FLUCONAZOLE

Diflucan

 Reviewed by Dr Carl Kuschel, Dr Liz Wilson, Brenda Hughes, and Robyn Wilkinson
March 2002
Administration Newborn Drug Protocol Index Newborn Services Home Page

Dose and Administration 1,2.3

  1. 6 mg/kg PO/IV every 72 hours (first 2 weeks of life), every 48 hours (weeks 2 to 4) and every 24 hours (over 4 weeks of age).
    Administer IV dose over 30 minutes.
  2. Prophylaxis while neutropenic: 3 – 12 mg/kg PO/IV every 72 hours (first 2 weeks of life), every 48 hours (weeks 2 to 4) and every 24 hours (over 4 weeks of age).
    Administer IV dose over 20 - 30 minutes

Indications

  1. Treatment of suspected systemic fungal infection and extensive cutaneous and confirmed Candidiasis once sensitivities confirmed.

Contraindications

  1. Hypersensitivity to fluconazole or related azole compounds.

Precautions

  1. Impaired renal or hepatic function. Dose reduction recommended in renal impairment – see "Special Considerations".

Clinical Pharmacology

Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 α-demethylation, thus inhibiting ergosterol synthesis. Ergosterol is an essential component of the fungal cell membrane, and instability of the cell membrane results in cell death.

It is water-soluble and is well absorbed from the gastrointestinal tract, although it is not generally used via this route in neonates. Oral absorption is unaffected by food intake. It has good CSF penetration and is excreted largely unchanged in urine, therefore dose adjustments are necessary in the presence of impaired renal function. Neonates have a greater volume of distribution and decreased elimination rates compared to older children and adults. The plasma half life in neonates is approximately 70 hours (30 hours in adults). In preterm infants fluconazole was found to have a plasma half life=73 hours (at birth), 53 hours (6 days of age), and 46 hours (at 12 days of age).3

Possible Interactions 3,5

Amphotericin Currently not established if the combination is beneficial or of reduced benefit in terms of antifungal reponse. There is theoretical antagonism seen in vitro but not in vivo.
Caffeine Possible increase in caffeine levels.
Cisapride Increases risk of arrhythmias
Hydrochlorothiazide Given orally with oral fluconazole may increase fluconazole levels
Midazolam Increases half-life of midazolam (more likely with higher doses long term)
Theophylline Raises theophylline levels 
Phenytoin Raises phenytoin levels – (measure serum levels and reduce phenytoin dose if necessary); possible decrease in fluconazole levels; increase in LFTs
Rifampicin Decreases fluconazole levels, possible increase in LFTs
Zidovudine Increase in zidovudine levels

Possible Adverse Effects

  1. Diarrhoea, flatulence, nausea, rash, increase in LFTs, severe hepatotoxicity in patients with underlying hepatic disease.
  2. Rarely: leukopenia, thrombocytopenia, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Special Considerations

  1. Monitor: Renal & hepatic function Consider reducing dose if there is renal impairment:
  2. Do NOT give by IM or direct IV bolus injection. Continuous infusion is not recommended 4
  3. Systemic Candidiasis is rare without evidence of superficial infection or colonisation.
  4. Not effective against some Candida species (i.e. C.krusei, C.glabrata)
  5. Amphotericin is still the drug of choice for proven Candida infection until sensitivity to Fluconazole is confirmed. However, Fluconazole therapy for established infection can be considered in consultation with the Infectious Diseases service.