg/doseevery 48 hours8 to 28 days12 mg/kg/doseevery 36 hours29 days orolder12 mg/kg/doseevery 24 hours5230 to 34 weeks0 to 7 days12 mg/kg/doseevery 36 hours8 days orolder12 mg/kg/doseevery 24 hours35 weeks or more All12 mg/kg/doseevery 24 hoursHughes, 2017Dosage AdjustmentCoadministration with ibuprofen: Prolong the dosing interval by 10 hours whenibuprofen is administered [3].Hypothermia/Asphyxia: Dose interval was prolonged by 10 hours in neonates withasphyxia in a pharmacokinetic study [3]. Alternatively, dose adjustment was suggested basedon a population pharmacokinetic modeling and simulation of retrospectively collected data fornear term neonates with perinatal asphyxia treated with therapeutic hypothermia (n=56) [5]combined with published data of preterm and term neonates (n=874) [3][6]. Proposedregimen: 15 mg/kg/dose every 48 h for children between 1,200 g and 2,800 g and 15-mg/kg/ dose every 42 h for neonate above 2,800 g for the first 2 consecutive doses duringhypothermia (33.5 degrees C) for target concentrations greater than 24 mg/L for peak andless than 5 mg/L for trough. Less than 17% of dose simulations had trough concentrationsmore than 5 mg/L [5]Renal Impairment: Either prolong intervals or reduce dose [7].UsesAmikacin was effective for infections caused by gram-negative bacilli that are resistant toother aminoglycosides. Usually used in combination with a β-lactam antibiotic for neonatalsepsis and other severe infections because of the possibility of infections due to gram-positive organisms such as streptococci or pneumococci [7].Infective endocarditis: The following recommendations are based on a consensus ofexperts [13]. The full pediatric guidelines can be found here: https://doi.org/10.1161/CIR.0000000000000298Organism Directed TherapyOrganism First-ChoiceAlternativeChoiceStreptococciHighly susceptibleto penicillin G(MBC 0.1 mcg/mLor less); includesmost viridansstreptococci,groups A, B, C, Gnonenterococcal,group DPenicillin G orCefTRIAXoneVancomycin orFirst-generationcephalosporinorCefTRIAXone53streptococci (Sbovis, S equinus)Relativelyresistant topenicillin (MBC0.2 mcg/mL ormore); less-susceptibleviridansstreptococciorenterococciPenicillin G orAmpicillin +Gentamicin(for first 2weeks, orentire courseforenterococci)Vancomycin +Gentamicin forenterococciAmpicillin +CefTRIAXone(foraminoglycoside(AMG)-resistantenterococci orAMG-intolerantpatient)CefTRIAXone +gentamicin (notfor enterococcalendocarditis)Resistant topenicillinConsult aninfectiousdiseasespecialist.---Staphylococci (Saureus orcoagulase-negativestaphylococci) †Penicillin Gsusceptible (1mcg/mL or less)(rare)PenicillinG Oxacillin orNafcillin orFirst-generationcephalosporinorVancomycinPenicillin Gresistant (0.1mcg/mL)Oxacillin orNafcillinwith orwithoutGentamicinVancomycin (forthose highlyallergic to beta-lactamantibiotics) orFirst-generationcephalosporinOxacillin (MRSA)resistant (4mcg/mL)Vancomycin Daptomycin forright-sidedendocarditis,maybe for left-sidedVancomycinresistant orintolerantDaptomycin Unknown†When prosthetic materialpresent add riFAMpin +gentamicin (for first 2 weeks)for all staphylococci54Gram-negativeenteric bacilliCefTAZidimeorCefepime orCefotaxime orCefTRIAXonePlusgentamicin(ortobramycin oramikacin,depending onsusceptibility)Broad-spectrumpenicillinPlus gentamicin(or tobramycinor amikacin)HACEK groupCefTRIAXoneorCefotaxime orAmpicillin-sulbactamAmpicillin(whensusceptible)PlusaminoglycosideKEY: AMG = aminoglycosides; HACEK =Haemophilus species, Aggregatibacter species,Cardiobacterium hominis, Eikenella corrodens,and Kingella species; MBC = minimumbactericidal concentration, MRSA = methicillin-resistant Staphylococcus aureus (includesresistance to oxacillin, nafcillin, andcephalosporins)Baltimore, 2015SepsisOptimal treatment for suspected, early-onset sepsis is broad-spectrum antimicrobial coverageusing a combination of ampicillin and an aminoglycoside (usually gentamicin); once apathogen is identified, therapy should be narrowed unless synergism is required. Therapyshould be discontinued at 48 hours if the probability of sepsis is low. Duration of treatment isusually 10 days for bacteremia without an identifiable focus [14].There was no difference in failure rate between a 7-day vs 10-day duration of empirictreatment with IV cefTRIAXone and amikacin for culture-proven sepsis in 132 neonates, 1.5kg or more and gestational age 32 weeks or more, who remitted clinically by day 5 in arandomized study. The follow-up period was 28 days. The median age at presentation was 3days (2 to 4 days) and 56.8% had early-onset sepsis. The majority of organisms in bloodcultures were Klebsiella spp. (40.9%), Staphylococcus aureus (22.7%), Enterobacter spp.(16.7%), and MRSA (7.6%) [15].Pediatric FDA-Approved IndicationsShort-term treatment of serious infections caused by susceptible strains of Gram-negativebacteria, including Pseudomonas species, E. coli, species of indole-positive and indole-negative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, andAcinetobacter (Mima-Herellea) species [7].Administration55Dilute to a final concentration of 2.5 to 10 mg/mL [8][9][10][11] and administer as IVinfusion by syringe pump over 60 to 120 minutes [12]; in neonatal studies amikacin wasinfused over 20 minutes [3] and in neonatal pharmacokinetic modeling studies infusion ratesof 20 to 30 minutes were applied [6].Administer as a separate infusion from penicillin-containing compounds. IM injection isassociated with variable absorption, especially in the very small infant.MEDICATION SAFETYContraindications/PrecautionsPrecautionsAdministration: In vitro mixing of aminoglycosides with beta-lactam antibiotics (penicillinor cephalosporins) may result in a significant mutual inactivation. A reduction in serum half-life or serum level may occur when an aminoglycoside or penicillin-type drug is administeredby separate routes. Inactivation of the aminoglycoside is clinically significant only in patientswith severely impaired renal function. Inactivation may continue in specimens of body fluidscollected for assay, resulting in inaccurate aminoglycoside readings. Such specimens shouldbe properly handled (assayed promptly, frozen or treated with betalactamase) [7]Gastrointestinal: Clostridium difficile associated diarrhea has been reported and rangedfrom mild diarrhea to fatal colitis; discontinue use if suspected [7].Immunologic: Allergic-type reactions, including anaphylaxis and life-threatening or lesssevere asthmatic reactions, may occur in patients with sulfite sensitivity as preparationcontains sodium metabisulfite [7].Neurologic: Use caution in patients with myasthenia gravis or parkinsonism; muscleweakness may be aggravated [7].Topical irrigation: Irreversible deafness, renal failure, and death due to neuromuscularblockade have been reported following irrigation of both small and large surgical fields withaminoglycoside preparations [7].Adverse EffectsTransient and reversible renal tubular dysfunction may occur, resulting in increased urinarylosses of sodium, calcium, and magnesium. Vestibular and auditory ototoxicity may occur.The addition of other nephrotoxic and/or ototoxic medications (eg, furosemide, vancomycin)may increase these adverse effects. Increased neuromuscular blockade (ie, neuromuscularweakness and respiratory failure) may occur when used with pancuronium or otherneuromuscular blocking agents and in patients with hypermagnesemia.Black Box Warning56•Patients treated with parenteral aminoglycosides should be under close clinical observationbecause of the potential ototoxicity and nephrotoxicity associated with their use. Safety fortreatment periods which are longer than 14 days has not been established.•Neurotoxicity, manifested as vestibular and permanent bilateral auditory ototoxicity, canoccur in patients with preexisting renal damage and in patients with normal renal functiontreated at higher doses and/or for periods longer than those recommended. The risk ofaminoglycoside-induced ototoxicity is greater in patients with renal damage. High frequencydeafness usually occurs first and can be detected only by audiometric testing. Vertigo mayoccur and may be evidence of vestibular injury. Other manifestations of neurotoxicity mayinclude numbness, skin tingling, muscle twitching and convulsions . The risk of hearing lossdue to aminoglycosides increases with the degree of exposure to either high peak or hightrough serum concentrations . Patients developing cochlear damage may not have symptomsduring therapy to warn them of developing eighth-nerve toxicity, and total or partialirreversible bilateral deafness may occur after the drug has been discontinued.Aminoglycoside-induced ototoxicity is usually irreversible.•Aminoglycosides are potentially nephrotoxic. The risk of nephrotoxicity is greater in patientswith impaired renal function and in those who receive high doses or prolonged therapy.•Neuromuscular blockade and respiratory paralysis have been reported following parenteralinjection, topical instillation (as in orthopedic and abdominal irrigation or in local treatment ofempyema), and following oral use of aminoglycosides. The possibility of these phenomenashould be considered if aminoglycosides are administered by any route, especially in patientsreceiving anesthetics; neuromuscular blocking agents such as tubocurarine, succinylcholine,decamethonium; or in patients receiving massive transfusions of citrate-anticoagulated blood.If blockage occurs, calcium salts may reverse these phenomena, but mechanical respiratoryassistance may be necessary.•Renal and eighth-nerve function should be closely monitored especially in patients withknown or suspected renal impairment at the onset of therapy and also in those whose renalfunction is initially normal but who develop signs of renal dysfunction during therapy. Serumconcentrations of amikacin should be monitored when feasible to assure adequate levels andto avoid potentially toxic levels and prolonged peak concentrations above 35 micrograms permL. Urine should be examined for decreased specific gravity, increased excretion of proteinsand the presence of cells or casts . Blood urea nitrogen, serum creatinine or creatinineclearance should be measured periodically. Serial audiograms should be obtained wherefeasible in patients old enough to be tested, particularly high risk patients . Evidence ofototoxicity (dizziness, vertigo, tinnitus , roaring in the earsand hearing loss) or nephrotoxicityrequires discontinuation of the drug or dosage adjustment.•Concurrent and/or sequential systemic, oral or topical use of other neurotoxic or nephrotoxicproducts, particularly bacitracin, cisplatin, amphotericin B, cephaloridine, paromomycin,viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides should be avoided.Other factors that may increase risk of toxicity are advanced age and dehydration.•The concurrent use of amikacin with potent diuretics (ethacrynic acid or furosemide) shouldbe avoided since diuretics by themselves may cause ototoxicity. In addition, whenadministered intravenously, diuretics may enhance aminoglycoside toxicity by alteringantibiotic concentrations in serum and tissue [7].Solution CompatibilityD5W, D10W, D20W, and NS.57Terminal Injection Site CompatibilityAcyclovir, aminophylline, amiodarone, aztreonam, caffeine citrate, calcium chloride, calciumgluconate, cefazolin, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone,chloramphenicol, cimetidine, clindamycin, dexamethasone, enalaprilat, epinephrine, esmolol,fluconazole, furosemide, heparin (concentrations of 1 unit/mL or less), hydrocortisonesuccinate, hyaluronidase, linezolid, lorazepam, magnesium sulfate, metronidazole,midazolam, milrinone, morphine, nicardipine, penicillin g, pentobarbital, phenobarbital,potassium chloride, ranitidine, remifentanil, sodium bicarbonate, vancomycin, vitamin K1, andzidovudine.Terminal Injection Site IncompatibilityFat emulsion. Amphotericin B, ampicillin, azithromycin, heparin (concentrations greater than1 unit/mL), imipenem/cilastatin, mezlocillin, nafcillin, oxacillin, phenytoin, propofol,thiopental, and ticarcillin/clavulanate.MonitoringMeasure serum concentrations when treating for more than 48 hours. Obtain peakconcentration 30 minutes after end of infusion, and trough concentration just prior to thenext dose. When treating patients with serious infections or significantly changing fluid orrenal status consider measuring the serum concentration 24 hours after a dose, and use thechart below for the suggested dosing interval. Blood samples obtained to monitor serum drugconcentrations should be spun and refrigerated or frozen as soon as possible.Therapeutic serum concentrationsPeak: 20 to 30 mcg/mL (or Cmax /MIC ratio greater than 8:1)(Draw 30 minutes after end of infusion, 1 hour after IM injection.)Trough: 2 to 5 mcg/mLSuggested Dosing IntervalsLevel at24 hrs(mcg/mL)Half-life(hours)SuggestedDosing Interval(hours)≤5 ~ 9 245.1 to 8.0 ~ 12 368.1 to 10.5 ~ 16 4858≥10.6Measure levelin 24 hoursMECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of action: Amikacin, a semi-synthetic aminoglycoside [7] bactericidal antibiotic,inhibits normal protein synthesis in susceptible microorganisms [16]. Amikacin resistsdegradation by most aminoglycosides inactivating enzymes known to affect gentamicin,tobramycin, and kanamycin [7].Pharmacokinetics[4]PostmenstrualAgePostnatalAgeHalf-lifeVolume ofdistribution29 weeks or less0 to 7 days(n=41)11hours0.414 L/kg8 to 28days (n=9)9.64hours0.472 L/kg29 days orolder(n=2)4.93hours0.353 L/kg30 to 34 weeks0 to 7 days(n=49)7.96hours0.462 L/kg8 days orolder(n=16)6.20hours0.454 L/kg35 weeks ormoreAll ages(n=170)6.21hours0.433 L/kgComorbidityCongenital heart disease(n=38)*6.97hours0.449 L/kg*Congenital heart disease = cyanotic heart defector acyanotic heart defect requiring surgicalintervention prior to or during amikacin therapyHughes et al, 2017Volume of distribution: 0.833 L in 874 neonates (postnatal age 1 to 30; gestational age24 to 43 weeks) [6]Clearance: 0.493 L/hr in 874 neonates (postnatal age range, 1 to 30; gestational age range,24 to 43 weeks). Coadministration of ibuprofen reduced clearance [6].0.84 L/hr/70 kg at 28 weeks postmenstrual age (PMA), 1.23 L/hr/70 kg at 34 weeks PMA,and 1.56 L/hr/70 kg at 40 weeks PMA in a pharmacokinetic study of 715 neonates (PMA 24to 43 weeks; weight 0.385 to 4.78 kg). Clearance was affected the most by size (66%), PMA(17%), and renal function (9%) [17].59Therapeutic Hypothermia for Asphyxia: Clearance was reduced by 40.6% in neonateswith perinatal asphyxia treated with therapeutic hypothermia (PATH) compared withneonates without PATH in model-based approach pharmacokinetic study. Volume ofdistribution did not change [5].ABOUTSpecial Considerations/PreparationAvailability: 250 mg/mL in 2-mL and 4-mL vials [7]For IV use, dilute with a compatible solution to a concentration of 2.5 to 10 mg/mL [7][8].Stability: Solutions, 0.25 and 5 mg/mL, are stable for 24 hours at room temperature.Solutions stored for 60 days at 4 degrees C and then stored at 25 degrees C had utility timesof 24 hours. At concentrations of 0.25 and 5 mg/mL, solutions frozen (-15 degrees C) for 30days, thawed, and stored at 25 degrees C had utility times of 24 hours [7]© Merative US L.P. 1973, 202460Aminocaproic AcidNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseHemorrhage ProphylaxisExtracorporeal membrane oxygenation (ECMO): 100 mg/kg followed by 30 mg/kg/hr.Administer directly to the patient via IV or through the ECMO circuit. Duration of infusion 72hours or longer if bleeding persists or shorter if cannula is removed [1][2]UsesHemorrhage ProphylaxisCardiopulmonary bypass (CPB): In a neonatal subgroup analysis (n=4426) of a largeobservational study (n=22,258), aminocaproic acid had greater bleeding requiring surgicalintervention compared with aprotinin [4]. There was higher blood loss with aminocaproic acid(46 mL/kg) compared with aprotinin (36 mL/kg), but no differences in need for transfusion orrequirement for surgical revision in 235 neonates who underwent CPB in a nonrandomizedstudy [5]. There was no difference in blood loss, requirement for surgical revision due tobleeding, or need for transfusion between tranexamic acid and aminocaproic acid in 105neonates who underwent CPB in a nonrandomized study [6]. Various dosing regimens areavailable. A pharmacokinetic study in 10 neonates proposed 40 mg/kg IV loading dosefollowed by 30 mg/kg/hr infusion and a priming dose of 100 mg/L [7]. In clinical studies, 75mg/kg IV over 10 minutes was administered at the beginning and end of CPB. Additionally,75 mg/100 mL was added to the priming volume of the CPB system [5][6]. Apharmacokinetic study identified the following regimen to achieve therapeutic concentrations:75 mg/kg IV loading dose over 10 minutes followed by 75 mg/kg/hr IV until the end ofsurgery. Additionally, add 75 mg/kg in the priming volume of the CPB system (venousreservoir) [8].Hemorrhage ProphylaxisExtracorporeal membrane oxygenation (ECMO): Empiric bleeding protocols includedaminocaproic acid 100 mg/kg followed by 30 mg/kg/hr. Duration of infusion was for 72 hoursor longer if bleeding persisted or shorter when cannula was removed. Administration waseither directly to the patient or through the ECMO circuit [1][2]. Surgical site bleeding wasreduced with aminocaproic acid (7%) compared with no aminocaproic acid (12%) [2].However, aminocaproic acid did not reduce the incidence of neonatal intracranial hemorrhagecompared with no aminocaproic acid in 2 studies (n=327) [2][9]. Reduced circuit times dueto clotting may not be a concern, as a retrospective analysis of 164 patients on ECMOdemonstrated that a bleeding protocol, which included aminocaproic acid, did not shortencircuit times [1].61AdministrationIV: Rapid administration of undiluted injection into a vein is not recommended .The manufacturer recommends a concentration of 16 to 20 mg/mL [3].MEDICATION SAFETYContraindications/PrecautionsContraindicated in DIC without concomitant heparin [10][3].Intrarenal obstruction and glomerular capillary thrombosis has been reported in patients withupper urinary tract bleeding.Avoid use in patients with hematuria of upper urinary tractorigin or use with caution if benefit of therapy outweighs the risk. Rare cases of skeletalmuscle weakness, necrosis of muscle fibers, and rhabdomyolysis have been reported withprolonged administration. Neurological deficits, including hydrocephalus, cerebral ischemia,and cerebral vasospasm, have been reported with the use of antifibrinolytic agents inpatients with subarachnoid hemorrhage (causality is unknown). Only use whenhyperfibrinolysis (hyperplasminemia) has been definitively diagnosed. Rapid injection mayresult in hypotension, bradycardia, and/or arrhythmia. Thrombophlebitis may occur. Avoidconcomitant use with factor IX complex concentrates or anti-inhibitor coagulant concentrate[10][3].Injection contains benzyl alcohol, which has been associated with serious adverse effects,including death, in neonates and low-birth-weight infants [3].Adverse EffectsRenal risk (28.6% vs 36.8%), renal injury (3.6% vs 9.5%), renal failure (1.4% vs 1.2%),vascular thrombosis (12.1% vs 8.4%), seizures (2.9% vs 3.2%), intracranial bleeding (3.6%vs 4.2%), stroke (1.4% vs 0%), and in-hospital mortality (6.4% vs 8.4%) occurred in 235neonates undergoing cardiopulmonary bypass and administration of aminocaproic acid andaprotinin, respectively [5]. A fatal case of aortic thrombosis in a neonate on extracorporeallife support and receiving aminocaproic acid occurred [11].Solution CompatibilityD5W, NS, Ringer injection.62Terminal Injection Site CompatibilityAminocaproic acid 20 mg/mLAmikacin (5 mg/mL), aminophylline (2.5 mg/mL), amphotericin B conventional colloidal (0.6mg/mL), amphotericin B liposome 1 mg/mL), ampicillin (20 mg/mL), ampicillin/sulbactam(20/10 mg/mL), atracurium (0.5 mg/mL), azithromycin (2 mg/mL), aztreonam (40 mg/mL),bumetanide (40 mcg/mL), calcium chloride (40 mg/mL), calcium gluconate (40 mg/mL),cefazolin (20 mg/mL), cefepime (20 mg/mL), cefotaxime (20 mg/mL), cefotetan (20 mg/mL),cefoxitin 20 (mg/mL), ceftazidime (40 mg/mL), ceftazidime (l-arginine) (40 mg/mL),ceftriaxone (20 mg/mL), cefuroxime (30 mg/mL), cimetidine (12 mg/mL), cisatracurium (0.5mg/mL), clindamycin (10 mg/mL), cyclosporine (5 mg/mL), dexamethasone (1 mg/mL),digoxin (0.25 mg/mL), diltiazem (5 mg/mL), diphenhydramine (2 mg/mL), dobutamine (4mg/mL), dopamine (3.2 mg/mL), enalaprilat (0.1 mg/mL), epinephrine (50 mcg/mL),erythromycin (5 mg/mL), esmolol (10 mg/mL), famotidine (2 mg/mL), fentanyl (50 mcg/mL),fluconazole (2 mg/mL), foscarnet (24 mg/mL), fosphenytoin (20 mgPE/mL), furosemide (3mg/mL), gentamicin (5 mg/mL), granisetron (50 mcg/mL), haloperidol (0.2 mg/mL), heparin(100 units/mL), hydrocortisone (1 mg/mL), hydromorphone (0.5 mg/mL),imipenem/cilastatin (5 mg/mL), isoproterenol (20 mcg/mL), ketorolac (15 mg/mL), labetalol(2 mg/mL), levofloxacin (5 mg/mL), lidocaine (10 mg/mL), linezolid (2 mg/mL), lorazepam(0.5 mg/mL), magnesium (100 mg/mL), mannitol (150 mg/mL) (15%), meropenem (2.5mg/mL), methylprednisolone (5 mg/mL), metoclopramide (5 mg/mL), metronidazole (5mg/mL), milrinone (0.2 mg/mL), morphine (15 mg/mL), nalbuphine (10 mg/mL), naloxone(0.4 mg/mL), nitroglycerin (0.4 mg/mL), nitroprusside (2 mg/mL), ondansetron (1 mg/mL),pancuronium (0.1 mg/mL), pentobarbital (5 mg/mL), phenobarbital (5 mg/mL),phenylephrine (1 mg/mL), piperacillin (40 mg/mL), piperacillin/tazobactam (40/5 mg/mL),potassium chloride (0.2 mEq/mL), procainamide (20 mg/mL), propranolol (1 mg/mL),ranitidine (2 mg/mL), rocuronium (1 mg/mL), sargramostim (10 mcg/mL), sodiumbicarbonate (1 mEq/mL), succinylcholine (2 mg/mL), sulfamethoxazole/trimethoprim (4/0.8mg/mL), tacrolimus (20 mcg/mL), ticarcillin/clavulanate (31 mg/mL), tobramycin (5 mg/mL),vancomycin (10 mg/mL), vecuronium (1 mg/mL), verapamil (2.5 mg/mL), zidovudine (4mg/mL).Aminocaproic acid 50 mg/mLAmphotericin B lipid complex (1 mg/mL), argatroban (1 mg/mL), bivalirudin (5 mg/mL),daptomycin (10 mg/mL), dexmedetomidine (4 mcg/mL), ertapenem (20 mg/mL),moxifloxacin (1.6 mg/mL), octreotide (5 mcg/mL), palonosetron (50 mcg/mL), pantoprazole(0.4 mg/mL), vasopressin (1 unit/mL), voriconazole (4 mg/mL).Terminal Injection Site IncompatibilityAcyclovir, amiodarone, caspofungin, ciprofloxacin, diazepam, dolasetron, doxycycline hyclate,filgrastim, ganciclovir, midazolam, mycophenolate mofetil, nicardipine, phenytoin,quinupristin/dalfopristin.Compatibility information refers to physical compatibility and is derived from Trissel’s™ 2Clinical Pharmaceutics Database. The determination of compatibility is based onconcentrations for administration recommended herein. Drug compatibility is dependent on63multiple factors (eg, drug concentrations, diluents, storage conditions). This list should not beviewed as all-inclusive and should not replace sound clinical judgment. The user is referred toTrissel’s™ 2 for more complete details.Trissel’s™ 2 Clinical Pharmaceutics Database, version updated on 09/15/2013.MonitoringMonitor CPK levels in patients on long-term therapy. Assess the amount of fibrinolysis presentduring therapy [10][3].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAminocaproic acid inhibits fibrinolysis through plasminogen activator inhibition (principal) andantiplasmin activity (lesser extent). Apparent Vd (mean +/- SD), 23.1 +/- 6.6 L (oral) and 30+/- 8.2 L (IV). Distributes throughout extravascular and intravascular compartments,penetrating RBCs and other tissues with prolonged administration. Primarily excreted renallyas unchanged drug (65%) and the metabolite adipic acid (11%). Renal clearance, 116mL/min. Total body clearance, 169 mL/min. Terminal elimination half-life, approximately 2hours [10][3].A suggested regimen of aminocaproic acid 40 mg/kg IV loading dose followed by a 30mg/kg/hr infusion and a priming dose of 100 mg/L would achieve a target concentrationabove 50 mg/L in most neonates during cardiopulmonary bypass surgery. The aminocaproicacid regimen was developed using aminocaproic pharmacokinetic values from 10 neonateswho underwent elective cardiac surgery with cardiopulmonary bypass [7].The minimum effective concentration of aminocaproic acid required to inhibit fibrinolysis inplasma from 20 term neonates 44.2 mcg/mL, which was significantly less than that for adults(131.4 mcg/mL) [12].Aminocaproic acid concentration range was 39 to 433 mcg/mL (mostly within 110 to 350mcg/mL) in 42 neonates on extracorporeal membrane oxygenation and receivingaminocaproic acid 100 mg/kg IV bolus followed by 30 mg/kg/hr IV. Concentration exceeded1000 mcg/mL in one neonate with renal and hepatic insufficiency; no complications occurred[13].ABOUTSpecial Considerations/PreparationIV solution: Available as an IV solution containing 250 mg/mL aminocaproic acid with 0.9%64benzyl alcohol. [3].Dilute with NS, D5W, or LR. Sterile water for injection may also be used, but will produce ahypo-osmolar solution [3].© Merative US L.P. 1973, 202465AminophyllineNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseLoading dose: 8 mg/kg IV infusion over 30 to 60 minutes, or orally.Maintenance dose: 1.5 to 3 mg/kg/dose orally, or IV every 8 to 12 hours (startmaintenance dose 8 to 12 hours after the loading dose).In preterm infants, changing from IV aminophylline to oral theophylline requires no doseadjustment.UsesApnea: Pharmacological treatment with caffeine is the standard of care for apnea ofprematurity [7].Treatment of neonatal apnea, including post-extubation, post-anesthesia, and prostaglandinE1-induced. Bronchodilator. May improve respiratory function.AdministrationIntravenous bolus over 30 to 60 minutes [1][2][3][4][5]. May give as 25-mg/mLconcentration or further dilute to as low as 1 mg/mL for continuous infusion [6].MEDICATION SAFETYAdverse EffectsGI irritation. Hyperglycemia. CNS irritability and sleeplessness. May be associated with renalcalcifications when used concurrentlywith furosemide and/or dexamethasone.Signs of toxicity: Sinus tachycardia, failure to gain weight, vomiting, jitteriness,hyperreflexia, and seizures.Treatment of Serious Theophylline Toxicity: Activated charcoal, 1 g/kg as a slurry bygavage tube every 2 to 4 hours. Avoid sorbitol-containing preparations: They may causeosmotic diarrhea.66Solution CompatibilityD5W, D10W, and NS.Terminal Injection Site CompatibilityAcyclovir, ampicillin, amikacin, aztreonam, caffeine citrate, calcium gluconate, ceftazidime,chloramphenicol, cimetidine, dexamethasone, dopamine, enalaprilat, erythromycinlactobionate, esmolol, famotidine, fluconazole, flumazenil, furosemide, heparin,hydrocortisone succinate, lidocaine, linezolid, meropenem, metoclopramide, midazolam,morphine, nafcillin, nicardipine, nitroglycerin, pancuronium bromide, pentobarbital,phenobarbital, piperacillin, piperacillin/tazobactam, potassium chloride, propofol,prostaglandin E1, ranitidine, remifentanil, sodium bicarbonate, vancomycin, and vecuronium.Terminal Injection Site IncompatibilityAmiodarone, cefepime, ceftriaxone, ciprofloxacin, clindamycin, dobutamine, epinephrine,hydralazine, insulin, isoproterenol, methylprednisolone, and penicillin G.MonitoringMonitor heart rate and check blood glucose periodically with reagent strips. Assess foragitation and feeding intolerance.Consider withholding next dose if heart rate is greater than 180 beats per minute.When indicated by lack of efficacy or clinical signs of toxicity, serum trough concentrationshould be obtained. Therapeutic ranges are:1) Apnea of prematurity: 7 to 12 mcg/mL.2) Bronchospasm: 10 to 20 mcg/mL (older infants with bronchospasm may need thesehigher levels because of increased protein binding).MECHANISM OF ACTION/PHARMACOKINETICSPharmacology67Stimulates central respiratory drive and peripheral chemoreceptor activity. May increasediaphragmatic contractility. Cerebral blood flow is acutely decreased following IV bolus dose.Renal effects include diuresis and increased urinary calcium excretion. Stimulates gastric acidsecretion and may cause gastroesophageal reflux. Cardiac output is increased due to highersensitivity to catecholamines. Elimination in preterm infants is primarily as unchanged drug,although significant interconversion to caffeine occurs. In the very immature neonate, theserum half-life of theophylline is prolonged (20 to 30 hours). Theophylline metabolism andclearance mature to adult values by 55 weeks postmenstrual age. Aminophylline salt is78.9% theophylline. Theophylline administered orally is approximately 80% bioavailable;therefore, no dosage adjustment is necessary when changing from IV aminophylline to oraltheophylline.ABOUTSpecial Considerations/PreparationAvailability: Aminophylline for IV use (25 mg/mL) in 10- and 20-mL vials. Dilute 1 mL (25mg) with 4 mL NS or D5W to yield a final concentration of 5 mg/mL. Stable for 4 daysrefrigerated.Oral theophylline is available only as an elixir at a concentration of 80 mg/15 mL (5.33mg/mL) and contains 20% alcohol.Aminophylline oral solution is no longer available.Extemporaneous SuspensionOral aminophylline 3 mg/mL liquid suspension made with aminophylline injection 25 mg/mLand mixed with 1:1 Ora Sweet/Ora Plus was stable for 91 days at 4°C and 25° C. Store inamber glass bottle [8]© Merative US L.P. 1973, 202468AmiodaroneNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseIV Loading Dose: 5 mg/kg IV infusion given over 20 to 60 minutes, preferably in a centralvein.Maintenance Infusion: 7 to 15 mcg/kg/minute (10 to 20 mg/kg per 24 hours). Begin at 7mcg/kg/minute and titrate by monitoring effects. For infusions lasting longer than 1 hour,amiodarone IV concentrations should not exceed 2 mg/mL unless using a central line.Consider switching to oral therapy within 24 to 48 hours.Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating treatment[1].Oral: 5 to 10 mg/kg/dose every 12 hours.UsesArrhythmias: Treatment of life-threatening or drug-resistant refractory supraventricular(SVT), ventricular tachyarrhythmias (VT), and postoperative junctional ectopic tachycardia(JET) - see Adverse Effects.AdministrationDilute the IV loading dose to 1.5 mg/mL [2] and infuse over 20 to 60 minutes [3]. For IVinfusion, dilute to a concentration of 1 to 6 mg/mL in compatible diluent. For infusionslasting longer than 1 hour (eg, continuous infusion), amiodarone IVconcentrations should not exceed 2 mg/mL unless using a central line. Wheninfusing the original amiodarone product, infusions lasting longer than 2 hoursshould be administered in glass or polyolefin bottles containing D5W; use ofevacuated glass containers is not recommended as precipitation may occur fromthe buffer [4]. An in-line filter should be used during administration. Administration via acentral catheter is preferred [5].Extravasation ManagementNeonatal data are limited to pooled data from 10 casereports/case series (n=237) and are not specific to amiodarone extravasation; subcutaneoussaline irrigation with or without hyaluronidase infiltration was commonly used. Nostandardized management was established. An option for more severe injuries (stages 3 and4) is subcutaneous irrigation with saline, but this is not advocated as standard treatment.69Conservative management is appropriate for mild extravasation (stages 1 and 2) [6].Although not neonatal-specific, the following are recommendations for extravasation of acidicor alkaline agents (amiodarone is acidic with a pH ranging from 3.5 to 4.5) [7]◦ General:◦ Stop and disconnect infusion; do not remove the cannula or needle◦ Attempt to gently aspirate as much extravasated agent as possible; avoid manualpressure◦ Remove cannula or needle◦ Dry heat and elevation◦ Closely monitor for signs of coagulation and ischemia◦ Avoid attempt at pH neutralization (amiodarone - pH 3.5 to 4.5)◦ Monitor and consider the need for surgical management such as surgical flushing withnormal saline or debridement and excision of necrotic tissue (especially if pain persistsfor 1 to 2 weeks). In cases of compartment syndrome, surgical decompression may berequired◦ Refractory Events:◦ Hyaluronidase 15 units intradermally along injection site and edematous area. Give asfive, 0.2-mL intradermal injections along extravasation site and edematous tissue.◦ Inadvertent Intraarterial Administration:◦ Leave inadvertent intraarterial line in place for diagnostics◦ Systemic heparin titrated to therapeutic anticoagulant effect.◦ Stellate ganglion blockMEDICATION SAFETYContraindications/PrecautionsContraindicationsCardiogenic shock [9][19]Hypersensitivity to amiodarone or to any of its components, including iodine [9][19]Sick sinus syndrome, second- or third-degree atrioventricular block, bradycardia leading tosyncope without a functioning pacemaker [1].Severe sinus bradycardia or second or third degree atrioventricular block, if no pacemaker ispresent [9]PrecautionsAdministration: The IV formulation should only be administered when access to facilitiesequipped to monitor for effectiveness and side effects are available, and by physiciansexperienced in the treatment of life-threatening arrhythmias [20].Adverse events: Due to the long half-life, adverse events can persist for several weeksfollowing discontinuation [1]70Cardiovascular: Hypotension, including some refractory and fatal cases, has been reported,particularly with IV administration; monitoring recommended [9].Cardiovascular: Exacerbation of presenting arrhythmia, new ventricular fibrillation,incessant ventricular tachycardia, increased resistance to cardioversion, and polymorphicventricular tachycardia with QTc prolongation (Torsade de Pointes) may occur [1]Cardiovascular: Bradycardia has been reported,[12] especially with concomitant use ofdrugs that slow heart rate (eg, digoxin, beta blockers,verapamil, diltiazem, ivabradine,clonidine) or by presence of electrolyte disorders [1]) and with concomitant use ofledipasvir/sofosbuvir or sofosbuvir with simeprevir [1]. Monitoring recommended withconcomitant use or recent discontinuation of amiodarone when starting antiviral treatment[1] Discontinuation or dose adjustment may be required [12]..Cardiovascular: Atrioventricular block has been reported. Discontinuation or doseadjustment may be required [12].Cardiovascular: Preexisting implanted defibrillator or pacemaker may result in changes toelectrical conduction properties (pacing or defibrillating thresholds) of heart; monitoringrecommended with oral administration [1].Cardiovascular: Hypotension, including some refractory and fatal cases, has been reported,particularly with IV administration; monitoring recommended [9][19].Concomitant use: Avoid drugs that prolong the QT interval [9].Concomitant use: Avoid grapefruit juice [9].Dermatologic: Phlebitis has been reported, especially with IV concentrations greater than 3mg/mL [12].Dermatologic: Photosensitivity has been reported and may be reduced with sun-barriercreams or protective clothing. Blue-gray skin discoloration may occur with prolonged use;some reversal of discoloration may occur upon discontinuation [1].Discontinuation: Treatment discontinuation or dosage adjustment of oral therapy maycause unpredictable recurrence of previously controlled life-threatening arrhythmia; patientmay require prolonged hospitalization [19].Endocrine and metabolic: Thyroid abnormalities, including hypothyroidism,hyperthyroidism and myxedema coma (sometimes fatal), thyroid nodules, and thyroid cancer,have been reported; increased risk for potentially fatal thyrotoxicosis and arrhythmiabreakthrough or exacerbation; monitoring recommended and dosage adjustment ordiscontinuation may be necessary [1].Endocrine and metabolic: Thyroid abnormalities including increased triiodothyronine (T3)and inactive reverse (T3) may occur in euthyroid patients; monitoring recommendedparticularly in elderly patients and any patient with a history of thyroid nodules, goiter, orother thyroid dysfunction [12]Endocrine and metabolic: Hyperthyroidism, including arrythmia breakthrough, andhypothyroidism may occur; dose adjustment or discontinuation may be necessary [12]Endocrine and metabolic: Preexisting hypokalemia or hypomagnesemia may exaggeratedegree of QT prolongation and increase potential for torsade de pointes; increased risk inpatients with severe or prolonged diarrhea or those receiving diuretics, laxatives, systemiccorticosteroids, or amphotericin B. Correct prior to treatment [1] when possible [9].Endocrine and metabolic: Prior inadequate dietary iodine intake may increase incidence ofamiodarone-induced hyperthyroidism [9].Hepatic: Elevation of liver enzymes has been reported [9]; life-threatening hepatic injurymay occur with histology similar to alcoholic hepatitis or cirrhosis. Monitoring recommendedand discontinuation or dose reduction may be necessary [1].Hepatic: Hepatocellular necrosis leading to hepatic coma, acute renal failure, and deathhave occurred with IV administration at higher than recommended loading dose71concentration and rate of infusion [9].Immunologic: Potentially fatal anaphylactic or anaphylactoid reactions have been reportedwith IV administration, including shock (sometimes fatal), cardiac arrest, and the followingmanifestations: hypotension, tachycardia, hypoxia, cyanosis, rash, flushing, hyperhidrosis,and cold sweat [20].Neurologic: Chronic administration may lead to peripheral neuropathy, which may notresolve when therapy is discontinued [1]Ophthalmic: Optic neuritis and optic neuropathy, in some cases resulting in visualimpairment that led to blindness, have been reported and may occur at any time duringtherapy. Discontinuation may be required [1]; monitoring recommended [9].Ophthalmic: Corneal microdeposits have been reported and may result in visual halos orblurred vision; usually resolve upon dose reduction or discontinuation but asymptomaticmicrodeposits do not require dose change or discontinuation [1].Ophthalmic: Corneal refractive laser surgery is contraindicated by most manufacturers ofcorneal refractive laser surgery devices [9].Respiratory: Pulmonary toxicity, sometimes fatal, may occur presenting with cough andprogressive dyspnea and resulting from either indirect (hypersensitivity pneumonitis,including eosinophilic pneumonia) or direct toxicity (interstitial/alveolar pneumonitis).Monitoring recommended. Consider alternative antiarrhythmic therapy if the patientexperiences signs or symptoms of pulmonary toxicity [1].Respiratory: Pulmonary infiltrates or fibrosis have been reported [19] and is sometimesfatal. Monitoring recommended [12]Surgery: Increases sensitivity to myocardial depressant and conduction effects ofhalogenated inhalational anesthetics; perioperative monitoring recommended [1]Adverse EffectsCommon: In adult clinical trials: hypo- or hyperthyroidism, congestive heart failure, cardiacarrhythmias, SA node dysfunction, nausea, vomiting, constipation, anorexia, abdominal pain,solar dermatitis/photosensitivity, malaise/fatigue, tremor/abnormal involuntary movementsand other neurologic adverse events, visual disturbances, abnormal liver function tests,pulmonary infiltration or fibrosis, flushing, coagulation abnormalities. Blue skin discoloration,rash, hypotension, and cardiac conduction abnormalities were reported less commonly [1].Endocrine: In 190 pediatric patients, 33 (17.3%) developed subclinical hypothyroidismwithin a median time of 7 days (2 to 23 days) of amiodarone initiation and 26 (13.7%)developed hypothyroidism within 11 days (6 to 17 days) in a retrospective chart review.Those with subclinical hypothyroidism became euthyroid (21 out of 33) without thyroidhormone replacement. Those with hypothyroidism experienced normalization (7 out of 26) ofthyroid stimulating hormone within a median of 30 days (18 to 67 days). Of the remaining 18patients with hypothyroidism, 15 started on levothyroxine. Hyperthyroidism occurred in 4(2.1%) patients with 3 of the 4 treated with methimazole [10].Short-term toxicity: Bradycardia and hypotension (possibly associated with rapid rates ofinfusion) may occur. Hypotension may be due, in part, to the co-solvents, polysorbate 80 andbenzyl alcohol, which are components of the original amiodarone product [21][22]. In astudy of pediatric patients (n=61), ages 30 days to 15 years, hypotension and bradycardiawere reported in 36% and 20% of patients, respectively. AV block was reported in 15% ofpatients [23]. Acute pulmonary toxicity was reported in an infant after IV administration [24].72May potentiate development of ventricular tachycardia and cardiac arrest in the presence ofcongenital long QT syndrome [25]. Irritating to the peripheral vessels (concentrations greaterthan 2 mg/mL). Administration through central vein preferred [26].Long-term toxicity: Thyroid abnormalities (6.3% to 20%) including hyperthyroidism (dueto inhibition of T4 to T3) and hypothyroidism (due to high concentration of inorganic iodine)may occur. Photosensitivity reactions (2% to 40%), keratopathy (12% to 30%), rash (3%),and sleep disturbances/behavioral changes (6%) are common adverse events in children.Elevations in liver enzymes have been reported. Hepatitis and cholestatic hepatitis occurrarely (3%). Nausea and vomiting (greater than 10%), optic neuritis (4% to 9%), andpulmonary fibrosis (4% to 9%) have been reported with prolonged oral use in adults. Genericformulation contains 2% benzyl alcohol (20 mg/mL) [27][28][29].Black Box WarningWarning: Pulmonary, Hepatic and Cardiac ToxicityAmiodarone oral tablet is intended for use only in patients with the indicated life-threateningarrhythmias because its use is accompanied by substantial toxicity.Amiodarone can cause pulmonary toxicity (hypersensitivityor other adverse effects [12]Fever reduction and treatment of mild to moderate pain: The decision to useacetaminophen should be weighed against the epidemiological evidence of an associationbetween acetaminophen use and asthma, atopy, rhinoconjunctivitis, or eczema; althoughcausality has not been established [13][14][15]. The IV route may be considered when theoral or rectal route is not possible [16].FDA Pediatric ApprovalIntravenousManagement of mild to moderate pain and moderate to severe pain with adjunctive opioidanalgesics in children 2 years or older. Indicated in fever in neonates or older [1].AdministrationIntravenous: Administer IV over 15 minutes (10 mg/mL). Withdraw appropriate dose andadminister in bottle, bag, or IV syringe; dose should be administered within 6 hours [1].Exercise caution when calculating the dose in milligrams and administering the dose inmilliliters [5][6][7]. The administered volume in a neonate should always be 7.5 mL or less[7].MEDICATION SAFETYContraindications/Precautions2Intravenous formulation contraindicated in patients with severe hepatic impairment orsevere active liver disease. Hypersensitivity reactions, including life-threatening anaphylaxis,have been reported [18].Rare but serious skin reactions, including Stevens-Johnson syndrome, toxic epidermalnecrolysis, and acute generalized exanthematous pustulosis, have been associated with theuse of acetaminophen. Reactions may occur after one use or at any time. Discontinue useimmediately if rash or other hypersensitivity symptoms occur [19].Use with caution in patients