FLUCONAZOLE

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FLUCONAZOLE
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Infant Data


Results


MEDICAL INFORMATIONS

INDICATIONS

  • Treatment of systemic infections, meningitis, and severe superficial mycoses: caused by Candida species. Resistance has been reported with C glabrata and C krusei and in patients receiving long-term suppressive therapy.
  • Neonatal Candidiasis, Including CNS Infection.
    • Invasive candidiasis and candidemia, or very low-birth weigh infants with asymptomatic candiduria .
      • Amphotericin B deoxycholate is recommended.
      • Fluconazole IV or oral is an alternative for those who have not been receiving prophylaxis 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 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 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 fluconazole-susceptible isolates in 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
  • Prophylaxis of invasive candidiasis: One recommendation is to limit the use of prophylactic fluconazole to high-risk premature infants when the rate of invasive candidiasis is greater than 2% to 5%. The odds of invasive candidiasis (OR 0.2 (95% CI, 0.08 to 0.51) and Candida colonization (OR 0.28 (95% CI, 0.18 to 0.41) occurred less often in the fluconazole compared with placebo group in an evaluation of 4 trials of prophylaxis in premature infants in the United States. Mortality was not different (11% for fluconazole and 14% for placebo). There was no difference between groups in adverse events (ALT, AST, alkaline phosphatase, or conjugated bilirubin levels). Resistance to Candida isolates were not different between the groups. Further evidence suggest prophylactic fluconazole be limited to when the incidence is moderate to high (specific incidence not identified). Although fluconazole prophylaxis reduced the rates of invasive candidiasis (3% vs 9% (p=0.02)), it did not reduce the primary outcome of incidence of death or invasive candidiasis in infants weighing less than 750 g (median, 25 weeks gestation and 120 hours or younger) compared with placebo in a multicenter study (n=361). The dose of oral or IV fluconazole was 6 mg/kg/dose twice weekly for 42 days. The duration of treatment is important; the overall combined relative risks of invasive fungal infection were 0.8 (95% CI, 0.48 to 1.35) with a 28-day treatment and 0.3 (95% CI, 0.15 to 0.58) with a 42-day treatment of prophylactic fluconazole in a meta-analysis (5 studies; 1006 preterm neonates with birthweight less than 1500 g).
  • cidioidomycosis: Empiric fluconazole is recommended for neonates born to mothers with coccidioidomycosis. Discontinue fluconazole once coccidioidomycosis has been ruled out.

CONTRAINDICATIONS

Contraindicated in patients receiving cisapride, due to precipitation of life-threatening arrhythmias terfenadine, in patients receiving multiple doses of fluconazole 400 mg or higher; and QT-prolonging drugs metabolized by CYP3A4 (eg, astemizole, cisapride, erythromycin, pimozide, or quinidine).

PRECAUTIONS

  • Cardiovascular:
    • QT prolongation and torsade de pointes have been reported rarely, primarily in seriously ill patients with multiple confounding risk factors such as structural heart disease, electrolyte abnormalities, and concomitant medications; additional caution advised with use in patients with potentially proarrhythmic conditions.
    • Increased risk of life-threatening ventricular arrhythmias and torsades de pointes in patients with hypokalemia and advanced cardiac failure.
  • Concomitant Use:
    • Narrow therapeutic index drugs that are metabolized by CYP2C9 or CYP3A4; monitoring recommended.
    • Avoid voriconazole.
  • dermatologic:
    • Exfoliative skin disorders have been reported rarely with some fatal cases reported in patients with serious underlying diseases.
  • Endocrine and metabolic:
    • Adrenal insufficiency, including reversible cases, have been reported.
  • Hepatic:
    • Hepatic toxicity, including fatalities, has been reported rarely; monitoring recommended and discontinue if signs of liver disease develop.
    • Use caution in patients with liver dysfunction due to increased risk of hepatic toxicity; monitoring recommended and discontinue if condition worsens.
  • Immunologic:
    • Use caution in patients with hypersensitivity to other azole antifungal agents; cross-hypersensitivity not yet determined.
    • Anaphylaxis has been reported rarely.
    • Deep seated fungal infection and presence of rash; monitoring recommended and discontinue if lesions progress.
    • Superficial fungal infection; discontinue if rash occurs and is attributed to drug.
  • Renal:
    • Preexisting renal dysfunction.
  • Special populations:
    • Sucrase-isomaltase deficiency or heredity fructose or glucose/galactose malabsorption;avoid powder for oral suspension as it contains sucrose.

