NEODOSE

INDICATIONS

Treatment of systemic fungal infections and severe superficial mycoses.

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

• Administration:
  • Rapid infusion may result in hypotension, hypokalemia, arrhythmias, and shock; infuse over 2 to 6 hours.
  • If therapy is interrupted for a period longer than 7 days, therapy should be resumed by starting with the lowest dosage level and increased gradually
• 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 improve tolerance to treatment. A single test dose is recommended in some patients to assess tolerance.
• Neurologic:
  • Leukoencephalopathy has occurred; total body irradiation may put patient at risk.
• Renal:
  • Use with caution in patients with reduced renal function; some patients may need hydration and sodium repletion prior to administration to reduce risk of nephrotoxicity.

ADVERSE EFFECTS

• 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 children 16 years oryounger.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
• 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 intensivecare unit.The median gestational age was 26 weeks (range, 23 to 41 weeks) and median birthweight was 863 g (range, 546 to 4000 g).
• 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:
  • Serum creatinine increased at least 0.4 mg/dL at any time during amphotericin B therapy in 16% (15 out of 92) of infants, 90 days or younger, in the neonatal intensive care unit. None of the values exceeded 2 mg/dL. By the end of therapy, elevated creatinine values normalized in 8 of the 15 infants; 3 had resolving values, and 4 had values that remained elevated. The median gestational age was 26 weeks (range, 23 to 41 weeks) and median birth weight was 863 g (range, 546 to 4000 g). The mean cumulative dose was 13.5 mg/kg and duration was 16.3 days for infants who both developed and did not develop nephrotoxicity; no difference in dose or duration between groups.
  • 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.
  • Sodium intake of more than 4 mEq/kg/day was associated with a decrease in the incidence of amphotericin B-induced nephrotoxicity in extremely premature infants with a birth weight of less than 1250 g . Nephrotoxicity developed in 13 out of 21 neonates in the control group compared with 3 out of 16 in the high-sodium intake group (p=0.02). The additional sodium was administered by either increasing the amount of sodium in the total parenteral nutrition (TPN) or normal saline in those who could tolerate excess fluid until sodium could be adjusted in the TPN. All neonates in the high sodium group received 1 mg/kg/day by 2 days of age.

BLACK BOX WARNING

This drug should be used primarily for treatment of patients with progressive and potentially life-threatening fungal infections; it should not be used to treat noninvasive forms of fungal disease such as oral thrush, vaginal candidiasis and esophageal candidiasis in patients with normal neutrophil counts. 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

ADMINISTRATION

Infuse over 2 to 6 hours at a concentration not to exceed 0.1 mg/mL; some institutions have used 0.5 mg/mL concentrations in pediatric patients. Avoid rapid administration (hypotension, hypokalemia, arrhythmias, and shock can occur). Do not flush IV or mix amphotericin with saline solution; precipitation will occur. In-line filter with pore diameter no less than 1 micron may be used. To avoid febrile reactions, administration of acetaminophen or diphenhydramine may be considered . Some suggest starting with 0.25 mg/kg/day, followed by increases of 0.25 mg/kg/day until the target dose is reached. However, for patients with severe infections the dose should be initiated at the target dose.

MONITORING

Laboratory Parameters:

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