with hepatocellular insufficiency, severe renal insufficiency,glucose 6 phosphate dehydrogenase deficiency, chronic malnutrition, ordehydration/hypovolemia [16].A modest reduction in blood pressure and heart rate may occur in neonates (preterm andfull-term) after IV administration of acetaminophen. Neonates with pre-existing low arterialpressure may be at greater risk for hypotension [20].Epidemiological evidence demonstrated an association between acetaminophen use andasthma [15], rhinoconjunctivitis, eczema [14] and atopy [13]. Confirmatory studies areneeded; however, in a meta-analysis, the odds ratio (OR) was 1.6 (95% CI, 1.48 to 1.74) forthe risk of asthma in children among users of acetaminophen in the year prior to asthmadiagnosis and the first year of life and 1.96 (95% CI, 1.5 to 2.56) for the risk of wheezingand acetaminophen use in the previous year of life [15]. In 2 observational studies, the ORwas 3.61 (95% CI, 1.33 to 9.77) for atopy and acetaminophen exposure before the age of 15months [13], and up to 2.39 (95% CI, 2.24 to 2.55) for rhinoconjunctivitis symptoms or 1.99(95% CI, 1.82 to 2.16) for eczema symptoms and acetaminophen exposure in the previous12 months in adolescents [14]Adverse EffectsInjection site events (pain and site reactions; 15%) and vomiting (5%) occur with IVacetaminophen [16]. Rash, fever, thrombocytopenia, leukopenia, and neutropenia have beenreported in children [18][21][22][23][24]. Serious skin reactions have been reported frompatients who were rechallenged with acetaminophen and had a recurrence of a serious skinreaction [19].Hypothermia did not develop in 99 neonates (93 normothermic and 6 with fever)administered IV acetaminophen [25].Although data are limited for neonates, in children liver toxicity occurs with excessive doses[16][18] or after prolonged administration (greater than 48 hours) of therapeutic doses.Hepatotoxicity occurred in less than 0.01% of children administered therapeutic doses ofacetaminophen, in a systemic review (n=32,424; studies=62). The estimated risk for minoror major hepatic events was 0.031% (95% CI, 0.015% to 0.057%) [26]. No significantincreases in liver enzymes were observed after a median duration of 60 hours (6 to 480hours) and a median of 9 (2 to 80) doses of IV acetaminophen (20 mg/kg loading dose; 10mg/kg (every 6 hours for more than 36 weeks postmenstrual age (PMA), every 8 hours for31 to 36 weeks PMA, and every 12 hours for less than 31 weeks postmenstrual age) in 189infants (1 day to 182 days of age; 30 to 55 weeks PMA), in a retrospective analysis [27].3Acute liver failure occurred in an 11-month-old boy who received therapeutic doses of oralacetaminophen for a prolonged duration (10 days) [28].Black Box WarningPrevent acetaminophen injection dosing errors, which may result in accidental overdose anddeath, by confirming that doses in milligrams (mg) are not confused with doses in milliliters(mL); that patients under 50 kg receive weight-based doses; that infusion pumps areprogrammed correctly; and that the total dose of acetaminophen from all routes and from allsources does not exceed daily limits. Life-threatening cases of acute hepatic failure leading toliver transplant or death have been linked with acetaminophen use. In most cases of hepaticinjury, acetaminophen doses exceeded maximum daily limits and often involved the use ofmore than 1 acetaminophen-containing product [17].MonitoringAssess for signs of pain. Monitor temperature. Assess liver function. Serum acetaminophenconcentration is obtained only to assess toxicity.MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyNonnarcotic analgesic and antipyretic. Peak serum concentration occurs approximately 60minutes after an oral dose. Absorption after rectal administration is variable and prolonged.Extensively metabolized in the liver, primarily by sulfation with a small amount byglucuronidation. Metabolites and unchanged drug are excreted by the kidney. Eliminationhalf-life is approximately 3 hours in term neonates, 5 hours in preterm neonates greater than32 weeks gestation, and up to 11 hours in more immature neonates. Elimination is prolongedin patients with liver dysfunction.IV: A dose of 12.5 mg/kg/dose IV administered to a neonate (greater than 32 weeksgestational at birth) provided similar concentrations as those achieved in infants, children,and adolescents treated with 15 mg/kg/dose and in adults treated with a 1000-mg dose [1].A 20 mg/kg loading dose achieved a Cmax of 15 to 25 mg/L in 19 neonates (27 to 42 weeksgestational age) included in the PARANEO study. An effect compartment concentration of 10mg/L was associated with a pain score reduction of 3.4 units [29]. A mean plasmaconcentration of 11 mg/L after acetaminophen IV 10 mg/kg every 6 hours (with or without a20 mg/kg loading dose) was predicted from a pharmacokinetic analysis of 158 neonates (32to 44 weeks postmenstrual age) [30].Based on a population pharmacokinetic analysis of 220 patients varying from preterm infantsthrough adults, the following table provides IV doses to achieve an acetaminophenconcentration of 9 mg/L and pharmacokinetic parameters [31]:4Acetaminophen (population pharmacokinetics)To Achieve TargetAverageAcetaminophenConcentrationof 9 mg/LPharmacokineticparametersWeightrange(kg)LoadingDose IV(mg/kg)MaintenanceDoseIV every 6hours(mg/kg)Cl(L/hr)Vd(L)half-life(hrs)0.5 to111.2 5.1 0.047 0.18 2.61 to1.512.1 6 0.11 0.36 2.21.5 to212.2 6.8 0.19 0.54 22 to 3 13.3 7.4 0.27 0.72 1.83 to 5 12.8 8.5 0.47 1.08 1.65 to 8 13.5 10.4 0.96 1.79 1.38 to 9 16.1 12.4 1.8 2.87 1.19 to 15 16.8 12.9 2.1 3.23 115 to2019.2 14.8 4.1 5.38 0.920 to3518.4 15.4 5.7 7.17 0.935 to5018.3 15.2 9.9 12.55 0.950 17.4 14.5 13.4 17.93 0.9Oral/Rectal: Target concentrations above 10 mg/L are predicted in 50% of patientsadministered acetaminophen (30 mg/kg orally loading dose, 15 mg/kg/dose orally every 8hours and 37.5 mg/kg rectally loading dose, 20 mg/kg/dose every 8 hours) in a populationpharmacokinetic analysis (n=30, 1 to 90 days old, 31 to 40 weeks gestational age) [32].ABOUTSpecial Considerations/PreparationOral: Available orally in various liquid formulations containing 160 mg/5 mL (32 mg/mL), 80mg/0.8 mL (100 mg/mL), and 500 mg/15 mL (33.33 mg/mL).pneumonitis or interstitial/alveolarpneumonitis) that has resulted in clinically manifest disease at rates as high as 17% in someseries of patients. Pulmonary toxicity has been fatal about 10% of the time. Obtain abaseline chest X-ray and pulmonary-function tests, including diffusion capacity, when therapyis initiated. Repeat history, physical exam, and chest X-ray every 3 to 6 months.Amiodarone can cause hepatoxicity, which can be fatal. Obtain baseline and periodic livertransaminases and discontinue or reduce dose if the increase exceeds three times normal, ordoubles in a patient with an elevated baseline. Discontinue if the patient experiences signs orsymptoms of clinical liver injury.Amiodarone can exacerbate arrhythmias. Initiate in a clinical setting where continuouselectrocardiograms and cardiac resuscitation are available [1].Solution CompatibilityD5W, and NS at concentrations of 1 to 6 mg/mL.Terminal Injection Site CompatibilityAmikacin, amphotericin B, atropine, calcium chloride, calcium gluconate, ceftizoxime,ceftriaxone, cefuroxime, clindamycin, dobutamine, dopamine, epinephrine, famotidine,fentanyl, fluconazole, furosemide, esmolol, erythromycin, gentamicin, insulin, isoproterenol,lidocaine, lorazepam, metronidazole, midazolam, milrinone, morphine, nitroglycerin,norepinephrine, penicillin G, phentolamine, potassium chloride, procainamide, tobramycin,vancomycin, and vecuronium.73Terminal Injection Site IncompatibilityAminophylline, ampicillin, ceftazidime, cefazolin, digoxin, heparin, imipenem-cilastatin,mezlocillin, micafungin, piperacillin, piperacillin-tazobactam, sodium bicarbonate, and sodiumnitroprusside.MonitoringTherapeutic MonitoringPhysical Exam• Arrhythmia control is indicative of efficacy [8].• Stabilization of ventricular arrhythmias is indicative of efficacy [9]Toxic MonitoringLaboratory Parameters• Obtain baseline and periodic liver transaminases [1].• Monitor thyroid function prior to treatment and periodically thereafter, particularly inpatients with a history of thyroid nodules, goiter, or other thyroid dysfunction [1][9].Investigators recommended weekly monitoring of complete thyroid-function panel for thefirst 5 weeks after initiation of amiodarone, then less frequently (e.g. every 3 months) ormore frequently if signs or symptoms developed for thyroid dysfunction based on aretrospective study of 190 pediatric patients on amiodarone with thyroid-function testing[10].• Monitor hemodynamic status carefully (eg, lactate levels), especially in young infants andhemodynamically compromised patients [11].Physical Exam• Perform baseline chest x-ray and pulmonary-function tests,[12] including diffusion capacity;reevaluate with history, physical exam, and chest x-ray every 3 to 6 months thereafter or ifsymptoms occur [1], especially in patients receiving chronic treatment [12].• Perform regular ophthalmic examinations, including funduscopy and slit-lamp examination[1] especially if symptoms of visual impairment appear [12]. Early detection of optic neuritisor neuropathy may be improved with ophthalmologic examinations within the first 12months, and especially within the first 4 months of therapy [13].• Assess pacing and defibrillation thresholds at initiation and during therapy in patients withimplanted defibrillators or pacemakers [1].• Monitor for QTc prolongation during IV infusion [9]• Carefully monitor for evidence of progressive liver injury [9]• Monitor heart rate in patients receiving concomitant drugs that slow heart rate, such asdrugs with depressant effects on the sinus and AV node (eg, digoxin, beta blockers,verapamil, diltiazem, ivabradine, clonidine) [14][15].• Monitor heart rate in patients taking or recently discontinuing amiodarone when startingantiviral treatment [1][14].• Monitor for new respiratory symptoms [12]• Monitor hemodynamic status carefully (eg, blood pressure, heart rate), especially in younginfants and hemodynamically compromised patients [11].74• Ophthalmologic exams (funduscopy and slit-lamp examination) should be performedregularly to detect any visual disturbances [16][17][18]MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyClass III antiarrhythmic agent that is an iodinated benzofuran compound. Electrophysiologicactivity is accomplished by prolonging the duration of the action potential and increasing theeffective refractory period. Increases cardiac blood flow and decreases cardiac work andmyocardial oxygen consumption. Highly protein bound (95%) in adults. Extensivelymetabolized to an active metabolite by the cytochrome CYP3A isoenzyme system (limited inpreterm infants). Drug-drug interaction potentially occur when given in combination withdrugs that inhibit cytochrome CYP3A: phenytoin, fosphenytoin, clarithromycin, erythromycin,azole antifungals (e.g. fluconazole, ketoconazole, itraconazole), protease inhibitors (e.g.indinavir, ritonavir), class IA and class III antiarrhythmics (e.g. quinidine, procainamide,sotalol) and cimetidine (amiodarone levels increase). Amiodarone and its major metabolitemay inhibit CYP2C9, CYP2C19, CYP2D6, CYP3A, CYP2A6, CYP2B6, and CYP2C8, as well asthe transporters P-glycoprotein and organic cation transporter (OCT2). Amiodarone preventsthe elimination of digoxin resulting in high digoxin levels. Half-life reported to be 26 to 107days in adults. No data in preterm infants. Accumulates in tissues; serum levels can bedetected for months. Contains 37.3% iodine by weight. Adheres to PVC tubing: low infusionrates in neonates may lead to reduced drug delivery during continuous infusions. Oralabsorption is variable with approximately 50% bioavailability.ABOUTSpecial Considerations/PreparationIV: The preferred formulation is Nexterone®, available as 1.5 mg/mL (150 mg/100 mL) and1.8 mg/mL (360 mg/200 mL) concentrations in premix bags. Nexterone® does not containbenzyl alcohol or polysorbate 80, and therefore does not carry a warning regarding benzylalcohol and fatal gasping syndrome in neonates. There are also no limitations regardingcompatibility and stability with plastics and isotonic infusion fluids. Store at room temperatureand protect from light.Generic amiodarone is also available as 50 mg/mL concentration in 5, 10, and 20 mL vials.Contains 2% (20 mg/mL) of benzyl alcohol and 10% (100 mg/mL) polysorbate (Tween) 80as a preservative. Store at room temperature and protect from light.Preparation(Premixed injection) is available as a single-use, ready-to-use, iso-osmotic solution indextrose for intravenous IV administration. No further dilution is required. Discard anyunused portion after use [12].(Premixed injection) If the administration port protector is damaged, detached, or not75present, discard the container as the solution path sterility may be compromised. Check forminute leaks prior to use by squeezing the bag firmly. If leaks are detected, discard solutionas sterility may be impaired. Protect from light until ready to use [12].Oral:Supplied in 100-mg, 200-mg, 300-mg, and 400-mg tablets.Extemporaneous Oral Suspension (5 mg/mL)Amiodarone 5 mg/mL oral suspension [30]:◦ Crush five 200-mg tablets into a mortar and make to a fine powder.◦ For the vehicle: Mix 100 mL of Ora-Sweet (or Ora-Sweet Sugar Free) with 100 mL ofOra-Plus, then adjust pH. Use sodium bicarbonate solution (5 gm/100 mL in distilledwater) to adjust pH between 6 and 7.◦ Add a small amount of vehicle to powder in mortar and make a uniform paste.◦ Add additional vehicle in geometric portions while mixing.◦ Transfer to graduate and add sufficient amount of vehicle to a total volume of 200 mLThe 5 mg/mL suspension in plastic bottles is stable for at least 42 days at 25 degrees C and91 days at 4 degrees CAlternatively, an oral suspension with a final concentration of 5 mg/mL may be made asfollows: crush a 200-mg tablet, slowly mix in 20 mL of 1% methylcellulose, and then add in20 mL of simple syrup tomake a total volume of 40 mL. Stable for six weeks at roomtemperature and three months refrigerated when stored in glass or plastic [31].© Merative US L.P. 1973, 202476AmoxicillinNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseUsual dose:Max 30 mg/kg/day orally divided every 12 hours (manufacturer recommended) . Continuefor a minimum of 48 to 72 hours after patient becomes asymptomatic or bacteria has beeneradicated. For infections caused by Streptococcus pyogenes, duration of treatment shouldbe at least 10 days. Durations of several weeks may be required for some infections [1]. 100mg/kg/day orally in 2 divided doses in neonates 2 kg or more [2][3][4][5] and 75 mg/kg/dayorally in 2 divided doses in neonates less than 2 kg have been used in infants 0 to 59 dayswith possible serious infections [3][4][5].Anthrax[6]32 to 37 weeks gestational age0 to 1 week of age: 50 mg/kg/day orally divided every 12 hours1 to 4 weeks of age: 75 mg/kg/day orally divided every 8 hoursTerm newborn0 to 4 week of age: 75 mg/kg/day orally divided every 8 hoursDuration: For prophylaxis, continue for 60 days after exposure. For naturally acquiredcutaneous infection, 7 to 10 days. As follow-up therapy for severe anthrax, complete coursefor 14 days or longer until clinical criteria for stability are met [6].Urinary Tract Infection, Prophylaxis: 10 to 15 mg/kg/day orally once daily [7][8].Dose Adjustments There are no data available for dosing amoxicillin in pediatric patientswith renal impairment. In adults, based on the severity of the infection, the lower end of thedose and/or frequency are recommended [1].UsesAnthrax, Treatment and Prophylaxis [6]:Postexposure prophylaxis for Bacillus anthracis (Oral)Penicillin-resistant strains or prior to susceptibility testing◦ Preferred: Ciprofloxacin or doxycycline Alternatives in order of preference:clindamycin, levofloxacin.◦ Penicillin-susceptible strains◦ Preferred: Amoxicillin Alternative: penicillin VK.Cutaneous Anthrax treatment, without systemic involvement (Oral)All strains, regardless of penicillin susceptibility or if susceptibility is unknown77◦ Preferred: Ciprofloxacin. Alternatives in order of preference: doxycycline, clindamycin,levofloxacin.◦ Alternatives for penicillin-susceptible strains◦ Preferred: Amoxicillin Alternative: penicillin VK.Oral follow-up therapy for severe anthraxCombination Oral Therapy◦ Preferred: Ciprofloxacin. Alternative: levofloxacin. If strains are penicillin-susceptible,amoxicillin (preferred) or penicillin VK (alternative).◦ PLUS◦ Preferred: Clindamycin. Alternatives in order of preference: doxycycline or linezolid.Urinary Tract Infection (UTI), Prophylaxis: Some experts recommend amoxicillinprophylaxis starting at birth and continuing until vesicoureteral reflux (VUR) is ruled out inneonates with hydronephrosis [7], though there are no studies in neonates to supportprophylaxis.The use of prophylactic antibiotics for VUR is controversial [11]. When no prophylacticantibiotics were administered, the 2-year rate for recurrent UTI in children (2 months to 71months of age) was 25.4% and 17.3% with VUR and without VUR, respectively [12]. Inchildren 2 months to 71 months with vesicoureteral reflux, trimethoprim/sulfamethoxazoleprophylaxis reduced the risk of infections but did not reduce renal scarring at 2 years [13];therefore, evidence for routine use of prophylaxis is not established [14].Pediatric FDA Approved Indications:For infection caused by β-lactamase-negative organisms onlyEar, nose and throat infections caused by Streptococcus species (alpha- and beta-hemolytic strains only), S pneumoniae, Staphylococcus species, or Haemophilusinfluenzae[1]. For individuals without a penicillin allergy, penicillin or amoxicillin are theagents of choice for the treatment of group A streptococcal pharyngitis [15].Genitourinary tract infections caused by Escherichia coli, Proteus mirabilis, orEnterococcus faecalis[1].Skin and skin structure infections caused by Streptococcus species (alpha- and beta-hemolytic strains only), Staphylococcus species, or E coli[1].Lower respiratory tract infections caused by Streptococcus species (alpha- and beta-hemolytic strains only), S pneumoniae, Staphylococcus species, or H influenza[1].AdministrationSuspension: Shake well before measuring the dose; place on tongue for swallowing; maymix the dose with formula, milk, fruit juice, water, ginger ale, or cold drinks; after mixing,administer immediately and completely [9]. May also dissolve amoxicillin powder in breastmilk to a concentration of 50 mg/mL [10].78MEDICATION SAFETYContraindications/PrecautionsEndocrine and metabolic: False positive readings for glucose urine tests may occur withClinitest(R), Benedict Solution, or Fehling Solution. Use enzymatic glucose oxidase reaction-type tests [1].Dermatologic: Severe cutaneous adverse reactions (SCAR) such as Stevens-Johnsonsyndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia andsystemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP) mayoccur; monitoring recommended and discontinuation may be necessary [16].Gastrointestinal: Clostridioides difficile-associated diarrhea, including mild diarrhea to fatalcolitis, has been reported and may occur over 2 months from last dose. Ongoing antibioticuse not directed against c difficile may need to be discontinued [16].Immunologic: Severe anaphylactic reactions, including fatalities, have been reported,especially in patients with a history of penicillin hypersensitivity or sensitivity to multipleallergens [1].Mononucleosis: Avoid use due to a high risk of developing an erythematous skin rash [1]Renal: Severe renal impairment (ie, GFR less than 30 mL/min) or hemodialysis; doseadjustment recommended [1].Adverse EffectsCommon adverse effects include rash, diarrhea, nausea, and vomiting [1].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAn analog of ampicillin, amoxicillin is a semisynthetic antibiotic that inhibits the biosynthesisof the cell wall. It has a broad-spectrum bactericidal activity against most strains of gram-positive and gram-negative microorganisms [1].Rapidly absorbed, with time to peak concentration of 1 to 2 hours after administration.Widely distributed into most body tissues and fluids, except brain and spinal fluid. Maypenetrate brain when meninges are inflamed. Protein binding is approximately 20%, andrenal excretion is mostly unchanged at approximately 60%. Half-life of immediate-releaseamoxicillin is 61.3 minutes [1].Pharmacokinetics- Neonates[17][18][19][20]79Neonates Administered IV Amoxicillin*Gestationalage (GA)Postnatalage (PNA)Range(mean)Vd(mean)Half-life(mean)Clearance(mean)Author,year(N)GA = 25 to42 weeks(34.6weeks)PNA = 0 to9 days(0.76 days)0.65L/kg5.2hours *0.096L/kg/hrPullen,2006N=150GA = 26 to41 weeks(33.7weeks)PNA = 10to 52 days(24.7 days)0.66L/kg3 hours*0.18L/kg/hrPullen,2007N=32GA = 24 to32 (28.9weeks)PNA = 1 to3 days (1.1day)0.603L/kg6.9hours *5.2hours**0.061L/kg/hr *0.0805L/hr **Charles,1997N=40GA = (29weeks)PNA = (3days)0.671L/kg6.7hours**0.066L/kg/hr**Huisman-de boer,1995N=17*Gentamicin coadministered**Gentamicin not coadminsiteredABOUTSpecial Considerations/PreparationAvailability: Oral suspension (125, 200, 250, or 400 mg/5mL). Also available as chewabletablets (125, 200, 250, and 400 mg), oral capsules (250 or 500 mg), or oral tablets (500 or875 mg) [1][21][9].Storage: Store at a controlled room temperature between 20 and 25 degrees C (68 and 77degrees F) [1][21][9]Reconstitution: Tab the bottle until all of the powder flows freely. Add approximately one-third of the total amount of water for reconstitution and shake vigorously. Add remainder ofwater and shake again [9].80Mixed with BreastMilkAmoxicillin suspension (50 mg/mL) reconstituted with breast milk was bioequivalent toamoxicillin reconstituted with water in 16 healthy, adult, fasted (10 hours before and 4 hoursafter dose) volunteers [10].© Merative US L.P. 1973, 202481Amphotericin B Lipid ComplexNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseAspergillosis, InvasiveDosage (alternative therapy): 5 mg/kg IV every 24 hours [1]Candidiasis, InvasiveDosage (alternative therapy): 2.5 to 5 mg/kg/dose IV infusion every 24 hours; dosebased on a pharmacokinetic study in neonates; optimal regimen for hematogenous Candidameningoencephalitis is unknown [2][3].Duration of Therapy: Use for 2 weeks after documented clearance of Candida from thebloodstream and resolution of symptoms [4]. For CNS infection, continue until all signs,symptoms, and CSF and radiological abnormalities have resolved [4][3].UsesTreatment of systemic fungal infections resistant to conventional amphotericin B therapy or inpatients with renal or hepatic dysfunction.Neonatal Candidiasis, Including CNS Infection[4]Invasive candidiasis and candidemia, or very low-birth weight infants with asymptomaticcandiduria .◦ Amphotericin B deoxycholate is recommended.◦ Fluconazole IV or oral is an alternative for those who have not been receivingprophylaxis with fluconazole.◦ Lipid formulation amphotericin B agent is an alternative; however, use with caution,especially in the presence of urinary tract involvement.◦ Echinocandins (caspofungin, anidulafungin, or micafungin) should be limited to salvagetherapy or scenarios of resistance or toxicity to amphotericin B deoxycholate orfluconazoleCentral nervous system infections◦ Amphotericin B deoxycholate is recommended.◦ Liposomal amphotericin B agent is an alternative.◦ Salvage therapy with flucytosine may be added in those patients who have notresponded to initial therapy.◦ Fluconazole may be used as step-down therapy for those patients who respond to initialtherapy82Neonatal intensive care unit (with greater than 10% rate of invasive candidiasis)◦ Prophylaxis with IV or oral fluconazole for 6 weeks is recommended for neonates withbirth weights of less than 1000 g◦ Prophylaxis with oral nystatin is an alternative in neonates with birth weights of lessthan 1500 g when fluconazole is unavailable or fluconazole resistance is presentInfective endocarditis: The following recommendations are based on a consensus ofexperts [6]. The full pediatric guidelines can be found here: https://doi.org/10.1161/CIR.0000000000000298Organism Directed TherapyOrganism First-Choice Alternative ChoiceFungiCandidaspp,AspergillussppSurgicalresection plusAmphotericinBWith orwithoutflucytosineAmphotericin Bfollowed by imidazole(eg, fluconazole,itraconazole,voriconazole)suppression if surgerycannot be performed.Lifelong suppressionmay be necessary ifsurgery cannot beperformed or relapseoccurs after surgery.Baltimore, 2015AdministrationAdminister by IV infusion over 2 hours (2.5 mg/kg/hour) at a concentration of 1 to 2 mg/mL.If infusion lasts longer than 2 hours, shake the bag to mix the contents every 2 hours. Flushexisting IV line with D5W prior to infusion or administer in a separate IV line. Do not infusewith saline solutions (precipitation will occur). Do not use an in-line filter to administer [5].MEDICATION SAFETYAdverse EffectsAnemia, thrombocytopenia, hypokalemia, nausea/vomiting, and fever/chills.Solution Compatibility83D5W at 1 to 2 mg/mL dilution.Solution IncompatibilityNS.MonitoringSerum amphotericin B concentrations are not routinely followed. Monitor urine output.Periodic CBC for thrombocytopenia, electrolytes for hypokalemia, BUN, serum creatinine, andhepatic transaminases.For candidemia, monitor blood cultures daily or every other day until Candida is cleared [4].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAmphotericin B lipid complex consists of amphotericin B complexed with two phospholipids ina 1:1 drug-to-lipid ratio. Acts by binding to the sterol component of a cell membrane leadingto alterations in the cell wall permeability and death. Penetrates the cell wall of susceptiblefungi. Concentrates in the liver and spleen. Less nephrotoxic than conventional amphotericinB. Mean serum half-life in adults 24 to 38 hours. The pharmacokinetics of amphotericin Blipid complex is nonlinear.ABOUTSpecial Considerations/PreparationAvailable as a suspension containing 100-mg Abelcet® in 20-mL (5 mg/mL). Shake the vialgently until there is no evidence of any yellow sediment on the bottom. Withdraw theappropriate dose into a syringe using an 18 gauge needle. Remove the needle and replacewith the supplied 5 micron filter needle. Dilute the drug with D5W so that the final infusionconcentration is 1 to 2 mg/mL. Shake until thoroughly mixed. Check for complete dispersion.The diluted admixture is stable for 48 hours refrigerated and an additional 6 hours at roomtemperature [5].Do not freeze. Protect from light.Do not flush IV or mix Abelcet® with saline solutions - precipitation willoccur.84© Merative US L.P. 1973, 202485Amphotericin B LiposomeNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDose2.5 to 7 mg/kg/dose every 24 hours IV infusion [1].UsesTreatment of systemic fungal infections resistant to conventional amphotericin B therapy or inpatients with renal or hepatic dysfunction.Neonatal Candidiasis, Including CNS Infection[4]Invasive candidiasis and candidemia, or very low-birth weight infants with asymptomaticcandiduria .◦ Amphotericin B deoxycholate is recommended.◦ Fluconazole IV or oral is an alternative for those who have not been receivingprophylaxis with fluconazole.◦ Lipid formulation amphotericin B agent is an alternative; however, use with caution,especially in the presence of urinary tract involvement.◦ Echinocandins (caspofungin, anidulafungin, or micafungin) should be limited to salvagetherapy or scenarios of resistance or toxicity to amphotericin B deoxycholate orfluconazoleCentral nervous system infections◦ Amphotericin B deoxycholate is recommended.◦ Liposomal amphotericin B agent is an alternative.◦ Salvage therapy with flucytosine may be added in those patients who have notresponded to initial therapy.◦ Fluconazole may be used as step-down therapy for those patients who respond to initialtherapyNeonatal intensive care unit (with greater than 10% rate of invasive candidiasis)◦ Prophylaxis with IV or oral fluconazole for 6 weeks is recommended for neonates withbirth weights of less than 1000 g◦ Prophylaxis with oral nystatin is an alternative in neonates with birth weights of lessthan 1500 g when fluconazole is unavailable or fluconazole resistance is presentComparison with Echinocandins: There was no difference in clinical response between86echinocandins and amphotericin B (OR 1.38; 95% CI, 0.68 to 2.8) for the treatment ofsuspected or confirmed invasive candidiasis in a meta-analysis (n=5; 354 neonates andchildren). Antifungals included were micafungin, caspofungin, amphotericin B deoxycholate,and liposomal amphotericin B. Subanalysis demonstrated no difference in other comparisonsincluding mycological response, mortality, recurrence of candida infection, type ofechinocandin, different risk groups (high-risk, low-risk, or neutropenic groups), and type ofuse (targeted or empirical). Discontinuation due to adverse effects were higher withamphotericin B than the echinocandins (OR 0.3; 95% CI, 0.12 to 0.76) [5].Infective endocarditis: The following recommendations are based on a consensus ofexperts [6]. The full pediatric guidelines can be found here: https://doi.org/10.1161/CIR.0000000000000298Organism Directed TherapyOrganism First-Choice Alternative ChoiceFungiCandidaspp,AspergillussppSurgicalresection plusAmphotericinBWith orwithoutflucytosineAmphotericinBfollowed by imidazole(eg, fluconazole,itraconazole,voriconazole)suppression if surgerycannot be performed.Lifelong suppressionmay be necessary ifsurgery cannot beperformed or relapseoccurs after surgery.Baltimore, 2015AdministrationAdminister by IV infusion at a concentration of 1 to 2 mg/mL over a period of approximately60 (if well tolerated) to 120 minutes. To provide sufficient volume for infusion, a finalconcentration of 0.2 to 0.5 mg/mL may be appropriate for infants and small children [2]. Therecommended standard concentrations are 1 or 2 mg/mL [3]. May increase infusion time ifpatient experiences intolerance during the infusion. Flush existing IV line with D5W prior toinfusion or administer in a separate IV line. In-line filter with pore diameter no less than 1micron may be used [2].MEDICATION SAFETYContraindications/Precautions87PrecautionsImmunologic: Anaphylaxis has been reported; discontinue immediately and do notreinitiate [7].Adverse EffectsSafety has not been established in pediatric patients younger than 1 month [7].Common Hypokalemia (37% vs 55%), chills (29% vs 68%), vomiting (27% vs 55%), andhypertension (10% vs 21%) were reported for amphotericin liposome compared withamphotericin B deoxycholate in a double-blind study in 95 children 16 years or younger [7].Endocrine/Metabolic:•Hypokalemia occurred at the end of treatment in 21.2% (7 out of 33 pediatric patients) inthe liposomal amphotericin B group compared with 28.6% (16 out of 56 pediatric patients)for the conventional amphotericin B group when drugs were administered as recommended(3 to 5 mg/kg/day over at least 1 hour for liposomal and 0.5 to 1.5 mg/kg/day over at least 4hours for conventional). Potassium replacement therapy was administered to 87.9% ofpatients in the liposomal amphotericin B group and 89.3% of patients in the conventionalgroup. In those younger than 90 days (n=16), 100% vs 87.5%, respectively, receivedpotassium replacement therapy [8].Hepatic:•Hepatotoxicity was more common in pediatric patients who received liposomal amphotericinB compared with conventional amphotericin B in a retrospective study; but whenconcomitant hepatotoxic drugs were accounted for there was no difference. Additionally, themajority of these children with hepatoxicity had at least 1 enzyme abnormality at baseline. Of65 pediatric patients with baseline and end-of-treatment liver function test, amphotericin-related hepatotoxicity was 82.8% (24/29) for liposomal amphotericin B and 55.6% (20/36)for conventional amphotericin B (OR 3.8 (1.2 to 12.3; p=0.024)). The LFTs that weredifferent between the 2 groups were gamma-glutamyl transferase (GGT) and bilirubin; GGTwas up to 5 x the upper limit of normal (ULN) in 41.4% in the liposomal group comparedwith 16.7% (p=0.049) in the conventional group and bilirubin was more than 3 to 10 x theULN in 17.2% and 0%, respectively [8].Infusion-Related Reactions:•Infusion-related reactions (rigors, fever, tachycardia, and rash) occurred in 9.1% (3 out of33 pediatric patients) in the liposomal amphotericin B group compared with 23.2% (13 out of56 pediatric patients; p=0.15) for the conventional amphotericin B group when drugs wereadministered as recommended (3 to 5 mg/kg/day over at least 1 hour for liposomal and 0.5to 1.5 mg/kg/day over at least 4 hours for conventional). None of the reactions occurred inchildren younger than 90 days (n=16) [8].Renal:•Compared with older individuals, pediatric patients appear to have more tolerance for thenephrotoxic effects of amphotericin B deoxycholate [7]. Creatinine elevation (doubling ofbaseline serum creatinine concentration) occurred in 21.2% (7 out of 33 pediatric patients) inthe liposomal amphotericin B group compared with 14.3% (8 out of 56 pediatric patients;p=0.4) for the conventional amphotericin B group when drugs were administered asrecommended (3 to 5 mg/kg/day over at least 1 hour for liposomal and 0.5 to 1.5 mg/kg/dayover at least 4 hours for conventional). The mean number of concomitant nephrotoxic drugswas 2.5 for the liposomal group compared with 2 for the conventional group [8].88Solution CompatibilityD5W, D10W, D20W, D25W.Solution IncompatibilityNS.MonitoringLaboratory Exam: Monitor renal function frequently during therapy. Liver function, serumelectrolytes (especially magnesium and potassium), and CBC should be assessed regularlyduring therapy [7].For candidemia, monitor blood cultures daily or every other day until Candida is cleared [4].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAmBisome® consists of amphotericin B intercalated within a single bilayer liposomal drugdelivery system. Acts by binding to the sterol component of a cell membrane leading toalterations in the cell wall permeability and death. Penetrates the cell wall of susceptiblefungi. Concentrates in the liver and spleen but penetrates the CNS less than conventionalamphotericin B. Less nephrotoxic than conventional amphotericin B. Mean serum half-life inadults 24 to 38 hours. The pharmacokinetics of amphotericin B liposome is nonlinear.ABOUTSpecial Considerations/PreparationAvailable as powder for injection in 50 mg vials. Reconstitute by adding 12 mL of sterilewater for injection to a yield a concentration of 4 mg/mL. Immediately shake vial vigorouslyfor 30 seconds. Check for complete dispersion. Reconstituted suspension stable for 24 hoursrefrigerated.89Do not freeze. Protect from light.Before administration, AmBisome® must be diluted with D5W to a final concentration lessthan 2 mg/mL. A 1 mg/mL dilution may be made by filtering (using 5 micron filter) 1 mL ofreconstituted solution into 3 mL of D5W. Use one filter per vial of AmBisome®. Use solutionwithin 6 hours of dilution.Do not flush IV or mix Ambisome® with saline solutions-precipitation will occur.© Merative US L.P. 1973, 202490Amphotericin BNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseFungal Infections, Suspected or Documented1 mg/kg every 24 hours IV infusion [1][2][3][4][5]. A dose range of 1 to 1.5 mg/kg/day hasbeen suggested for invasive aspergillosis [6].Candidiasis, Invasive1 mg/kg/dose IV every 24 hours for neonates with disseminated candidiasis, including CNSinfections [1][2][3][4][5].Duration of Therapy: Use for 2 weeks after documented clearance of Candida from thebloodstream and resolution of symptoms [7]. For CNS infection, continue until all signs,symptoms, and CSF and radiological abnormalities have resolved [7][5]UsesTreatment of systemic fungal infections and severe superficial mycoses.Neonatal Candidiasis, Including CNS Infection[7]Invasive candidiasis and candidemia, or very low-birth weight infants with asymptomaticcandiduria .◦ Amphotericin B deoxycholate is recommended.◦ Fluconazole IV or oral is an alternative for those who have not been receivingprophylaxis with fluconazole.◦ Lipid formulation amphotericin B agent is an alternative; however, use with caution,especially in the presence of urinary tract involvement.◦ Echinocandins (caspofungin, anidulafungin, or micafungin) should be limited to salvagetherapy or scenarios of resistance or toxicity to amphotericin B deoxycholate orfluconazoleCentral nervous system infections◦ Amphotericin B deoxycholate is recommended.◦ Liposomal amphotericin B agent is an alternative.◦ Salvage therapy with flucytosine may be added in those patients who have notresponded to initial therapy.◦ Fluconazole may be used as step-down therapy for those patients with fluconazole-susceptible isolates who respond to initial therapy91Neonatal intensive care unit (with greater than 10% rate of invasive candidiasis)◦ Prophylaxis with IV or oral fluconazole for 6 weeks is recommended for neonates withbirth weights of less than 1000 g◦ Prophylaxis with oral nystatin is an alternative in neonates with birth weights of lessthan 1500 g when fluconazole is unavailableor fluconazole resistance is presentComparison with Echinocandins: There was no difference in clinical response betweenechinocandins and amphotericin B (OR 1.38; 95% CI, 0.68 to 2.8) for the treatment ofsuspected or confirmed invasive candidiasis in a meta-analysis (n=5; 354 neonates andchildren). Antifungals included were micafungin, caspofungin, amphotericin B deoxycholate,and liposomal amphotericin B. Subanalysis demonstrated no difference in other comparisonsincluding mycological response, mortality, recurrence of candida infection, type ofechinocandin, different risk groups (high-risk, low-risk, or neutropenic groups), and type ofuse (targeted or empirical). Discontinuation due to adverse effects were higher withamphotericin B than the echinocandins (OR 0.3; 95% CI, 0.12 to 0.76) [13].Infective endocarditis: The following recommendations are based on a consensus ofexperts [14]. The full pediatric guidelines can be found here: https://doi.org/10.1161/CIR.0000000000000298Organism Directed TherapyOrganism First-Choice Alternative ChoiceFungiCandidaspp,AspergillussppSurgicalresection plusAmphotericinBWith orwithoutflucytosineAmphotericin Bfollowed by imidazole(eg, fluconazole,itraconazole,voriconazole)suppression if surgerycannot be performed.Lifelong suppressionmay be necessary ifsurgery cannot beperformed or relapseoccurs after surgery.Baltimore, 2015AdministrationInfuse over 2 to 6 hours [8][9][10] at a concentration not to exceed 0.1 mg/mL [8]; someinstitutions have used 0.5 mg/mL concentrations in pediatric patients [11]. Avoid rapidadministration (hypotension, hypokalemia, arrhythmias, and shock can occur). Do not flushIV or mix amphotericin with saline solution; precipitation will occur. In-line filterwith pore diameter no less than 1 micron may be used [8].To avoid febrile reactions, administration of acetaminophen or diphenhydramine may beconsidered [12]. Some suggest starting with 0.25 mg/kg/day, followed by increases of 0.25mg/kg/day until the target dose is reached[4]. However, for patients with severe infections92the dose should be initiated at the target dose [12].MEDICATION SAFETYContraindications/PrecautionsPrecautionsAdministration: Rapid infusion may result in hypotension, hypokalemia, arrhythmias, andshock; infuse over 2 to 6 hours [15].Administration: If therapy is interrupted for a period longer than 7 days, therapy should beresumed by starting with the lowest dosage level and increased gradually [15].Infusion Reactions: Acute reactions (fever, shaking, chills, hypotension, anorexia, nausea,vomiting, headache, and tachypnea) are common 1 to 3 hours after initiating infusion.Pretreatment with antipyretics, antihistamines, corticosteroids, or meperidine may improvetolerance to treatment. A single test dose is recommended in some patients to assesstolerance [15].Neurological: Leukoencephalopathy has occurred; total body irradiation may put patient atrisk [15].Renal: Use with caution in patients with reduced renal function; some patients may needhydration and sodium repletion prior to administration to reduce risk of nephrotoxicity [15].Adverse EffectsCommon Hypokalemia (37% vs 55%), chills (29% vs 68%), vomiting (27% vs 55%), andhypertension (10% vs 21%) were reported for amphotericin liposome compared withamphotericin B deoxycholate in a double-blind study in children 16 years or younger [16].Other common events with amphotericin B include fever, malaise, weight loss, hypotension,tachypnea, anorexia, nausea, diarrhea, dyspepsia, cramping epigastric pain, anemia(normochromic, normocytic), pain at the injection site with or without phlebitis orthrombophlebitis, generalized pain (including muscle and joint pains), headache, decreasedrenal function, and renal function abnormalities [15]Endocrine/Metabolic:•Hypokalemia (serum K+ less than 3 mmol/L) occurred in 17% of infants, younger than 30days of age who received amphotericin B deoxycholate, in the neonatal intensive care unit.The median gestational age was 26 weeks (range, 23 to 41 weeks) and median birth weightwas 863 g (range, 546 to 4000 g) [17].•Hypokalemia occurred at the end of treatment in 21.2% (7 out of 33 pediatric patients) inthe liposomal amphotericin B group compared with 28.6% (16 out of 56 pediatric patients)for the conventional amphotericin B group when drugs were administered as recommended(3 to 5 mg/kg/day over at least 1 hour for liposomal and 0.5 to 1.5 mg/kg/day over at least 4hours for conventional). Potassium replacement therapy was administered to 87.9% ofpatients in the liposomal amphotericin B group and 89.3% of patients in the conventionalgroup. In those younger than 90 days (n=16), 100% vs 87.5%, respectively, received93potassium replacement therapy [18].Hepatic:•Hepatotoxicity was more common in pediatric patients who received liposomal amphotericinB compared with conventional amphotericin B in a retrospective study; but whenconcomitant hepatotoxic drugs were accounted for there was no difference. Additionally, themajority of these children with hepatoxicity had at least 1 enzyme abnormality at baseline. Of65 pediatric patients with baseline and end-of-treatment liver function test, amphotericin-related hepatotoxicity was 82.8% (24/29) for liposomal amphotericin B and 55.6% (20/36)for conventional amphotericin B (OR 3.8 (1.2 to 12.3; p=0.024)). The LFTs that weredifferent between the 2 groups were gamma-glutamyl transferase (GGT) and bilirubin; GGTwas up to 5 x the upper limit of normal (ULN) in 41.4% in the liposomal group comparedwith 16.7% (p=0.049) in the conventional group and bilirubin was more than 3 to 10 x theULN in 17.2% and 0%, respectively [18].Infusion-Related Reactions:•Infusion-related reactions (rigors, fever, tachycardia, and rash) occurred in 9.1% (3 out of33 pediatric patients) in the liposomal amphotericin B group compared with 23.2% (13 out of56 pediatric patients; p=0.15) for the conventional amphotericin B group when drugs wereadministered as recommended (3 to 5 mg/kg/day over at least 1 hour for liposomal and 0.5to 1.5 mg/kg/day over at least 4 hours for conventional). None of the reactions occurred inchildren younger than 90 days (n=16) [18].Renal:•Serum creatinine increased at least 0.4 mg/dL at any time during amphotericin B therapy in16% (15 out of 92) of infants, 90 days or younger, in the neonatal intensive care unit. Noneof the values exceeded 2 mg/dL. By the end of therapy, elevated creatinine valuesnormalized in 8 of the 15 infants; 3 had resolving values, and 4 had values that remainedelevated. The median gestational age was 26 weeks (range, 23 to 41 weeks) and medianbirth weight was 863 g (range, 546 to 4000 g). The mean cumulative dose was 13.5 mg/kgand duration was 16.3 days for infants who both developed and did not developnephrotoxicity; no difference in dose or duration between groups [17].