ADVERSE EFFECTS

  • Common: Vomiting (5%), abdominal pain (3%), nausea (2%), and diarrhea (2%) with fluconazole in doses up to 15 mg/kg/day for a maximum of 1616 days (n=577; age range, 1 day to 17 years).
  • Hepatic: Mean AST at 4 weeks was significantly greater with fluconazole prophylaxis (16.8 units/L) compared with placebo (13.1 units/L) while mean ALT was not significantly different between fluconazole and placebo groups (22.8 units/L vs 19.5 units/L), in a randomized, double-blind trial of 322 very-low-birth-weight infants. No clinical signs of hepatotoxicity or cholestasis were observed. No treatment for cholestasis or phototherapy for hyperbilirubinemia was required. Prophylactic fluconazole doses were 3 or 6 mg/kg/dose every third day for the first 2 weeks, then every other day for a total duration of 6 weeks for extremely-low-birth-weight infants and for a total duration of 4 weeks for neonates weighing 1000 to 1500 g. Conjugated hyperbilirubinemia (greater than 2 mg/dL) occurred significantly more frequently in extremely-low-birth-weight (ELBW) infants with fluconazole prophylaxis (42.9%; n=140) compared with that of ELBW infants not given fluconazole prophylaxis (8.8%; n=137), in a retrospective study with historical controls. Prolonged duration of conjugated hyperbilirubinemia and treatment with ursodeoxycholic acid was performed more often in the fluconazole group. At discharge, the rate of conjugated hyperbilirubinemia was similar between groups. Fluconazole dosage was 3 mg/kg/dose every 72 hours for 2 weeks, then every 48 hours for 2 weeks, then every day for 2 weeks

ADMINISTRATION

    • Intravenous: Infuse at concentration of 2 mg/mL over 1 to 2 hours (maximum rate 200 mg/hour). Solutions for intravenous infusion are supplied premade (glass bottle or Viaflex® plastic bag) in a concentration of 2 mg/mL.

    • In the preparation and administration of injections, National Institute for Occupational Safety and Health (NIOSH) recommends the use of double gloves and a protective gown. Prepare in a biological safety cabinet or a compounding aseptic containment isolator; eye/face and respiratory protection may be needed. Prepare compounds in a closed system drug transfer device. During administration, if there is a potential that the substance could splash or if the patient may resist, use eye/face protection. Administer certain dosage forms via a closed system drug transfer device.

    • Oral: May be given with or without food

    • The National Institute for Occupational Safety and Health (NIOSH) recommends the use of single gloves by anyone handling intact tablets or capsules or administering from a unit-dose package.

    • In the preparation of tablets or capsules, including cutting, crushing, or manipulating, or the handling of uncoated tablets, NIOSH recommends the use of double gloves and a protective gown. Prepare in a ventilated control device, if possible. Use respiratory protection if not prepared in a control device. During administration, wear single gloves, and wear eye/face protection if the formulation is hard to swallow or if the patient may resist, vomit, or spit up.

    NIOSH recommends the use of double gloves and a protective gown by anyone handling a hazardous oral liquid or preparing any hazardous drug for administration via a feeding tube. Prepare in a control device, if possible. Use respiratory, eye, and face protection if not done in a control device. During administration, eye/face protection is needed if the patient may resist, or if there is potential to vomit or spit up.

MONITORING

Monitor for more serious hepatic injury in patients who develop abnormal liver function tests during therapy. For candidemia, monitor blood cultures daily or every other day until Candida is cleared.

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