NEODOSE

INDICATIONS

Treatment of systemic fungal infections resistant to conventional amphotericin B therapy or in patients with renal or hepatic dysfunction.

Neonatal Candidiasis, Including CNS Infection

• Invasive candidiasis and candidemia, or very low-birth weight infants with asymptomatic candiduria:
  • Amphotericin B deoxycholate is recommended.
  • Fluconazole IV or oral is an alternative for those who have not been receiving rophylaxis with fluconazole.
  • Lipid formulation amphotericin B agent is a alternative; however, use with caution, especially in the presence of urinar tract involvement.
  • Echinocandins (caspofungin, anidulafungin, o micafungin) should be limited to salvage therapy or scenarios of resistance or toxicity to amphotericin B deoxycholate or fluconazole
• Central 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 not responded to initial therapy.
  • Fluconazole may be used as step-down therapy for those 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 with birth weights of less than 1000 g.
  • Prophylaxis with oral nystatin is an alternative in neonates with birth weights of less than 1500 g when fluconazole is unavailable or fluconazole resistance is present

• Comparison with Echinocandins: There was no difference in clinical response between echinocandins and amphotericin B (OR 1.38; 95% CI, 0.68 to 2.8) for the treatment of suspected or confirmed invasive candidiasis in a meta-analysis (n=5; 354 neonates and children). Antifungals included were micafungin, caspofungin, amphotericin B deoxycholate, and liposomal amphotericin B. Subanalysis demonstrated no difference in other comparisons including mycological response, mortality, recurrence of candida infection, type of echinocandin, different risk groups (high-risk, low-risk, or neutropenic groups), and type of use (targeted or empirical). Discontinuation due to adverse effects were higher with amphotericin B than the echinocandins
• Infective Endocarditis:Infective endocarditis: The following recommendations are based on a consensus of experts. The full pediatric guidelines can be found here:

PRECAUTIONS

• Immunologic: Anaphylaxis has been reported; discontinue immediately and do not reinitiate .

ADVERSE EFFECTS

Safety has not been established in pediatric patients younger than 1 month.

• Common: Hypokalemia (37% vs 55%), chills (29% vs 68%), vomiting (27% vs 55%), and amphotericin B deoxycholate in a double-blind study in 95 children 16 years or younger
• Endocrine & Metabolic: Hypokalemia occurred at the end of treatment in 21.2% (7 out of 33 pediatric patients) in the 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 4 hours for conventional). Potassium replacement therapy was administered to 87.9% of patients in the liposomal amphotericin B group and 89.3% of patients in the conventional group. In those younger than 90 days (n=16), 100% vs 87.5%, respectively, received potassium replacement therapy.
• Hepatic: Hepatotoxicity was more common in pediatric patients who received liposomal amphotericin B compared with conventional amphotericin B in a retrospective study; but when concomitant hepatotoxic drugs were accounted for there was no difference. Additionally, the majority of these children with hepatoxicity had at least 1 enzyme abnormality at baseline. Of 65 pediatric patients with baseline and end-of-treatment liver function test, amphotericinrelated 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 were different between the 2 groups were gamma-glutamyl transferase (GGT) and bilirubin; GGT was up to 5 x the upper limit of normal (ULN) in 41.4% in the liposomal group compared with 16.7% (p=0.049) in the conventional group and bilirubin was more than 3 to 10 x the ULN in 17.2% and 0%, respectively.
• Infusion-related Reactions: Infusion-related reactions (rigors, fever, tachycardia, and rash) occurred in 9.1% (3 out of 33 pediatric patients) in the liposomal amphotericin B group compared with 23.2% (13 out of 56 pediatric patients; p=0.15) 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 4 hours for conventional). None of the reactions occurred in children younger than 90 days (n=16).
• Renal: Compared with older individuals, pediatric patients appear to have more tolerance for the nephrotoxic effects of amphotericin B deoxycholate. Creatinine elevation (doubling of baseline serum creatinine concentration) occurred in 21.2% (7 out of 33 pediatric patients) in the 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 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 4 hours for conventional). The mean number of concomitant nephrotoxic drugs was 2.5 for the liposomal group compared with 2 for the conventional group

ADMINISTRATION

Administer by IV infusion at a concentration of 1 to 2 mg/mL over a period of approximately 60 (if well tolerated) to 120 minutes. To provide sufficient volume for infusion, a final concentration of 0.2 to 0.5 mg/mL may be appropriate for infants and small children. The recommended standard concentrations are 1 or 2 mg/mL. May increase infusion time if patient experiences intolerance during the infusion. Flush existing IV line with D5W prior to infusion or administer in a separate IV line. In-line filter with pore diameter no less than 1 micron may be used.

MONITORING

Laboratory Exams:

Monitor renal function frequently during therapy. Liver function, serum electrolytes (especially magnesium and potassium), and CBC should be assessed regularly during therapy . For candidemia, monitor blood cultures daily or every other day until Candida is cleared.