•Compared with older individuals, pediatric patients appear to have more tolerance for thenephrotoxic effects of amphotericin B deoxycholate [19]. Creatinine elevation (doubling ofbaseline serum creatinine concentration) occurred in 21.2% (7 out of 33 pediatric patients) inthe liposomal amphotericin B group compared with 14.3% (8 out of 56 pediatric patients;p=0.4) for the conventional amphotericin B group when drugs were administered asrecommended (3 to 5 mg/kg/day over at least 1 hour for liposomal and 0.5 to 1.5 mg/kg/dayover at least 4 hours for conventional). The mean number of concomitant nephrotoxic drugswas 2.5 for the liposomal group compared with 2 for the conventional group [18].•Sodium intake of more than 4 mEq/kg/day was associated with a decrease in the incidenceof amphotericin B-induced nephrotoxicity in extremely premature infants with a birth weightof less than 1250 g [20][21]. Nephrotoxicity developed in 13 out of 21 neonates in thecontrol group compared with 3 out of 16 in the high-sodium intake group (p=0.02).Theadditional sodium was administered by either increasing the amount of sodium in the totalparenteral nutrition (TPN) or normal saline in those who could tolerate excess fluid untilsodium could be adjusted in the TPN. All neonates in the high sodium group received 1mg/kg/day by 2 days of age [21].Black Box Warning94This drug should be used primarily for treatment of patients with progressive and potentiallylife-threatening fungal infections; it should not be used to treat noninvasive forms of fungaldisease such as oral thrush, vaginal candidiasis and esophageal candidiasis in patients withnormal neutrophil counts [15]The product name and dosage should verified if the prescribed dose exceeds 1.5 mg/kg.Overdose can result in potentially fatal cardiac or cardiorespiratory arrest [15].Solution CompatibilityD5W, D10W, D15W, and D20W.Solution IncompatibilityNSTerminal Injection Site CompatibilityAmiodarone, heparin, hydrocortisone, sodium bicarbonate, and zidovudine.Terminal Injection Site IncompatibilityFat emulsion. Amikacin, aztreonam, calcium chloride, calcium gluconate, cefepime,cimetidine, ciprofloxacin, dopamine, enalaprilat, fluconazole, gentamicin, linezolid,magnesium sulfate, meropenem, penicillin G, piperacillin/tazobactam, potassium chloride,propofol, ranitidine, remifentanil, and tobramycin.MonitoringLaboratory Parameters: Monitor renal function frequently during therapy. Liver function,serum electrolytes (especially magnesium and potassium), CBC, and hemoglobin should beassessed regularly during therapy [15].For candidemia, monitor blood cultures daily or every other day until Candida is cleared [7].MECHANISM OF ACTION/PHARMACOKINETICS95PharmacologyMechanism of Action: Amphotericin B binds to ergosterol in the membrane of sensitivefungi and may be fungicidal or fungistatic depending on the concentrations achieved in bodyfluids/tissue [16].The therapeutic concentration range is not well-defined. Highly protein-bound (greater than90%). Elimination half-life is approximately 15 days. Drug may accumulate in tissues to asignificant concentration and be excreted renally for months [15].After 5 days of amphotericin B IV in 13 neonates (2 to 55 days of life; mean gestational age27.4 +/- 5 weeks (24 to 40 weeks)). Dose was increased from 0.1 to 0.5 mg/kg/day over thefirst 4 to 6 days in 10 infants. The other 3 infants started on 0.8 to 1 mg/kg/day which wasreduced to 0.5 mg/kg/day. The mean dose for all patients was 0.54+/-0.16 mg/kg/day. Oral5-fluorocytosine was started on the same day as amphotericin B [22]Peak concentration: 0.96 mcg/mL (range 0.5 to 4 mcg/mL) [22]Vd: 1.5 L/kg (range, 0.1 to 17.5 hours) [22]CSF Distribution: 40% to 90% of serum (n=5) [22]Clearance: 18 mL/min/1.73 m2(range 7.7 to 72.3 mL/min/1.73 m2) [22]Half-life: 14.8 hours (range 5 to 82 hours) beta half-life, weeks to months for alphaelimination phase [22]ABOUTSpecial Considerations/PreparationAvailable as powder for injection in 50-mg vials. Protect the vials from light. Reconstitutewith 10 mL of D5W or preservative free sterile water to a concentration of 5 mg/mL, thendilute further using D5W to a concentration no greater than 0.1 mg/mL for infusion.Reconstituted solution stable for 24 hours at room temperature or 7 days in refrigerator. Donot flush IV or mix amphotericin with saline solution; precipitation will occur. Mayfilter if necessary; mean pore diameter should not be less than 1 micron. The manufacturerrecommends protecting the solution from light during administration [8]. However, there areavailable data that demonstrate protection from light to be unnecessary in typical hospitallighting if administered within 24 hours of preparation [23].Intravitreal injection: amphotericin B deoxycholate 5 to 10 mcg/0.1 mL of sterile water[7].© Merative US L.P. 1973, 202496AmpicillinNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseGeneral Dosage (see below for specific indications)25 to 50 mg/kg/dose [1][2] by IV slow push, or IM.Renal function and drug elimination are most strongly correlated with postmenstrual age(PMA; equivalent to gestational age plus postnatal age). PMA is the primary determinant ofdosing interval, with postnatal age as the secondary qualifier.Dosing Interval ChartPMA(weeks)PostNatal(days)Interval(hours)≤290 to 28>2812830 to 360 to 14>1412837 to 440 to 7>7128≥45 ALL 6Anthrax[3]32 up to 34 weeks gestational age0 to 1 week: 50 mg/kg/dose IV every 12 hours1 to 4 weeks: 50 mg/kg/dose IV every 8 hours34 weeks gestational age or older0 to 1 week: 50 mg/kg/dose IV every 8 hours1 to 4 weeks: 50 mg/kg/dose IV every 6 hoursDuration: 2 to 3 weeks or more until stable. Continue antimicrobial course of prophylaxis(usually oral therapy) for up to 60 days from onset of illness [3].Bacteremia, Group B Streptococcal Disease; Empiric and Definitive Therapy (Early-and late-onset) [4]Guideline DosageGestationalAgePostnatal age Duration7 days oryounger†Older than 7days‡34 weeksor less50mg/kg/doseIV every 12hours75mg/kg/doseIV every 12hours10 days forbacteremiawithout afocus;longerdurations97may benecessaryforprolonged orcomplicatedcourses.Greaterthan 34weeks50mg/kg/doseIV every 8hours50mg/kg/doseIV every 8hours† Use with an aminoglycoside for empiricaltherapy in full-term newborns 7 days or younger.‡ Use with ceftazidime for empirical therapy forpreviously healthy infants, 8 to 28 days of age, inthe community when critical illness and meningitisare absent.Puopolo, 2019Bacteremia (Septicemia)FDA Dosage[5]GestationalAgePostnatal Age Duration7 days oryounger8 days toyoungerthan 28daysContinue fora minimum of48 to 72hours afterasymptomaticor evidenceof bacterialeradication.For group Abeta-hemolyticstreptococci,treat for atleast 10 days.34 weeksor less50mg/kg/doseIV every 12hours75mg/kg/doseIV every 12hourGreaterthan 34weeks28 days or younger50 mg/kg/dose IV every8 hoursProduct Information, 2017Meningitis, Group B Streptococcal Disease; Empiric and Definitive Therapy (Early-and late-onset) [4]Guideline DosagePostnatalageDosage Duration7 days oryounger†100 mg/kg/doseIV every 8 hours14 days foruncomplicatedmeningitis; longerdurations may benecessary forprolonged orcomplicatedcourses.Older than 7days75 mg/kg/doseIV every 6 hours† Use with an aminoglycoside for empiricaltherapy in full-term newborns 7 days or younger.‡ Use with ceftazidime and vancomycin for98empirical therapy for previously healthy infants, 8to 90 days of age.Puopolo, 2019Meningitis, BacterialFDA Dosage[5]GestationalAgePostnatal Age Duration7 days oryounger8 days toyoungerthan 28daysContinue fora minimum of48 to 72hours afterasymptomaticor evidenceof bacterialeradication.For group Abeta-hemolyticstreptococci,treat for atleast 10 days.34 weeksor less50mg/kg/doseIV every 12hours75mg/kg/doseIV every 12hourGreaterthan 34weeks28 days or younger50 mg/kg/dose IV every8 hoursProduct Information, 2017UsesBroad-spectrum antibiotic useful against group B streptococcus, Listeria monocytogenes, andsusceptible E coli species.Anthrax[3]:Systemic Anthrax when meningitis can be ruled out (IV)Combination IV Therapy◦ Preferred: Ciprofloxacin. Alternatives in order of preference: meropenem, levofloxacin,imipenem/cilastatin, or vancomycin. If strains are penicillin-susceptible, then penicillin G(preferred) or ampicillin (alternative).◦ Plus◦ Preferred: Clindamycin. Alternatives in order of preference: linezolid, doxycycline (notfor neonates 37 weeks gestation or younger), or rifampin.Systemic Anthrax (meningitis or disseminated infection and meningitis cannot beruled out) (IV)Triple IV Therapy◦ Preferred: Ciprofloxacin. Alternatives in order of preference: levofloxacin ormoxifloxacin◦ Plus99◦ Preferred: Meropenem. Alternatives in order of preference: imipenem/cilastatin ordoripenem. If strains are penicillin-susceptible, then penicillin G (preferred) or ampicillin(alternative).◦ Plus◦ Preferred: Linezolid. Alternatives in order of preference: clindamycin or rifampin or asa last resort, chloramphenicolGroup B Streptococcal (GBS) Disease:DefinitiveThe preferred antibiotic for early-onset and late-onset, culture confirmed-GBS disease ispenicillin G and the alternative is ampicillin [4].EmpiricPreterm infants: The choice is based on multiple factors in those continuously hospitalizedbeyond 72 hours of age. Empirical choices include group B streptococci-susceptibleantibiotics including a β-lactam, cephalosporin, or vancomycin [4].7 days or younger: The preferred empiric therapy is ampicillin plus an aminoglycoside. Ifthere is compelling reason to suspect an ampicillin-resistant infection in a critically illneonate, especially very-low-birth-weight neonates, then consider the addition of a broader-spectrum antibiotic [4].8 to 28 days: Ampicillin plus ceftazidime is preferred for previously healthy infants in thecommunity when critical illness and meningitis are absent [4].29 to 90 days: Ceftriaxone is recommended for critically ill infants with meningitis [4].8 to 90 days: Adding vancomycin to empiric therapy is recommended for previously healthyinfants in the community if there is evidence of meningitis or critical illness to expandcoverage, including for β-lactam-resistant Streptococcus pneumoniae[4].Infective endocarditis: The following recommendations are based on a consensus ofexperts [8]. The full pediatric guidelines can be found here: https://doi.org/10.1161/CIR.0000000000000298Organism Directed TherapyOrganism First-ChoiceAlternativeChoiceStreptococciHighly susceptibleto penicillin G(MBC 0.1 mcg/mLor less); includesmost viridansstreptococci,groups A, B, C, Gnonenterococcal,group Dstreptococci (Sbovis, S equinus)Penicillin G orCefTRIAXoneVancomycin orFirst-generationcephalosporinorCefTRIAXoneRelativelyresistant topenicillin (MBC0.2 mcg/mL orPenicillin G orAmpicillin +Gentamicin(for first 2Vancomycin +Gentamicin forenterococciAmpicillin +100more); less-susceptibleviridansstreptococciorenterococciweeks, orentire courseforenterococci)CefTRIAXone(foraminoglycoside(AMG)-resistantenterococci orAMG-intolerantpatient)CefTRIAXone +gentamicin (notfor enterococcalendocarditis)Resistant topenicillinConsult aninfectiousdiseasespecialist.---Staphylococci (Saureus orcoagulase-negativestaphylococci) †Penicillin Gsusceptible (1mcg/mL or less)(rare)Penicillin G Oxacillin orNafcillin orFirst-generationcephalosporinorVancomycinPenicillin Gresistant (0.1mcg/mL)Oxacillin orNafcillinwith orwithoutGentamicinVancomycin (forthose highlyallergic to beta-lactamantibiotics) orFirst-generationcephalosporinOxacillin (MRSA)resistant (4mcg/mL)Vancomycin Daptomycin forright-sidedendocarditis,maybe for left-sidedVancomycinresistant orintolerantDaptomycin Unknown†When prosthetic materialpresent add riFAMpin +gentamicin (for first 2 weeks)for all staphylococciGram-negativeenteric bacilliCefTAZidimeorCefepime orCefotaxime orCefTRIAXonePlusBroad-spectrumpenicillinPlus gentamicin(or tobramycinor amikacin)101gentamicin (ortobramycin oramikacin,depending onsusceptibility)HACEK groupCefTRIAXoneorCefotaxime orAmpicillin-sulbactamAmpicillin(whensusceptible)PlusaminoglycosideKEY: AMG = aminoglycosides; HACEK =Haemophilus species, Aggregatibacter species,Cardiobacterium hominis, Eikenella corrodens,and Kingella species; MBC = minimumbactericidal concentration, MRSA = methicillin-resistant Staphylococcus aureus (includesresistance to oxacillin, nafcillin, andcephalosporins)Baltimore, 2015Meningitis: Empiric agents for the treatment of meningitis in neonates are ampicillin,gentamicin, and cefotaxime [9]. Reassess therapy based on culture and sensitivity results[10].Sepsis, Early-OnsetAmpicillin plus gentamicin are the agents of choice for empirical treatment of early-onsetsepsis (EOS) in neonates at most risk for EOS. Broad-spectrum antibiotics may be necessaryin neonates who are severely ill, particularly preterm neonates at high risk for EOS afterprolonged antepartum maternal antibiotic treatment [11][12].Gestational age 34 6/7 weeks or youngerHighest risk for EOS: Administer empirical antibiotics in those at highest risk; neonatesborn preterm because of maternal cervical incompetence, preterm labor, premature ruptureof membranes, clinical concern for intraamniotic infection, or acute onset of unexplainednonreassuring fetal status [11]Low risk: Consider empirical antibiotics based on the risks and benefits. Those at low riskare those born preterm by cesarean delivery because of maternal noninfectious illness orplacental insufficiency in the absence of labor, attempts to induce labor, or rupture ofmembranes before delivery [11]Gestational age 35 0/7 weeks or older: Administer empirical antibiotics based on levelof risk. Multiple approaches of determining risk may be used including categorical algorithms,multivariate risk assessments, or serial physical examinations [12].Duration:•Discontinue antibiotics by 36 to 48 hours when blood cultures are sterile, unless a site-specific infection has been identified, for preterm and full term neonates [11][12].•Procalcitonin values in addition to perinatal risk factors, signs and symptoms, and laboratoryvalues may aid in the determination to discontinue antibiotic therapy in neonates withsuspected early-onset sepsis. The duration of antibiotic therapy was reduced by 9.9 hourswith a procalcitonin-guided algorithm compared with standard care in a multicenterrandomized control trial of 1710 neonates born after 34 weeks of gestational age withpossible or unlikely sepsis. Re-infection and mortality was not different between the groups102(risk difference 0.1% (95% CI, -5.2% to 5.3%) [13].Pediatric FDA Approved Indications•Bacterial meningitis caused by E coli, group B streptococci, and other gram-negativebacteria (Listeria monocytogenes, N meningitides). Addition of an aminoglycoside mayincrease effectiveness against gram-negative bacteria [5].•Septicemia caused by susceptible gram-positive organisms including Streptococcus species,penicillin G-susceptible staphylococci, and enterococci. Gram-negative sepsis caused by Ecoli, P mirabilis and Salmonella species. Addition of an aminoglycoside may enhanceeffectiveness [5].AdministrationIntravenousDoses 500 mg or less should be administered slowly over 3 to 5 minutes IV and over at least10 to 15 minutes for doses 1 g or greater [6]. Recommended concentrations are 30, 40, 50,and 100 mg/mL for intermittent IV [7].IntramuscularMix to a final concentration of 250 mg/mL for IM administration [6].MEDICATION SAFETYAdverse EffectsVery large doses may result in CNS excitation or seizure activity. Moderate prolongation ofbleeding times (by approximately 60 seconds) has been reported after the third or fourthdose in neonates 33 to 41 weeks GA receiving 50 to 100 mg/kg every 12 hours[15].Prolongation of bleeding times (by approximately 2 minutes) has also been reported after atleast 10 doses in preterm very low birth-weight neonates 23 to 30 weeks GA receiving 50 to100 mg/kg every 12 hours [16]. The clinical implications of the prolonged bleeding time isunknown. Hypersensitivity reactions (maculopapular rash, urticarial rash, or fever) are rare inneonates.Solution CompatibilityD5W, D5W in 0.45% sodium chloride, lactated ringer's solution, NS, sterile water.Stability is dependent on storage temperature and duration, and concentration ofampicillin[6].103Solution IncompatibilityD10W, D5NS, D5W in 0.45% sodium chloride (Trissel's 2 ClinicalPharmaceutics Database).Ampicillin may be compatible with D5W in 0.45% sodium chloride, depending upon storagetemperature and duration, and concentration of ampicillin[6]Terminal Injection Site CompatibilityAcyclovir, alprostadil, aminophylline, aztreonam, calcium gluconate, cefepime,chloramphenicol, cimetidine, clindamycin, enalaprilat, famotidine, furosemide, heparin,hydrocortisone succinate, insulin, lidocaine, linezolid, magnesium sulfate, metronidazole,milrinone, morphine, phytonadione, potassium chloride, propofol, ranitidine, remifentanil, andvancomycin.Terminal Injection Site IncompatibilityAmikacin, amiodarone, dopamine, epinephrine, erythromycin lactobionate, fluconazole,gentamicin, hydralazine, metoclopramide, midazolam, nicardipine, sodium bicarbonate, andtobramycin.Ampicillin 100 mg/mL: TPN formulas with TrophAmine 2% and TrophAmine 3%Monitoring•Periodic assessment of renal, hepatic, and hematopoietic function in patients receivingextended treatment [14].•After 2 consecutive procalcitonin measurements within the normal range and when there isa low risk for infection (assessed by perinatal risk factors, clinical symptoms, and otherlaboratory findings), consider discontinuation of antibiotics for suspected early-onset sepsis inneonates (34 weeks or older) categorized as infection possible or unlikely. All neonatesshould receive a minimum of 24 hours of antibiotics before discontinuation [13].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAmpicillin is a semisynthetic penicillin that is bactericidal. Clearance is primarily by the renal104route and is inversely related to postnatal age. Serum half-life in term infants younger than 7days is approximately 4 hours.Population pharmacokinetic parameters were determined in a multicenter trial [17]:Pharmacokinetic ParametersGestationalAgePostnatalAgeClearance* Volume*Half-life*34 weeksor less7 days orless(n=21)0.055(0.03 to0.07)L/hr/kg0.4 (0.4to 0.4)L/kg5 (3.9to9.4)hours8 to 28days(n=7)0.07 (0.03to 0.07)L/hr/kg0.4 (0.4to 0.41)L/kg4 (3.8to8.3)hoursGreaterthan 34weeks7 days orless(n=27)0.086(0.04 to0.13)L/hr/kg0.4 (0.4to 0.4)L/kg3.2(2.2to6.2)hours8 to 28days(n=18)0.11 (0.06to 0.13)L/hr/kg0.4 (0.4to 0.41)L/kg2.4(2.1to4.7)hours*median (ranges)Controlled HypothermiaPharmacokinetic Parameters: The mean (+/-SD) pharmacokinetic parameters in 13neonates (median gestational age 39 weeks and mean estimated glomerular filtration rate of43 mL/min/1.732) with hypoxic-ischemic encephalopathy undergoing controlled hypothermiawere 0.43+/-0.12 mL/min/kg for total body clearance, 0.35+/-0.46 L/kg for volume of thecentral compartment, and 0.52+/-0.28 L/kg for total volume of distribution [18].Potential Dosage: Doses of 25 mg/kg or 50 mg/kg IV every 24 hours achieved optimaltrough concentrations in dose simulations using gestational age of 36 to 41 weeks, estimatedcreatinine clearance of 27 to 76 mL/min/1.732, and weight of 2.4 to 4.85 kg (mimickingneonates with hypoxic-ischemic encephalopathy undergoing controlled hypothermia). Steadystate trough concentrations remained above an MIC of 8 mcg/mL for 100% of the dosinginterval with a probability of at least 94% [18].ABOUTSpecial Considerations/PreparationAvailable as powder for injection in 125-, 250-, 500-mg, 1-g, 2-g, and 10-g vials.105Reconstitute using sterile water for injection. Maximum concentration for IV infusion is100 mg/mL. Mix to a final concentration of 250 mg/mL for IM administration.Reconstituted solution must be used within 1 hour of mixing because of loss ofpotency.© Merative US L.P. 1973, 2024106AnidulafunginNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseCandidiasisFull term infants when intolerant to or resistant to fluconazole or amphotericin BLoading dose: 3 mg/kg IV for 1 dose [1][2]. A higher dose may be required in patientsreceiving extracorporeal membrane oxygenation (ECMO) [1].Maintenance dose: 1.5 mg/kg IV once daily [1][2]. Higher doses may be required inpatients receiving extracorporeal membrane oxygenation (ECMO) [1]. Duration of therapy forcandidemia, without metastatic complications, is 2 weeks after documented clearance ofCandida from the bloodstream and resolution of symptoms [3].UsesNeonatal Candidiasis, Including CNS Infection[3]Invasive candidiasis and candidemia, or very low-birth weight infants with asymptomaticcandiduria .◦ Amphotericin B deoxycholate is recommended.◦ Fluconazole IV or oral is an alternative for those who have not been receivingprophylaxis with fluconazole.◦ Lipid formulation amphotericin B agent is an alternative; however, use with caution,especially in the presence of urinary tract involvement.◦ Echinocandins (caspofungin, anidulafungin, or micafungin) should be limited to salvagetherapy or scenarios of resistance or toxicity to amphotericin B deoxycholate orfluconazoleCentral nervous system infections◦ Amphotericin B deoxycholate is recommended.◦ Liposomal amphotericin B agent is an alternative.◦ Salvage therapy with flucytosine may be added in those patients who have notresponded to initial therapy.◦ Fluconazole may be used as step-down therapy for those patients who respond to initialtherapyNeonatal intensive care unit (with greater than 10% rate of invasive candidiasis)◦ Prophylaxis with IV or oral fluconazole for 6 weeks is recommended for neonates withbirth weights of less than 1000 g◦ Prophylaxis with oral nystatin is an alternative in neonates with birth weights of less107than 1500 g when fluconazole is unavailable or fluconazole resistance is presentIn a safety and pharmacokinetic study, doses of 1.5 mg/kg/day for 5 days in 8 neonates (6out of 8 preterm) provided similar anidulafungin exposures compared to children and adults(100 mg/day) [1]. Despite sensitivity to amphotericin B, fungal peritonitis was not cleared ina full-term neonate until anidulafungin was added to liposomal amphotericin B; Candidaalbicans had been cultured from the peritoneum while the patient was receiving amphotericinB monotherapy [2]. Doses for hematogenous Candida meningoencephalitis (HCME) areexpected to be much higher than those used for other indications, based upon a translationalstudy which used neonatal (6 out of 8 were preterm) pharmacokinetic data applied to ananimal model of the disease [5].FDA Approved IndicationsTreatment of candidemia and intra-abdominal abscess and peritonitis due to Candida inpatients 1 month or older [4]..Limitations of UseAnidulafungin has not been studied in adult and pediatric patients with endocarditis,osteomyelitis, and meningitis due to Candida, and has not been studied in sufficient numbersof neutropenic patients to determine efficacy in this group. The dosage of anidulafungin forthe treatment of Candida dissemination into the CNS and the eye has not been established[4].Anidulafungin is associated with high relapse rates in esophageal candidiasis [4]AdministrationAdminister by IV Infusion [4]over 60 minutes [1]; not to exceed 1.1 mg/minute (equivalentto 1.4 mL/min or 84 mL/hr) [4].MEDICATION SAFETYContraindications/PrecautionsContraindicationsHypersensitivity to other echinocandins [4].Known or suspected Hereditary Fructose Intolerance (HFI) [4]PrecautionsHepatic: Liver function test abnormalities have been reported. Hepatitis, hepatic failure, andsignificant hepatic dysfunction occurred in patients with underlying medical conditionsreceiving multiple concomitant medications; monitoring recommended [4]Immunologic: Anaphylactic reactions, including shock, have been reported; discontinue use[4]Immunologic: Infusion-related reactions (eg rash, urticaria, flushing, pruritus,bronchospasm, dyspnea, and hypotension) have been reported; dosage adjustment108recommended [4]Low-birth-weight infants: Contains polysorbate 80; risk of toxicity, includingthrombocytopenia,renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension, andmetabolic acidosis in low-birth weight infants receiving high doses of polysorbate(unapproved use) [4]Special population: Contains fructose; metabolic crisis, including life-threateninghypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure may occur in patientswith hereditary fructose intolerance (HFI). Obtain history of HFI symptoms withfructose/sucrose exposure prior to treatment initiation [4]Adverse EffectsAdverse events reported were hypotension (1), adrenal insufficiency (1), abnormal X-ray ofkidneys, ureter, and bladder (1), death (1), infection (1), pulmonary edema (1), and oliguriaor uremia (2) in a safety study of 8 neonates [1].Solution CompatibilityD5W, NS.Terminal Injection Site CompatibilityAnidulafungin 0.5 mg/mLAcyclovir (7 mg/mL), amikacin (5 mg/mL), aminocaproic acid (50 mg/mL), aminophylline (2.5mg/mL), amiodarone (4 mg/mL), amphotericin B lipid complex (1 mg/mL), amphotericin Bliposome (1 mg/mL), ampicillin (20 mg/mL), ampicillin/sulbactam (20 and 10 mg/mL),argatroban (1 mg/mL), atracurium (0.5 mg/mL), azithromycin (2 mg/mL), aztreonam (40mg/mL), bivalirudin (5 mg/mL), bumetanide (40 mcg/mL), calcium chloride (40 mg/mL),calcium gluconate (40 mg/mL), caspofungin (0.5 mg/mL), cefazolin (20 mg/mL), cefepime(20 mg/mL), cefotaxime (20 mg/mL), cefotetan (20 mg/mL), cefoxitin (20 mg/mL),ceftazidime (40 mg/mL), ceftriaxone (20 mg/mL), cefuroxime (30 mg/mL), chloramphenicol(20 mg/mL), cimetidine (12 mg/mL), ciprofloxacin (2 mg/mL), cisatracurium (0.5 mg/mL),clindamycin (10 mg/mL), cyclosporine (5 mg/mL), dexamethasone (1 mg/mL),dexmedetomidine (4 mcg/mL), digoxin (0.25 mg/mL), diltiazem (5 mg/mL), diphenhydramine(2 mg/mL), dobutamine (4 mg/mL), dolasetron (2 mg/mL), dopamine (3.2 mg/mL),doxycycline hyclate (1 mg/mL), enalaprilat (0.1 mg/mL), epinephrine (50 mcg/mL),erythromycin (5 mg/mL), esmolol (10 mg/mL), famotidine (2 mg/mL), fentanyl (50 mcg/mL),fluconazole (2 mg/mL), foscarnet (24 mg/mL), fosphenytoin (20 mgPE/mL), furosemide (3mg/mL), ganciclovir (20 mg/mL), gentamicin (5 mg/mL), glycopyrrolate (0.2 mg/mL),granisetron (50 mcg/mL), haloperidol (0.2 mg/mL), heparin (100 units/mL), hydralazine (1mg/mL), hydrocortisone (1 mg/mL), hydromorphone (0.5 mg/mL), imipenem/cilastatin (5mg/mL), insulin (1 unit/mL), isoproterenol (20 mcg/mL), ketorolac (15 mg/mL), labetalol (2109mg/mL), levofloxacin (5 mg/mL), lidocaine (10 mg/mL), linezolid (2 mg/mL), lorazepam (0.5mg/mL), mannitol (150 mg/mL; 15%), meropenem (2.5 mg/mL), methotrexate (12.5mg/mL), methyldopate (10 mg/mL), methylprednisolone (5 mg/mL), metoclopramide (5mg/mL), metronidazole (5 mg/mL), midazolam (1 mg/mL), milrinone (0.2 mg/mL), morphine(15 mg/mL), moxifloxacin (1.6 mg/mL), mycophenolate mofetil (6 mg/mL), nafcillin (20mg/mL), naloxone (0.4 mg/mL), nicardipine (1 mg/mL), nitroglycerin (0.4 mg/mL),nitroprusside (2 mg/mL), norepinephrine (0.12 mg/mL), octreotide (5 mcg/mL), ondansetron(1 mg/mL), palonosetron (50 mcg/mL), pancuronium (0.1 mg/mL), pantoprazole (0.4mg/mL), pentobarbital (5 mg/mL), phenobarbital (5 mg/mL), phenylephrine (1 mg/mL),piperacillin/tazobactam (40 and 5 mg/mL), potassium chloride (0.1 mEq/mL), procainamide(20 mg/mL), propranolol (1 mg/mL), quinupristin/dalfopristin (5 mg/mL), ranitidine (2mg/mL), rocuronium (1 mg/mL), succinylcholine (2 mg/mL), sulfamethoxazole-trimethoprim(4 and 0.8 mg/mL), tacrolimus (20 mcg/mL), ticarcillin/clavulanate (31 mg/mL), tobramycin(5 mg/mL), vancomycin (10 mg/mL), vasopressin (1 unit/mL), vecuronium (1 mg/mL),verapamil (2.5 mg/mL), voriconazole (4 mg/mL), zidovudine (4 mg/mL).Terminal Injection Site IncompatibilityAmphotericin B conventional colloidal, diazepam, ertapenem, magnesium sulfate, nalbuphine,phenytoin, sodium bicarbonate.Compatibility information refers to physical compatibility and is derived from Trissel’s™ 2Clinical Pharmaceutics Database. The determination of compatibility is based onconcentrations for administration recommended herein. Drug compatibility is dependent onmultiple factors (eg, drug concentrations, diluents, storage conditions). This list should not beviewed as all-inclusive and should not replace sound clinical judgment. The user is referred toTrissel’s™ 2 for more complete details.Trissel’s™ 2 Clinical Pharmaceutics Database, version updated on 06/15/2012.MonitoringTherapeutic Laboratory Monitoring•For candidemia, monitor blood cultures daily or every other day until Candida is cleared [3].Prior to initiation, obtain specimens for fungal culture and other relevant laboratory studies(including histopathology) [4].Toxic Laboratory MonitoringMonitor liver function tests [4].Toxic Physical MonitoringMonitor for signs and symptoms of worsening hepatic function in patients who developabnormal liver function tests during therapy [4]110MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAnidulafungin, a semi-synthetic echinocandin, is a non-competitive inhibitor of beta-(1,3)-D-glucan synthase; this enzyme is responsible for formation of the polysaccharide,beta-(1,3)-glucan, an essential fungal cell wall component [6]. Anidulafungin is most active(MIC90 in mcg/mL) against Candida albicans (0.06), C glabrata (0.12), C tropicalis (0.06),and C krusei (0.12) isolates, but less potent against C parapsilosis (2) and C guilliermondii(2). It has demonstrated activity against the biofilms of C. albicans and C. parapsilosis. Theminimum effective concentration 90 against Aspergillus fumigatus is 0.008 mcg/mL [7].Candida isolates with reduced susceptibility to anidulafungin have been reported. The clinicalrelevance of these reports is unknown, but the development of drug resistance may bepossible. Extensively bound to plasma proteins (greater than 99%). No hepatic metabolism;not a substrate, inducer, or inhibitor of CYP450. Undergoes slow chemical degradation atphysiologic temperature and pH to a ring-opened peptide (inactive). In a single-dose study,less than 1% was recovered in urine and approximately 30% was recovered in the feces over9 days, of which less than 10% was intact anidulafungin. Not removed by hemodialysis [6].In a pharmacokinetic and safety study following 3 to 5 days of anidulafungin (n=15; age 2days to 2 years), neonates (n=8; 6 out of 8 premature) demonstrated a median weightadjusted clearance of 0.02 L/kg/hr (range 0.013 to 0.049), median half-life of 78 hours(range 40 to 219), and median exposure of 74.9 mcg*hr/mL (30.4 to 108.9). The lowestexposure was seen in 2 neonates who received extracorporeal membrane oxygenation(ECMO), a process which may alter volume of distribution and/or clearance, and thereforedrug exposure. The inclusion of data from the ECMO patients in the calculations likelyskewed the median pharmacokinetic values for the entire neonatal study population [1].ABOUTSpecial Considerations/PreparationAvailability: 50-mg and 100-mg single-use vials of anidulafungin lyophilized powder forsolution. The 50-mg and 100-mg vials also contain fructose (50 mg and 100 mg,respectively) and mannitol (250 mg and 500 mg, respectively) [6].StorageStore powder in the refrigerator between 2 and 8 degrees C (36 and 46 degrees F); do notfreeze. Excursions for 96 hours up to 25 degrees C (77 degrees F) are permitted, and the vialcan be returned to storage between 2 and 8 degrees C (36 and 46 degrees F) [4].Store reconstituted solution at a temperature up to 25 degrees C (77 degrees F) for up to 24hours [4].Store diluted solution at a temperature up to 25 degrees C (77 degrees F) for up to 48 hours;do not freeze [4].Preparation111Reconstitute with Sterile Water for Injection only. After reconstitution, drug should be furtherdiluted in D5W or NS only; do not dilute with other solutions or co-infuse with othermedications or electrolytes [4].Reconstitute 50-mg vial with 15 mL SWFI, and reconstitute 100-mg vial with 30 mL SWFI;concentrationof reconstituted vials is 3.33 mg/mL [4].Doses 50 mg or greater: Final concentrations are 0.77 mg/mL. For 50 mg dose, furtherdilute the reconstituted contents of the 50-mg vial with 50 mL solution (total volume, 65mL); for 100 mg dose, further dilute the reconstituted contents of 100-mg vial (or two 50 mgvials) with 100 mL solution (total volume, 130 mL); for 200 mg dose, further dilute thereconstiuted contents of two 100 mg vials (or four 50 mg vials) with 200 mL solution (totalvolume, 260 mL). [4].Doses below 50 mg:• First, calculate the volume (mL) of reconstituted anidulafungin required; volume ofreconstituted anidulafungin (mL) = dose of anidulafungin (mg) divided by 3.33 mg/mL [4].• Then, calculate the total volume of the infusion solution (mL) that contains a finalconcentration of 0.77 mg/mL; total volume of infusion solution (mL) = dose of anidulafungin(mg) divided by 0.77 mg/mL [4].• Then, calculate the volume of diluent required to prepare the infusion solution; volume ofdiluent (mL) = total volume of final infusion solution (mL) minus the volume of reconstitutedanidulafungin (mL) [4].© Merative US L.P. 1973, 2024112ArginineNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseAcute Hyperammonemia - Urea Cycle DisordersPending Definitive Diagnosis of Urea Cycle Enzyme Deficiency:Premedication for loading dose: Ondansetron 0.15 mg/kg IV [1]Loading dose: Arginine hydrochloride 600 mg/kg in combination with sodium phenylacetate250 mg/kg and sodium benzoate 250 mg/kg as an IV infusion over 90 to 120 minutes [2][3][4][5].Maintenance dose: Arginine hydrochloride 600 mg/kg in combination with sodiumphenylacetate 250 mg/kg and sodium benzoate 250 mg/kg as an IV infusion over 24 hours[2][3][4][5].Alternative dose: 250 to 400 mg/kg IV bolus in combination with sodium phenylacetate250 mg/kg and sodium benzoate 250 mg/kg IV bolus over 90 to 120 minutes, followed bymaintenance infusions of arginine 250 mg/kg/day in combination with sodium phenylacetate250 to 500 mg/kg/day and sodium benzoate 250 to 500 mg/kg/day. Maximum argininedose 12 g/day, sodium phenylacetate 12 g/day and sodium benzoate 12 g/day [1]Known CPS, OTC, or NAGS Deficiency:Premedication for loading dose: Ondansetron 0.15 mg/kg IV [1]Loading dose: Arginine hydrochloride 200 mg/kg in combination with sodium phenylacetate250 mg/kg and sodium benzoate 250 mg/kg as an IV infusion over 90 to 120 minutes [2][3][6][4][5].Maintenance dose: Arginine hydrochloride 200 mg/kg in combination with sodiumphenylacetate 250 mg/kg and sodium benzoate 250 mg/kg as an IV infusion over 24 hours[2][3][6][4][5].Alternative dose: 250 mg/kg IV bolus in combination with sodium phenylacetate 250mg/kg and sodium benzoate 250 mg/kg IV bolus over 90 to 120 minutes, followed bymaintenance infusions of arginine 250 mg/kg/day in combination with sodium phenylacetate250 to 500 mg/kg/day and sodium benzoate 250 to 500 mg/kg/day. Maximum argininedose 12 g/day, sodium phenylacetate 12 g/day and sodium benzoate 12 g/day [1]Known ASS or ASL Deficiency:Premedication for loading dose: Ondansetron 0.15 mg/kg IV [1]Loading dose: Arginine hydrochloride 600 mg/kg in combination with sodium phenylacetate250 mg/kg and sodium benzoate 250 mg/kg as an IV infusion over 90 to 120 minutes [2][3][6][4][5].Maintenance dose: Arginine hydrochloride 600 mg/kg in combination with sodiumphenylacetate 250 mg/kg and sodium benzoate 250 mg/kg as an IV infusion over 24 hours[2][3][6][4][5].Alternative dose (ASS Deficiency): 250 mg/kg IV bolus in combination with sodiumphenylacetate 250 mg/kg and sodium benzoate 250 mg/kg IV bolus over 90 to 120 minutes,followed by maintenance infusions of arginine 250 mg/kg/day in combination with sodiumphenylacetate 250 to 500 mg/kg/day and sodium benzoate 250 to 500 mg/kg/day.113Maximum arginine dose 12 g/day, sodium phenylacetate 12 g/day and sodiumbenzoate 12 g/day [1]Alternative dose (ASL Deficiency): 200 to 400 mg/kg IV bolus in combination withsodium phenylacetate 250 mg/kg and sodium benzoate 250 mg/kg IV bolus over 90 to 120minutes, followed by maintenance infusions of arginine 200 to 400 mg/kg/day in combinationwith sodium phenylacetate 250 to 500 mg/kg/day and sodium benzoate 250 to 500mg/kg/day. Maximum arginine dose 12 g/day, sodium phenylacetate 12 g/day andsodium benzoate 12 g/day [1]Repeating the loading dose within 24 hours of the initial loading dose should beconsidered only for patients with a severe disorder receiving dialysis[5].CPS = carbamyl phosphate synthetase; OTC = ornithine transcarbamylase; NAGS = N-acetylglutamate synthase; ASS = argininosuccinic acid synthetase; ASL = argininosuccinic acidlyaseUsesAdjunctive treatment of acute hyperammonemia in neonates with urea cycle disorders.Sodium phenylacetate/sodium benzoate should be used concomitantly with argininehydrochloride. Hemodialysis is the primary treatment of acute hyperammonemia during theearly management period [3][6][4][5][7].AdministrationFor treatment of acute hyperammonemia, must be administered through a central line.For loading and maintenance doses, dilute arginine and sodium phenylacetate/sodiumbenzoate in 25 to 35 mL/kg of D10W prior to administration [5].MEDICATION SAFETYContraindications/PrecautionsArginine hydrochloride contains 47.5 mEq of chloride in 100 mL. Hyperchloremic metabolicacidosis has been reported in 2 pediatric patients receiving excessive arginine. Extravasationcan cause tissue necrosis. Arginine is a nitric oxide precursor. Excessive arginineaccumulation can result in nitric oxide overproduction with potential for vasodilation andhypotension [6][4][5][8].114Solution CompatibilityD10W and sodium phenylacetate/sodium benzoate 10%.MonitoringPlasma ammonia levels every hour during dialysis until levels stabilize to less than 200 to 300micromoles/L. Capillary blood should not be used for monitoring ammonia levels. Monitorelectrolytes and acid-base status closely during the acute phase (eg, every 4 hours). Monitoramino acids daily to assess the effectiveness of citrulline/arginine replacement and glutamineremoval [4][5].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyThe use of arginine provides an alternative pathway for waste nitrogen excretion in patientswith urea cycle disorders, attenuating the risk for ammonia- and glutamine-inducedneurotoxicity. Arginine increases the synthesis of citrulline which contains a nitrogen fromammonia and is efficiently excreted in the urine. In addition, certain defects in the urea cycleprevent the formation of citrulline which decreases the synthesis of arginine. This results inarginine becoming an essential amino acid in patients with urea cycle disorders [6][4][7].ABOUTSpecial Considerations/PreparationArginine hydrochloride is supplied as a 10% solution. The product is hypertonic (950mOsmol/liter), acidic (average pH 5.6), and contains 47.5 mEq of chloride in 100 mL. Theproduct should be stored at room temperature. Solution that has been frozen should not beused [8].© Merative US L.P. 1973, 2024115Ascorbic AcidNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseAdequate Intake:40 mg/day orally or enterally [1].Enteral NutritionPreterm: 18 to 24 mg/kg/day enterally [1].Term:40 mg/day enterally [1].Parenteral NutritionPreterm: 15 to 25 mg/kg/day IV. Multivitamin formulations (80 mg/5 mL): 5 mL for infants3 kg or more; 3.25 mL for infants 1 to 3 kg, and 1.5 mL for infants less than 1 kg [1]Term: 80 mg/day IV [1].UsesPediatric FDA Approved IndicationsAscor® is indicated for the short-term (up to 1 week) treatment of scurvy in patients 5months or older for whom oral administration is not possible, is insufficient, or iscontraindicated [3].Limitations of UseNot indicated for the treatment of vitamin C deficiency not associated with signs andsymptoms of scurvy [3].AdministrationInjection•Dilute into a largeSome formulations are alcohol,dye, and sugar free.Rectal: Suppositories strengths are 80,120, 325, and 650 mg. Inaccurate dosing may occurwith rectal administration because of unequal distribution of acetaminophen in thesuppositories.5Injection: Intravenous formulation available in a 100-mL glass vial containing 1000 mg (10mg/mL). Do not refrigerate or freeze. Vial is for single use only and should be used within 6hours of opening. [18]. However, IV acetaminophen remained stable for up to 84 hours atroom temperature when withdrawn into syringes (100 mg, 250 mg, and 500 mg) and in theoriginal vial (250 mg and 900 mg). Sterility was not tested [33].Extemporaneous Preparation50 mg/mL Oral Suspension• Measure 5 g acetaminophen; reduce particle size to a fine powder [34].• Add a small portion of SyrSpend SF PH 4 to form a smooth paste [34].• Add sufficient SyrSpend SF PH 4 geometrically, mixing after each addition, to a final volumeof 100 mL [34].• Package in a tight, light-resistant container and label to shake well before use [34].• Use a beyond-use date of up to 90 days when packaged in low actinic, light-resistantcontainers and stored at room temperature or refrigerated temperatures [34].© Merative US L.P. 1973, 20246AcetaZOLAMIDENeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseMetabolic Alkalosis: 5 mg/kg IV every 6 to 8 hours [1][2][3][4]Posthemorrhagic Ventricular Dilation, Adjunct; Prevention of Shunt Placement:Ineffective and associated with increased neurologic morbidity compared with standard ofcare [5].UsesMetabolic Alkalosis:Retrospective studies of critically ill neonates and pediatric patients with metabolic alkalosishave reported that acetazolamide is effective at significantly reducing pH and serumbicarbonate, and significantly increasing serum chloride measurements; however, clinicaloutcomes have generally not been reported [8][1][2][3][4][9]. Dosages studied in neonatesinclude 5 mg/kg IV every 6 to 8 hours [1][4], 30 mg/kg/day IV in 3 or 4 divided doses [2], 5mg/kg IV or orally once daily for 3 days [9], and 3 to 5 mg/kg IV every 6 hours for 4 doseswithin 24 hours [3].Posthemorrhagic ventricular dilation (PHVD), adjunct; Prevention of shuntplacement: Use of acetaZOLAMIDE and furosemide in preterm infants with PHVD wasassociated with a higher rate of shunt placement, death, and increased neurologicalmorbidity as compared to standard therapy alone, in a multicenter, randomized, controlledtrial (n=177). Infants less than 3 months beyond the expected date of delivery and with aventricular width more than 4 mm above the 97th percentile after intraventricularhemorrhage received either standard therapy plus acetaZOLAMIDE 100 mg/kg daily andfurosemide 1 mg/kg daily (n=88) or standard therapy alone (n=89). Mean gestation age was28.5 weeks and median postnatal age was 23.5 days in the drug therapy group. Mediantreatment duration of acetaZOLAMIDE was 35 days. Assessments at 1 year showed thatdeath or shunt placement had occurred in 56 infants (63.3%) in the drug therapy group andin 46 (52.2%) allocated to standard therapy (11.1% (CI, -3.2% to 25.2%; p=0.15). Adverseeffects were reported in 38 infants, 23 of whom required permanent discontinuation of drugtherapy [5]. In a small cohort study, 9 of 10 preterm infants with raised intracranialhypertension secondary to PVHD treated with acetaZOLAMIDE and furosemide avoidedplacement of a ventriculoperitoneal shunt; in comparison, 3 of 6 patients who received seriallumbar puncture avoided shunt placement. acetaZOLAMIDE was started at 20 mg/kg/day andincreased by 10 mg/kg up to 100 mg/kg/day in 3 divided doses administered orally or ifnecessary, IV; dose of furosemide was 1 mg/kg daily orally or IV. Mean gestational age was28.4 weeks [10]. Limited use of acetaZOLAMIDE may be warranted in infants with PVHD andraised intracranial hypertension based on the findings of Kennedy et al, 2001 [5].7Pediatric FDA Approved IndicationsOral extended-release capsules:Indicated in patients 12 years or older for the prevention or amelioration of symptomsassociated with acute mountain sickness despite gradual ascent. Also indicated in patients 12years or older as adjunctive treatment of open-angle glaucoma, secondary glaucoma, andpreoperatively in acute closed-angle glaucoma when delay of surgery is indicated in order tolower intraocular pressure. Safety and efficacy of oral extended-release capsules notestablished in pediatric patients younger than 12 years [11].IV and oral immediate-release:Safety and efficacy of IV injection [12] and oral immediate-release tablets [13] notestablished in pediatric patients.AdministrationIV Injection: IV route preferred; IM use not recommended [6]. Recommendedconcentrations for intermittent IV are 50 mg/mL or 100 mg/mL [7].MEDICATION SAFETYContraindications/PrecautionsContraindicationsChronic noncongestive angle-closure glaucoma; long-term use may mask symptoms ofworsening glaucoma [12][11][13]Cirrhosis or marked liver disease or dysfunction ; risk of hepatic encephalopathy [12][11][13]Hyperchloremic acidosis [12][11][13]Hypersensitivity to sulfonamides or other sulfonamide derivatives; cross-sensitivity may occur[12][11]Hypokalemia [12][11][13]Hyponatremia [12][11][13]Renal dysfunction or marked disease [12][11][13]Suprarenal gland failure [12][11][13]PrecautionsConcomitant Use: Use with other carbonic anhydrase inhibitors is not recommended [11]Concomitant Use: Use caution in patients also receiving high-dose aspirin; anorexia,tachypnea, lethargy, coma, and death have been reported [13][13][11].Endocrine and Metabolic: Electrolyte and acid/base imbalances may occur, especially inpatients with diabetes mellitus or impaired glucose tolerance; monitoring recommended[12][11]Hematologic: Blood dyscrasias such as agranulocytosis and aplastic anemia, with fatalcases, have been reported with sulfonamides; monitoring recommended and discontinuation8may be necessary [12][11][13]Immunologic: Hypersensitivity reactions such as Stevens-Johnson syndrome, toxicepidermal necrolysis, fulminant hepatic necrosis, anaphylaxis, and blood dyscrasias, with fatalcases, have been reported with sulfonamides; discontinue if hypersensitivity or other seriousreactions occur [12][11][13]Renal: Patients with impaired renal function may experience electrolyte and acid/baseimbalances [11]Respiratory: Pulmonary obstruction or emphysema patients, especially with alveolarventilation impairment, may experience precipitated or aggravated acidosis [12][11][13]Respiratory: Give cautiously to patients with alveolar ventilation impairment as electrolyteand acid/base imbalances may occur [11][13]Adverse EffectsNephrocalcinosis, per renal ultrasound, occurred more frequently in theacetaZOLAMIDE/furosemide group than standard therapy group (24% vs 4% (difference19%, CI 9% to 30%), in a randomized, controlled trial (n=177) of preterm infants (meangestation age 28.5 weeks and median postnatal age was 23.5 days) with post-hemorrhagicventricular dilation. Median treatment duration of acetaZOLAMIDE was 35 days. [5].Hypercalciuria occurred in 7 of 12 infants exposed to furosemide and acetaZOLAMIDE;nephrocalcinosis developed in 5 of the 7 patients with hypercalciuria [10]. A transientincrease in intracranial pressure was demonstrated in 6 of 8 infants (25 to 37 weeksgestation, 16 to 121 postnatal days) with post-hemorrhagic hydrocephalus administered IVacetaZOLAMIDE 50 mg/kg. No increase was observed with oral administration. In all 4preterm infants with chronic lung disease, discontinuation of acetaZOLAMIDE (IV and oral)was necessary due to the inability to compensate for the rise in pCo2[16].Black Box WarningSevere reactions to sulfonamides (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis,fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias)have occurred, rarelyvolume such as normal saline or dextrose [2].•Too rapid administration should be avoided [2].MEDICATION SAFETYContraindications/Precautions116CONTRAINDICATIONSNone [2]PRECAUTIONSAdministration: Avoid rapid administration [2]Adverse EffectsToo rapid IV administration of the solution may cause temporary faintness or dizziness [2].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of actionAscorbic acid (vitamin C) is a water-soluble vitamin. Ascorbic acid is involved in tyrosinemetabolism, conversion of folic acid to folinic acid, carbohydrate metabolism, synthesis oflipids and proteins, iron metabolism, resistance to infections, and cellular respiration [2].DistributionAscorbic acid is widely distributed in the body. Large concentrations are found in the liver,leukocytes, platelets, glandular tissues, and eye lens [3].MetabolismThe major route of metabolism involves conversion of ascorbic acid to urinary oxalate,presumably through intermediate formation of dehydroascorbic acid [3].ExcretionAscorbic acid is excreted by the kidney in large amounts only when plasma concentrationsexceed 1.4 mg/100 mL [3].Half-life: 7.4 +/- 1.4 hours [3]ABOUTSpecial Considerations/PreparationInjectionAvailability: Ascorbic acid 500 mg/mL [2]Storage: Store under refrigerated conditions between 2 and 8 degrees C (36 and 46degrees F). Protect from light [2]117Preparation:[2]•Pressure may develop within vial during storage; relieve pressure by first inserting sterileempty syringe into vial to allow pressure to equilibrate.•Once vial is punctured, complete all dispensing from the vial within 4 hours and use eachdose immediately; discard unused portion .•Dilute dose in compatible infusion solution.OralAvailability: Multiple forms and strengths, such as 100 mg, 250 mg, 500 mg, 1000 mg oraltablets; 500 mg chewable tablet; 500 mg and 1000 mg extended-release oral tablet; 60 mgmucous membrane lozenge/troche; 500 mg oral wafer.© Merative US L.P. 1973, 2024118AspirinNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseAcute Ischemic Stroke (AIS), Recurrent: 1 to 5 mg/kg orally once daily [1][2].Thrombosis; Prophylaxis1 to 5 mg/kg orally once daily [1][3][4][5].Higher doses (6 to 10 mg/kg/day) have been used in neonates undergoing heart surgery[1][6][7][8].UsesAcute Ischemic Stroke (AIS): Secondary prevention of recurrent AIS [1][2][5].Thrombosis; Prophylaxis: Aspirin is recommended as thromboprophylaxis after Fontansurgery, in patients with systemic-to-pulmonary shunts, in patients after ventricular assistdevice placement, and in patients with mechanical heart valves who have had thromboticevents while receiving therapeutic antithrombotic therapy or patients in whom there is acontraindication to full-dose vitamin K antagonists [1][3][4][5][9]. In a prospective,multicenter, randomized study (n=111) of warfarin vs aspirin for primary thromboprophylaxisin children after Fontan surgery, the thrombosis event rate at 2 years was 19% with nosignificant difference between warfarin and aspirin therapy (24% vs 14%; p=0.45); minorbleeding was more common in the warfarin group (33% vs 14%) [3].AdministrationAdminister without regard to feedings.MEDICATION SAFETYContraindications/PrecautionsAspirin use has been associated with a potentially fatal condition called Reye's syndrome.Association has been shown to be mainly dose dependent, occurring with anti-inflammatorydoses (greater than 40 mg/kg/day), rather than lower doses used for antiplatelet effects119[11][12][5][13][14]. Use caution in patients with bleeding disorders, peptic ulcer disease,renal impairment, or severe hepatic impairment. Severe allergic reactions, including asthma,hives, and facial swelling, may occur [15].Adverse EffectsMild gastrointestinal symptoms (nausea, vomiting, abdominal pain, GI upset) are the mostcommon adverse effects. Headache and tinnitus have also been reported frequently inchildren. Elevations in serum transaminases may occur [16][17]. Mild salicylism ischaracterized by headache, dizziness, tinnitus, hearing and vision impairment, sweating,nausea, vomiting, nasal congestion, and slight hyperpyrexia. Symptoms of severe salicylatetoxicity include hyperventilation, mental confusion, restlessness, irritability, hyperthermia, andalterations in acid-base balance, primarily respiratory alkalosis [10].MonitoringMild salicylism is characterized by headache, dizziness, tinnitus, hearing and visionimpairment, sweating, nausea, vomiting, nasal congestion, and slight hyperpyrexia.Symptoms of severe salicylate toxicity include hyperventilation, mental confusion,restlessness, irritability, hyperthermia, and alterations in acid-base balance, primarilyrespiratory alkalosis [10].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of action: The main mechanism of action of aspirin is through inhibition ofprostaglandin biosynthesis. Prostaglandins are produced from arachidonic acid via COX(cyclooxygenase; also known as prostaglandin endoperoxide synthase). Aspirin is a morespecific inhibitor against COX-1 over COX-2 [18]. Aspirin is a more potent inhibitor of bothprostaglandin synthesis and platelet aggregation than its other salicylic derivatives due to theacetyl group on the aspirin molecule, which inactivates cyclooxygenase via acetylation [19].The antithrombotic effect of aspirin occurs by an irreversible inhibition of plateletcyclooxygenase. This enzyme inhibition blocks the formation of thromboxane A2 fromarachidonic acid which would reduce platelet shape change, aggregation, and the releasereaction [20][21][22][23].Platelet inhibition occurs at lower doses (1 to 5 mg/kg/day). Rapidly absorbed following oraladministration with peak concentration achieved in 2 hours. Rapidly hydrolyzed by esterasesin the liver, intestine, and blood to salicylic acid. Has a low Vd and is extensively bound toalbumin (80% to 90%). Eliminated through hepatic metabolism and renal excretion with120elimination pathways dependent on dose. At therapeutic doses, most elimination occursthrough hepatic metabolism to 3 major metabolites (all inactive); less than 10% is excretedunchanged in the urine. At higher doses, when saturation of metabolic pathways occurs,renal excretion dominates with greater than 50% of unchanged salicylic acid eliminated inthe urine. Renal excretion dependent on urinary pH (alkaline urine increases elimination).Elimination half-life is approximately 2 to 3 hours at low dose and 12 hours at anti-inflammatory doses [18].ABOUTSpecial Considerations/PreparationAvailability: 81-mg chewable tablets; 300- and 600-mg rectal suppositories.Storage, rectal suppositories: Store in a cool place between 8 and 15 degrees C (46 to59 degrees F) or refrigerate.© Merative US L.P. 1973, 2024121AtropineNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseBradycardiaIV: 0.01 to 0.03 mg/kg/dose IV [1][2] over 1 minute, or IM. Dose can be repeated every 10to 15 minutes to achieve desired effect, cumulative maximum dose of 0.04 mg/kg.ET: 0.01 to 0.03 mg/kg/dose immediately followed by 1 mL NS.Oral: Begin with 0.02 mg/kg/dose given every 4 to 6 hours. May increase gradually to 0.09mg/kg/dose.Premedication for Intubation0.01 to 0.02 mg/kg IV over 1 minute immediately prior to other premedications [3][4][5][6][7].Organophosphate PoisoningGuideline: 0.02 mg/kg IV, doubled every 5 minutes; maintenance infusion, 10% to 20% ofthe total loading dose/hr, MAX dosage 2 mg/hr (from adult dosing); titrate to reversalof bronchorrhea, bronchospasm, bradycardia, and hypotension [2]Autoinjector (Atropen®)Less than 7 kg, 2 or more mild symptoms and exposure is known or suspected:0.25 mg IM (yellow label) into the mid-lateral thigh at first signs of poisoning; wait 10 to 15minutes and if severe symptoms do not occur no further injections are necessary; if severesymptomsdevelop after treatment, administer an additional 2 injections (0.25 mg each;yellow label) in rapid succession [8]Less than 7 kg, severe symptoms or unconscious: 3 IM injections of 0.25 mg each(yellow label) into the mid-lateral thigh in rapid succession at first signs of poisoning; ifseizure is suspected in the unconscious patient, consider concurrent anticonvulsant,preferably a benzodiazepine [8]Concomitant medications: A cholinesterase reactivator (eg, pralidoxime) may be given asadjunctive therapy [8]• Closely supervise all patients for at least 48 to 72 hours following therapy [8]Mild Symptoms Severe SymptomsBlurred vision, miosisStrange or confusedbehaviorExcessive, unexplainedteary eyes*Severe difficulty breathingor copious secretions fromlungs/airwayExcessive, unexplainedrunny nose*Severe muscular twitchingand general weakness**Increased salivationsuch as suddenunexplained excessivedroolingInvoluntary urination anddefecation*122Chest tightness ordifficulty breathingConvulsionsTremors throughoutthe body or musculartwitchingUnconsciousnessNausea and/orvomitingUnexplainedwheezing, coughing orincreased airwaysecretionsAcute onset ofstomach crampsTachycardia orbradycardia* These symptoms are sometimes observed inhealthy infants and young children. In this agegroup, these symptoms are less reliable thanother symptoms listed. Symptoms must beconsidered collectively when nerve agent orpesticide exposure is known or suspected.**Infants may become drowsy or unconscious,with muscle floppiness rather than muscletwitching soon after exposure to nerve agent orinsecticides.Atropen® Product Information November, 2020UsesBradycardiaGuidelines: Severe bradycardia may occur due to poisoning with beta-blocker, calciumchannel blocker, digoxin or local anesthetic agents. Treatment with atropine is recommended,and is a common first-line agent. Atropine has been used successfully to improve heart rateand blood pressure, although most supporting data are from case reports [2].In addition to reversal of severe sinus bradycardia due to parasympathetic influences on theheart (digoxin, beta-blocker drugs, hyperactive carotid sinus reflex), atropine has also beenadministered in neonates to prevent bradycardia associated with agents used duringendotracheal or nasotracheal intubation [3][4][5][6][7].Organophosphate or Carbamate PoisoningGuidelines: Organophosphates and carbamates, found in pesticides, nerve agents, andsome medications, inhibit acetylcholinesterase and result in parasympathetic and nicotinicexcess, and CNS effects. Atropine blocks parasympathetic overstimulation to mitigatebronchorrhea, bradycardia, bronchospasm, and CNS effects; it does not block acetylcholineexcess at the neuromuscular junction or nicotinic ganglia and therefore does not reverseparalysis. Immediate administration of atropine is recommended for severe poisoning; earlyatropine administration improved survival in a clinical trial. Doses required are typically much123larger for this indication versus typical bradycardia. Dermal decontamination, earlyendotracheal intubation for life-threatening poisoning, and benzodiazepines for seizurecontrol are also recommended [2].Pediatric FDA Approved IndicationsAtropine IM auto-injection is indicated for the treatment of poisoning by susceptibleorganophosphorus nerve agents having cholinesterase activity as well as organophosphorusor carbamate insecticides in adult and pediatric patients [8].AdministrationIntramuscular:• Organophosphate poisoning: Autoinjectors (AIs) are recommended for IM delivery asopposed to IM administration with the needle and syringe method. AIs provide superiordelivery by releasing the medication as the needle punctures the tissue compared withtraditional IM delivery which creates a small pool of medication. AIs produce a quicker peak(less than 5 minutes) compared with the needle and syringe method (25 minutes), which isnecessary for severe cholinergic crisis [9].Atropen® Auto-injector 0.25 mg)• Remove the gray safety release, bunch up the thigh to provide a thicker area for injectionand inject at a 90-degree angle against the mid-lateral thigh; the device will activate anddeliver medication [8].• Hold the autoinjector firmly in place for at least 10 seconds to allow the injection to finish;remove the autoinjector and massage the injection site for several seconds [8].• If the needle is not visible after injection, check to be sure the gray safety release has beenremoved, and repeat injection, but press harder [8].Intravenous: Concentrations are 0.05-, 0.1-, 0.4-, and 1-mg/mL [10]. Administer IV over 1minute [6] as undiluted drug (0.05- or 0.1-mg/mL).Atropine may also be diluted in 4 mL of D5 W or NS when used as a premedication [11].Oral: May give IV dosage form orally.MEDICATION SAFETYAdverse EffectsCardiovascular effects: Cardiac arrhythmias can occur, particularly during the first 2minutes following IV administration; usually a simple A-V dissociation, more often caused bysmaller rather than larger doses.Gastrointestinal: Abdominal distention with decreased bowel activity, esophageal reflux.Ophthalmic: Mydriasis and cycloplegia.124Other: Fever, especially in brain-damaged infants.Respiratory: Post-operative respiratory acidosis was associated with pre-operative atropine0.01 mg/kg IV compared with no atropine (22.9% vs 7.3%; p=0.016) in a retrospectiveanalysis of 150 Asian neonates undergoing surgical ligation for patent ductus arteriosus. Themean capillary CO2 was higher in the atropine compared with no atropine group (49.35 vs38.85 mmHg; p=0.0004). The mean capillary pH was lower in the atropine compared with noatropine group (7.33 vs 7.43 mmHg; p=0.0001) [12].Solution CompatibilityD5W and NS.Terminal Injection Site CompatibilityAmiodarone, cimetidine, dobutamine, famotidine, fentanyl, furosemide, glycopyrrolate,heparin, hydrocortisone succinate, meropenem, methadone, metoclopramide, midazolam,milrinone, morphine, nafcillin, netilmicin, pentobarbital, potassium chloride, propofol,ranitidine, and sodium bicarbonate.Terminal Injection Site IncompatibilityPhenytoin, sulfamethoxazole/trimethoprim.MonitoringToxic Physical MonitoringHeart rate.MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAnticholinergic. Increases heart rate by decreasing the effects of the parasympathetic systemwhile increasing the effects of the sympathetic system. Peak tachycardia is 12 to 16 minutes125after dose is given. Relaxes bronchial smooth muscle, thus reducing airway resistance andincreasing dead space by 30%. Motor activity in the stomach and small and large intestinesis reduced. Esophageal sphincter tone is reduced. Salivary secretion is inhibited. Duration ofaction is 6 hours. Primarily excreted renally unchanged.ABOUTSpecial Considerations/PreparationInjectionsSupplied in multiple concentrations (0.05-, 0.1-,0.4-, and 1-mg/mL) for injection. May give IVdosage form orally.IM, AutoinjectorAvailability: 0.25 mg/0.3 mL, 0.5 mg/0.7 mL, 1 mg/0.7 mL, 2 mg/0.7 mL in prefilled single-dose autoinjectors [8]Storage: Store auto-injector at a controlled room temperature between 20 and 25 degreesC (68 and 77 degrees F), with excursions permitted between 15 and 30 degrees C (59 and86 degrees F). Do not freeze. Protect from light [8].© Merative US L.P. 1973, 2024126AzithromycinNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseKIDs List: Avoid use in neonates (unless treating Bordetella pertussis orChlamydia trachomatis pneumonia; consider risk/benefit ratio when using forUreaplasma) due to risk of hypertrophic pyloric stenosis [1].Treatment and Prophylaxis of Pertussis Infections: 10 mg/kg/dose orally once dailyfor 5 days [2]; IV dose is unknown.Ophthalmia neonatorum caused by Chlamydia trachomatis: 20 mg/kg/dose orally oncedaily for 3 days [3][4].Ureaplasma Eradication24 to 28 weeks gestational age: 20 mg/kg IV once daily for 3 days [5][6][7]UsesBordetella; Treatment and Postexposure Prophylaxis: Azithromycin is the preferredagent for the treatment and postexposure prophylaxis of pertussis in infants younger than 1month of age. Treat infants younger than 1 year within 6 weeks of cough onset. Prophylaxisshould be administered within 21 days of onset of cough in the index patient [2].Chlamydia Infections: Erythromycin base or ethylsuccinate is the first-line agent andazithromycin a second-line agent for the treatment of ophthalmia neonatorum caused byChlamydia trachomatis ; however, data are limited on azithromycin [3].Ureaplasma Eradication and Prevention of Bronchopulmonary Dysplasia (BPD)Summary: Azithromycin 20 mg/kg IV for 3 days has been shown to be safe and effective forthe eradication of Ureaplasma species in the respiratory tract of preterm neonates [5][6][7];however, this has not translated into strong evidence that azithromycin treatment andUreaplasma eradication have a preventative effect on the development of BPD. Someevidence points to the greatest benefit being in the subpopulation of neonates with lowerrespiratory tract colonization [10][5]Eradication: Azithromycin at doses of 20 mg/kg IV for 3 days is effective for eradication ofUreaplasma colonization of the respiratory tract in preterm neonates [5][6][7], and has beenfound to be more effective than doses of 10 mg/kg/day [6]. Azithromycin was administeredto neonates 24 to 28 weeks gestational age, with a postnatal age less than 72 hours, andpositive pressure ventilation for at least 1 hour. All patients with positive Ureaplasma culturesbecame culture-negative after azithromycin treatment. No abnormal vital signs, arrhythmias,or episodes of feeding intolerance or infantile hypertrophic pyloric stenosis were reported in127the 3 studies (N=121[5]; N=15[6]; N=13[7]).Prevention of BPD: Meta-analyses have reported conflicting evidence regarding the effectof azithromycin on the prevention of chronic lung disease in preterm neonates; however, thestudies included in these meta-analyses have predominantly used azithromycin doses of 10mg/kg/day for varying durations [11][12]. Other studies have found doses of 20 mg/kg/dayto be more effective for Ureaplasma eradication [5][6][7]. Bronchopulmonary dysplasia at 36weeks postmenstrual age (PMA) was reported in 45% treated with azithromycin 20 mg/kg IVfor 3 days compared with 33% given placebo (N=121). Among the subgroup withUreaplasma positive cultures (n=44), rates were 47% and 38%. Both are statisticallynonsignificant results [5]. A 2-year follow up study reported that the composite endpoint ofdeath or serious respiratory morbidity was not significantly different in those treated withazithromycin (34.8%) compared with placebo (30.4%); neurodevelopmental outcomes werealso not significantly different between groups. A post-hoc analysis of those who wereintubated and had a tracheal aspirate positive for Ureaplasma (lower respiratory tractcolonization) found significantly higher rates of the composite endpoint of death or seriousrespiratory morbidity compared with those who were Ureaplasma negative, representing asubpopulation that may receive a greater benefit from azithromycin therapy; more studiesare needed [10].AdministrationIntravenous: Dilute reconstituted solution (100 mg/mL) to a final concentration of 1 to 2mg/mL. Give the 1 mg/mL concentration over 3 hours or 2 mg/mL concentration over 1 hour[8].Oral: Oral suspension can be given with or without feeding [9].MEDICATION SAFETYContraindications/PrecautionsContraindicated in patients allergic to macrolide or ketolide antibiotics and patients with ahistory of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin[13].PrecautionsCardiovascular: QT-interval prolongation has been reported including cases of torsade depointes. Patients with known or congenital QT prolongation, history of torsade de pointes,bradyarrhythmias, uncompensated heart failure, ongoing proarrhythmic conditions (eg,significant bradycardia, uncorrected hypokalemia or hypomagnesemia, or those receivingclass IA or class III antiarrhythmic agents), or concomitant drugs known to prolong the QTinterval are at increased risk [14][15][16].Cardiovascular: A possible increased risk of acute cardiovascular death has been observed.Risk was noted to be greater during the first 5 days of therapy. Consider balancing risk withtreatment benefits [17].128Cardiovascular: Compared with penicillin or a cephalosporin, azithromycin was notassociated with greater prevalence of cardiac arrest, overall mortality, or ventriculararrhythmias in a retrospective cohort study of 82,982 pediatric patients (median age 2.6years) with community acquired pneumonia [18].Gastrointestinal: Infantile hypertrophic pyloric stenosis has been reported in neonates upto 42 days of life treated with azithromycin [19].Gastrointestinal: Clostridioides difficile associated diarrhea (CDAD) has been reported; mayrange in severity from mild diarrhea to fatal colitis. If CDAD is confirmed, discontinue therapyand initiate appropriate fluid/electrolyte management, protein supplementation, antibacterialdrug treatment for C difficile, and surgical evaluation if clinically indicated [17].Hepatic: Hepatotoxicity (eg, abnormal liver function, hepatitis, cholestatic jaundice, hepaticnecrosis, and hepatic failure), including fatalities, has been reported; if signs and symptomsof hepatitis occur, discontinue therapy [13].Immunologic: Serious and sometimes fatal allergic reactions, including angioedema,anaphylaxis, and dermatologic reactions such as acute generalized exanthematous pustulosis(AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnsonsyndrome, and toxic epidermal necrolysis, have been reported. Immediate discontinuationrecommended; however, recurrence of allergic symptoms without further azithromycinexposure may occur [20][21].Long-term use: Avoid long-term azithromycin use for prophylaxis of bronchiolitis obliteranssyndrome (unapproved use) to patients who undergo donor stem cell transplants due to theincreased potential for cancer relapse and death [22].Neurologic: Worsening of myasthenia gravis symptoms as well as new onset of myastheniagravis has been reported rarely in association with azithromycin [13][23].Adverse EffectsDiarrhea and/or vomiting occur in 5% to 12% of patients. Irritability, rash, and blood in stoolhave also been reported.The most frequently reported gastrointestinal symptoms were vomiting, diarrhea, abdominaltenderness, and feeding intolerance in a systematic review of 11 articles (n=473 neonates)[24]The use of macrolide antibiotics was associated with infantile hypertrophic pyloric stenosiswith a 30-fold increased risk in infants exposed at 0 to 13 days of age and 3-fold increasedrisk in infants exposed at 14 to 120 days of age in an observational study (n=6591) [25].Similar outcomes (highest risk of pyloric stenosis when exposed within the first couple weeksof life; although risk still present at 6 weeks of life) were demonstrated in anotherobservational study (n= 4875 exposed to azithromycin) [26].Solution CompatibilityD5W, NS, 5% Dextrose in 0.45% NaCl with 20 mEq/L KCl, and Lactated Ringer's.129Terminal Injection Site CompatibilityCaspofungin.Terminal Injection Site IncompatibilityAmikacin, aztreonam, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, clindamycin,famotidine, fentanyl, furosemide, gentamicin, imipenem-cilastatin, morphine, piperacillin-tazobactam, potassium chloride, ticarcillin-clavulanate, and tobramycin.MonitoringAssess gastrointestinal tolerance.MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAzithromycin is classified as an azalide, a subclass of macrolide antibiotics. In vitro activityhas been demonstrated against Bordetella pertussis, aswell as Streptococci (Groups C, F, Gand Viridans), Ureaplasma urealyticum, and Peptostreptococcus species. Eradication of B.pertussis in unimmunized individuals (e.g., neonates) takes longer and requires higher dosesthan immunized individuals. Oral bioavailability is 38% in adults and children and is notaffected by food. Primarily excreted unchanged in the bile, with some hepatic metabolism toinactive metabolites. The prolonged terminal half-life (approximately 80 hours) is thought tobe due to extensive uptake and subsequent release of drug from tissues.ABOUTSpecial Considerations/PreparationOralAvailability: Oral suspension is available in 300, 600, 900, and 1,200 mg bottles.Reconstitute 300 mg bottle with 9 mL of water to provide a final concentration of 100 mg per5 mL (20 mg/mL). Shake well before administration.130Storage: Do not refrigerate. Use within 10 days once bottle has been opened.InjectionAvailability: Azithromycin for intravenous injection is supplied in single use vials containing500 mg lyophilized powder. Reconstitute by adding 4.8 mL Sterile Water for Injection, thenshake the vial until all the drug is dissolved. The concentration of the reconstituted solution is100 mg/mL.Storage: It is stable at room temperature for 24 hours.Dilute prior to administration using a compatible solution to a final concentration of 1 to2 mg/mL. Diluted solution stable for 24 hours at room temperature or 7 days in refrigerator.Do not use higher concentrations due to local IV site reactions. Infuse over at least 60minutes.© Merative US L.P. 1973, 2024131AztreonamNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDose30 mg/kg/dose IV or IM.Antibiotic Dosing Chart:Renal function and drug elimination are most strongly correlated with Postmenstrual Age(PMA; equivalent to Gestational Age plus Postnatal Age). PMA is the primary determinant ofdosing interval, with Postnatal Age as the secondary qualifier.Dosing Interval ChartPMA(weeks)PostNatal(days)Interval(hours)≤290 to 28>2812830 to 360 to 14>1412837 to 440 to 7>7128≥45 ALL 6UsesTreatment of neonatal sepsis caused by susceptible gram-negative organisms (e.g. E coli, Hinfluenzae, Klebsiella, Pseudomonas, and Serratia). Generally used in combination withampicillin (empirical treatment of sepsis) or an aminoglycoside (for synergism againstPseudomonas and Enterobacteriaceae).AdministrationIntravenousGive IV push over 3 to 5 minutes, or IV infusion over 20 to 60 minutes at a finalconcentration not to exceed 20 mg/mL[1][2].IntramuscularFor IM administration, concentrations range from 66 mg/mL to 333 mg/mL [1].132MEDICATION SAFETYAdverse EffectsAztreonam contains 780 mg L-arginine per gram of drug (23.4 mg/kg body weight per dose).Adequate amounts of glucose must be provided to prevent hypoglycemia. Side effects arerare but include eosinophilia, elevation of serum transaminases, and phlebitis at the injectionsite.Solution CompatibilityD5W, D10W, and NS.Terminal Injection Site CompatibilityAmikacin, aminophylline, ampicillin, bumetanide, calcium gluconate, caspofungin, cefazolin,cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, cimetidine, clindamycin,dexamethasone, dobutamine, dopamine, enalaprilat, famotidine, fluconazole, furosemide,gentamicin, heparin, hydrocortisone succinate, imipenem, insulin, linezolid, magnesiumsulfate, metoclopramide, mezlocillin, morphine, netilmicin, nicardipine, piperacillin,piperacillin/tazobactam, potassium chloride, propofol, quinupristin/dalfopristin, ranitidine,remifentanil, sodium bicarbonate, ticarcillin/clavulanate, tobramycin, vancomycin, andzidovudine.Terminal Injection Site IncompatibilityAcyclovir, amphotericin B, azithromycin, ganciclovir, lorazepam, metronidazole, and nafcillin.MonitoringCheck serum glucose one hour after administration. Measuring serum concentration is notusually necessary. Periodic CBC, AST, ALT.MECHANISM OF ACTION/PHARMACOKINETICS133PharmacologyMechanism of action: Aztreonam is a synthetically-produced monocyclic beta-lactamantibiotic. Although bactericidal against aerobic gram-negative bacteria, it has virtually noactivity against aerobic gram-positive and anaerobic bacteria, thereby producing littlealteration of bowel flora [1].Good tissue and fluid penetration has been demonstrated in adults, along with protein-binding of 50 to 65%. Eliminated renally, primarily as unchanged drug. Serum half-life inneonates is 3 to 9 hours. Aztreonam does not interfere with bilirubin-albumin binding.ABOUTSpecial Considerations/PreparationAvailability: Powder for injection in 1-g and 2-g vials [3]Reconstitution (Shake immediately and vigorously):◦ For infusion, reconstitute 1-g with at least 3 mL of sterile water for injection (SWFI) andfurther dilute to a concentration of no greater than 20 mg/mL.◦ For bolus, reconstitute 1-g or 2-g vial with 6 to 10 mL of SWFI.◦ For IM administration, dilute 1-g with at least 3 mL of appropriate diluent.Storage: Prior to reconstitution, store in original package at a controlled room temperature;avoid excessive heat [3].Solutions at concentrations not exceeding 2% weight/volume must be used within 48 hours ifstored at a controlled room temperature between 15 and 30 degrees C (59 and 86 degreesF) or within 7 days if refrigerated between 2 and 8 degrees C (36 and 46 degrees). Discardany unused portion. [3].Solutions at concentrations exceeding 2% weight/volume, except those prepared with SterileWater for Injection or Sodium Chloride Injection, should be used promptly after preparation;the 2 excepted solutions must be used within 48 hours if stored at a controlled roomtemperature between 15 and 30 degrees C (59 and 86 degrees F) or within 7 days ifrefrigerated between 2 and 8 degrees C (36 and 46 degrees). Discard any unused portion[3].© Merative US L.P. 1973, 2024134BeractantNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseRespiratory Distress Syndrome (RDS)4 mL/kg/dose (100 mg of phospholipids/kg/dose) intratracheally in 4 quarter-dose aliquotswith the infant in a different position for each aliquot [1]Prophylaxis: First dose is given as soon as possible, preferably within 15 minutes of birth,up to 4 doses may be administered in first 48 hours of life, if indicated. Do not give morefrequently than every 6 hours. Obtain radiographic confirmation of respiratory distresssyndrome before administering additional doses[1].Rescue treatment of RDS : First dose is as soon as possible, preferably by 8 hours of age;up to 4 doses may be administered in first 48 hours of life, if indicated. Do not give morefrequently than every 6 hours [1]UsesPrevention and treatment of respiratory distress syndrome (RDS) in prematureinfants. Routine continuous positive airway pressure (CPAP) is considered superior toprophylactic surfactant therapy. It is strongly recommended that CPAP immediately after birthwith subsequent selective surfactant administration be considered as an alternative to routineintubation with prophylactic or early surfactant administration in preterm infants. Severe RDSin preterm infants born younger than 30 weeks gestation who need mechanical ventilationshould be administered surfactant after initial stabilization. Consider the use of rescuesurfactant for infants with hypoxic respiratory failure attributable to secondary surfactantdeficiency, such as meconium aspiration syndrome or sepsis/pneumonia[2].Animal-derived surfactants (beractant, calfactant, and poractant alfa) had comparableoutcomes for air leak syndromes, death, and bronchopulmonary dysplasia in a retrospectivestudy (n=51,282; median birth weight of 1435 g; median gestational age of 30 weeks (27 to33 weeks)) [3]. In a prospective randomized trial, the animal-derived surfactants all improvedFiO2 need, PaO2 values, chest x-ray findings, and lung ultrasonography (LUS)scores (N=62,gestational age range 24 to 34 weeks, birthweight range 560 to 2500 g). However, theresults were significantly better with poractant alfa and beractant compared with calfactant.The FiO2 values at 24 hours post-surfactant for poractant alfa, beractant, and calfactant were36.8%, 33.6%, and 53.1%, respectively. The PaO2 values at 24 hours post-surfactant forporactant alfa, beractant, and calfactant were 64.7, 66.3, and 61.3 mmHg, respectively. TheLUS scores at 24 hours post-surfactant for poractant alfa, beractant, and calfactant were 3.8,4.3, and 6.9, respectively. Significantly more calfactant-treated patients required repeatdosing. Mechanical ventilation duration and hospital length of stay were similar between all 3groups [4].Neonatal FDA-Approved Indications: Indicated for prevention and treatment (“rescue”)135of Respiratory Distress Syndrome (RDS) (hyaline membrane disease) in premature infants.Beractant significantly reduces the incidence of RDS, mortality due to RDS, and air leakcomplications [1].Administration• For intratracheal use only [1]• Administration is facilitated if one person administers the dose while another personpositions and monitors the infant [1].• At discretion of the clinician, the endotracheal tube may be suctioned prior toadministration of beractant; allow infant to stabilize before proceeding with dosing [1].• Slowly withdraw the contents of the vial into a plastic syringe through a large gauge needle(eg, at least 20 gauge). Attach the premeasured 5 French end-hole catheter to the syringeand fill the catheter with beractant, discarding any excess product through the catheter sothat only the total dose to be given remains in the syringe [1].• Administer in 4 quarter-dose aliquots with the infant in a different position for each aliquotas follows: 1) head and body inclined 5 to 10 degrees down, head turned to right; 2) headand body inclined 5 to 10 degrees down, head turned to left; 3) head and body inclined 5 to10 degrees up, head turned to right; 4) head and body inclined 5 to 10 degrees up, headturned to left [1]• For each quarter-dose aliquot, insert the 5-French end-hole catheter into the endotrachealtube with the tip of the catheter protruding just beyond the end of the endotracheal tubeabove the infant's carina; do not instill product into a mainstem bronchus. Gently inject thealiquot through the catheter over 2 to 3 seconds then remove the catheter and manuallyventilate the infant for at least 30 seconds or until clinically stable. Use sufficient oxygen toprevent cyanosis and sufficient positive pressure to provide adequate air exchange and chestwall excursion [1].• When the infant is stable following administration of an aliquot, reposition for instillation ofthe next quarter dose and then instill the dose using the same procedures [1].• Once the final quarter-dose is administered, remove the catheter without flushing it. Do notsuction the infant for 1 hour after dosing unless signs of significant airway obstruction occur[1].• Each vial is for single-use only; discard unused product [1]MEDICATION SAFETYContraindications/PrecautionsContraindicationsNo specific contraindications have been determined [1]PrecautionsCardiovascular: Transient bradycardia and decreased oxygen saturation have beenreported. Interrupt therapy and institute treatment as necessary [1]136Respiratory: Rapid effects on oxygenation and lung compliance occur with administration;intubation and ventilator management must be immediately available and frequentmonitoring is required [1]Immunologic: Post-treatment nosocomial sepsis may occur [1]Respiratory: Rales and moist breath sounds have been reported after administration;endotracheal suctioning is not necessary unless airway obstruction present [1]Adverse EffectsMost common reactions reported include transient bradycardia (11.9% of doses) and oxygendesaturation (9.8% of doses). Other adverse events include hypotension, endotracheal tubereflux or blockage, hypertension, hypercarbia, hypocarbia, vasoconstriction, pallor, andapnea. In a pooled analysis of all controlled studies, the incidence of intracranial hemorrhage(ICH) was not different between the Survanta® group and the control group; however, in 2of the studies (single-dose rescue study and multiple-dose prevention study), the incidenceof ICH was significantly higher in patients who received Survanta® compared with those inthe control group (63.3% vs 30.8%; p=0.001 and 48.8% vs 34.2%; p=0.047, respectively)[5].MonitoringMonitor systemic oxygen and carbon dioxide levels with arterial or transcutaneousmeasurements frequently during therapy [5].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologySurvanta® is a modified natural bovine lung extract containing phospholipids, neutral lipids,fatty acids, and surfactant-associated proteins B and C, to which colfosceril palmitate(dipalmitoylphosphatidylcholine (DPPC)), palmitic acid, and tripalmitin are added. Resultingdrug provides 25 mg/mL phospholipids (including 11 to 15.5 mg/mL disaturatedphosphatidylcholine), 0.5 to 1.75 mg/mL triglycerides, 1.4 to 3.5 mg/mL fatty acids, and lessthan 1 mg/mL protein. Survanta® is suspended in NS and heat sterilized. Animal metabolismstudies show that most of a dose becomes lung-associated within hours of administration,and lipids enter endogenous surfactant pathways of reuse and recycling [5].ABOUT137Special Considerations/PreparationAvailability: 4- and 8-mL single-use vials (25 mg phospholipids/mL) [5]Storage: Refrigerate at 2 to 8 degrees C (36 to 46 degrees F) and protect from light.Inspect Survanta® for discoloration; normal color is off-white to light-brown. If settlingoccurs during storage, swirl vial gently. Do not shake. Vials should be entered only once.Used vials with residual drug should be discarded. Unopened vials that have been warmed toroom temperature one time may be refrigerated within 24 hours and stored for future use.Should not be warmed and returned to the refrigerator more than once [5].Preparation•If a prevention dose is to be given, begin preparation of product prior to infant's birth [1]•After removing unopened vial from the refrigerator, warm at room temperature for at least20 minutes or warm in hand for at least 8 minutes, do not warm by artificial warmingmethods [6]•Do not shake vial; swirl gently to redisperse. Some foaming at the surface may occur duringhandling and is inherent in the nature of the product [6].•Do not filter product [6]•After warming vial, unopened vials can be returned to refrigerator within 24 hours ofwarming to store only once, record date and time when vial is removed from the refrigerator.Vials may not be out of refrigerator for more than 24 hours [6].•Does not require reconstitution or sonication before use [6]© Merative US L.P. 1973, 2024138BevacizumabNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseLong-term benefits and safety and optimal regimens are unknown[1].Retinopathy of prematurity, Type 1Most common dose used in studies was 0.625 mg in 0.025 mL per eye via intravitrealinjection for 1 dose [2][3].Uncontrolled trials evaluated lower doses [4][5][6]; 0.312 mg in 0.025 mL [5] and 0.16 mgin 0.025 mL [4].A phase 1 dose de-escalation study, demonstrated improvement by 5 days and no recurrencerequiring additional treatment within 4 weeks for bevacizumab doses of 0.25 mg in 11 of 11eyes, 0.125 mg for 14 of 14 eyes, 0.063 mg for 21 of 24 eyes, and 0.031 mg for 9 of 9 eyesof infants with severe ROP, type 1 [6].Combination bevacizumab 0.25 mg in 0.01 mL with zone 1 sparing laser or deferred lasertreatment was used [7].Retreatment may be needed after 55 weeks' postmenstrual age [8]. Some infants requiredretreatment at a mean of 9.8 weeks (6 to 15 weeks) after the initial injection [4]Premedication/Post-procedure medicationIn infants, eyes were prepared with a topical anesthesia(0.5% proparacaine or 0.5%tetracaine) and ophthalmic antiseptic (5% [9][3][2] or 10% [10] povidone iodine) . After theprocedure ophthalmic antibiotic drops were administered for 7 days [2].UsesRetinopathy of Prematurity (ROP)A systematic review (5 randomized or semi-randomized studies) demonstrated no reductionin retinal detachment or recurrent ROP in infants treated with intravitreal bevacizumab (n=4studies) or ranibizumab (n=1 studies) compared with laser therapy; however, refractiveerrors were reduced. In a subgroup analysis, the risk of recurrence was lower in type 1, buthigher in type 2 ROP. Intravitreal bevacizumab was well tolerated but long-term systemiceffects are unknown [1]. If bevacizumab is offered, consider only for type 1 ROP treatment inpatients with zone I or posterior zone II disease [8].In infants with stage 3+ ROP in each eye, intravitreal 0.625 mg bevacizumab significantlyreduced the rate of recurrence compared with conventional laser therapy (6% vs 26%;P=0.002) at 54 weeks' postmenstrual age in a randomized trial (N=143 infants). However, asignificant treatment effect was observed for zone I but not zone II posterior ROP.(Bevacizumab Eliminates the Angiogenic Threat of ROP (BEAT-ROP) Trial) [2]. At 2.5 years ofage (n=109), a follow-up of the BEAT-ROP trial detected more myopia and very high myopiain laser-treated eyes compared with bevacizumab-treated eyes [11].In a retrospective study of 241 infants, the ROP recurrence rate was 8.3% with bevacizumab.The recurrence rate was higher in those infants with APROP (31.6%) compared with infants139with stage 3+ ROP (6.3%; P less than 0.001) [12]. A follow-up (n=39 eyes) with fluoresceinangiograph in infants at 4 years of age detected significant ocular-vascular abnormalities inbevacizumab (0.5 mg)-treated eyes compared with laser-treated eyes treated for type 1,zone I ROP [13]For 2 months after intravitreal bevacizumab (0.625 mg/dose per eye or 0.25 mg/dose pereye), serum vascular endothelial growth factor (VEGF) and insulin-like growth factor-1concentrations had greater suppression compared with laser surgery in 24 infants. Serumvascular endothelial growth factor concentrations for intravitreal bevacizumab groups (0.5 mgand 1.25 mg) were 50% lower from day 2 to day 60 compared with laser-treated groups (nobevacizumab). There were no significant differences in serum VGEF concentrations betweenthe 2 bevacizumab doses. The clinical significance of these findings is unknown [14].Pediatric FDA Approved IndicationsSafety and effectiveness have not been established in pediatric patients [15].AdministrationIntravitreal Administration• Bevacizumab concentration was 25 mg/mL [2][3]. Diluted concentrations, 3.1 mg/mL to12.5 mg/mL, have been used with smaller doses [4][5][6].•In pediatric patients a sterile 30-gauge [4][9], 31-gauge [3], or 32-gauge [10] 4-mm needleinjected intravitreally 0.75 mm [10] to 1 mm [4][10][3] or 1.5 mm [9] to 2 mm [4] posteriorto the temporal limbus into the vitreous cavity [10].MEDICATION SAFETYContraindications/PrecautionsContraindicationsSpecific contraindications have not been determined [18]PrecautionsIV AdministrationCardiovascular: Increased risk for severe (Grade 3 or 4) hypertension; interruption ordiscontinuation may be necessary [18]Cardiovascular: Congestive heart failure (CHF) and decline in LVEF have been reported;discontinuation may be necessary [18]Concomitant use: Not indicated for use with anthracycline-based chemotherapy [18]Dermatologic: Necrotizing fasciitis, including fatal cases, has been reported; usuallysecondary to wound healing complications, gastrointestinal perforation, or fistula formation;discontinuation may be necessary [18].Fistulae: Non-gastrointestinal fistulae (ie, tracheoesophageal, bronchopleural, biliary,vaginal, renal, bladder), which may be serious and/or fatal, have been reported;140discontinuation may be required [18]Gastrointestinal: Gastrointestinal: Serious gastrointestinal fistulae, includinggastrointestinal-vaginal fistula, have been reported and may be accompanied by bowelobstruction requiring surgical interventions; discontinuation may be necessary [18]Gastrointestinal: Serious and sometimes fatal gastrointestinal perforation has beenreported, with highest incidence within 50 days of the first dose and in patients with a historyof prior pelvic radiation; perforation may be complicated by intra-abdominal abscess, fistulaformation, and need for diverting ostomies; discontinuation may be necessary [18]Gastrointestinal: Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinicalsymptoms of bowel obstruction [18]Hematologic: Thrombotic microangiopathy has been reported; monitoring recommendedand discontinuation may be needed [18]Hematologic: Serious and sometimes fatal arterial thrombotic events (ie, cerebralinfarction, angina, transient ischemic attack, myocardial infarction) have been reported, withan increased risk in patients with a history of arterial thromboembolism or diabetes. Thehighest incidence was reported in patients with glioblastoma. Discontinue use if severe eventis suspected [18]Hematologic: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding,hematemesis, CNS hemorrhage, epistaxis, and vaginal bleed, and minor hemorrhage havebeen reported; screening may be required and discontinuation may be necessary. Do notadminister in patients with recent history of hemoptysis of 0.5 teaspoon or more of red blood[18].Hematologic: Venous thromboembolic events have been reported; discontinuation may berequired [18]Immunologic: Infusion reactions (ie, hypertension, hypertensive crisis with neurologicalsigns and symptoms, wheezing, oxygen desaturation, hypersensitivity andanaphylactoid/anaphylactic reactions (Grade 3), chest pain, headache, rigors, anddiaphoresis) have been reported; if severe reaction occurs, stop infusion and instituteappropriate therapy [18]Neurologic: Posterior reversible encephalopathy syndrome (PRES) has been reported,occurring from 16 hours up to 1 year after treatment initiation. MRI is required to confirmdiagnosis. Discontinue use in patients developing PRES [18]Renal: Nephrotic syndrome, sometimes fatal, has been reported; discontinue use [18]Renal: Proteinuria has been reported; interruption of therapy may be necessary [18]Reproductive: Ovarian failure has been reported [18]Respiratory: Serious and/or fatal pulmonary hemorrhage has been reported; discontinueuse if suspected. Do not administer in patients with recent history of hemoptysis of 0.5teaspoon or more of red blood [18]Surgery and wound healing: The incidence of wound healing and surgical complicationswas increased in patients receiving bevacizumab; discontinuation may be necessary. Withholdbevacizumab for at least 28 days prior to elective surgery and do not administer bevacizumabfor at least 28 days following major surgery until adequate wound healing [18].Adverse EffectsCardiovascular: Hypotension was reported in a male preterm infant twin 1 day after141intravitreal bevacizumab for retinopathy of prematurity. At 9 weeks, intravitreal injection ofbevacizumab 0.625 mg/0.025 mL was administered in each eye under IV ketamine (0.3 mg)and local atropine (0.25%). Feeding intolerance, hypotension (42/24 mmHg), and oxygendesaturation (arterial oxygen saturation, 80%) were observed 22 hours after bevacizumabadministration and continued the following day. Shortness of breath with apnea and lethargywere also noted. Intubation for mechanical ventilation, treatment with DOPamine, andprophylactic antibiotics were instituted. Blood pressure normalized on day 3 and his generalcondition improved. On day 6, DOPamine and antibiotics were discontinued. He wassuccessfully extubated on day 7 and arterial oxygen saturation was normal. The siblingreceivedbevacizumab with no episodes of hypotension [19]Musculoskeletal: Non-mandibular osteonecrosis has been reported in patients youngerthan 18 years who received IV bevacizumab [15].Neurologic: In a retrospective study (n=125), the adjusted odds ratio was 3.1 (95% CI, 1.2to 8.4) for severe neurodevelopmental disability in intravitreal bevacizumab-treatedcompared with laser-treated preterm infants at 18 months corrected age after adjusting forgestational age, gender, maternal education, Score for Neonatal Acute Physiology-II score,bronchopulmonary dysplasia, sepsis, and severe brain injury [20].Ophthalmic: More high myopia was seen in eyes treated with bevacizumab (14.6%) thanthose treated with ranibizumab (0%; p=0.03) at 1 year of age in a retrospective study (n=37infants) [21].Black Box WarningIV AdministrationGastrointestinal Perforations: The incidence of gastrointestinal perforation, some fatal, inpatients receiving bevacizumab ranged from 0.3 to 3%. Discontinue bevacizumab in patientswho develop gastrointestinal perforation.Surgery and Wound Healing Complications: The incidence of wound healing andsurgical complications, including serious and fatal complications, is increased in patientsreceiving bevacizumab. Discontinue bevacizumab in patients who develop wound healingcomplications that require medical intervention. Withhold bevacizumab at least 28 days priorto elective surgery. Do not administer bevacizumab for at least 28 days after surgery anduntil the wound is fully healed.Hemorrhages: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding,hematemesis, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleedingoccur up to 5-fold more frequently in patients receiving bevacizumab. Do not administerbevacizumab to patients with a recent history of hemoptysis. Discontinue in patients whodevelop Grade 3 to 4 hemorrhage [15]Solution CompatibilityNS142Solution IncompatibilityD5WMonitoringThe duration for follow-up is unknown but will require longer follow-up compared with lasertreatment [12][8] due to delayed or incomplete vascularization, significant rates ofrecurrence and need for retreatment, and potential for developmentally abnormal or atypicalretinal vascular features [8].In a retrospective case series recurrent ROP occurred a mean of 51.2 weeks (range, 45.7 to64.9 weeks) adjusted age after intravitreal bevacizumab in 20 infants [12]. Additionallyretinal detachment had occurred in 2 treated patients at the age of 2.5 years [16] and 3years [17].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of actionBevacizumab, a recombinant humanized monoclonal immunoglobulin-1 antibody, binds tovascular endothelial growth factor (VEGF) and inhibits the interaction of VEGF to Flt1 andKDR receptors on the surface of endothelial cells. In the process, it prevents the proliferationof endothelial cells and formation of new blood vessels [15].PharmacokineticsIntravitreal Administration in infantsSerum concentrations0.5 mg (0.25 mg/dose per eye): 0 on day 0, 72.9 ng/mL on day 2, 424 ng/mL on day 14,172.5 ng/mL on day 42, and 78.7 ng/mL on day 60 [14]1.25 mg (0.625 mg/dose per eye): 0 on day 0, 203.4 ng/mL on day 2, 1002 ng/mL onday 14, 444.4 ng/mL on day 42, and 305.6 ng/mL on day 60 [14]Half-life: 21 days in 17 infants after intravitreal administration [14].IV Administration in adultsClearance: 0.23 L/day [15].Distribution: 2.9 L [15].Half-life: 20 days (range, 11 to 50 days) [15]143ABOUTSpecial Considerations/PreparationAvailability: 100 mg/4 mL (25 mg/mL) and 400 mg/16 mL (25 mg/mL) sterile solution forIV infusion [15]Storage: Store in the original carton and under refrigerated conditions between 2 and 8degrees C (36 and 46 degrees F). Protect from light. Do not freeze or shake. Diluted solutionmay be stored between 2 and 8 degrees C (36 and 46 degrees) for up to 8 hours if not usedimmediately [18].Stability (Bevacizumab for intravitreal injection is not commercially available andbevacizumab IV solution is frequently repackaged for this use.)• Over a 6 month period, the stability of bevacizumab 25 mg/mL IV solution in polycarbonateand polypropylene syringes (0.13 mL/syringe) was compared with bevacizumab in glass vialsduring storage at a constant temperature of 2 to 8 degrees C. There was no significantdifference in the quality of vascular endothelial growth factor (VEGF) binding and proteinphysical stability of bevacizumab in the syringes compared with the glass vials [22].•The stability of bevacizumab 25 mg/mL IV solution repackaged as 1.25 mg/0.05 mL and2.5 mg/0.1 mL using 1 mL plastic, latex-free, tuberculin syringes was evaluated whenstored under refrigeration at 4 degrees C for 1 week, 3 weeks, 3 months, and 6 months, andwhen frozen at -10 degrees C. Stability was evaluated based on binding activity to vascularendothelial growth factor (VEGF-165). The refrigerated syringes lost approximately 1.6% and0% binding activity at 1 and 3 weeks, and lost 8.8% and 15.9% binding activity at 3 and 6months. The frozen syringes lost 12% binding activity at 6 months. Pierced vials lost 9.6%and 12.7% binding activity at 3 and 6 months when stored under refrigeration [23].© Merative US L.P. 1973, 2024144BumetanideNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDose0.005 to 0.05 mg/kg/dose IV slow push, IM, or orally. Doses up to 0.1 mg/kg have been usedin neonates; however, there are no pharmacodynamic data showing doses greater than 0.05mg/kg provide additional benefit [1][2][3].Preterm infants less than 34 weeks gestation in the first 2 months of life: every 24hours.Afterward: every 12 hours.Preterm infants 34 weeks or more gestation and term infants in the first month oflife: every 24 hours.Afterward: every 12 hours.Infants with lung disease and normal renal function should be started on a low dose. Infantswith congestive heart failure or abnormal renal function will need a higher dose.In a dose-range evaluation of bumetanide pharmacodynamics in critically ill neonates andinfants, single IV doses ranging from 0.005 to 0.1 mg/kg (increases in increments of 0.005mg/kg) were given over 1 to 2 minutes. All doses were associated with at least a 2-foldincrease in urine output and electrolyte excretion rates. The dose range corresponding to themaximal effect was 0.035 to 0.04 mg/kg. There were no pharmacodynamic advantages(urine output and electrolyte excretion rate) to doses greater than 0.05 mg/kg [1]. Althoughdoses of 0.05 and 0.1 mg/kg have been studied in neonates, only pharmacokinetic endpointswere determined, and no pharmacodynamic endpoints were reported [2]. In a retrospectivestudy in preterm infants with oliguric renal failure and inadequate response to furosemide,bumetanide was effective in significantly increasing urine output in 29 of 35 infants. Themean bumetanide dose and duration of therapy were 0.03 +/- 0.016 mg/kg every 12 to 24hours and 5.9 days, respectively. Urine output increased from 0.6 +/- 0.6 mL/kg/hour to 3+/- 2.1 mL/kg/hour [3].Diuresis, in Critically-Ill Patients: 1 to 10 mcg/kg/hr continuous IV infusion; mean studydose, 5.7 mcg/kg/hr; median duration, 3.3 days [4].UsesDiuresis, in Critically-Ill Patients: Preliminary evidence shows that the use ofbumetanide as a continuous infusion in critically-ill pediatric patients (7 neonates and 33children) improves urine output and helps patient achieve negative fluid balance. Urineoutput increased from 2.5 mL/kg/hr before bumetanide continuous infusion to 4.4 mL/kg/hrat the midpoint of the 30 mcg/kg/hr bumetanide infusion [6]. In a second study, negative145fluid balance was achieved by 54% of patients within 12 hours and 76% of patients by 48hours when given a mean dose of 5.7 mcg/kg/hr bumetanide continuous infusion (N=95).Median age was 0.2 years (range, 0 to 15.7 years) [4]. The median duration of therapyranged from 3.3 to4.1 days [6][4]. One study reported potassium less than 3 mEq/L in 33%and SCr 1.5x or greater above baseline in 5% [4].Heart Failure or Edema: Diuretic used in patients with renal insufficiency, congestive heartfailure, or significant edema that is refractory to furosemide.In neonates with pulmonary hypertension, supportive care with diuretics may be usedcautiously for signs of right-sided heart failure [7].AdministrationIntravenous: Give undiluted over 1 to 2 minutes [1].Oral: The intravenous formulation, diluted in sterile water and given orally, has been usedsuccessfully in infants with congenital heart disease [5].MEDICATION SAFETYContraindications/PrecautionsContraindicated:[8].◦ Anuria◦ Hepatic coma until the condition is improved or corrected◦ Severe electrolyte depletion until the condition is improved or correctedPrecautions:Concomitant use: Use with lithium, probenecid, indomethacin, aminoglycosides, and drugswith ototoxic or nephrotoxic potential is not recommended [8].Endocrine and metabolic: Hypokalemia may occur; therefore, use caution in patients onlow-salt diets, receiving digitalis and diuretics for congestive heart failure, with hepaticcirrhosis and ascites, in states of aldosterone excess with normal renal function, potassium-losing nephropathy, certain diarrheal states, or other states where hypokalemia may addrisks to the patient (eg, history of ventricular arrhythmias); monitoring and possible additionof potassium supplementation or potassium-sparing diuretics recommended [8].Endocrine and metabolic: Hypocalcemia, hypomagnesemia, and hyperuricemia mayoccur; monitoring recommended [8].Hematologic: Thrombocytopenia has been reported; monitoring recommended [8].Hepatic: Sudden electrolyte alterations in patients with hepatic cirrhosis and ascites mayprecipitate hepatic encephalopathy and coma; initiation should be done on an inpatient basiswith small doses and careful monitoring [8].Immunologic: Patients with a sulfonamide allergy may show hypersensitivity to bumetanide[8].146Neurologic: Kernicterus could occur in critically ill or jaundiced neonates at risk forkernicterus; bumetanide displaces bilirubin [8].Otic: Ototoxicity may occur, with an increased risk with IV therapy, frequent and high doses,and impaired renal function [8].Renal: Reversible elevations in BUN and creatinine may occur, particularly in patients withdehydration and renal insufficiency [8].Renal: Progressive renal disease with a marked increase in BUN or creatinine ordevelopment of oliguria; discontinue [8].Adverse EffectsWater and electrolyte imbalances occur frequently, especially hyponatremia, hypokalemia,and hypochloremic alkalosis. Potentially ototoxic, but less so than furosemide. May displacebilirubin from albumin binding sites when given in high doses or for prolonged periods.Black Box WarningBumetanide is a potent diuretic which, if given in excessive amounts, can lead to profounddiuresis with water and electrolyte depletion. Therefore, careful medical supervision isrequired, and dose and dosage schedule have to be adjusted to the individual patient's needs[8].Solution CompatibilityD5W and NS.Terminal Injection Site CompatibilityAztreonam, cefepime, furosemide, lorazepam, milrinone, morphine, piperacillin/tazobactam,and propofol.Terminal Injection Site IncompatibilityDobutamine and midazolam.147MonitoringSerum electrolytes and urine output. Assess patients receiving digoxin concurrently forpotassium depletion. Follow weight changes.MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyBumetanide is a loop diuretic with a similar mechanism of action to furosemide. Inhibitschloride reabsorption in the ascending limb of Henle's loop and inhibits tubular sodiumtransport, causing major loss of sodium and chloride. Increases urinary losses of potassium,calcium, and bicarbonate. Urine sodium losses are lower with bumetanide than furosemide,but urine calcium losses are higher. Decreases CSF production by weak carbonic anhydraseinhibition. Decreases pulmonary transvascular fluid filtration. Increases renal blood flow andprostaglandin secretion. Highly protein bound (greater than 97%). Data from adults indicateexcellent oral bioavailability and significant hepatic metabolism (40%) via the cytochromeCYP pathway. Serum half-life varies from 4 to 19 hours in neonates, determined bygestational age, postnatal age, and disease state.ABOUTSpecial Considerations/PreparationSupplied as 2-, 4-, and 10-mL vials (0.25-mg/mL solution). Contains 1% (10 mg/mL) benzylalcohol; pH adjusted to 7.A 0.125-mg/mL dilution may be made by adding 3 mL of 0.25-mg/mL injectable solution to 3mL preservative-free normal saline for injection. Refrigerated dilution is stable for 24 hours.Discolors when exposed to light.There is no oral dosing formulation available for neonates. The intravenous formulation,diluted in sterile water and given orally, has been used successfully in infants with congenitalheart disease [5].© Merative US L.P. 1973, 2024148BupivacaineNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseThe dose varies with anesthetic procedure, the area to be anesthetized, the vascularity of thetissues, the number of neuronal segments to be blocked, the depth of anesthesia and degreeof muscle relaxation required, the duration of anesthesia desired, individual tolerance, andthe physical condition of the patient. Use the lowest dose and concentration to achieve thedesired result [1][2]. The USES section provides dosage ranges; however, other resourcesshould be consulted for specific techniques and procedures.Dose AdjustmentsRenal impairment: Select dose carefully since bupivacaine is excreted by the kidneys[3][2][1]Hepatic impairment (moderate or severe): Consider reducing the dose with increasedmonitoring, especially with repeat doses [3][2][1]Acutely ill and debilitated patients: Use a reduced doses commensurate with their ageand physical status [3][2][1]Methemoglobinemia: Discontinue use and manage medically [3][2][1]Risk Factors for Seizures: When bupivacaine is administered by continuous infusion,reduce the rate in neonates who are at risk for seizures. Risk factors include increased uptakeinto the circulation (eg, pulmonary arteriovenous malformation) or lowered seizure threshold(eg, history of febrile convulsions during the postoperative period, hypomagnesemia, orhyponatremia due to free water overload) [4].UsesEpidural anesthesia: Epidural anesthesia, whether by caudal or lumbar route, is effectivein the neonate [6]. Typical doses of bupivacaine 0.125% to 0.25% are 1.25 mg/kg to 2.5mg/kg for caudal epidural anesthesia [7], 2 mg/kg up to a maximum of 2.5 mg/kg forepidural anesthesia (other than caudal route) [7][8][4], and 0.2 mg/kg/hr up to a maximumof 0.25 mg/kg/hr for continuous epidural infusion [7][8][9][4] for a maximum duration of 24to 36 hours [9]. Data are lacking in premature infants. Although, one study used 3.125mg/kg of 0.5% bupivacaine by the caudal route as an adjunct to general anesthesia in 20premature infants (0 to 60 days; 520 to 2750 grams). No neonate experienced elevated heartrate or blood pressure at the time of incision [10]. In a retrospective analysis of 750 children(2 days to 16 years of age), bupivacaine 0.25% provided longer postoperative pain relief (upto 5 hours) than lidocaine 0.5% or 1.5% when administered caudally [11].Peripheral nerve block: For neonatal circumcision a dorsal nerve block with a localanesthetic is recommended [7]. A penile nerve block is appropriate for urethral dilation andhypospadias repair [6]. Solutions containing epinephrine should NOT be used near end-artery149areas (eg, digits, nose, external ear, penis) or areas of compromised blood supply [12].Efficacy data are lacking in neonates; however, in 2 pharmacokinetic studies bupivacainenerve blocks were used in neonates without associatedtoxic concentrations or observedadverse events [13][14]. Doses of bupivacaine were 2 mg/kg for interpleural nerve block in 8very low birthweight infants (700 g to 1022 g) [13] and 1.5 mg/kg for intercostal block in 11full-term neonates (1 to 27 days of age) [14].Spinal anesthesia: The use of spinal anesthesia is common in neonates, even preterminfants. In comparison to adults, the dose is greater in neonates [6]. Dose range is 0.5 to 1mg/kg [6][15][16] with usual doses of 0.6 mg/kg of 0.75% hyperbaric bupivacaine in 8.25%dextrose [6][16] and 0.8 mg/kg of 0.5% isobaric bupivacaine [6]. The duration of effectivespinal blockade (lack of hip flexion) was 84+/-16 minutes in 11 infants (range: 0.1 to 7months of age; 2.8 to 9.3 kg) who received 0.75% bupivacaine 0.6 mg/kg in 8.25% dextrosesolution with 0.02 mL of 1:1000 epinephrine [16]. Efficacy data are lacking in prematureinfants.Pediatric FDA Approved IndicationsIndicated for the production of local or regional anesthesia or analgesia for surgicalprocedures, dental and oral surgery procedures, and diagnostic and therapeutic procedures.Use is not recommended in pediatric patients younger than 12 years [3][2][1].Marcaine™ Spinal: Indicated for production of subarachnoid block (spinal anesthesia). Usein patients younger than 18 years is not recommended [17].AdministrationBupivacaine is contraindicated for intravenous regional anesthesia (Bier Block) [3][2][1].Epidural anesthesia:• Use only single-dose ampules and single-dose vials for caudal or epidural anesthesia asmultiple dose vials contain a preservative [3][2].• Administer slowly in 3- to 5-mL incremental doses with sufficient time between doses todetect signs/symptoms of unintentional intravascular or intrathecal injection [3][2]• Perform syringe aspirations before and during each supplemental injection in continuous(intermittent) catheter techniques [3][2]• Administer a test dose, which contains epinephrine, and monitor the effects prior to the fulldose and with all subsequent doses when a catheter is in place [3][2][1]. The use of a localanesthetic in the test dose is probably unwarranted and may lead to toxicity [5].• Avoid rapid injection of large volumes of anesthetic solutions. When possible, use fractional(incremental) doses [3][2][1].Local infiltration and peripheral nerve blocks:• Check aspiration for blood or cerebrospinal fluid (when applicable) prior to injecting anylocal anesthetic, both initial and subsequent doses [3][2][1].• Avoid rapid injection of large volumes of anesthetic solutions. When possible, use fractional(incremental) doses [3][2][1].MEDICATION SAFETY150Contraindications/PrecautionsContraindications• Arrhythmias (eg, complete heart block) which severely restrict cardiac output (spinalinjection) [17]• Hypersensitivity to bupivacaine, to other amide-type anesthetics, or to any component ofthe product [25][17][3][2]• Local infection at the site of proposed lumbar puncture (spinal injection) [17]• Obstetrical paracervical block anesthesia [25][2][3]• IV regional anesthesia (Bier Block) [25][2][19]• Septicemia (spinal injection) [17]• Severe hemorrhage (spinal injection) [17]• Severe hypotension (spinal injection) [17]• Shock (spinal injection) [17]PrecautionsAdministration: Avoid intravascular injection; use proper technique (spinal injection) [17].Administration: Risk of significant increase in plasma concentrations with repeated localadministration [2].Administration: Head and neck area (including retrobulbar, dental, and stellate ganglionblocks) administration has been associated with events that occur with systemic toxicity(convulsion, confusion, respiratory depression and/or respiratory arrest, and cardiovascularstimulation or depression); monitoring recommended [2].Administration: Systemic toxicities, including CNS or cardiorespiratory depression andcoma, leading to respiratory arrest, underventilation or apnea, have been reported withunintended intravascular or intrathecal injection [2]Cardiovascular: Serious dose-related arrhythmias may occur with use of bupivacaine incombination with vasoconstrictors such as epinephrine during or after use of potentinhalation anesthetics [2].Cardiovascular: Use caution in patients with a history of cardiac rhythm disturbances,shock, heart block, or hypotension [17].Cardiovascular: Blood-flow restriction in end-artery areas (eg, digits, nose, external ear,penis) or areas of compromised blood supply may occur and cause ischemic injury ornecrosis; increased risk in patients with hypertensive vascular disease [2].Concomitant use: Avoid use of solutions containing antimicrobial preservatives (eg,multiple-dose vials) for epidural or caudal anesthesia [2].Cardiovascular: Concomitant use with epinephrine or other vasopressors may increase riskof severe prolonged hypertension [2].Concomitant use: Mixing or the prior or concurrent use of any other local anesthetic is notrecommended for spinal injection [17].Endocrine and metabolic: Familial malignant hyperthermia may be triggered byanesthetics; supportive therapy may be required [17].Gastrointestinal: Inadvertent trauma to tongue, lips, and buccal mucosa may occur whenused for dental injections [25].Hematologic: Methemoglobinemia has been reported with use of local anesthetics;increased risk in patients with glucose-6-phosphate dehydrogenase deficiency, congenital oridiopathic methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months ofage, and concurrent exposure to oxidizing agents or their metabolites and other drugsassociated with methemoglobinemia; if use is required in at-risk patients monitoring is151recommended. Medical management and discontinuation of therapy is required [2].Hepatic: Increased risk of developing toxic plasma concentrations in patients with severehepatic disease, especially with repeat doses; monitoring recommended and dosageadjustment may be required [2].Immunologic: Bupivacaine with epinephrine solutions contain sodium metabisulfite;patients with sulfite sensitivity may experience allergic-type reactions including anaphylaxisand life-threatening or less severe asthmatic episodes in certain susceptible people [25]Musculoskeletal: Chondrolysis has been reported with postoperative intra-articularinfusions of local anesthetics (unapproved use) [2].Neurological: Dose-related neurotoxicity may occur; delay in proper management,underventilation from any cause, or altered sensitivity may result in acidosis, cardiac arrest,and death. Monitoring recommended [2]Renal: Increase risk of toxic reactions in patients with renal impairment; monitoringrecommended [17].Reproductive: Spinal anesthetics should not used during uterine contractions [17].Respiratory: Respiratory arrest has been reported during retrobulbar blocks following localanesthetic injection; monitoring recommended [2].Respiratory: Upper airway obstruction, requiring intubation; pulmonary edema; andtachydysrhythmia may occur with inadvertent vagal blockade in patients undergoingglossopharyngeal nerve block with bupivacaine for pain relief after tonsillectomy [26]. Vocalcord paralysis is a potential complication when bupivacaine is infiltrated in the peritonsillarregion [27].Special populations: Debilitated and acutely ill patients may have lower tolerance toelevated blood levels; dose adjustment recommended [3].Adverse EffectsAs with other amide-type local anesthetics, adverse effects are related to excessiveconcentrations due to overdosage, inadvertent intravascular injection, or slow metabolism ofbupivacaine. These adverse events are serious, typically dose-related, and generally affectthe central nervous and cardiovascular system. Central nervous system reactions includerestlessness, anxiety, dizziness, tinnitus, blurred vision, tremors, convulsions, drowsiness,unconsciousness, respiratory depression, nausea, vomiting, chills, and pupillary constriction.Cardiovascularreactions include depression of myocardium, decreased cardiac output, heart-block, hypotension, bradycardia, ventricular arrhythmias (ventricular tachycardia andventricular fibrillation), and cardiac arrest [25][17][3][2].Rare allergic reactions may occur. Risks with epidural and spinal anesthesia or nerve blocksnear the vertebral column include underventilation or apnea with inadvertent subarachnoidinjection; and hypotension secondary to loss of sympathetic tone and respiratory paralysis orunderventilation when motor blockade extends cephaladly. Other risks of epidural and spinalanesthesia include urinary retention, fecal and urinary incontinence, loss of perinealsensation, persistent anesthesia, paraesthesia, weakness, paralysis of the lower extremitiesand loss of sphincter control, headache, backache, septic meningitis, meningismus, andcranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid. Risk of otherroutes of anesthesia include persistent anesthesia, paresthesia, weakness, paralysis, all ofwhich may have slow, incomplete, or no recovery [25][17][3][2].152In pharmacokinetic studies, no adverse events were reported in 11 neonates followingintercostal nerve block with bupivacaine [14], 8 very low birthweight infants followinginterpleural nerve block with bupivacaine [13], or 20 newborns (including 18 prematureneonates) administered spinal anesthesia with bupivacaine [15].Black Box WarningThere have been reports of cardiac arrest with difficult resuscitation or death during use ofbupivacaine for epidural anesthesia in obstetrical patients. In most cases, this has followeduse of the 0.75% (7.5 mg/mL) concentration. Resuscitation has been difficult or impossibledespite apparently adequate preparation and appropriate management. Cardiac arrest hasoccurred after convulsions resulting from systemic toxicity, presumably followingunintentional intravascular injection. The 0.75% (7.5 mg/mL) concentration of bupivacainehydrochloride injection is not recommended for obstetrical anesthesia and should be reservedfor surgical procedures where a high degree of muscle relaxation and prolonged effect arenecessary [2][3].Solution CompatibilityD5W, NS.Compatibility information refers to physical compatibility and is derived from Trissel’s™ 2Clinical Pharmaceutics Database. The determination of compatibility is based onconcentrations for administration recommended herein. Drug compatibility is dependent onmultiple factors (eg, drug concentrations, diluents, storage conditions). This list should not beviewed as all-inclusive and should not replace sound clinical judgment. The user is referred toTrissel’s™ 2 for more complete details.MonitoringTherapeutic Physical Monitoring• Monitor the level of anesthesia, which is not always controllable with spinal techniques(spinal injection) [18].Toxic Laboratory Monitoring• Closely monitor for signs and symptoms of methemoglobinemia in at-risk patients (eg,glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia,cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposureto oxidizing agents or their metabolites) [19].• In general, monitoring bupivacaine concentrations is not warranted; however, when there isa concern for accumulation then it may be appropriate. Consider monitoring concentrationswhen a local anesthesia is administered by continuous infusion at doses greater than 0.5mg/kg/hr [20].153Toxic Physical Monitoring• Monitor cardiovascular vital signs (heart rate and blood pressure) continuously after eachlocal anesthetic injection [18][21][22]; especially blood pressure during the early phases ofanesthesia in the elderly [18].• Closely monitor for signs and symptoms of methemoglobinemia in at-risk patients (eg,glucose-6-phosphate dehydrogenase deficiency, congenital or idiopathic methemoglobinemia,cardiac or pulmonary compromise, infants under 6 months of age, and concurrent exposureto oxidizing agents or their metabolites) [19].• Monitor respiratory vital signs for adequate ventilation continuously after each localanesthetic injection [18][21][22].• Monitor the patient's state of consciousness continuously after each local anestheticinjection [18][21][22].• Monitor continuously for systemic toxicity including confusion, convulsions, respiratorydepression or arrest, and cardiovascular stimulation or depression following retrobulbar,dental, ophthalmic, and stellate ganglion blocks [21][22]. Continuously monitor for level ofpain control, using an appropriate pain assessment tool [7][23].• Monitor heart rate and blood pressure, and check for circumoral pallor, palpitations, andnervousness following epidural anesthesia test dose [21][22].• Test the level of anesthesia at T5-6 every 2 hours during epidural administration .[24].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyBupivacaine is a local anesthetic agent. It acts by blocking the conduction and generation ofnerve impulses, probably by increasing the threshold that produces electrical excitation in thenerve, by reducing the rate of rise of the action potential, and by slowing the nerve impulsepropagation. Systemic absorption depends on total dose and concentration, route ofadministration, vascularity of administration site, and presence or absence of epinephrine inthe anesthetic solution. Onset of action is rapid. Compared with other local anesthetics, theduration of bupivacaine is longer. Analgesia persists beyond the return of sensation. Proteinbinding: 95%. Distributed to some extent to all body tissue, with the highest concentrationsin highly perfused organs. After regional block, time to peak is 30 to 45 minutes, followed bya decline to insignificant levels during the next 3 to 6 hours. Metabolized primarily in the livervia conjugation with glucuronic acid. Mainly excreted through kidney; 6% excretedunchanged in the urine. Half-life is 2.7 hours and 8.1 hours in adults and neonates,respectively [25][17][3][2]. The bupivacaine concentrations considered toxic are 2 to 4mg/mL [7].Unbound bupivacaine did not accumulate in neonates and young infants (postmenstrual age,40 to 59 weeks) administered single epidural injection (n=6; 1.5 mg/kg of 0.25%) andcontinuous epidural infusion (n=5; 0.2 mg/kg/hr starting 2 hours after single-injection). Themedian Cmax of unbound bupivacaine was 0.024 mg/L (0.013 to 0.12 mg/L) after a singleinjection and 0.052 mg/L (0.015 to 0.08 mg/L) after a continuous infusion; the correspondingvalues for total bupivacaine were 0.55 mg/L (0.37 to 1.61 mg/L) and 0.88 mg/L (0.58 to 1.91mg/L), respectively [8]. Free bupivacaine concentrations were not elevated in 20 newborns154(including 18 premature neonates) administered spinal anesthesia with 0.5% isobaricbupivacaine 1 mg/kg with or without epinephrine 1:200,000. Total and free bupivacaineconcentrations were 0.31+/-0.17 mcg/mL and 0.047+/-0.032 mcg/mL, respectively, for thewithout epinephrine group and 0.25+/-0.09 mcg/mL and 0.062+/-0.025 mcg/mL,respectively, for the with epinephrine group [15]. The volume of distribution, half-life,clearance, and peak concentration were 4.67 L/kg, 453 minutes, 7.9 mL/kg/min, and 0.52mcg/mL, respectively, in 8 very low birthweight infants (700 g to 1022 g) after interpleuralnerve block with bupivacaine 2 mg/kg [13]. In comparison with 11 full-term neonates (1 to27 days of age) administered intercostal block with 1.5 mg/kg bupivacaine 0.25% , thevalues were 2.56 L/kg, 132 minutes, 16.93 mL/kg/min, and 0.82 mcg/mL, respectively [14].ABOUTSpecial Considerations/PreparationMarcaine™: Available as 0.25% (2.5 mg/mL), 0.5% (5 mg/mL), and 0.75% (7.5 mg/mL) ofbupivacaine in 10-mL and 30-mL single-dose vials (0.25%, 0.5%, and 0.75% strengths)without methylparaben and 50-mL multidose vials (0.25% and 0.5% strengths) containingmethylparaben as a preservative. May be autoclaved at 15-pound pressure, 121 degreesresulting in fatality. Sensitizations may recur. Discontinue use ifhypersensitivity or other serious reactions occur. Anorexia, tachypnea, lethargy, coma, anddeath have been reported with concomitant high-dose aspirin and acetaZOLAMIDE [15].MonitoringToxic Laboratory MonitoringObtain a CBC and platelet count at baseline and at regular intervals during therapy [12][11].Monitor electrolytes periodically during therapy [12][11].Consider monitoring urinary pH in patients on acetaZOLAMIDE concomitantly with otherantiepileptic drugs, particularly valproate [14].9MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of action: acetaZOLAMIDE, a nonbacteriostatic sulfonamide, inhibits carbonicanhydrase from catalyzing the reversible hydration of carbon dioxide and dehydration ofcarbonic acid. In the eye, carbonic anhydrase inhibition reduces aqueous humor productionresulting in a decrease in intraocular pressure. It also delays abnormal, paroxysmal excessivedischarge from CNS neurons and affects promotion of diuresis and urinary alkalinization[6][17][15].ABOUTSpecial Considerations/PreparationIV InjectionAvailability: Available as an IV lyophilized powder for solution containing acetaZOLAMIDE500 mg/vial [6].Storage: Store vials at a controlled room temperature between 20 and 25 degrees C (68and 77 degrees F). Reconstituted solution is stable (ie, retains physical and chemicalproperties) for 3 days under refrigeration between 2 and 8 degrees C (36 and 46 degrees F)or 12 hours when stored at a room temperature between 20 and 25 degrees C (68 and 77degrees F) [12].Oral Extended-Release CapsuleAvailability: Available as an oral extended-release capsule containing acetaZOLAMIDE 500mg [17].Storage: Store at a controlled room temperature between 20 and 25 degrees C (68 and 77degrees F) [11].Oral TabletAvailability: Available as an oral tablet containing acetaZOLAMIDE 125 mg or 250 mg; alsocontains lactose monohydrate [15].Storage: Store in a tightly closed container at a controlled room temperature between 20and 25 degrees C (68 and 77 degrees F), with excursions permitted between 15 and 30degrees C (59 and 86 degrees F) [13].PreparationIV Injection: Prior to use, reconstitute each 500-mg vial with at least 5 mL of sterile waterfor injection [6].Extemporaneous Compounding:acetaZOLAMIDE 25 mg/mL in a 1:1 mixture of ora-sweet and ora-plus, in a 1:1 mixture ofora-sweet SF and ora-plus, and in cherry syrup (concentrated cherry syrup diluted 1:4 withsimple syrup) was stable for up to 60 days at 5 and 25 degree C. The liquids were protected10from light [18].acetaZOLAMIDE 25 mg/L in 70% sorbitol solution with a suspension vehicle, sweeteners,flavoring agents, preservatives, humectants, and pH adjusters was stable for at least 79 daysat 5, 22, and 30 degrees C. Maintain at a pH 4 to 5 and protected from light. The followingare directions for compounding 300 mL of a 25 mg/mL acetaZOLAMIDE suspension(alexander, 1991)[19]:◦ Triturate 30 acetaZOLAMIDE 250-mg tablets in a glass mortar.◦ Slowly add approximately 30 mL of 70% sorbitol solution and levigate the powder.◦ Slowly add 1.5 g of sodium carboxymethylcellulose to 50 mL of warm purified water,USP, and allow the mixture to hydrate for 15 to 20 minutes.◦ Add 1.5 g of aluminum magnesium silicate to a separate 50 mL portion of purifiedwater, USP.◦ Combine the hydrated sodium carboxymethylcellulose and dispersed aluminummagnesium silicate with the levigated powder in the glass mortar.◦ Geometrically incorporate 60 mL of syrup, USP, 7.5 mL of glycerin, USP, and 6 mL ofparaben stock solution (2.5% methylparaben and 1% propylparaben in propyleneglycol) with constant agitation until a homogeneous mixture forms.◦ Transfer contents of mortar to a 500-mL graduated cylinder.◦ Add 0.015 g of FD&C Red No. 40 and 0.3 mL of strawberry flavor.◦ Rinse the mortar with a 30-mL portion of purified water, USP, and transfer to agraduated cylinder. Repeat this step until the volume of the liquid reaches 300 mL.◦ Homogenize utilizing a suitable blender.◦ Adjust the pH to 5 using 36% w/w hydrochloric acid (usually 1 to 3 drops).◦ Transfer into an amber glass bottles with constant stirring. Add a "Shake well beforeusing" auxiliary label.© Merative US L.P. 1973, 202411AcetylcysteineNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseAcetaminophen Overdose, AcuteLoading Dose ProtocolIf the time of acute acetaminophen ingestion is unknown, administer a loading doseimmediately, and use acetaminophen concentration levels to determine need for continuedtreatment [1][2].If acetaminophen concentrations cannot be obtained or are uninterpreted within 8 hours ofacetaminophen ingestion or signs of acetaminophen toxicity are present, administer aloading dose immediately and continue treatment [1][2].If the patient presents more than 8 hours after ingestion and the time of ingestion is known,administer a loading dose immediately and use acetaminophen concentration levels todetermine the need for continued treatment [1][2].To determine if acetylcysteine is indicated, a revised Rumack-Matthew nomogram based onblood acetaminophen concentrations relative to ingestion time can be utilized between 4 and24 hours after an acute ingestion. Levels drawn earlier than 4 hours from ingestion are notappropriate for use, and use of the nomogram is not indicated in the setting of repeatedsupratherapeutic ingestion extending beyond 24 hours, at which point treatment should beinitiated if the level is 20 mcg/mL or greater or if transaminase levels (AST/ALT) areabnormal and other findings are consistent with acetaminophen toxicity [3].Revised Rumack-Matthew Nomogram for theAcute Ingestion of AcetaminophenTime SinceIngestion(hours)AcetaminophenConcentrationRequiringTreatment*AcetaminophenConcentrationsDefined as High-Risk^4 150 mcg/mL 300 mcg/mL8 70 mcg/mL 150 mcg/mL12 35 mcg/mL 75 mcg/mL16 18 mcg/mL 35 mcg/mL20 9 mcg/mL 18 mcg/mL24 4.5 mcg/mL 9 mcg/mL*Treatment is indicated when acetaminophenlevel is at or above the listed concentration at agiven time point since ingestion; ^levels indicatean increased risk of liver injuryLevels drawn earlier than 4 hours from ingestionare not appropriate for use with the nomogram,nor is it indicated in the setting of repeatedsupratherapeutic ingestion extending beyond 24hours12◦ If acute overdose was from extended-release formulation and the acetaminophen levelis below the possible toxicity line but greater than 10 mcg/mL at 4 to 12 hours postingestion, draw a second sample 4 to 6 hours after the first level was drawn.◦ If acetaminophen concentrations are below the possible toxicity line, but time ofingestion is unknown or sample was taken less than 4 hours post ingestion,administer a loading dose.◦ If acetaminophen concentrations are below the possible toxicity line, time of ingestion isknown, and the sample was taken more than 4 hours post ingestion, do notadminister acetylcysteine as the probability of hepatotoxicity is minimal.Maintenance Dose Protocol[1][2]Determine the need for continued therapy after the loading dose, based on theacetaminophen concentration:◦ If the acetaminophen concentration is above the possible toxicity line according to thenomogram, or if the concentration was not obtained, continue treatment with themaintenance dose.◦ If the acetaminophen concentration is below the possible toxicity line, the time ofingestion is known, and the sample was taken more than 4 hours post ingestion,discontinue treatment.◦ If the acetaminophen concentration was in the non-toxic range, but time of ingestion isnot known or less than 4 hours, obtain a second sample and consider clinicalcondition of patient in deciding whether to continue treatment. A complete treatmentcourse if recommended if there is any uncertainty regarding the patient's risk forhepatotoxicity.ContinuedC(250 degrees F) for 15 minutes [3].Marcaine™ with epinephrine 1:200,000: Available as 0.25% (2.5 mg/mL) of bupivacainein 10-mL and 30-mL single-dose vials and a 50-mL multidose vial and as 0.5% (5 mg/mL) ofbupivacaine in 10-mL and 30-mL single-dose vials, and a 50-mL multidose vial. Each mL alsocontains 0.0091 mg of epinephrine and 0.5 mg of sodium metabisulfite. Multidose vialscontain methylparaben as a preservative. Do not autoclave. Protect from light [25].Marcaine™ Spinal: Available as 2-mL single-dose ampules containing 15 mg of bupivacaineand 165 mg of dextrose. May be autoclaved once at 15-pound pressure, 121 degrees C (250degrees F) for 15 minutes. Does not contain preservatives [17].Marcaine™ products should be stored at a controlled room temperature between 20 and 25degrees C (68 and 77 degrees F); excursions permitted between 15 and 30 degrees C (59and 86 degrees F) [28]. Discard unused portion of solution in single-dose vials [3] andampules [17].Sensorcaine®: Available as 0.25% and 0.5% of bupivacaine in 50-mL multidose vials. EachmL contains 1 mg methylparaben (preservative) [2].Sensorcaine®- methylparaben free (MPF): Available as 0.25%, 0.5%, and 0.75% ofpreservative-free bupivacaine in 10-mL and 30-mL single-dose vials [1].Sensorcaine® with epinephrine 1:200,000: Available as 0.25% and 0.5% ofbupivacaine in 50-mL multidose vials. Each mL contains 0.005 mg epinephrine, 0.5 mgsodium metabisulfite, and 1 mg methylparaben (preservative). Protect from light [29].Sensorcaine®-MPF with epinephrine 1:200,000: Available as 0.25% (10-mL and 30-mL single-dose vials), 0.5% (10-mL and 30-mL single-dose vials), and 0.75% (30-mL single-dose vial) of preservative-free bupivacaine. Each mL contains 0.005 mg epinephrine and 0.5mg sodium metabisulfite. Protect from light [30].Sensorcaine® products should be stored at a controlled room temperature between 20 and25 degrees C (68 and 77 degrees F), with excursions permitted between 15 and 30 degreesC (59 and 86 degrees F). Protect from light [29][30].155Also available as a 100 mg bupivacaine hydrochloride (equivalent to 88.8 mg bupivacaine)implant; each collagen implant is white to off-white in color and is approximately 5 cm x 5 cmx 0.5 cm in size. Store between 20 and 25 degrees C (68 and 77 degrees F), with excursionspermitted between 15 and 30 degrees C (59 and 86 degrees F). Protect from moisture andavoid contact with liquids prior to placement. Avoid excessive handling and compression ofimplant. Brief exposure to temperatures up to 40 degrees C (104 degrees F) may betolerated provided the mean kinetic temperature does not exceed 25 degrees C (77 degreesF); however, such exposure should be minimized [31].© Merative US L.P. 1973, 2024156BuprenorphineNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseNeonatal abstinence syndrome: Initial dose, 15.9 mcg/kg/day sublingually in 3 divideddoses, Maximum 60 mcg/kg/day and Maximum number of up-titrations = 6..Titrate dose up in 25% increments. Taper in 10% decrements until the dose is 10% of theinitial dose, then discontinue [1][2][3][4].UsesNeonatal abstinence syndrome (NAS): Buprenorphine would be a reasonable choice forNAS if the neonate was exposed prenatally to buprenorphine [5].Sublingual buprenorphine was associated with the largest reduction in length of treatmentand length of stay for NAS in a network meta-analysis of 18 randomized controlled trials(n=1072) of buprenorphine, clonidine, diluted tincture of opium and clonidine, dilutedtincture of opium, morphine, methadone, and phenobarbital. Morphine was the leasteffective opioid [6]. The findings should be interpreted with caution due to significant studylimitations [6][7]Compared with Methadone or Morphine: There was a 3-day reduction in the length oftreatment with sublingual buprenorphine compared with conventional opioids (eithermorphine or methadone) in an observational trial of 360 infants (34 weeks or longergestation) with NAS. Opioid treatment duration was 7.4 days (6.3 to 8.5 days) in thebuprenorphine group compared with 10.4 days (9.3 to 11.5 days; p less than 0.001) in theconventional opioid group and the length of stay was 12.4 days (11.3 to 13.6 days) and 15.2days (14.1 to 16.4 days; p less than 0.001), respectively. These reductions were consistentacross the different types of intrauterine opioid exposure (short-acting opioids, methadone,buprenorphine, or combination of types). The initial dosage of buprenorphine was 4.5mcg/kg/dose sublingual every 8 hours; with titrations/tapering of 1.5 mcg/kg/dose. Clonidineand/or phenobarbital were optional adjunct agents [8].Compared with Methadone: A shorter duration of opioid treatment (9.4 vs 14 days) andshorter length of inpatient stay (16.3 vs 20.7 days) with a sublingual buprenorphine protocolcompared with oral methadone protocol was demonstrated in a retrospective analysis of 201infants (34 weeks' gestation or older) with NAS. Infants exposed in utero to methadone wereexcluded [9].Compared with Morphine: Sublingual buprenorphine reduced the duration of treatmentfor neonatal abstinence syndrome compared with oral morphine (15 days vs 28 days; p lessthan 0.001) in a double-blind, double-dummy, single-center study (n=63). Preterm infantsand infants exposed to benzodiazepines in utero were excluded. Median length of hospitalstay was 21 vs 33 days (p less than 0.001) and use of supplemental phenobarbital was 15%vs 23% (p=0.36) for buprenorphine and morphine, respectively. Rates of adverse eventswere not different between the 2 groups [1].157AdministrationAfter administration sublingually, place a pacifier in the infant's mouth. For a volume of thedose greater than 0.5 mL, give in 2 administrations separated by at least 2 minutes [1].MEDICATION SAFETYContraindications/PrecautionsContraindicated with significant respiratory depression, acute or severe bronchial asthma(in an unmonitored setting or in the absence of resuscitative equipment), or known orsuspected gastrointestinal obstruction (including paralytic ileus) [11].Addiction potential: Opioid-type physical dependence may occur [12]Alcoholism: Use cautiously in patients with acute alcoholism and delirium tremens [11]Cardiovascular: QTc prolongation has been reported [11]Cardiovascular:: Avoid use in patients with a history of long QT Syndrome, or animmediate family member with the syndrome [11]Cardiovascular: Severe orthostatic hypotension and syncope in ambulatory patients mayoccur, especially in patients with compromised ability to maintain blood pressure[11][13][12], and in patients with reduced blood volume, or with concurrent administrationof CNS depressants (eg, general anesthetics, phenothiazines) [11]Cardiovascular: Avoid use in patients with circulatory shock [11].Concomitant Use: Avoid use with Class 1A antiarrhythmic medications (eg, quinidine,procainamide, disopyramide) or Class 3 antiarrhythmic medications (eg, sotalol, amiodarone,dofetilide), or other medications that prolong the QT interval [11].Concomitant Use: Patients requiring acute pain management or anesthesia are at risk. usenon-opioid analgesia when possible; if opioid needed treat with high-affinity full opioidanalgesia under supervision of physician with particular attention to respiratory function.Higher doses may be required. Use extreme care when using opioids as part of anesthesia[13].Concomitant use: Concomitant use with benzodiazepines or other CNS depressants mayresult in an increased risk for overdose, death; monitoring and dose adjustmentrecommended. Consider prescribing naloxone for the emergency treatment of opioidoverdose [14]Dermatologic: Use implant with caution in patients with history of keloid formation orconnective tissue disease (eg, scleroderma) [13].Endocrine and metabolic: Use with caution in patients with myxedema, hypothyroidism,or adrenal cortical insufficiency [11][13][12].Endocrine and metabolic:Adrenal insufficiency may occur with opioids. If suspected,perform diagnostic testing. If confirmed wean patient off of opioid if appropriate, treat withcorticosteroids, and continue to assess adrenal function [11][13][15]Gastrointestinal: Use may obscure diagnosis or clinical course in patients with acuteabdominal conditions [13][12].158Gastrointestinal: Severe constipation may occur [11]Hepatic: Sphincter of Oddi spasm may occur with morphine use [11]Hepatic: Use caution with severe hepatic impairment [11]Hepatic: Use cautiously in patients with biliary dysfunction [11]Hepatic: Cytolytic hepatitis, hepatitis with jaundice, and hepatotoxicity, sometimes fatal, hasbeen reported, with an increased risk with pre-existing liver enzyme abnormalities, comorbidhepatitis B or C virus, concomitant hepatotoxic drugs, or IV drug abuse [13]Hepatic: Avoid use with preexisting moderate to severe hepatic impairment anddiscontinuation may be necessary if this occurs during treatment (subdermal implants) [13]Hepatic: Increased intracholedochal pressure has been reported. Use cautiously in patientswith biliary dysfunction [12]Immunologic: Anaphylactic shock, bronchospasm, and angioneurotic edema has beenreported [13][12]Immunologic: Hypersensitivity reactions (eg, pruritus, rashes, hives) have been reported[13] including acute and chronic reactions [11]Immunologic: Infection may occur at site of implant insertion or removal. Increased riskwith excessive palpation after insertion and improper removal [13]Immunologic: Use implant with caution in patients with history of recurrent MRSAinfections [13].Musculoskeletal: Use cautiously with kyphoscoliosis [11]Musculoskeletal: Use implant with caution in patients with kyphoscoliosis [13].Neurologic: Elevation of cerebrospinal fluid (CSF) pressure may occur and interfere withevaluation of patients with head injuries, intracranial lesions, or other conditions that increaseCSF pressure [12]Neurologic: Increased intracranial pressure may occur in susceptible patients (eg, braintumors or head injury) due to decreased respiratory drive and carbon dioxide retention [11]Neurologic: Avoid use with impaired consciousness or coma [11].Neurologic: Use implant with caution in patients with CNS depression or coma [13][12]Neurologic: New or worsening seizures may occur [11]Neurologic: Potentially life-threatening serotonin syndrome may occur, particularly withconcomitant use of serotonergic drugs [11][15].Opioid overdose: Consider prescribing naloxone for the emergency treatment of opioidoverdose based on the patient's risk factors for overdose (eg, concomitant use of CNSdepressants, history of opioid use disorder, or prior opioid overdose) and if the patient hashousehold members (including children) or other close contacts at risk for accidentalexposure or overdose [14].Psychologic: Use with caution in patients with toxic psychoses, acute alcoholism, ordelirium tremens [13][12].Psychologic: Use with caution in patients with toxic psychoses [11]Renal: Use with caution in prostate hypertrophy or urethral stricture [11][13][12]Renal: Use caution with severe renal impairment [11].Reproductive: Long-term use of opioids may be associated with decreased sex hormonelevels and symptoms such as reduced interest in sex, impotence, or infertility. Laboratoryevaluation may be warranted [15].Respiratory: Increased risk for further respiratory depression, particularly during treatmentinitiation and titration in patients with chronic pulmonary disease or otherwise impairedrespiration [13][12]Respiratory: Life-threatening respiratory depression may occur, especially with concomitantuse of benzodiazepines or other CNS depressants [11][13][12] and particularly in the elderly,cachectic, or debilitated patients, those with chronic obstructive pulmonary disease or cor159pulmonale, and patients with substantially decreased respiratory reserve, hypoxia,hypercapnia, or preexisting respiratory depression [11].Respiratory: Sleep-related breathing disorders including central sleep apnea and sleep-related hypoxemia may occur and risk increases in a dose-dependent fashion; dose reductionmay be necessary [16].Special populations: Mental or physical impairment may occur, especially when beginningtreatment or adjusting dosage. Avoid driving or operating dangerous machinery [12].Special populations: Fatal respiratory depression may occur in children who areaccidentally exposed to buprenorphine. Keep expelled implants away from children [13][12].Special populations: Use implant with caution in debilitated patients [13].Withdrawal: Abrupt withdrawal may result in severe withdrawal symptoms and should beavoided [13][12].Adverse EffectsNo buprenorphine-related adverse effects were reported in 2 open-label trials (n=50) [3][4].Black Box WarningThere are serious risks, including profound sedation, respiratory depression, coma, and/ordeath, associated with combined use of opioids and benzodiazepines, other drugs thatdepress the CNS, or alcohol. Concomitant use should be reserved for patients with noalternative treatment. If necessary, use the lowest initial dose and titrate based on clinicalresponse. Monitor patients closely for sedation and respiratory depression. Screen patientsfor risk of substance-use disorders [10].Solution CompatibilityD5W, D5NS, NS, LRTerminal Injection Site CompatibilityBuprenorphine 0.04 mg/mL: Acyclovir sodium (7 mg/mL), allopurinol (3 mg/mL),aminocaproic acid (20 mg/mL), amiodarone hydrochloride (3 mg/mL), amphotericin B lipidcomplex (1 mg/mL), amphotericin B liposome (1 mg/mL), anidulafungin (0.5 mg/mL),argatroban (1 mg/mL), atenolol (0.5 mg/mL), azithromycin (2 mg/mL), aztreonam (40mg/mL), bivalirudin (5 mg/mL), capreomycin sulfate (10 mg/mL), cefepime hydrochloride (20mg/mL), cisatracurium besylate (0.1 mg/mL), cytarabine (25 mg/mL), daptomycin (10mg/mL), dexmedetomidine HCl (4 mcg/mL), diltiazem HCl (5 mg/mL), dolasetron mesylate (2160mg/mL), ertapenem sodium (20 mg/mL), fenoldopam mesylate (80 mcg/mL), filgrastim (30mcg/mL), foscarnet sodium (24 mg/mL), fosphenytoin sodium (20 mg/mL), gatifloxacin (2mg/mL), granisetron HCl (50 mcg/mL), hetastarch 6% (Hextend), lepirudin (0.4 mg/mL),leucovorin calcium (2 mg/mL), levofloxacin (5 mg/mL), linezolid (2 mg/mL), lorazepam (0.5mg/mL), methotrexate sodium (15 mg/mL), metronidazole (5 mg/mL), milrinone lactate (0.2mg/mL), mivacurium chloride (0.5 mg/mL), mycophenolate mofetil HCl (6 mg/mL), nesiritide(6 mcg/mL), nicardipine HCl (0.1 mg/mL), octreotide acetate (5 mcg/mL), palonosetron HCl(50 mcg/mL), pamidronate disodium (0.3 mg/mL), pancuronium bromide (0.1 mg/mL),pemetrexed disodium (20 mg/mL), piperacillin sodium-tazobactam sodium (40 mg/mL and 5mg/mL), potassium acetate (0.2 mEq/mL), propofol (10 mg/mL), quinupristin-dalfopristin (5mg/mL), remifentanil HCl (0.25 mg/mL), rocuronium bromide (1 mg/mL), sodium acetate(0.04 mEq/mL), tacrolimus (20 mcg/mL), teniposide (0.1 mg/mL), tigecycline (1 mg/mL),tirofiban HCl (0.1 mg/mL), vecuronium bromide (1 mg/mL), voriconazole (4 mg/mL),zoledronic acid (40 mcg/mL)Buprenorphine 0.15 mg/mL: Alfentanil hydrochloride (0.25 mg/mL), amikacin sulfate (20mg/mL), ascorbic acid injection (250 mg/mL), atracurium besylate (5 mg/mL), atropinesulfate (0.5 mg/mL), benztropine mesylate (0.5 mg/mL), bretylium tosylate (40 mg/mL),bumetanide (0.125 mg/mL), butorphanol tartrate (1 mg/mL), calcium chloride (50 mg/mL),calcium gluconate (50 mg/mL), cefamandole nafate (333 mg/mL), cefazolin sodium (220mg/mL), cefoperazone (80 mg/mL), cefotaxime (285 mg/mL), cefotetan disodium (400mg/mL), cefoxitin (450 mg/mL), ceftazidime (400 mg/mL), ceftizoxime (400 mg/mL),ceftriaxone sodium (165 mg/mL), cefuroxime (125 mg/mL), chloramphenicol sodiumsuccinate (333 mg/mL), chlorpromazine HCl (4 mg/mL), cimetidine HCl (24 mg/mL),clindamycin phosphate (48 mg/mL), cyanocobalamin (0.5 mg/mL), cyclosporine (2 mg/mL),dexamethasonesodium phosphate (12 mg/mL), digoxin (0.125 mg/mL), diphenhydramineHCl (25 mg/mL), dobutamine HCl (6.25 mg/mL), dopamine HCl (12.8 mg/mL), doxycyclinehyclate (4 mg/mL), enalaprilat (0.625 mg/mL), ephedrine sulfate (12.5 mg/mL), epinephrinehydrochloride (0.5 mg/mL), epoetin alfa (5000 units/mL), erythromycin lactobionate (20mg/mL), esmolol HCl (40 mg/mL), famotidine (5 mg/mL), fentanyl citrate (25 mcg/mL),fluconazole (2 mg/mL), gentamicin sulfate (6.4 mg/mL), glycopyrrolate (0.1 mg/mL), heparinsodium (160 units/mL), hydrocortisone sodium succinate (62.5 mg/mL), hydroxyzine HCl (25mg/mL), imipenem-cilastatin sodium (5 mg/mL), inamrinone lactate (2.5 mg/mL), regularinsulin (50 units/mL), isoproterenol HCl (80 mcg/mL), ketorolac tromethamine (15 mg/mL),labetalol HCl (2.5 mg/mL), lidocaine HCl (10 mg/mL), magnesium sulfate (250 mg/mL),mannitol (150 mg/mL), meperidine HCl (50 mg/mL), metaraminol bitartrate (4 mg/mL),methyldopate HCl (25 mg/mL), methylprednisolone sodium succinate (125 mg/mL),metoclopramide hydrochloride (2.5 mg/mL), metoprolol tartrate (0.5 mg/mL), midazolam HCl(2.5 mg/mL), minocycline hydrochloride (0.8 mg/mL), morphine sulfate (4 mg/mL), multiplevitamins injection (0.08 mL/mL), nafcillin sodium (250 mg/mL), nalbuphine HCl (10 mg/mL),naloxone HCl (16 mcg/mL), netilmicin sulfate (50 mg/mL), nitroglycerin (1.6 mg/mL),nitroprusside sodium (0.8 mg/mL), norepinephrine bitartrate (0.5 mg/mL), ondansetron HCl(1 mg/mL), oxacillin sodium (160 mg/mL), oxytocin (0.08 units/mL), papaverine HCl (15mg/mL), penicillin G potassium (500,000 units/mL), penicillin G sodium (500,000 units/mL),pentamidine isethionate (24 mg/mL), pentazocine lactate (15 mg/mL), phentolaminemesylate (5 mg/mL), phenylephrine HCl (4 mg/mL), phytonadione (5 mg/mL), piperacillinsodium (320 mg/mL), polymyxin B sulfate (0.667 mg/mL), potassium chloride (1 mEq/mL),procainamide HCl (250 mg/mL), prochlorperazine edisylate (2.5 mg/mL), promethazine HCl(25 mg/mL), propranolol HCl (0.5 mg/mL), protamine sulfate (5 mg/mL), pyridoxine HCl (50mg/mL), quinidine gluconate (40 mg/mL), ranitidine HCl (2 mg/mL), streptokinase (80,000161units/mL), succinylcholine chloride (8 mg/mL), sufentanil citrate (25 mcg/mL), theophylline(4 mg/mL), thiamine HCl (50 mg/mL), ticarcillin disodium (345 mg/mL), ticarcillin disodium-clavulanate potassium (195 mg/mL), tobramycin sulfate (6.4 mg/mL), tolazoline HCl (12.5mg/mL), urokinase (50,000 units/mL), vancomycin HCl (20 mg/mL), vasopressin (4units/mL), verapamil HCl (1.25 mg/mL)Buprenorphine 0.3 mg/mL: Acetaminophen (10 mg/mL)Terminal Injection Site IncompatibilityAminophylline (12.5 mg/mL), amphotericin B cholesteryl (0.83 mg/mL), ampicillin sodium (80mg/mL), azathioprine sodium (13.33 mg/mL), dantrolene sodium (0.8 mg/mL), diazepam(2.5 mg/mL), diazoxide (7.5 mg/mL), indomethacin sodium trihydrate (1 mg/mL),lansoprazole (0.55 mg/mL), pantoprazole sodium (0.4 mg/mL), pentobarbital sodium (25mg/mL), phenobarbital sodium (65 mg/mL), phenytoin sodium (25 mg/mL), sodiumbicarbonate (0.5 mEq/mL), sulfamethoxazole-trimethoprim (20 mg/mL and 4 mg/mL)MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of action: Buprenorphine hydrochloride, a narcotic analgesic, is a partial mu-opioid receptor agonist and an antagonist at the kappa-opioid receptor. Lower propensity forphysical dependence and longer duration of action compared with morphine [17].Pharmacokinetics - Pharmacodynamics: Higher average concentrations (Cavg) ofbuprenorphine were associated with shorter time to neonatal abstinence stabilization in astudy of 28 neonates (37 weeks or more gestation; mean birth weight, 3.1 kg) exposedprimarily to methadone in utero. No respiratory depression was observed. A dose of 15mcg/kg/dose SL every 8 hours was predicted to achieve a target buprenorphine Cavg of 0.8ng/mL; for some neonates 10 mcg/kg/dose may be sufficient and others 20 mcg/kg/dosemay be necessary [18].Plasma concentrations of buprenorphine ranged from less than 0.1 ng/mL (35.6% ofsamples) to 0.6 ng/mL with high intra-subject variability in 13 term infants administeredbuprenorphine (13.2 to 39 mcg/kg/day) sublingually. There were 3 out of 202 samples thatwere outliers. An infant receiving the starting dose of 13.2 mcg/kg/day had a level of (3.69ng/mL). The outlier values of, 1.8 ng/mL, and 0.85 ng/mL occurred in 1 patient receiving themaximum protocol specified dose of 39 mcg/kg/day [4].Bioavailability: Sublingual, neonates: 7% in a retrospective population pharmacokineticanalysis of 24 neonates with neonatal abstinence syndrome. Median gestational age in theneonates was 39.2 weeks (range, 36.6 to 41.2 weeks) and median weight was 2.9 kg (range,2.2 to 4.1 kg) [19].162Protein binding: approximately 96% protein bound (primarily alpha and beta globulin)[17].Vd: Sublingual: 142 L in 28 neonates (37 weeks or more gestation; mean birth weight, 3.1kg) [18]Metabolism: N-dealkylation, mediated primarily to CYP3A4, to norbuprenorphine as well asglucuronidation. Norbuprenorphine can undergo further glucuronidation [17].Clearance: Sublingual: 3.5 L/hr/kg in a neonate (postnatal age, 5.4 days; weighing amedian of 2.9 kg) [19]; 203 L/hr in 28 neonates (37 weeks or more gestation; mean birthweight, 3.1 kg) [18]Elimination half-life: predicted half-life was 11 hours for sublingual buprenorphine in aretrospective population pharmacokinetic analysis of 24 neonates with neonatal abstinencesyndrome and 5 adults (for model development). Median gestational age in the neonates was39.2 weeks (range, 36.6 to 41.2 weeks) and median weight was 2.9 kg (range, 2.2 to 4.1kg). Phenobarbital did not affect the clearance of buprenorphine. [19]. 31 to 35 hours [17].ABOUTSpecial Considerations/PreparationSublingual routeA 0.075 mg/mL (75 mcg/mL) buprenorphine solution was compounded by mixingbuprenorphine for injection in 100% ethanol USP (30% total volume) and simple syrup USP(85 gm sucrose/100 mL). The solution is stable for 30 days at room temperature when storedin glass bottles and 7 days at room temperature when stored in syringes [20][3].© Merative US L.P. 1973, 2024163Caffeine CitrateNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseApnea of PrematurityFDA-Approved Dosage (28 to less than 33 weeks gestation)Loading dose: 20 mg/kg (1 mL/kg) IV over 30 minutes [1][2]Maintenance dose: 5 mg/kg (0.25 mL/kg) IV over 10 minutes OR orally every 24 hours;initiate 24 hours after loading dose [1][2]Off-label Dosage22 to 28 weeks gestational ageLoading dose: Median, 20 mg/kg IV (range, 19 to 23 mg/kg) [3]Maintenance dose: Median, 8 mg/kg/day (range 5 to 10 mg/kg/day) [3]Duration of therapy: Median, 60 days (range 46 to 75 days) [3]Dose AdjustmentHepatic Impairment: Monitor serum caffeine concentrations and adjust dose as necessaryto prevent toxicity [1][2].Renal Impairment: Monitor serum caffeine concentrations and adjust dose as necessary toprevent toxicity [1][2].UsesHigh-dose therapy vs Standard-dose therapy:A meta-analysis that include 7 studies (894 very preterm infants) found no significantdifference in mortality rates or adverse effects when high-dose caffeine therapy wascompared with standard-dose caffeine therapy (low certainty evidence), though high-dosetherapy was associated with a significant reduction in rates of bronchopulmonary dysplasia(BPD; chronic lung disease) at 36 weeks post-menstrual age (moderate certainty evidence)[4].• Primary outcomes: All-cause mortality was not significantly different with high-dosecaffeine therapy compared with standard dose therapy when used for any indication (relativerisk{[RR], 0.86; 95% CI, 0.53 to 1.38; 5 studies, 723 patients). Similar results were obtainedwhen broken down by indication (treatment of apnea, prevention of apnea, or prevention ofreintubation) [4]. Neurodevelopmental disability outcomes at 3 to 5 years of age werereported in 1 study (46 patients) and no significantdifferences were reported (very lowcertainty evidence) [4][5].• Secondary outcomes: BPD was significantly reduced by 25% with high-dose caffeinetherapy compared with standard-dose therapy when used for any indication (RR, 0.75; 95%CI, 0.6 to 0.94; 5 studies, 723 patients). When broken down by indication, the results wereonly significantly in favor of high-dose caffeine in those treated for prevention of164reintubation; findings were not significant for treatment or prevention of apnea [4].• Adverse effects: There was no significant difference between treatment groups in ratesof adverse effects leading to a dose reduction or discontinuation of therapy (eg, tachycardia,feeding intolerance, agitation; 5 studies, 593 patients). There was also no significantdifference in seizures, though this result was from very low certainty evidence (1 study, 74patients) [4],• Dosage regimens: High dose regimens were defined as those with a loading dose greaterthan 20 mg/kg and maintenance dose greater than 10 mg/kg/day. Among the includedstudies, high-dose regimen loading doses ranged from 30 to 80 mg/kg and maintenancedoses from 12 to 30 mg/kg/day. Standard dose regimens were defined as those with aloading dose of 20 mg/kg or less and a maintenance dose of 10 mg/kg/day or less. Amongthe included studies, standard-dose regimen loading doses ranges from 6 to 25 mg/kg andmaintenance doses from 3 to 10 mg/kg/day [4].• Inclusion criteria and patient characteristics: Randomized controlled trials (RCTs),quasi-RCTs, and cluster RCTs comparing high-dose and standard-dose caffeine regimenswere included. Apnea prevention studies included preterm infants born at less than 34 weeksgestation at risk for apnea; apnea treatment studies included preterm infants born at lessthan 37 weeks gestation with signs of apnea; and studies for the prevention of reintubationincluded preterm infants born at less than 34 weeks gestation given caffeine prior toextubation [4].High-dose therapyA retrospective study of 410 infants 28 weeks gestational age (GA) or younger (median GA,26 weeks) treated with caffeine citrate at higher doses and for longer durations than is FDA-approved (median loading dose, 20 mg/kg; median maintenance dose, 8 mg/kg/day; medianduration, 60 days) reported the following [3]:• Significantly reduced odds of necrotizing enterocolitis (NEC) with increased caffeine dose(odds ratio, 0.78; 95% CI, 0.63 to 0.92) [3]• Significantly reduced odds of needing patent ductus arteriosus (PDA) ligation withincreased caffeine dose (odds ratio, 0.74; 95% CI, 0.61 to 0.86) [3]• No significant association between dose and bronchopulmonary dysplasia (BPD) [3]• No significant association between increasing duration of therapy and BPD, NEC, or PDAligation [3]A significant reduction in extubation failure (22% vs 47%), the frequency of apnea (9 vs 16),and days of documented apnea (2.5 days vs 5 days) were observed with high-dose oralcaffeine citrate compared with standard dose (20 mg/kg/day loading dose, 10 mg/kg/daymaintenance) in a randomized, double-blind study in 120 preterm (less than 32 weeksgestation; 10 days or younger) with apnea of prematurity. Tachycardia was significantly morefrequent (23% vs 8%) in the high-dose vs low-dose group [6].Apnea: Pharmacological treatment with caffeine is the standard of care for apnea ofprematurity [7].The rate of bronchopulmonary dysplasia in neonates with apnea of prematurity was reducedwith caffeine, started within the first 10 days of life, in a randomized, placebo-controlled trial(n=1917). Caffeine was started to prevent apnea, treat apnea, or to facilitate the removal ofan endotracheal tube [8]. A follow-up of the study at 18 months corrected age demonstratedthat the risk of death or disability (cerebral palsy, cognitive delay, severe hearing loss, andbilateral blindness) was reduced with caffeine [9]. At a 5-year follow-up, there was nodifference in disability or death between the caffeine and placebo group [10]. At an 11-yearfollow-up, the combined rate of academic, motor, and behavioral impairment did not differ165between the caffeine and placebo group. There was a reduced risk of motor impairment withcaffeine compared with placebo (adjusted OR 0.66 (95% CI, 0.48 to 0.9)) [11]. A secondaryanalysis (n=675) of a retrospective, multicenter cohort study demonstrated an association ofless frequent early acute kidney injury in preterm neonates with caffeine administered by 7days of life; 11.2% vs 31.6% with and without caffeine, respectively (adjusted odds ratio 0.2(95% CI, 0.11 to 0.34)) [12].Initiation:The optimal time to start treatment with caffeine is unknown. A reasonableapproach is to start caffeine when apnea develops in infants greater than 28 weeks'gestation who do not require positive pressure support. Earlier (younger than 3 days)prophylactic caffeine in infants who require mechanical ventilation compared with later (3days or older) has been studied but the safety and efficacy need further study [7].Caffeine administered within the first 24 hours of life was associated with less mechanicalventilation (71.3% vs 83.2%) and a shorter duration of mechanical ventilation (mean 5 vs10.8 days) than later caffeine initiation (median of 4 days) in an analysis of an observationalstudy (n=286). Lower rates of patent ductus arteriosus and intraventricular hemorrhage(IVH) were associated with early versus late initiation; however, higher grades of IVH werenot reduced. Premature infants (32 weeks' gestational age or less) with respiratory distresssyndrome and treated with surfactant were included [13].Duration: The optimal duration of treatment with caffeine is unknown. Consider a trial off ofcaffeine in infants who have been free of clinically significant apnea/bradycardia events after5 to 7 days off positive pressure or at 33 to 34 weeks postmenstrual age, which ever comesfirst [7]. Extending caffeine treatment beyond when it is normally discontinued (apnearesolution) reduced the number and severity of intermittent hypoxia episodes in infants;however, the long-term benefits and risks to extended treatment are unknown. Thepostmenstrual age (PMA) at randomization to caffeine or placebo was 34 to 37 weeks (n=95)and continuous pulse oximeter data were collected up until 39 weeks PMA [14]. More studiesare needed before implementing extended caffeine treatment beyond apnea resolution [7].Mechanical Ventilation Weaning: The age at first successful extubation did not differbetween early caffeine use (median 24 days of age; interquartile range (IQR), 10 to 41 days)and placebo group (median 20 days of age; IQR, 9 to 43 days; p=0.703) in preterm infantsborn at 23 to 30 weeks of gestation requiring mechanical ventilation in the first 5 postnataldays in a randomized, double-blind, placebo-controlled trial (n=83). Additionally, nodifferences were detected in secondary outcomes (duration of mechanical ventilation andoxygen supplementation, bronchopulmonary dysplasia, or death). The trial was terminatedearly due to a trend of higher mortality; 22% for caffeine and 12% (p=0.22) for placebo.The mean ages were approximately 3 hours at intubation and 2 days at randomization. Thedosage for caffeine citrate was 20 mg/kg followed by 5 mg/kg/day [15].Pediatric FDA-approved UseIndicated for the short-term treatment of apnea of prematurity in infants between 28 toyounger than 33 weeks of gestational age [2].The use of caffeine for sudden infant death syndrome prophylaxis or prior to extubation inmechanically-ventilated infants has not been established [2].Administration166Administer the IV loading dose over 30 minutes and the maintenance dose over 10 minutes[1]MEDICATION SAFETYContraindications/PrecautionsPrecautionsCardiovascular: Use with caution in infants with cardiovascular disease [1].Gastrointestinal: Necrotizing enterocolitis has been reported; careful monitoringrecommended [1].Hepatic: Use withcaution in infants with impaired hepatic function; monitoringrecommended and dosage adjustment may be required [1].Neurologic: Use with caution in infants with seizure disorders [1].Renal: Use with caution in infants with impaired renal function; monitoring recommendedand dosage adjustment may be required [1].Adverse EffectsCommon: Feeding intolerance (8.7% vs 5.1% with placebo); rash (8.7% vs 7.7%). Otherreported adverse effects include CNS stimulation (restlessness, irritability), cardiovasculareffects (tachycardia, increased left ventricular output), and renal effects (increased urineoutflow, increased creatinine clearance, increased sodium and calcium excretion [1].Serious: Necrotizing enterocolitis was reported in 5 patients exposed to caffeine (with 3deaths) compared with 1 patient exposed to placebo (N=85). A larger study (N=2000) foundno difference in the rate of necrotizing enterocolitis with caffeine compared with placebo [1].MonitoringLaboratory MonitoringConcentration•Measuring serum concentrations is probably not necessary [7].•Obtain baseline caffeine levels in neonates previously treated with theophylline andneonates born to mothers who consumed caffeine prior to delivery [1].•Monitor serum concentrations in the presence of renal or hepatic impairment [1].•If monitoring of serum drug concentration is performed, measure the trough level onapproximately day 5 of therapy. Therapeutic trough serum concentration is 5 to 25 mcg/mL.Concentrations greater than 40 to 50 mcg/mL are toxic [1].Other Laboratory Values•Periodically monitor serum glucose [1].Physical Findings167•Watch for signs and symptoms of necrotizing enterocolitis [1].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of Action: Caffeine is structurally related to other methylxanthines,theophylline, and theobromine. It is a bronchial smooth muscle relaxant, a CNS stimulant, acardiac muscle stimulant, and a diuretic. Although the mechanism action of caffeine in apneaof prematurity is not known, several mechanisms have been hypothesized. These include: (1)stimulation of the respiratory center, (2) increased minute ventilation, (3) decreasedthreshold to hypercapnia, (4) increased response to hypercapnia, (5) increased skeletalmuscle tone, (6) decreased diaphragmatic fatigue, (7) increased metabolic rate, and (8)increased oxygen consumption. Most of these effects have been attributed to antagonism ofadenosine receptors, both A1 and A2 subtypes, by caffeine, which has been demonstrated inreceptor binding assays and observed at concentrations approximating those achievedtherapeutically [1].Therapeutic Drug ConcentrationPeak concentration•Cmax, single-dose, 10 mg, preterm neonates: 6 to 10 mg/mL [1]Time to peak concentration•Tmax: 30 minutes to 2 hours in preterm neonates [1]Absorption•Effect of food: Not affected by formula feeding[1]DistributionTissue and Fluid Distribution:• Brain: Rapidly distributed [1]• CSF: Similar to plasma levels in preterm neonates [1]Vd: 0.8 to 0.9 L/kg in infants [1]Metabolism: Via CYP1A2; limited in preterm neonates due to immature hepatic enzymes.Approximately 3 to 8% of a dose in preterm neonates may convert to theophylline [1]Excretion•Renal Elimination: 86% as unchanged drug within 6 days of a dose in neonates; by 9months about 1% is eliminated as unchanged drug (similar to adult values) [1]Elimination Half-Life•Parent compound: 3 to 4 days in neonates; by 9 months half-life is 5 hours (similar toadult values) [1]ABOUT168Special Considerations/PreparationBoth injectable and oral caffeine citrate solutions are preservative free and available in 3-mLsingle use vials. Each mL contains 20 mg of caffeine citrate (equivalent to 10 mg caffeinebase). Store at room temperature [1][2].Extemporaneous compoundsInjectable solution 20 mg/mL caffeine citrateDissolve 10 g of caffeine citrate powder in 250 mL of sterile water for injection USP.Transfer the solution to a 500-mL empty evacuated container (EEC). Add sufficient sterilewater for injection for a total volume of 500 mL. Filter the solution through a 0.22 micronfilter set into an empty 500-mL EEC, then transfer the filtered solution into sterile, empty 10-mL vials. Autoclave the vials at 121 degrees Centigrade for 15 minutes and allow to cool.Quarantine the product until sterility and pyrogen testing are completed. Stable for 90 daysunder refrigeration [16].Oral solution 20 mg/mL caffeine citrateDissolve 10 g of caffeine citrate powder in 250 mL of sterile water for irrigation USP. Add a2:1 mixture of simple syrup and cherry syrup to make a total volume of 500 mL. Stable for90 days under refrigeration [16].Oral solution 10 mg/mL caffeine base (Note: 10 mg caffeine base = 20 mg ofcaffeine citrate)Alternatively, an oral solution may be prepared by dissolving 2.5 g of caffeine anhydrouspowder in 250 mL of water, yielding a final concentration of 10 mg/mL caffeine base.Solution is stable for 4 weeks refrigerated. Crystals form when stored at low temperature butdissolve at room temperature without loss of potency. Do not freeze.© Merative US L.P. 1973, 2024169Calcium - OralNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseHypocalcemia, non-acute: 20 to 80 mg/kg/day elemental calcium orally in 2 to 4 divideddoses scheduled around oral feedings.Calcium gluconate 10% IV formulation (9.3 mg/mL elemental calcium): 2 to 8 mL/kg/day.Calcium carbonate 250 mg/mL suspension (100 mg/mL elemental calcium): 0.2 to 0.8mL/kg/day.Calcium glubionate syrup (23 mg/mL elemental calcium): 1 to 3.5 mL/kg/day.RicketsPreterm neonates: Supplementation with 20 mg/kg/day of elemental calcium and 10 to 20mg/kg/day of elemental phosphorus. Increase as tolerated, to a maximum 70 to 80mg/kg/day of elemental calcium and 40 to 50 mg/kg/day of elementalphosphorus in preterm infants enterally fed [1]. Administer in 2 to 4 divided doses.Calcium gluconate 10% IV formulation (9.3 mg/mL elemental calcium): 2 to 8 mL/kg/day.Calcium carbonate 250 mg/mL suspension (100 mg/mL elemental calcium): 0.2 to 0.8mL/kg/day.Calcium glubionate syrup (23 mg/mL elemental calcium): 1 to 3.5 mL/kg/day.UsesHypocalcemia, non-acute in babies able to tolerate oral medications.Rickets: In enterally fed preterm infants with radiologic evidence of rickets, maximizenutrient intake by increasing human milk fortifier and/or volume of preterm formula. Ifmaximization cannot be tolerated, then supplementation with elemental calcium andphosphorus is recommended. Vitamin D status should be evaluated and target 25-hydroxyvitamin D concentrations of greater than 20 ng/mL (50 nmol/L). The recommendedintakes for enterally fed, very low birth weight infants are 150 to 220 mg/kg/day for calciumand 75 to 140 mg/kg/day for phosphorus [1].MEDICATION SAFETYAdverse Effects170Oral calcium preparations are hypertonic, especially calcium glubionate syrup. Gastricirritation and diarrhea occur often. Use with caution in infants who are at risk for necrotizingenterocolitis.MonitoringPeriodically measure serum calcium concentrations. Assess GI tolerance. Assess serumphosphorus and vitamin D levels when indicated.MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAbsorption of calcium administered orally is approximately 50%. Absorption takes placethroughout the small intestine, and is primarily regulated by 1,25-dihydroxy Vitamin D.Calcium carbonate significantly interferes with the absorption of levothyroxine. Theosmolarity of calcium glubionate syrup is 2500 mOsm/L, and of calcium gluconate is 700mOsm/L.ABOUTSpecial Considerations/PreparationCalcium carbonate (Roxane) is available as a 250 mg/mL suspension (equivalent to 100mg/mL elemental calcium) in 5-mL unit dose cups.Calcium glubionate syrup 360 mg/mL (1.8 g/5 mL) (Rugby/Watson) yields 23 mg/mLelemental calcium (1.16 mEq/mL) and is available in 473 mL bottles. Osmolarity is 2500mOsm/L.© Merative US L.P. 1973, 2024171Calcium ChlorideNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDose10% calcium chloride contains 100 mg/mL of calcium chloride which is equivalent to 27mg/mL (1.4 mEq/mL) of elemental calcium [1].Calcium Channel Blocker Toxicity: 20 mg/kg/dose calcium chloride (0.2 mL/kg calciumchloride 10%) IV/IO over 5 to 10 minutes Maximum single dose 2 g[2][3]; if initial dose isbeneficial, may start an infusion at 20 to 50 mg/kg/hour (PALS guideline dosage) [3] or 20 to40 mg/kg/hour, titrated to blood pressure [2].Cardiac Resuscitation (Use only for documented hypocalcemia, hyperkalemia, orhypermagnesemia): 20 mg/kg/dose calcium chloride (0.2 mL/kg calcium chloride 10%)slow IV infusion over 30 to 60 minutes or IO. A central line is recommended [3][4];Maximum single dose 1 g (AAP guideline dosage) [4].Exchange transfusion: 33 mg calcium chloride 10% per 100 mL citrated blood exchanged(equals 0.33 mL per 100 mL blood exchanged). Infuse IV over 10 to 30 minutes.Hypocalcemia:Calcium gluconate given at the same elemental calcium dose may be preferred as calciumchloride may cause a metabolic acidosis[5][6]FDA Dosage: 2.7 to 5 mg/kg IV of calcium chloride (0.027 to 0.05 mL/kg of 10% calciumchloride) MAX rate, 1 mL/min of 10% calcium chloride; no data on repeat doses but someexperts recommend repeat doses every 4 to 6 hours (FDA dosage) [1].Asymptomatic or mildly symptomatic hypocalcemia, or maintenance afterachievement of normal calcium values after IV therapy: 40 to 80 mg/kg/dayelemental calcium IV or orally in 3 to 4 divided doses (equivalent to 148 to 296 mg/kg/daycalcium chloride) [7][8]; adjust to achieve a daily urinary calcium excretion of less than 4mg/kg/day [7]Symptomatic hypocalcemia: 10 to 20 mg/kg elemental calcium (equivalent to 37 to 74mg/kg calcium chloride) IV over 10 to 30 minutes followed by continuous infusion of 50 to 80mg/kg/day elemental calcium (equivalent to 185 to 296 mg/kg/day calcium chloride) for 48hours. If calcium values are in normal range after 48 hours of continuous infusion, decreaseinfusion by 50% for the next 24 hours, then discontinue [7][8]UsesCalcium Channel Blocker (CCB) Toxicity: Administration of calcium is reasonable forCCB toxicity as improvements in heart rate, blood pressure, and conduction abnormalitieshave been reported. However, the available literature on calcium monotherapy for severe172CCB toxicity are limited, and most patients require additional treatment modalities. In onecase series, high doses of calcium gluconate (targeting ionized calcium concentrations up totwice normal) appeared more effective than lower doses[2].Cardiac Resuscitation: In newly born infants in a cardiac resuscitation setting, drugs arerarely needed [9][10]. Use calcium only in cases of documented hypocalcemia, hyperkalemia,hypermagnesemia, or calcium channel blocker toxicity. Routine use of calcium in cardiacresuscitation is not recommended. [11]. Calcium chloride or calcium gluconate may be used;but calcium chloride is preferred in cardiac arrest setting [3]. For hyperkalemia specifically,calcium will stabilize the cardiac cellular membrane but does not result in transcellular shift orexcretion of potassium; another therapy that results in the shift of intracellular potassium orexcretion of potassium is required [12]Hypocalcemia [7][5][6]. Hypocalcemia, usually defined as a serum ionized calciumconcentration less than 4.4 mg/dL (or total serum calcium less than approximately 8 mg/dL)for term and preterm infants weighing greater than 1500 g at birth and ionized calcium lessthan 4 mg/dL (or total calcium less than 7 mg/dL) for infants weighing less than 1500 g atbirth. Treatment is suggested when serum calcium is less than 6 mg/dL in preterm infantsand less than 7 mg/dL in term infants [7]. Calcium gluconate given at the same elementalcalcium dose may be preferred as calcium chloride may cause a metabolic acidosis [5][6],though calcium chloride may be preferred in cases of severe hypocalcemia with poor cardiacfunction, as liver metabolism is not required for the release of free calcium [8]FDA approve use: For hypocalcemia in those conditions requiring prompt increase inplasma calcium concentrations [1].Administration•Intravenous route only [1]; may also be administered by intraosseous [3].•Not for IM, subQ [1], or endotracheal use[3], or by intra-arterial route [6].•Administer slowly through a small needle in a large vein, preferably in a central or deep vein[1]. Central line is preferred but peripheral vein is acceptable in a cardiac arrest setting. Innon-arrest setting, calcium gluconate is recommended [3].•Warm solution to body temperature if time permits [1].•Rate should not exceed 1 mL/min of a 100 mg/mL calcium chloride solution [1]. May beadministered over 30 to 60 minutes [4] or may be diluted 1:1 with D5W and administeredover 10 to 30 minutes [8].•Avoid high concentrations of calcium from reaching heart due to risk of cardiac syncope [1].MEDICATION SAFETYContraindications/PrecautionsContraindications173•Ventricular fibrillation [1]•Risk of existing digitalis toxicity [1]PrecautionsAdministration: Do not inject into tissue because severe necrosis and sloughing may occur[1]Administration: Avoid extravasation or accidental injection into perivascular tissues [1]Administration: Rapid administration is associated with bradycardia or cardiac arrest [13].Concomitant Use: With digitalis drugs due to additive effect; use caution [1]Renal: Patients with impaired renal function, including premature neonates, may experiencealuminum toxicity with prolonged parenteral administration [1]Adverse EffectsPrecipitate in the infusion line with crystalline deposits in the lungs and kidneys has beenreported in some deceased neonates who were coadministered ceftriaxone IV and calcium-containing fluids, sometimes in the same infusion line. At least one neonatal fatality has beenreported following coadministration at different times and with separate infusion lines,though no crystalline deposits were found at autopsy in this neonate. These reports havebeen confined to neonates [14]. Cutaneous necrosis or calcium deposition occurs withextravasation. Bolus infusions by UAC have been associated with intestinal bleeding andlower-extremity tissue necrosis.Solution CompatibilityD5W, D10W, and NS.Terminal Injection Site CompatibilityAmikacin, amiodarone, chloramphenicol, dobutamine, dopamine, epinephrine, esmolol,hydrocortisone, isoproterenol, lidocaine, micafungin, milrinone, morphine, penicillin G,pentobarbital, phenobarbital, prostaglandin E1, and sodium nitroprusside.Terminal Injection Site IncompatibilityAmphotericin B, ceftriaxone, sodium bicarbonate, and phosphate and magnesium salts whenmixed directly.174MonitoringTherapeutic Laboratory MonitoringMonitor serum ionized calcium levels [1].Measure calcium levels every 8 to 12 hours during continuous infusion until normal valuesachieved [7].Therapeutic Physical MonitoringTitrate dose to blood pressure when used to reverse calcium channel blocker toxicity [2]Toxic Laboratory MonitoringContinuous ECG monitoring is recommended during the acute management of hyperkalemia[12] or during bolus dose infusion for the treatment of acute hypocalcemia [7][8].Do not exceed serum ionized calcium concentration 1.5 to 2 times the upper limits of normalwhen used to reverse calcium channel blocker toxicity [2]MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of Action: Calcium plays important physiological roles, many of which arepoorly understood. It is essential for the functional integrity of the nervous and muscularsystems. It is necessary for normal cardiac function and is one of the factors that operates inthe mechanisms involved in the coagulation of blood. Calcium chloride in water dissociatesthe provide calcium (Ca++) and chloride (Cl-) ions.They are normal constituents of the bodyfluids and are dependent on various physiological mechanisms for maintenance of balancebetween intake and output [1]Hyperkalemia: For hyperkalemia specifically, calcium will stabilize the cardiac cellularmembrane but does not result in transcellular shift or excretion of potassium; anothertherapy that results in the shift of intracellular potassium or excretion of potassium isrequired [12]PharmacodynamicsOnset: Immediate [4]ExcretionRenal Excretion: 20% [1]Fecal Excretion: 80% as insoluble salts [1]ABOUTSpecial Considerations/Preparation175Calcium chloride 10% injection yields 27 mg/mL elemental calcium (1.36 mEq/mL).Osmolarity is 2040 mOsm/L. Injectable calcium salts should be stored at room temperatureand are stable indefinitely [15].© Merative US L.P. 1973, 2024176Calcium GluconateNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDose10% calcium gluconate contains 100 mg/mL of calcium gluconate which is equivalent to 9.3mg/mL (0.465 mEq/mL) of elemental calcium[1]Calcium Channel Blocker Toxicity: Initial: 60 mg/kg calcium gluconate (0.28 mEqelemental calcium/kg) IV/IO Maximum single dose 6 g; maintenance 60 to 120 mg/hg/hr(0.28 to 0.56 mEq elemental calcium/kg/hr), titrated to blood pressure [2].Cardiac Resuscitation (documented hypocalcemia, hyperkalemia,hypermagnesemia, or calcium channel blocker overdose ): 60 to 100 mg/kg calciumgluconate slow IV push/IO; repeat dose as necessary for clinical effect (MAX: 2000mg/dose) (guideline dosage) [3][4].HypocalcemiaAsymptomatic or mildly symptomatic hypocalcemia, or maintenance afterachievement of normal calcium values after IV therapy: 40 to 80 mg/kg/dayelemental calcium IV or orally in 3 to 4 divided doses (equivalent to 430 to 860 mg/kg/daycalcium gluconate) [5][6]; adjust to achieve a daily urinary calcium excretion of less than 4mg/kg/day [5].Symptomatic Hypocalcemia: 10 to 20 mg/kg elemental calcium (equivalent to 100 to200 mg/kg calcium gluconate) IV over 10 to 30 minutes followed by continuous infusion of50 to 80 mg/kg/day elemental calcium (equivalent to 538 to 860 mg/kg/day calciumgluconate) for 48 hours [5][6][1]. If calcium values are in normal range after 48 hours ofcontinuous infusion, decrease infusion by 50% for the next 24 hours, then discontinue [5][6].Parenteral NutritionDaily RequirementPreterm neonates: 2 to 4 mEq/kg/day IV of calcium [7].Full-term neonates: 0.5 to 4 mEq/kg/day IV of calcium [7].Exchange transfusion: 100 mg calcium gluconate 10% per 100 mL citrated bloodexchanged (equals 1 mL per 100 mL blood exchanged). Infuse IV over 10 minutes.UsesCalcium Channel Blocker (CCB) Toxicity: Administration of calcium is reasonable forCCB toxicity as improvements in heart rate, blood pressure, and conduction abnormalitieshave been reported. However, the available literature on calcium monotherapy for severeCCB toxicity are limited, and most patients require additional treatment modalities. In one177case series, high doses of calcium gluconate (targeting ionized calcium concentrations up totwice normal) appeared more effective than lower doses[2].Cardiac resuscitation: In newly born infants in a cardiac resuscitation setting, drugs arerarely needed [9][10]. Use calcium only in cases of documented hypocalcemia, hyperkalemia,hypermagnesemia, or calcium channel blocker toxicity. Routine use of calcium in cardiacresuscitation is not recommended. [11]. Calcium chloride or calcium gluconate may be used;but calcium chloride is preferred in cardiac arrest setting [4]. For hyperkalemia specifically,calcium will stabilize the cardiac cellular membrane but does not result in transcellular shift orexcretion of potassium; another therapy that results in the shift of intracellular potassium orexcretion of potassium is required [12].Hypocalcemia [5][13][14]. Hypocalcemia, usually defined as a serum ionized calciumconcentration less than 4.4 mg/dL (or total serum calcium less than approximately 8 mg/dL)for term and preterm infants weighing greater than 1500 g at birth and ionized calcium lessthan 4 mg/dL (or total calcium less than 7 mg/dL) for infants weighing less than 1500 g atbirth. Treatment is suggested when serum calcium is less than 6 mg/dL in preterm infantsand less than 7 mg/dL in term infants [5]. Calcium gluconate is generally preferred overcalcium chloride, as calcium chloride may cause a metabolic acidosis [13][14]; calciumchloride may be preferred in cases of severe hypocalcemia with poor cardiac function, as livermetabolism is not required for the release of free calcium [6]Pediatric FDA Approved Indications:Indicated for the treatment of acute symptomatic hypocalcemia [1].Administration•For intravenous use [1].•Dilute to 10 to 50 mg/mL for bolus and 5.8 to 10 mg/mL for continuous infusion [1].•Administer bolus slowly [1] over 10 to [8] 30 minutes [6] and do not exceed 100 mg/min[1].•Avoid intra-arterial infusions of high calcium concentrations. Use caution with the use of anumbilical venous catheter with the tip close to or in the heart [8].•Administer via secure IV line to avoid calcinosis cutis and tissue necrosis [1].•Do not administer ceftriaxone and calcium gluconate via Y-site [1].•If ceftriaxone and calcium gluconate are administered sequentially, then infusions linesshould be thoroughly flushed between infusions with a compatible fluid [1].MEDICATION SAFETYContraindications/PrecautionsCalcium salts are contraindicated in patients with ventricular fibrillation or hypercalcemia(or when calcium levels are above normal). Coadministration of ceftriaxone sodium injectionwith calcium-containing IV solutions (including continuous calcium-containing infusions such178as parenteral nutrition) is also contraindicated due to the risk of precipitation of ceftriaxone-calcium [15].Product contains aluminum that may be toxic with prolonged IV administration and inpatients with impaired kidney function. Premature neonates are particularly at risk becausetheir kidneys are immature, and they require large amounts of calcium and phosphatesolutions, which contain aluminum. Studies showed that patients with impaired kidneyfunction, including premature neonates, who receive parenteral levels of aluminum at greaterthan 4 to 5 mcg/kg/day accumulate aluminum at levels associated with central nervoussystem and bone toxicity. Tissue loading may occur at even lower rates of administration.Rapid administration is associated with vasodilation, hypotension, bradycardia, syncope,cardiac arrhythmias, and cardiac arrest[15].Adverse EffectsPrecipitate in the infusion line with crystalline deposits in the lungs and kidneys has beenreported in some deceased neonates who were coadministered ceftriaxone IV and calcium-containing fluids, sometimes in the same infusion line. At least one neonatal fatality has beenreported following coadministration at different times and with separate infusion lines,though no crystalline deposits were found at autopsy in this neonate. These reports havebeen confined to neonates [15].Solution CompatibilityD5W, D10W, and NS.Terminal Injection Site CompatibilityAmikacin, aminophylline, amiodarone, ampicillin, aztreonam, caffeine citrate, cefazolin,cefepime, chloramphenicol, dobutamine, enalaprilat, epinephrine, famotidine, furosemide,heparin, hydrocortisone, lidocaine, linezolid, micafungin, midazolam, milrinone, netilmicin,nicardipine, penicillin G, phenobarbital, piperacillin-tazobactam, potassium chloride, propofol,remifentanil, tobramycin, and vancomycin.Terminal Injection Site IncompatibilityAmphotericin B, ceftriaxone, fluconazole, indomethacin, meropenem, methylprednisolone,metoclopramide, and phosphate and magnesium salts when mixed directly.179MonitoringTherapeutic Laboratory MonitoringMeasure serum calcium every 4 to 6 hours during intermittent infusions and every 1 to 4hours during continuous infusions.In patients with renal impairment, measure serum calciumevery 4 hours [1].MonitorECG during infusions [1].Therapeutic Physical MonitoringMonitor vital signs during infusions [1].Toxic Laboratory MonitoringMeasure serum calcium every 4 to 6 hours during intermittent infusions and every 1 to 4hours during continuous infusions. In patients with renal impairment, measure serum calciumevery 4 hours [1].Monitor ECG during infusions [1].Do not exceed serum ionized calcium concentration 1.5 to 2 times the upper limits of normalwhen used to reverse calcium channel blocker toxicity [2]Toxic Physical MonitoringMonitor vital signs during infusions [1].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of Action: Calcium gluconate increases serum ionized calcium level. Calciumgluconate dissociates into ionized calcium in plasma. Ionized calcium and gluconate arenormal constituents of body fluids [1]PharmacodynamicsOnset: Immediate [3]AbsorptionBioavailability (IV): 100% [1]Metabolism: Does not undergo direct metabolism [1]DistributionExtracellular fluid and soft tissues: 1% of total body calcium; the rest (99%) isdistributed to the skeleton [1]Albumin: 40%, serum calcium [1]Organic and inorganic acid: 8% to 10%, serum calcium [1]180ABOUTSpecial Considerations/PreparationCalcium gluconate 10% injection yields 9.3 mg/mL elemental calcium (0.46 mEq/mL).Osmolarity is 700 mOsm/L. Injectable calcium salts should be stored at room temperatureand are stable indefinitely.© Merative US L.P. 1973, 2024181CalfactantNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseInitial dose: 3 mL/kg/dose (containing 35 mg phospholipids/mL) intratracheally; may berepeated if needed every 12 hours up to a total of 3 doses. For prophylactic therapy inpremature infants less than 29 weeks of gestational age at significant risk for respiratorydistress syndrome, Infasurf® should be given as soon as possible, preferably within 30minutes after birth [1]. For rescue therapy, administer as soon as possible, preferably within2 hours after birth [2].In the Infasurf® versus Survanta® treatment trial, repeat doses were administered as earlyas 6 hours after the previous dose for a total of up to 4 doses if the infant was still intubatedand required at least 30% inspired oxygen to maintain a PaO2 of 80 torr or less [1].UsesRespiratory distress syndrome (RDS): Routine continuous positive airway pressure(CPAP) is considered superior to prophylactic surfactant therapy. It is strongly recommendedthat CPAP immediately after birth with subsequent selective surfactant administration beconsidered as an alternative to routine intubation with prophylactic or early surfactantadministration in preterm infants. Severe RDS in preterm infants born younger than 30 weeksgestation who need mechanical ventilation should be administered surfactant after initialstabilization. Consider the use of rescue surfactant for infants with hypoxic respiratory failureattributable to secondary surfactant deficiency, such as meconium aspiration syndrome orsepsis/pneumonia[2]. Animal-derived surfactants (beractant, calfactant, and poractant alfa)had comparable outcomes for air leak syndromes, death, and bronchopulmonary dysplasia ina retrospective study (n=51,282; median birth weight of 1435 g; median gestation age of 30weeks (27 to 33 weeks)) [4]. In a prospective randomized trial, the animal-derivedsurfactants all improved FiO2 need, PaO2 values, chest x-ray findings, and lungultrasonography (LUS) scores (N=62, gestational age range 24 to 34 weeks, birthweightrange 560 to 2500 g). However, the results were significantly better with poractant alfa andberactant compared with calfactant. The FiO2 values at 24 hours post-surfactant forporactant alfa, beractant, and calfactant were 36.8%, 33.6%, and 53.1%, respectively. ThePaO2 values at 24 hours post-surfactant for poractant alfa, beractant, and calfactant were64.7, 66.3, and 61.3 mmHg, respectively. The LUS scores at 24 hours post-surfactant forporactant alfa, beractant, and calfactant were 3.8, 4.3, and 6.9, respectively. Significantlymore calfactant-treated patients required repeat dosing. Mechanical ventilation duration andhospital length of stay were similar between all 3 groups [5].Late Administration: Calfactant administered at 7 to 14 days of age in infants (28 weeksof gestational age or younger) who required mechanical ventilation and were receivinginhaled nitric oxide did not improve survival without bronchopulmonary dysplasia (BPD) at 36weeks' or 40 weeks' postmenstrual age or improve the severity of BPD, in a randomized,182masked, multicenter trial (n=511). Infants were randomized to either calfactant every 24 to72 hours up to 5 doses, if the infants still required intubation, or sham. Due to unlikelybenefit the trial was terminated early [6]. At 1-year corrected age follow-up (n=450), homerespiratory support was reduced with late surfactant compared with inhaled nitric oxidealone. However, no improvement was noted on composite outcome of pulmonary morbidity(PM) (measured by use of medications, hospitalization, and home respiratory support) orpersistent PM [7].Neonatal FDA-Approved IndicationsInfasurf® is indicated for the prevention of respiratory distress syndrome (RDS) in prematureinfants less than 29 weeks of gestational age at significant risk for RDS. Treatment should begiven as soon as possible, preferably within 30 minutes after birth [1][8][9].Infasurf® is indicated for infants less than 72 hours of age with RDS (confirmed by clinicaland radiological findings) and requiring endotracheal intubation [1][8][10].AdministrationFor intratracheal administration only [3].Warming of suspension is not necessary [3]Calfactant intratracheal suspension may be administered by either of the following 2 methods[3]:◦ 1) Administration by instilling the suspension through a side-port adapter into theendotracheal tube. Two attendants are needed to facilitate dosing; one to instill thecalfactant, the other to monitor the patient and assist in positioning. The dose (3mL/kg) should be administered in 2 aliquots of 1.5 mL/kg each. After each aliquot isinstilled, the neonate should be positioned with either the right or the left sidedependent. Administration is made while ventilation is continued over 20 to 30 breathsfor each aliquot, with small bursts timed only during the inspiratory cycles. A pausefollowed by evaluation of the respiratory status and repositioning should separate thetwo aliquots.◦ 2) Administration by instilling the suspension through a 5 French feeding tube insertedinto the endotracheal tube. The total dose is instilled in 4 equal aliquots with thecatheter removed between each instillation and mechanical ventilation resumed for 0.5to 2 minutes. For even distribution of calfactant, each of the aliquots should beadministered with the neonate in 1 of 4 positions; prone, supine, right, and left lateral.MEDICATION SAFETYContraindications/PrecautionsTransient episodes of reflux of surfactant into the endotracheal tube, cyanosis, bradycardia,and airway obstruction have been reported during administration. A higher rate ofintraventricular hemorrhage and periventricular leukomalacia was observed in Infasurf®-183treated infants compared with Exosurf®-treated infants in clinical trials [1].Adverse EffectsMost common adverse reactions observed in clinical trials were cyanosis (65%), airwayobstruction (39%), bradycardia (34%), reflux of surfactant into the endotracheal tube(21%), requirement for manual ventilation (16%), and reintubation (3%). Reactions wereusually transient and not associated with severe complications or mortality [1].MonitoringMonitor closely for appropriate oxygen therapy and ventilatory support [1].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyPulmonary lung surfactants are essential for effective ventilation bymodifying alveolarsurface tension thereby stabilizing the alveoli. Infasurf® is a sterile, non-pyrogenic naturalsurfactant extracted from calf lungs containing phospholipids, neutral lipids, fatty acids, andsurfactant-associated proteins B and C. Preservative free. Each mL of Infasurf® contains 35mg of total phospholipids (26 mg of phosphatidylcholine of which 16 mg is disaturatedphosphatidylcholine) and 0.65 mg of proteins including 0.26 mg of SP-B [1].ABOUTSpecial Considerations/PreparationAvailable in 3-mL and 6-mL single-use vials. Refrigerate at 2 to 8 degrees C (36 to 46degrees F) and protect from light. The 3 mL vial must be stored upright. InspectInfasurf® for discoloration; normal color is off-white, and visible flecks and foaming at thesurface are normal. Suspension settles during storage; gently swirl vial in order to uniformlysuspend. Do not shake. Used vials with residual drug should be discarded. Unopened vialsthat have been warmed to room temperature one time may be refrigerated within 24 hoursand stored for future use. Should not be warmed and returned to the refrigerator more thanonce [1].184© Merative US L.P. 1973, 2024185CaptoprilNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseInitial dose: 0.01 mg/kg/dose orally every 12 hours. Incrementally increase dose [1][2].Adjust dose and interval based on response.Dosage: 0.1 to 0.4 mg/kg/dose orally every 6 hours [2][3] to 24 hours [3] has beensuggested for hypertension. In neonates with heart failure, 0.4 to 1.6 mg/kg/day orallydivided every 8 hours was recommended [4]; based on a retrospective study for congenitalheart disease 1 to maximum 1.5 mg/kg/day orally divided every 8 hours was suggested[5].A significant decrease in creatinine clearance in preterm and term neonates withcardiovascular disease warrants extreme care in term neonates treated with captopril andquestions the use of captopril in preterm neonates in a retrospective review (n=206) [6].UsesHeart failure: Afterload reduction in patients with congestive heart failure.Hypertension: Treatment of moderate to severe hypertension.AdministrationAdminister 1 hour before feeding; food decreases absorption.MEDICATION SAFETYContraindications/PrecautionsThe use of captopril is contraindicated in patients with bilateral renovascular disease orwith unilateral renal artery stenosis in a solitary kidney, as the loss of adequate renalperfusion could precipitate acute renal failure.Adverse Effects186Neonates are more sensitive to the effects of captopril than are older infants and children.Significant decreases in cerebral and renal blood flow have occurred in premature infantswith chronic hypertension who received higher doses (0.15 to 0.30 mg/kg per dose) thanthose recommended above. These episodes occurred unpredictably during chronic therapy,and some were associated with neurologic (seizures, apnea, lethargy) and renal (oliguria)complications. Hyperkalemia occurs primarily in patients receiving potassium-sparingdiuretics or potassium supplements [7].The CrCl significantly decreased in preterm and term neonates with cardiovascular diseaseafter initiation of ACEIs (captopril or enalapril) in a retrospective review (n=206). The bodysurface area was less than 0.33 m2 for all neonates [6].Monitoring•Frequent assessment of blood pressure, particularly after the first dose.•Periodic assessment of renal function•Periodic measurement of serum potassium.MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of action: Captopril is an angiotensin-converting enzyme (ACE) inhibitor thatblocks the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. It therebydecreases plasma and tissue concentrations of angiotensin II and aldosterone, and increasesplasma and tissue renin activity. Captopril also prevents the breakdown of bradykinin, apotent vasodilator. Vascular resistance is reduced without reflex tachycardia. Beneficial effectsare thought to be caused by a combination of afterload reduction and long-term inhibition ofsalt and water retention.Bioavailability is good in neonates, although food will decrease absorption.Onset of action is 15 minutes after a dose, with peak effects seen in 30 to 90 minutes.Duration of action is usually 2 to 6 hours, but may be significantly longer (greater than 24hours).ABOUTSpecial Considerations/PreparationAvailable in 12.5-mg, 25-mg, 50-mg, and 100-mg tablets.Extemporaneous Oral Compounds187Captopril 1 mg/mL oral solution was stable for 56 days at 4 degrees C and 28 days at 22degrees C. Two captopril 50-mg tablets were dissolved in 50 mL of water in a graduate. Oneascorbic acid 500-mg tablet was added and allowed to dissolve. Sufficient distilled water wasadded for a final volume of 100 mL. Shake well. Do not filter [8].Captopril 1 mg/mL oral solution was stable for 56 days at 4 degrees C and 14 days at 22degrees C. Two captopril 50-mg tablets were dissolved in 50 mL of water in a graduate.Sodium ascorbate injection 500 mg was added and mixed well. Sufficient distilled water wasadded for a final volume of 100 mL. Shake well. Do not filter [8].Captopril 0.03 mg/mL oral suspension was stable for 14 days at room temperature or56 days when refrigerated. Captopril 6.25 mg (one-half of a scored 12.5-mg tablet) wasdissolved in 10 mL of sterile water, 1000 mg of sodium ascorbate for injection (4 mL of 250-mg/mL solution) was added to decrease oxidation, then sufficient water was added to makea final volume of 200 mL. The final concentration was 0.03 mg/mL captopril and 5 mg/mLsodium ascorbate. Some undissolved excipients remained visible [9].Aqueous captopril solutions have been reported to degrade rapidly, and stability in differentsolutions is highly variable and dependent on many factors (pH, type of vehicle, drugconcentration, addition of preservative). There have been conflicting results in various studiesover the years. The data below represents some of the studies of various extemporaneouslyprepared captopril oral solutions [10][11][9].Captopril 1 mg/mL oral solution made with tablets and undiluted syrup was stable for 30days refrigerated (5 degrees C). In this study, different formulations of captopril solutionswere made using either tablets or powder with different vehicles used (sterile water, syrup,methylcellulose); edetate disodium was added to some of the formulations. Better stabilitywas noted when captopril tablets were used compared with powder, with undiluted versusdiluted syrup as the vehicle, and when edetate disodium was added as the preservative [11].To overcome potential stability problems, powder papers and compounded capsules havebeen utilized to extemporaneously prepare captopril solutions just prior to administration[12][13].© Merative US L.P. 1973, 2024188Carglumic AcidNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseCritical Dosing Notes:• Initiate carglumic acid treatment as soon as the diagnosis of N-acetylglutamate synthase(NAGS) deficiency is suspected, which may be as soon as at birth, and managed by aphysician and medical team experienced in metabolic disorders [1].• Initiate treatment of acute hyperammonemia in patients with a suspected or confirmeddiagnosis of propionic acidemia (PA) or methylmalonic acidemia (MMA) [1].Acute Hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency;AdjunctNote: Titrate dosage to maintain the plasma ammonia level within the normal range forpatient age and clinical condition[1]Usual dosage: 100 to 250 mg/kg/day orally or via NG tube divided into 2 to 4 doses perday (rounded to the nearest 100 mg) [1][2]Concomitant medications: During acute hyperammonemic episodes, administer withother ammonia-lowering therapies (eg, alternate pathway medications, hemodialysis andprotein restriction) [1]Chronic Hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency;MaintenanceNote: Titrate dosage to maintain the plasma ammonia level within the normal range forpatient age and clinical condition[1]Usual dosage: 10 to 100 mg/kg/day orally or via NG tube divided into 2 to 4 doses(rounded to the nearest 100 mg) [1]Concomitant medications: Use of other ammonia lowering therapies and proteinrestriction may be needed [1]Acute Hyperammonemia due to Propionic Acidemia (PA) or MethylmalonicAcidemia (MMA); AdjunctUsual dose, 15 kg or less: 150 mg/kg/day orally or via NG tube divided into 2 equaldoses; rounding up to next multiple of 50 mg. Administer doses 12 hours apart untilammonia level is less than 50 micromol/L and for a maximum duration of 7 days [1]Treatment duration: Continue until ammonia level is less than 50 mcmol/L and for amaximum duration of 7 days [1]Concomitant medications: Give with other ammonia lowering therapies (eg, IV glucose,insulin, L-carnitine, protein restriction, and dialysis) [1].Uses189Treatment of hyperammonemia due to various metabolic disorders [2][3]. Based upon use innewborns from case reports, carglumic acid, when administered in addition to standardtherapy, acutely reduces plasma ammonia levels in patients with branched-chain organicacidemias, such as methylmalonic aciduria (MMA), propionic aciduria (PA), and isovalericacidemia (IVA) . In these metabolic disorders, synthesis of N-acetylglutamate is inhibited dueto the build up of the respective branched-chain organic acid; once standard therapy hascorrected the acidemia, hyperammonemia is also resolved [4]. Doses used in these casesranged from 70 to 200 mg/kg/day, administered as a single dose [4] or over a 48-hourperiod [3].FDA Approved IndicationsIndicated as adjunctive therapy for the treatment of acute hyperammonemia due todeficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS) from the time of birth.Also indicated as maintenance therapy for chronic hyperammonemia due to NAGS deficiency[1].Indicated in pediatric patients as adjunctive therapy to standard of care for the treatment ofacute hyperammonemia due to propionic acidemia (PA) or methylmalonic acidemia (MMA)[1]AdministrationGeneral Information• Disperse tablets in water, do not swallow whole or crushed [1]• Tablets do not dissolve completely in water, and undissolved particles of the tablet mayremain in the mixing container [1]• Administer immediately before meals or feedings [1]• Do not mix in other foods or liquids other than water [1]Oral• Swallow mixture immediately; pieces of tablet(s) may remain in cup; add additional waterand swallow mixture immediately; repeat as needed until no pieces of the tablet are left inthe cup [1]• If using an oral syringe, draw up mixture after mixing and administer immediately; piecesmay remain in oral syringe; refill oral syringe with a minimum of 1 to 2 mL of water andadminister immediately; flush again, as needed until no pieces of the tablet are left [1]NG Tube• Draw up mixture into a catheter-tip syringe; administer immediately via NG or G-tube [1]• Pieces of tablet(s) may remain in catheter-tip syringe or feeding tube; flush immediatelywith 1 to 2 mL of water; repeat as needed until no pieces of the tablet are left in the syringe[1]MEDICATION SAFETY190Contraindications/PrecautionsContraindicationsSpecific contraindications have not been determined [1]PrecautionsSpecific precautions have not been determined [1]Adverse EffectsCommon, N-acetylglutamate synthase deficiency, 13% or greater: Abdominal pain(17%), anemia (13%), diarrhea (13%), ear infection (13%), headache (13%), infection(13%), nasopharyngitis (13%), pyrexia (17%), tonsillitis (17%), and vomiting (17%) [1][2].Common, propionic acidemia and methylmalonic acidemia, 5% or greater:Neutropenia (14%), anemia (12%), vomiting (7%), electrolyte imbalance (7%), decreasedappetite (5%), hypoglycemia (5%), lethargy/stupor (5%), encephalopathy (5%),pancreatitis/increased lipase (5%) [1]MonitoringTherapeutic and Toxic Laboratory MonitoringMonitor plasma ammonia levels and clinical response [1].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyMechanism of action: Carglumic acid is a synthetic analogue of N-acetylglutamate (NAG),a product of N-acetylglutamate synthase (NAGS). NAG is an essential activator of carbamoylphosphate synthetase 1 (CPS 1), which is the first enzyme in the urea cycle. Carglumic acidacts as a replacement for NAG in patients with NAGS deficiency, thereby activating CPS 1 [1].PharmacodynamicsPharmacodynamics onset, initial response• Ammonia level reduction: 24 hours [1]Therapeutic Drug ConcentrationsAUC• IV, 8 mg/kg, healthy volunteers: 24501 nanograms (ng) x hr/mL [1]• Oral, 100 mg/kg, healthy volunteers: 31426 nanograms (ng) x hr/mL [1]Peak concentration191• IV, 8 mg/kg, healthy volunteers: 8613 nanograms (ng)/mL [1]• Oral, 100 mg/kg, healthy volunteers: 3284 nanograms (ng)/mL [1]Time to peak concentration• IV, 8 mg/kg, healthy volunteers: 2 hours [1]• Oral, 100 mg/kg, healthy volunteers: 3 hours [1]AbsorptionBioavailability• Oral, 100 mg/kg, healthy volunteers: Approximately 10% [1]DistributionKinetics• IV, 8 mg/kg, healthy volunteers: 15 L/kg [1]MetabolismSites and kinetics: Intestinal bacteria [1]Metabolic enzymes and transporters• Substrate of: Human OAT1 transporter [1]ExcretionRenal excretion• Oral, 100 mg/kg, healthy volunteers: 9% (unchanged) [1]Feces• Oral, 100 mg/kg, healthy volunteers: 60% (unchanged) [1]Total body• IV, 8 mg/kg, healthy volunteers: 0.34 L/hr/kg [1]Elimination Half-Life• IV, 8 mg/kg, healthy volunteers: 31 hours [1]• Oral, 100 mg/kg, healthy volunteers: 25 hours [1]ABOUTSpecial Considerations/PreparationAvailability: 200 mg tablet for oral suspension, functionally scored with 3 lines for splittinginto 4 equal portions [1]Storage: Store in the original unopened container between 2 and 8 degrees C (36 and 46degrees F) [1].After opening, do not refrigerate and store at a room temperature between 15 and 30degrees (59 and 86 degrees F); protect from moisture [1].Discard one month after first opening [1].© Merative US L.P. 1973, 2024192CaspofunginNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseAspergillus or Candida Infection, Suspected or Documented:25 mg/m2/dose IV every 24 hours [1]. This dose has not been evaluated in clinical studies.Duration of therapy for candidemia, without metastatic complications, is 2 weeks afterdocumented clearance of Candida from the bloodstream and resolution of symptoms [2].Candidiasis - HIV InfectionEsophageal disease:• Less than 3 months (alternate therapy): 25 mg/m2 IV once daily for at least 3 weeksand for at least 2 weeks following resolution of symptoms [3]Invasive disease:• Critically-ill, less than 3 months: 25 mg/m2 IV once daily. Duration of treatment isbased on presence of deep-tissue foci and clinical response; in patients with candidemia,treat until 2 weeks after a positive blood culture [3]UsesAspergillus or Candida Infection:Treatment of patients with refractory Candidemia, intra-abdominal abscesses, peritonitis andpleural space infections, and those patients intolerant of amphotericin B. Treatment ofinvasive Aspergillosis in patients who are refractory to or intolerant of other therapies.There are case reports, but not controlled clinical trials, treating endocarditis, osteomyelitis,and meningitis due to Candida.Neonatal Candidiasis, Including CNS Infection[2]Invasive candidiasis, candidemia, or very low-birth weight infants with asymptomaticcandiduria .◦ Amphotericin B deoxycholate is recommended.◦ Fluconazole IV or oral is an alternative for those who have not been receivingprophylaxis with fluconazole.◦ Lipid formulation amphotericin B agent is an alternative; however, use with caution,especially in the presence of urinary tract involvement.◦ Echinocandins (caspofungin, anidulafungin, or micafungin) should beTherapy Following Completion of Loading and Maintenance Doses Protocol [2]◦ Consider therapy beyond the loading and maintenance doses in cases of suspectedmassive overdose, with concomitant ingestion of other substances, or in patients withpreexisting liver disease.◦ If acetaminophen levels are still detectable following the last maintenance dose, or ifALT/AST levels are still increasing or the INR remains elevated, continue maintenancedoses and contact a United States regional poison center at 1-800-222-1222 or thespecial health professional assistance line for acetaminophen overdose at1-800-525-6115.OralEffervescent Tablets and Oral solutionLoading dose: 140 mg/kg orally [1][4]Maintenance doses: 70 mg/kg orally every 4 hours for 17 doses starting 4 hours afterloading dose [1][4].IVLoading dose: 150 mg/kg IV in 3 mL/kg for those weighing 5 kg or more administered over1 hour. Adjust the total IV volume, as clinically necessary, to avoid fluid overload [5][6][7][2].Second dose: 50 mg/kg IV in 7 mL/kg for those weighing 5 kg or more administered over 4hours. Adjust the total IV volume, as clinically necessary, to avoid fluid overload [5][6][7][2].Third dose: 100 mg/kg IV in 14 mL/kg for those weighing 5 kg or more administered over16 hours. May continue beyond 21 hours if clinically indicated. Adjust the total IV volume, asclinically necessary, to avoid fluid overload [5][6][7][2].13Repeated Supra-therapeutic Acetaminophen IngestionEffervescent Tablets: Rumack-Matthew nomogram does not apply. Contact regional poisoncenter (1-800-222-1222) or a special health professional assistance line for specific dosageand administration information [1].UsesAcetaminophen overdose: For specific treatment management call 1-800-222-1222(regional poison center) or 1-800-525-6115 (special health professional assistance line) [8].To determine if acetylcysteine is indicated, a revised Rumack-Matthew nomogram based onblood acetaminophen concentrations relative to ingestion time can be utilized between 4 and24 hours after an acute ingestion. Levels drawn earlier than 4 hours from ingestion are notappropriate for use, and use of the nomogram is not indicated in the setting of repeatedsupratherapeutic ingestion extending beyond 24 hours, at which point treatment should beinitiated if the level is 20 mcg/mL or greater or if transaminase levels (AST/ALT) areabnormal and other findings are consistent with acetaminophen toxicity[3].Data in neonates treated with acetylcysteine are limited to case reports [9][10][5][6][7][11]with ages ranging from 1 day of age (3.78 kg) [11] to 22 days of age (4.1 kg) [5], includingpreterm neonates as young as postmenstrual age 27.3 weeks (12 days of age; weight 940grams) [10]. All neonates experienced full recovery with most experiencing no evidence ofliver toxicity during and after the course of acetylcysteine treatment. Although neonates maynot be as susceptible to liver injury compared to children or adults due to differences inhepatic development, acetylcysteine is the standard treatment.Gastric Lactobezoar: A gastric lactobezoar was successfully treated after 4 doses ofacetylcysteine 10 mg/kg/dose via nasogastric (NG) tube every 6 hours in a 1 month of agefull-term infant. Each dose was diluted in 50 mL of normal saline and administered over 30minutes, then the NG tube was clamped for 2 hours, followed by aspiration at 3 and 6 hoursafter the dose [12].Lung Disease, Non-Cystic Fibrosis: Evidence is limited and does not support the use oforal or inhaled acetylcysteine for non-cystic fibrosis lung disease such as primary ciliarydyskinesia, chronic lung disease of infancy, pneumonia, asthma, atelectasis, inhalation injury,or lower respiratory tract infection in pediatric patients or neonates [13]. A 6-day course ofIV acetylcysteine (16 to 32 mg/kg/day) started before the age of 36 hours did not improvemortality, the incidence of bronchopulmonary dysplasia, or lung function in a randomized,double-blind, placebo-control trial (n=391; weight range 500 to 999 g) [14][15].Furthermore, harm was demonstrated in 10 ventilated premature infants with chronic lungdisease and treated with intratracheally administered acetylcysteine for 7 days [16].Pediatric FDA Approved IndicationsInhalation Solution:Indicated as adjuvant therapy for patients with abnormal, viscid, or inspissated mucoussecretions in several conditions, including [4]:◦ Acute bronchopulmonary disease◦ Atelectasis due to mucous obstruction14◦ Chronic asthmatic bronchitis◦ Chronic respiratory disease◦ Diagnostic bronchial studies◦ Post-traumatic chest conditions◦ Pulmonary complications of cystic fibrosis◦ Respiratory complication of surgical procedure◦ Tracheostomy care◦ Use during anesthesiaOral/IV Solution:Indicated as an antidote to prevent or lessen hepatic injury that may occur following theingestion of a potentially hepatotoxic quantity of acetaminophen [4] in patients with acuteingestion or from repeated supratherapeutic ingestion [2].Effervescent Tablets:Indicated as an antidote to prevent or lessen hepatic injury that may occur following theingestion of a potentially hepatotoxic quantity of acetaminophen in patients with acuteingestion or repeated supra-therapeutic ingestion (exposure to higher than recommendeddosages for extended periods of time) [1].AdministrationEffervescent Tablet: Dissolve two 2.5-gram tablets in 100 mL of water for a 50 mg/mLsolution [1]Administer immediately or within 2 hours of preparation once tablets are dissolved. Ifvomiting occurs within 1 hour of administration, repeat dose. May be administered bynasoduodenal tube [1].Oral Solution: Dilute the 20% solution with diet cola or other diet soft drink to a finalconcentration of 5% (add 3 mL of diluent for each 1 mL of 20% solution; do not decreasethe proportion of diluent). If administered via gastric tube or Miller-Abbott tube, water maybe used as the diluent. Administer within 1 hour of dilution. Repeat dose if patient vomitswithin 1 hour of administration. Dilution may minimize vomiting. May be administered byduodenal intubation if persistent vomiting is present. Not for parenteral injection [4].If activated charcoal has been administered, then gastric lavage must be performed beforeadministration of oral acetylcysteine [4].IV Solution: Acetadote® is hyperosmolar (2600 milliosmoles/liter [mOsmol/L]) and theosmolarity of the solution is increased as the diluent volume is decreased; adjust osmolarityto physiologically safe level, generally not less than 150 mOsmol/L in children [8].Examples of Acetadote(R) Concentration andOsmolarity in 3 Solutions15AcetylcysteineConcentrationOsmolaritySterileWater forInjection1/2NormalSalineD5W7 mg/mL 91mOsmol/L*245mOsmol/L343mOsmol/L24 mg/mL 312mOsmol/L466mOsmol/L564mOsmol/L* Adjust osmolarity to a physiologically safe level(generally not less than 150 mOsmol/L forpediatric patients)Acetylcysteine IV injection product information,7/2016Concentration of vial is 200 mg/mL. See Dose Section for rate and infusion concentration [8].MEDICATION SAFETYContraindications/PrecautionsInhalation solution: Liquefied bronchial secretions may increase in volume, leading toairway obstruction if cough is inadequate; mechanical suction may be required.Bronchospasm may occur in asthmatics. As increased concentration of drug may occur fromsolvent evaporation, dilution of nebulizing solution with appropriate amounts of sterile waterfor injection is recommended [4].IV solution: Acute flushing and erythema may develop, usually within 30 to 60 minutesafter initiating therapy and usually will spontaneously resolve. However, serious acutehypersensitivity reactions, including fatal cases, have been reported. Use with caution inpatients with asthma due to risk of bronchospasm. In patients less than 40 kg and for thoserequiring fluid restriction, fluid overloadlimited to salvagetherapy or scenarios of resistance or toxicity to amphotericin B deoxycholate orfluconazole.193Central nervous system infections◦ Amphotericin B deoxycholate is recommended.◦ Liposomal amphotericin B agent is an alternative.◦ Salvage therapy with flucytosine may be added in those patients who have notresponded to initial therapy.◦ Fluconazole may be used as step-down therapy for fluconazole-susceptible isolates inthose patients who respond to initial therapy.Neonatal intensive care unit (with greater than 10% rate of invasive candidiasis)◦ Prophylaxis with IV or oral fluconazole for 6 weeks is recommended for neonates withbirth weights of less than 1000 g◦ Prophylaxis with oral nystatin is an alternative in neonates with birth weights of lessthan 1500 g when fluconazole is unavailable or fluconazole resistance is presentHIV Infection - Candidiasis: Caspofungin is recommended as a first-line agent to treatinvasive candidiasis in critically-ill patients with HIV co-infection [3].Comparison to Amphotericin B: There was no difference in clinical response betweenechinocandins and amphotericin B (OR 1.38; 95% CI, 0.68 to 2.8) for the treatment ofsuspected or confirmed invasive candidiasis in a meta-analysis (n=5; 354 neonates andchildren). Antifungals included were micafungin, caspofungin, amphotericin B deoxycholate,and liposomal amphotericin B. Subanalysis demonstrated no difference in other comparisonsincluding mycological response, mortality, recurrence of candida infection, type ofechinocandin, different risk groups (high-risk, low-risk, or neutropenic groups), and type ofuse (targeted or empirical). Discontinuation due to adverse effects were higher withamphotericin B than the echinocandins (OR 0.3; 95% CI, 0.12 to 0.76) [6].Pediatric FDA Approved IndicationsThe following indications are FDA approved for pediatric patients 3 months and older [7]:◦ Empirical therapy for presumed fungal infections in febrile, neutropenic patients.◦ Treatment of candidemia and the following Candida infections: intraabdominalabscesses, peritonitis and pleural space infections.◦ Treatment of esophageal candidiasis.◦ Treatment of invasive aspergillosis in patients who are refractory to or intolerant ofother therapies.AdministrationAdminister by slow IV infusion over approximately 1 hour at a concentration not toexceed 0.5 mg/mL.[4] The recommended concentration is 0.5 mg/mL [5]. Do not dilutein dextrose-containing solutions.194MEDICATION SAFETYContraindications/PrecautionsConcomitant Use: Increased risk of hepatotoxicity when used with cyclosporine [7].Dermatologic: Stevens-Johnson syndrome and toxic epiderma necrolysis, sometimes fatal,have been reported; discontinue at first sign or symptom [8]Hepatic: Hepatic abnormalities, including abnormal liver function tests and hepatic failure,have been reported; monitoring recommended [7].Hepatic: Dose adjustment may be required for hepatic impairment [7].Immunologic: Anaphylaxis and other hypersensitivity reactions have been reported;discontinue use if occurs [8].Immunologic: Histamine-mediated adverse reactions (eg, rash, facial swelling,angioedema, pruritus, sensation of warmth, bronchospasm) have been reported;discontinuation may be necessary [8].Adverse EffectsAdverse effects reported in neonates (small number of patients): thrombophlebitis,hypercalcemia, hypokalemia, elevated liver enzymes, and isolated direct hyperbilirubinemia.In pediatric studies, the primary adverse effects were fever, hypokalemia, diarrhea, increasedliver enzymes, rash, hypotension and chills.Solution CompatibilityNS, ½ NS, ¼ NS, LR.Solution IncompatibilityAll solutions containing dextrose.Terminal Injection Site CompatibilityAzithromycin, aztreonam, dobutamine, dopamine, famotidine, fluconazole, insulin, linezolid,meropenem, metronidazole, morphine, potassium chloride, and vancomycin.195Terminal Injection Site IncompatibilityAcyclovir, cefazolin, ceftriaxone, clindamycin, furosemide, heparin, andpiperacillin/tazobactam.MonitoringAssess IV site for signs of irritation. Periodic measurement of serum potassium, calcium, andhepatic transaminases.For candidemia, monitor blood cultures daily or every other day until Candida is cleared [2].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyCaspofungin is the first of a new class of antifungal agents (echinocandins) that inhibit thesynthesis of β-(1,3)-D-glucan, an integral component of the fungal cell wall. It is fungicidalagainst Candida species, but fungistatic against Aspergillus. The echinocandins are excretedprimarily by the liver, presumably metabolized through an O-methyltransferase. They are notmetabolized through the CYP enzyme system and therefore have significantly fewer drug-drug interactions than the azoles. Dexamethasone, phenytoin, carbamazepine, nevirapine,and rifampin all induce caspofungin drug clearance, lowering serum concentrations.In a pharmacokinetic study in infants less than 3 months (n=18) withesophageal/oropharyngeal candidiasis or invasive candidiasis, a dose of 25 mg/m2 appearedto provide similar drug exposure compared with adults receiving 50 mg/dose. The majority ofinfants were born premature (approximately 70%) and 12 of 18 infants were 4 weekspostnatal age or younger [9].ABOUTSpecial Considerations/PreparationCancidas® is supplied as a white to off-white powder cake in single-use vials, containingeither 50 or 70 mg. To prepare the 50-mg (5 mg/mL) or 70-mg (7 mg/mL) Cancidas® vial: 1)Equilibrate the refrigerated vial to room temperature. 2) Aseptically add 10.8 mL NormalSaline or Sterile Water for Injection to the vial. The powder cake will dissolve completely withgentle mixing. This reconstituted solution can be stored at room temperature for up to onehour. Visually inspect the reconstituted solution for particulate matter or discoloration. Do not196use if the solution is cloudy or has precipitated. Single-use vials: discard remaining unusedsolution. 3) Remove desired volume of drug based on calculated dose and further dilute incompatible solution (NS, ½ NS, ¼ NS, LR) to a final concentration not to exceed 0.5 mg/mL.The infusion solution can be stored for up to 24 hours at room temperature or up to 48 hoursrefrigerated. Do not use diluents containing dextrose.© Merative US L.P. 1973, 2024197CeFAZolinNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDose25 mg/kg/dose IV or IM.Antibiotic Dosing Chart:Renal function and drug elimination are most strongly correlated with Postmenstrual Age(PMA; equivalent to Gestational Age plus Postnatal Age). PMA is the primary determinant ofdosing interval, with Postnatal Age as the secondary qualifier.Dosing Interval ChartPMA(weeks)PostNatal(days)Interval(hours)≤290 to 28>2812830 to 360 to 14>1412837 to 440 to 7>7128≥45 ALL 6UsesUse in neonates is generally limited to perioperative infection prophylaxis and treatment ofurinary tract and soft tissue infections caused by susceptible organisms, e.g. penicillin-resistant Staph. aureus, Klebsiella, and Proteus.Infective endocarditis: The following recommendations are based on a consensus ofexperts [3]. The full pediatric guidelines can be found here: https://doi.org/10.1161/CIR.0000000000000298Organism Directed TherapyOrganism First-ChoiceAlternativeChoiceStreptococciHighly susceptibleto penicillin G(MBC 0.1 mcg/mLor less); includesmost viridansPenicillin G orCefTRIAXoneVancomycin orFirst-generationcephalosporinorCefTRIAXone198streptococci,groups A, B, C, Gnonenterococcal,group Dstreptococci (Sbovis, S equinus)Relativelyresistant topenicillin (MBC0.2 mcg/mL ormore); less-susceptibleviridansstreptococciorenterococciPenicillin G orAmpicillin +Gentamicin(for first 2weeks, orentire courseforenterococci)Vancomycin +Gentamicin forenterococciAmpicillinpotentially leading to hyponatremia, seizure, anddeath may occur; therefore, diluent volume needs to be adjusted [2].Oral solution: If encephalopathy due to hepatic failure occurs, discontinue treatment toavoid further exposure to nitrogenous substances. Evaluate risk versus benefit in patients atrisk of gastric hemorrhage (eg, esophageal varices, peptic ulcer) due to increased vomitingwith treatment [4].Adverse EffectsIV infusion of acetylcysteine did not produce adverse effects in one study of pretermnewborns (n=10; gestational age, 25 to 31 weeks; weight, 500 to 1380 g) whenadministered at a mean rate of 4.2 mg/kg/hr for 24 hours, or in a second study of newborns(n=6; gestational age, 26 to 30 weeks; weight, 520 to 1335 g) when administered at a rateof 0.1 to 1.3 mg/kg/hr for 6 days [8].Hypernatremia developed in a preterm infant (30 weeks gestation) administered oral16acetylcysteine solution (33.5 mmol/kg/day sodium from acetylcysteine) for meconium ileus.Sodium concentration returned to normal after acetylcysteine was discontinued [17].Solution CompatibilityD5 W; 0.45%NaCl.Terminal Injection Site CompatibilityAcetylcysteine 100 mg/mLVancomycin 10 mg/mL.Terminal Injection Site IncompatibilityCefepime, ceftazidime.Compatibility information refers to physical compatibility and is derived from Trissel’s™ 2Clinical Pharmaceutics Database. The determination of compatibility is based onconcentrations for administration recommended herein. Drug compatibility is dependent onmultiple factors (eg, drug concentrations, diluents, storage conditions). This list should not beviewed as all-inclusive and should not replace sound clinical judgment. The user is referred toTrissel’s™ 2 for more complete details.Trissel’s™ 2 Clinical Pharmaceutics Database, version updated on 06/15/2013.MonitoringInhalation Therapy: Monitor patients with asthma closely during inhalation therapy.Monitor renal and hepatic function and electrolytes throughout therapy [4].IV/Oral Therapy for Overdose:Obtain plasma or serum acetaminophen levels prior to detoxification. For acute ingestion,obtain as early as possible but no sooner than 4 hours postingestion [1][2].If extended-release acetaminophen was ingested and the acetaminophen concentration at 4hours post ingestion was below the possible toxicity line, draw a second sample at 8 to 10hours post ingestion [1][2] or 4 to 6 hours after the first level was drawn [3].Assess hepatic function (AST, ALT, bilirubin, INR, prothrombin time), renal function(creatinine and BUN), blood glucose, and electrolytes prior to detoxification, and throughouttreatment [1][2]; assess hepatic function at least every 12 to 24 hours [3].Assess acetaminophen levels as needed during treatment to determine need for continued17therapy [1][2], at least every 12 to 24 hours [3].Assess acetaminophen levels, ALT/AST, and INR after the last maintenance dose [1][2].Carefully monitor patients with asthma or with a history of bronchospasm during initiationand throughout therapy [1][2].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologySystemic: Acetylcysteine may protect against acetaminophen overdose-inducedhepatotoxicity by maintaining or restoring hepatic concentrations of glutathione, or by actingas an alternate substrate for conjugation with reactive acetaminophen metabolites [1][2].Glutathione is required to inactivate an intermediate metabolite of acetaminophen that isthought to be hepatotoxic. In acetaminophen overdose, excessive quantities of thismetabolite are formed because the primary metabolic pathways (glucuronide and sulfateconjugation) become saturated. CYP2E1 then metabolizes a larger fraction of the ingesteddose to form an increased amount of the toxic metabolite [4].Metabolism of acetylcysteine is believed to form cysteine and disulfides (N,N-diacetylcysteineand N-acetylcysteine), with further metabolism of cysteine to form glutathione and othermetabolites. Acetylcysteine steady-state Vd and protein binding were 0.47 L/kg and 66% to87%, respectively. Urinary recovery was 13% to 38% within 24 hours of a single oral dose.Mean total body clearance was 0.11 L/hr/kg with an estimated renal clearance of 30% of thetotal. Mean half-life was 5.6 hours [1][2].Mean elimination half-life was longer in premature newborns (11 hours) compared withadults (terminal half-life, 5.6 hours) [18]. Clearance (32 to 62 mL/kg/hr) and Vd (167 to 1010mL/kg) were correlated with weight and gestational age in 10 neonates (mean 27.7 weeksgestation; mean 863 grams) started on 4.2 mg/kg/hr IV acetylcysteine soon after birth; half-life did not correlate with either parameter. A mean steady-state concentration of 161micromole/L was attained within 2 to 3 days in 5 of 6 neonates (mean 27.6 weeks gestation;mean 894 grams) started on 0.3 to 1.3 mg/kg/hr IV acetylcysteine at the age of 24 hoursand continued for a duration of 6 days [18].]Inhalation: Acetylcysteine exerts its mucolytic action through its free sulfhydryl group,which opens the disulfide linkage in mucus and lowers its viscosity. This action increases withincreasing pH and is most significant at pH 7 to 9. The mucolytic action of acetylcysteine isnot affected by the presence of DNA [4].ABOUTSpecial Considerations/PreparationEffervescent Tablets:Supplied as 500 mg or 2.5 g effervescent tablets for oral solution. Dissolve effervescenttablets and use within 2 hours [1].18Store at a controlled room temperature between 20 and 25 degrees C (68 and 77 degrees F),with excursions permitted between 15 and 30 degrees C (59 and 86 degrees F). Store inoriginal packaging until ready for use and protect from moisture [1].IV Injection: Available as a 20% IV solution containing acetylcysteine 200 mg/mL in 30-mLsingle-dose vials [8].A color change of the solution to slight pink or purple may occur once the vial is punctured,but product quality is not affected. Contains no preservatives. Discard unused solution left invial after opening. Diluted solution may be stored at room temperature for up to 24 hours[8].Oral/Inhalation Solution: Available in 10-mL and 30-mL vials of a 10% (100 mg/mL) or20% (200 mg/mL) acetylcysteine sodium sterile, unpreserved solution for oral or inhalationuse (not for injection). Do not mix with antibiotics such as tetracycline, oxytetracycline, orerythromycin lactobionate. Opened vial may be refrigerated for up to 96 hours [4].Acetylcysteine inhalation therapy was chemically unstable with dornase alfa. Althoughchemically stable together, aerosol characteristics have not been studied when the followingwere combined with acetylcysteine cromolyn, salbutamol, ipratropium, or colistimethatesodium [19].© Merative US L.P. 1973, 202419AcyclovirNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseHerpes Simplex Virus Infection, Treatment and Preemptive TherapyFDA-Approved DosageLess than 34 weeks postmenstrual age: 20 mg/kg IV every 12 hours for 21 days; infuseeach dose at a constant rate over 1 hour [1]Postmenstrual age 34 weeks or older: 20 mg/kg IV every 8 hours for 21 days; infuseeach dose at a constant rate over 1 hour [1]Infections of the CNS, Skin, Eye, Mouth, or DisseminatedPopulation based pharmacokinetic/pharmacodynamic data supports alternative frequency ofadministration. See USES section for details.[2]Off-label DosageLess than 30 weeks postmenstrual age: 20 mg/kg IV every 8 [3][4][5] to 12 hours [2].30 weeks or more postmenstrual age: 20 mg/kg IV every 8 hours [6][4][2][5].Treat localized herpes simplex disease for 14 days and disseminated or CNS disease for 21days [6][4][5]. For CNS disease, continue IV therapy for another 7 days, when repeat DNApolymerase chain reaction (cerebrospinal fluid herpes simplex virus) is positive after 19 to 21days of acyclovir therapy. Continue IV therapy until PCR is negative [6]. The duration forpreemptive therapy without proven disease is 10 days [5].HerpesSimplex Virus Infection (CNS, Disseminated Disease, Skin, Eye, or Mouth),Chronic suppression: 300 mg/m2/dose orally 3 times a day when disease is severe andrecurrent. Begin suppressive therapy immediately after completion of IV treatment andcontinue for 6 months [6][7][8].Varicella-Zoster Virus Infection: 10 to 15 mg/kg/dose IV every 8 hours for 5 to 10 days[9][10][11][12].Dose AdjustmentsPreterm infant less than 33 weeks gestational age: give usual IV dose every 12 hours[13].RenalCrCl 25 to 50 mL/min/1.73 m(2) or serum creatinine (SCr) 0.8 to 1.1 mg/dL: giveusual IV dose every 12 hours [13].CrCl 10 to 25 mL/min/1.73 m(2) or SCr 1.2 to 1.5 mg/dL with decreasing urineoutput: give usual IV dose every 24 hours [13].CrCl less than 10 mL/min/1.73 m(2) or SCr greater than 1.5 mg/dL or urineoutput less than 1 mL/kg/hour: decrease IV dose by 50% and give every 24 hours [13].20UsesNeonatal herpes simplex virus (HSV) infections, known or suspected : Acyclovirtreatment should be initiated in all infants, including HIV-positive, with herpes disease. Inasymptomatic neonates born to women with active herpes lesions, initiation of acyclovir isdependent on risk of transmission to the neonate [6][4][5]. Adverse effects (AE) werecommon, but severe AEs were rare with a median dose of acyclovir 60 mg/kg/day IV in aretrospective review of Pediatrix Medical Group data (n=89 newborn infants) [18].Dose RegimenBased on results from a clinical trial, the standard dose and dosing interval is 20 mg/kg IVevery 8 hours (60 mg/kg/day). Although mortality rate was reduced when compared with the30 mg/kg/day (10 mg/kg/dose every 8 hours) regimen, the 60 mg/kg/day regimen stilldemonstrated a 24-month mortality rate of 31% among infants with disseminated HSVdisease and 6% among infants with CNS HSV disease. Furthermore, the dose did notimprove the rates of normal infant development [5][19]. Investigators of a small populationpharmacokinetic study proposed the following frequencies for a 20 mg/kg dose: every 12hours for infants less than 30 weeks postmenstrual age (PMA) (n=13 ), every 8 hours forinfants 30 to less than 36 weeks PMA (n=9), and every 6 hours for infants 36 to 41 weeksPMA (n=6) to achieve a surrogate pharmacodynamic acyclovir target concentration of 3 mg/Lor more. This target concentration theoretically would achieve CSF concentrations of 1 mg/Lor more. Safety and efficacy were not evaluated with these regimens. One infant experiencedan elevated serum creatinine, which was considered related to acyclovir. Doses greater than80 mg/kg/day (range 87 to 158 mg/kg/day) were administered to 47% of neonates (15 outof 32 infants) [2].Neonatal HSV infection, Chronic suppressive therapyBased on data reported from 2 parallel, phase III, double-blind, placebo-controlled studies(n=45 with CNS disease; n=29 with skin, eye, mouth (SEM) disease), 6 months ofsuppressive oral acyclovir therapy (300 mg/m2/dose 3 times a day) started immediately afterIV treatment for CNS HSV disease was associated with better neurological outcomes whencompared with placebo. Of the 28 infants with CNS disease assessed at 12 months(acyclovir=16; placebo=12), Bayley Scales of Infant Development (2nd Edition) MentalScores were significantly higher in patients receiving acyclovir compared with patientsreceiving placebo (88.24 vs 68.12; p=0.046). In patients with SEM disease receiving 6months of suppressive oral acyclovir therapy started immediately after IV treatment, the timeto 2 recurrences of skin lesions was 1.7 months longer in the treatment group compared withplacebo. Of the 15 infants with SEM disease assessed at 12 months, there were nodifferences in Bayley scores between acyclovir and placebo. An absolute neutrophil count of500 cells/mm3 or less was reported in 20% to 25% of patients receiving acyclovir comparedwith 5% to 7% receiving placebo; no patient had complications associated with neutropenia[7].Varicella-zoster virus infections with CNS and pulmonary involvement. Acyclovirtreatment is recommended in infants with varicella-zoster infection having CNS or pulmonaryinvolvement [9][10][11][12].21AdministrationIntravenous route: Administer as IV infusion over 1 hour at a concentration of 7 mg/mL orless in D5W or NS [14].Oral route: take with or without food; for suspension, shake well before measuring eachdose [15].Extravasation ManagementNeonatal data are limited to pooled data from 10 casereports/case series (n=237) and are not specific to acyclovir extravasation; subcutaneoussaline irrigation with or without hyaluronidase infiltration was commonly used. Nostandardized management was established. An option for more severe injuries (stages 3 and4) is subcutaneous irrigation with saline, but this is not advocated as standard treatment.Conservative management is appropriate for mild extravasation (stages 1 and 2) [16].Although not neonatal-specific, the following are recommendations for extravasation of acidicor alkaline agents (acyclovir is alkaline with a pH of 11) [17]◦ General:◦ Stop and disconnect infusion; do not remove the cannula or needle◦ Attempt to gently aspirate as much extravasated agent as possible; avoid manualpressure◦ Remove cannula or needle◦ Dry heat and elevation◦ Closely monitor for signs of coagulation and ischemia◦ Avoid attempt at pH neutralization (acyclovir - pH 11)◦ Monitor and consider the need for surgical management such as surgical flushing withnormal saline or debridement and excision of necrotic tissue (especially if pain persistsfor 1 to 2 weeks). In cases of compartment syndrome, surgical decompression may berequired◦ Refractory Events:◦ Hyaluronidase 15 units intradermally along injection site and edematous area. Give asfive, 0.2-mL intradermal injections along extravasation site and edematous tissue.◦ Inadvertent Intraarterial Administration:◦ Leave inadvertent intraarterial line in place for diagnostics◦ Systemic heparin titrated to therapeutic anticoagulant effect.◦ Stellate ganglion blockMEDICATION SAFETYContraindications/PrecautionsPrecautions22Administration: Rapid rate of infusion may lead to renal tubular damage [20]Hematologic: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome,including fatal cases, has been reported in immunocompromised patients [20].Neurologic: Encephalopathic changes (eg, lethargy, obtundation, tremors, confusion,hallucinations, agitation, seizures, or coma) have been reported; use with caution in patientswith underlying neurologic abnormalities, significant hypoxia, or serious renal, hepatic, orelectrolyte abnormalities [20].Renal: Impaired renal function may occur and is dependent upon rate of administration; riskis increased in patients with preexisting renal disease and dehydration, and with concomitantuse of other nephrotoxic drugs [20].Renal: Precipitation of acyclovir crystals in renal tubules may occur and can result in acuterenal failure; accompany administration with adequate hydration [20].Renal: Renal failure, including fatal cases, has been reported [20].Adverse EffectsCommon Adverse Effects: Common adverse events include nausea, vomiting, and rash[14].Cardiovascular: Hypotension requiring inotropes (9%) occurred in a retrospective review ofPediatrix Medical Group data (n=89 newborn infants treated for herpes simplex virusdisease) [18]Hepatic: Elevations of hepatic transaminases (1% to 2%) [20].Hematologic:Leukopenia (16%) and thrombocytopenia (25%), which occurred within a median of 1 to 2days, were common in a retrospective review of Pediatrix Medical Group data (n=89 newborninfants treated with high-dose acyclovir for herpes simplex virus disease). Neutropeniaoccurred in 6% of infants, most of whom were treated with granulocyte colony-stimulatingfactor. Severe hematologic events were rare (0% to 3%) [18].Among infants receiving high-dose acyclovir for neonatal HSV disease, the major toxicity wasneutropenia (absolute neutrophil count less than 1000/mm3), which was observed in 20% ofneonates [3]. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, resulting indeath, have been reported in some immunocompromised patients receiving acyclovir. Overall,hematologic abnormalities occurred in less than 1% [20][14].Immunologic: Development of certain acyclovir-resistant viruses may cause severe diseasein infants [20].Neurological: Seizures (9%) occurred in a retrospective review of Pediatrix Medical Groupdata (n=89 newborn infants treated with high-dose acyclovir for herpes simplex virusdisease) [18]Renal: Mild elevations of creatinine concentrations (2%) were reported in a retrospectivereview of Pediatrix Medical Group data (n=89 newborn infants treated with high-doseacyclovir for herpes simplex virus disease) [18]Renal failure, in some cases fatal, has been reported [20]..Vascular: Phlebitis at the injection site occurred in 9% of patients [20].23Solution CompatibilityD5W and NS.Terminal Injection Site CompatibilityAmikacin, ampicillin, aminophylline, cefazolin, cefotaxime, cefoxitin, ceftazidime, ceftriaxone,chloramphenicol, cimetidine, clindamycin, dexamethasone, erythromycin lactobionate,famotidine, fluconazole, gentamicin, heparin, hydrocortisone succinate, imipenem/cilastatin,linezolid, lorazepam, magnesium sulfate, metoclopramide, metronidazole, milrinone,morphine, nafcillin, oxacillin, penicillin G, pentobarbital, piperacillin, potassium chloride,propofol, ranitidine, remifentanil, sodium bicarbonate, theophylline, ticarcillin, tobramycin,trimethoprim/sulfamethoxazole, vancomycin, and zidovudine.Terminal Injection Site IncompatibilityFat emulsion. Aztreonam, caffeine citrate, caspofungin, cefepime, dobutamine, dopamine,meropenem, and piperacillin-tazobactam.MonitoringLaboratoryMonitor renal function at baseline and at least once weekly, particularly in patients withpreexisting renal dysfunction on prolonged therapy [3].MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAntiviral drug that is preferentially taken up by infected cells; inhibits viral DNA synthesis.CSF concentrations are 30% to 50% of serum concentrations. Oral absorption is 15% to30%. Most of administered dose is excreted unchanged in urine, primarily via glomerularfiltration. Protein binding and metabolism are minimal. Serum half-life is 3 to 4 hours inpatients with normal renal and hepatic function.The clearance increased with time in the premature neonate from 0.211 L/hr/kg for thoseless than 30 weeks postmenstrual age (PMA), 0.449 L/hr/kg for those 30 to less than 36PMA, and 0.589 L/hr/kg for those 36 to 41 PMA in a population pharmacokinetic study24(n=28). The corresponding half-lives were 10.2 hours, 6.55 hours, and 3 hours. For 20mg/kg doses, the IV frequency suggested was every 12 hours for infants less than 30 weeksPMA, every 8 hours for infants 30 to less than 36 weeks PMA, and every 6 hours for infants36 to 41 weeks PMA. These regimens were then assessed using a data set of 1000 infants tosimulate acyclovir exposure. The proposed dosing regimens predict that the steady stateplasma concentration at 50% of the dosing interval would be greater than or equal to 3 mg/Lin greater than 90% of infants. Although, toxic levels are unknown, concentrations associatedwith neurotoxicity in a small amount of patients have been identified as 50 to 70 mg/L.These predicted neurotoxic concentrations were exceeded in 0.9% and 0.3% of infants,respectively [2].Dosing simulations of the proposed and standard dose regimens using a database of 1000infants provide the following percentages of infants who would be expected to achieve atarget concentration of 3 mg/L or more [2].Regimens and Target ConcentrationsPostmenstrualAgeIV DoseNPercent of Infantswith Concentrationsof 3 mg/L or moreCmaxatsteadystateC50 atsteadystateCminatsteadystateProposed Regimen(Sampson, 2014)Less than 30weeks20mg/kg/doseevery 12hours218 100% 97% 89%30 to lessthan 36weeks20mg/kg/doseevery 8hours373 98% 94% 75%36 to 41weeks20mg/kg/doseevery 6hours409 96% 86% 56%Standard Dose Regimen(Kimberlin, 2001)Less than 30weeks20mg/kg/doseevery 8hours218 100% 100% 100%30 to lessthan 36weeks20mg/kg/doseevery 8hours373 98% 94% 74%36 to 41weeks20mg/kg/doseevery 8hours409 94% 70% 10%KEY: C50 at steady state = steady state plasmaconcentrations at 50% of the dosing interval25Sampson, 2014ABOUTSpecial Considerations/PreparationInjectionAvailability: Solution (50 mg/mL) or as powder for solution in 500-mg and 1-g vials.Prepare powder for solution by dissolving contents of 500-mg vial in 10 mL sterile water forinjection. Reconstituted solution is stable at room temperature for 12 hours. Do notrefrigerate[14].Infusion solution concentration should be no greater than 7 mg/mL[14].A 5-mg/mL dilution may be made by adding 1 mL of 50 mg/mL concentration to 9 mL ofpreservative-free normal saline. Dilution should be used within 24 hours.OralOral suspension available in 200-mg/5 mL concentration. Store at room temperature. Shakewell before administration [15].© Merative US L.P. 1973, 202426AdenosineNeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseParoxysmal Supraventricular Tachycardia (PSVT) ConversionInitial dose: 50 to 100 mcg/kg (0.05 to 0.1 mg/kg) rapid IV push [1].Repeat doses: If conversion of PSVT does not occur after 1 to 2 minutes, may repeat withdoses increasing in increments of 50 to 100 mcg/kg/dose (0.05 to 0.1 mg/kg/dose) IV [1]every 1 to 2 minutes as needed; maximum 0.3 mg/kg/dose or 12 mg/dose[1].UsesAcute treatment of sustained paroxysmal supraventricular tachycardia.It may also be useful in establishing the cause of the SVT.AdministrationAdminister as a rapid IV bolus either centrally or peripherally. Infuse directly into a vein or asclose to the patient as possible. Follow each dose with a rapid saline flush [1]. Intraosseousroute is an option during resuscitation [2].MEDICATION SAFETYContraindications/PrecautionsContraindicated in patients with second- or third-degree AV block and patients with sinusnode disease, such as sick sinus syndrome or symptomatic bradycardia (except patients withfunctioning pacemaker) [3].Cardiac arrest, in some cases fatal, sustained ventricular tachycardia (requiring resuscitation),and myocardial infarction have been reported following adenosine infusion. Patients withsigns or symptoms of acute myocardial ischemia (eg, unstable angina or cardiovascularinstability) have an increased risk for serious cardiovascular reactions with adenosineadministration; therefore, avoid use in these patients. Cardiac resuscitative measures shouldbe available prior to infusion [4].Hemorrhagic and ischemic cerebrovascular accidents have been reported. Seizures (new or27recurrent) have been reported and may require emergent management. Concomitant use ofaminophylline increases the risk of seizures [5].Hypersensitivity reactions, including dyspnea, tightening of the throat, flushing, erythema,rash, and chest discomfort, have been reported and may require symptomatic treatment orresuscitative measures [6].Adverse EffectsFlushing, dyspnea, and irritability occur frequently, but usually resolve within 1 minute.Transient (duration less than 1 minute) arrhythmias may occur between termination of SVTand onset of normal sinus rhythm. Apnea has been reported in one preterm infant.Recurrence of SVT occurs in approximately 30% of treated patients.Aminophylline/Theophylline and caffeine diminish adenosine's effect by competitiveantagonism.Solution CompatibilityD5W and NS.MonitoringContinuous EKG and blood pressure monitoring.MECHANISM OF ACTION/PHARMACOKINETICSPharmacologyAdenosine is the pharmacologically active metabolite of ATP. It acts by depressing sinus nodeautomaticity andAV node conduction. It does not have negative inotropic effects. Responseshould occur within 2 minutes of the dose. Estimated serum half-life is 10 seconds.ABOUTSpecial Considerations/Preparation28Availability: 2-mL vials containing 6 mg (3 mg/mL) adenosine in NS. Contains nopreservative.Storage: Store at room temperature. Do not refrigerate; crystallization will occur. Solutionmust be clear at the time of use [1].Dilutions can be made with NS for doses less than 0.2 mL (600 mcg). Use 1 mL (3000 mcg)with 9-mL NS to make a solution with a final concentration of 300 mcg/mL.© Merative US L.P. 1973, 202429Albumin (Human)NeoFax® Drug Monograph Summary - MICROMEDEXDOSING/ADMINISTRATIONDoseHemolytic disease of the newborn:1 g/kg of 25% albumin IV administered approximately 1 hour prior to exchange transfusion[1][2].Hypotension: 0.5 g/kg (10 mL/kg) of 5% albumin IV over 20 to 30 minutes; may berepeated [3][4][5][6] up to maximum of 3 doses[6].Septic shock: 0.5 g/kg (10 mL/kg) of 5% albumin IV over 5 to 10 minutes with repeatdoses as needed up to maximum 3 g/kg (60 mL/kg) in the first hour until perfusionimproves or hepatomegaly develop [7].UsesCardiopulmonary bypass, adjunct to priming fluids: The agents of choice for thepriming solution for cardiopulmonary bypass pumps are crystalloid solutions (for example,lactated Ringer's solution and NS). Nonprotein colloids in addition to crystalloids may bepreferred when pulmonary shunting is a concern. For postoperative volume expansion, thepreferred order of choice is crystalloids, nonprotein colloids (for example hetastarch, dextran,and synthetic colloids), and lastly albumin [15].In cardiopulmonary bypass performed in neonates, human albumin has been added to thepriming solution [16][17][18].In addition to other components, 5% albumin 200 mL replaced fresh frozen plasma [17] or20% albumin 100 mL replaced a portion of the fresh frozen plasma in the priming solution[16].Hemolytic disease of the newborn: Albumin may be used to bind free serum bilirubin ininfants with severe hemolytic disease prior to exchange transfusion [1]; it should not beadministered in conjunction with phototherapy [2]. Immunoglobulin, not albumin, isrecommended in infants with isoimmune hemolytic disease and an increasing total serumbilirubin despite intensive phototherapy or when bilirubin is within 2-3 mg/dL of exchangelevel [19].Hyperbilirubinemia, adjunct to exchange transfusion: Adjunctive albumin is notincluded in the American Academy of Pediatrics recommendations for management ofhyperbilirubinemia, [19]. however, guidelines from the University HealthSystem Consortiumstate albumin may be considered as an adjunct to exchange transfusion if administeredconcurrently, and not before, transfusion [15].At one institution, albumin is considered before exchange transfusion, especially if serum30albumin is less than 3.4 mg/dL [20]. Two studies of infants with intensive phototherapyfailure (n=92; 32 weeks or more gestation; weighing more than 1000 g) demonstrated lowerbilirubin levels at 6 and 12 hours post-exchange, shorter duration of phototherapy afterexchange, and need for second exchange transfusion in albumin-treated neonates comparedwith the control group [21][22]. The dosing regimen was 1 g/kg IV of 5% [22] or 20%albumin [21] administered 1 to 2 hours prior to exchange.Hyperbilirubinemia, adjunct to phototherapy: Adjunctive albumin is not included in theAmerican Academy of Pediatrics recommendations for management of hyperbilirubinemia[19]. In addition, the University HealthSystem Consortium states that albumin should not beadministered as an adjunct to phototherapy [15].Human 25% albumin 1 g/kg IV during the first 2 hours of intensive phototherapy rapidlyreduced (by 2 hours) unbound bilirubin values compared with no albumin in a retrospectivestudy (n=58; gestational age 39.4 weeks; birthweight 3245 g) of Japanese infants withhyperbilirubinemia. However, there was no difference in total bilirubin values [23]. A follow-up study identified abnormalities of auditory brainstem responses at 6 months in 3 of 38albumin-treated infants and 6 of 20 infants in the control group. At 2 years of age, abnormaldevelopment, including hearing loss, was not identified in either group [24].Hypoalbuminemia: Albumin is not considered appropriate for treatment ofhypoalbuminemia according to the University HealthSystem Consortium [15]. There is notenough evidence from randomized trials to determine if routine use of albumin (1 g/kg/day)in preterm neonates with hypoalbuminemia (less than 3 g/dL) is beneficial or harmful [25].Hypotension: Albumin may be considered for volume expansion in neonates if 10 mL/kg ofcrystalloid solution is unsuccessful [15], however, the majority of very low birth weight(VLBW) premature infants (weighing 1500 grams or less and younger than 3 postnatal days)with hypotension are not hypovolemic [26][27]. When hypovolemia is present, albumin isgenerally not recommended for use; isotonic saline is preferred when a volume expander isneeded [26].Dopamine increased blood pressure better than albumin in preterm hypotensive neonates(weighing 1500 grams or less) younger than 24 hours (n=39) [28]. Albumin was superior tonormal saline in neonates with hypotension in the first 24 hours of life in a randomized,double-blind study (n=101; mean birthweight 1528 to 1617 g; mean gestational age 30.1 to30.8 weeks). Over 70% of neonates weighing less than 1500 g failed bolus therapy witheither albumin or normal saline and required dopamine infusion. The rate for intraventricularhemorrhage was higher than the norm for both treatments; however, these hemorrhageswere less common and less severe in the albumin treated group [3]. In contrast, 2 studies(n=104) did not demonstrate a difference between albumin and isotonic saline in normalizingmean arterial pressure [29][6].Nephrotic syndrome, adjunct for edema: Diuretics alone are first line therapy, however,short-term use of 25% albumin may be considered in conjunction with a diuretic in patientswith acute several peripheral or pulmonary edema having failure with diuretic therapy alone[15][30][15]. In pediatric patients with severe edema secondary to nephrotic syndrome,diuretics (eg, loop and thiazide) and 25% albumin infusions may be required in addition to alow-sodium diet and fluid restriction [31][15]. The benefit of albumin and a diuretic istransient and furthermore, albumin may lead to hypertension, pulmonary edema, andcongestive heart failure [31].Studies are lacking in neonates. In one case-series (n=7) of full-term infants diagnosed with31congenital nephrotic syndrome, the regimen was 20% albumin 1 g/kg IV (based upon idealbody weight) over 4 hours followed by IV furosemide (0.5 to 1 mg/kg) when needed [32].Perioperative hemodynamic support: No differences in hemodynamics, fluid input, orfluid output were observed between perioperatively administered human 5% albumin and6% hydroxyethyl starch 130/0.4 (Voluven®) in newborns (at 30 weeks gestation) and infantsyounger than 24 months of age undergoing non-cardiac surgery in a randomized, open-labeltrial (n=82). Infusion volume and rate were adjusted to maintain stable hemodynamics [33].Polycythemia, adjunct to dilutional exchange transfusion: Crystalloid solutions, suchas normal saline or Ringers solution, are considered the solutions of choice for exchangetransfusion in neonates with polycythemia. Albumin is more expensive, frequently in shortsupply, and has a potential risk of infection. [34][35].Resuscitation: Albumin is not used during neonatal resuscitation. Isotonic crystalloidsolution or blood is recommended for volume expansion during resuscitation [36].Severe Sepsis and Septic Shock:[7][37]Hemodynamic Support - First 60 MinutesTimeManagement- Proceed to next step ifshock persists0minutesMaintain airway and establish access5minutesPush