Fluconazole

Pronunciation

Pronunciation: flew-KOE-nuh-zole
Class: Anti-infective, Antifungal

Trade Names

Diflucan
- Tablets 50 mg
- Tablets 100 mg
- Tablets 150 mg
- Tablets 200 mg
- Powder for Oral Suspension 10 mg/mL when reconstituted
- Powder for Oral Suspension 40 mg/mL when reconstituted

Fluconazole
- Injection 2 mg/mL

Apo-Fluconazole (Canada)
Apo-Fluconazole-150 (Canada)
Diflucan-150 (Canada)
Gen-Fluconazole (Canada)
PMS-Fluconazole (Canada)

Pharmacology

Interferes with the formation of fungal cell membrane, causing leakage of cellular contents and cell death.

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Pharmacokinetics

Absorption

Bioavailability is more than 90%. T max is 1 to 2 h.

Distribution

Apparent Vd is 0.65 L/kg, and it is 11% to 12% protein bound. Ratio of tissue (fluid) concentrations to concurrent plasma concentrations is as follows: CSF, 0.5 to 0.9; saliva, 1; sputum, 1; blister fluid, 1; urine, 10; normal skin, 10; nails, 1; blister skin, 2; vaginal tissue, 1; and vaginal fluid, 0.4 to 0.7.

Elimination

Mean body Cl is 0.23 mL/min/kg; half-life is 20 to 50 h. The drug is cleared primarily by renal excretion, approximately 80% in urine as unchanged drug and 11% excreted in urine as metabolites.

Hemodialysis

A 3-h session decreases plasma concentrations approximately 50%.

Special Populations

Renal Function Impairment

Pharmacokinetics are markedly affected; there is an inverse relationship between half-life and CrCl.

Children
9 mo to 15 y of age

Mean Cl is 0.4 to 0.66 mL/min/kg; half-life is 15.2 to 25 h. C max is 2.9 to 14.1 mcg/mL; Vd ss is 0.722 to 1.069.

Neonates (gestational age 26 to 29 wk)

Mean Cl is 0.18 to 0.333 mL/min/kg (increases with time after birth); half-life is 73.6 to 46.6 h (decreases with time after birth).

Indications and Usage

Oropharyngeal and esophageal candidiasis; vaginal candidiasis; prevention of candidiasis in bone marrow transplant; cryptococcal meningitis.

Contraindications

Coadministration of cisapride; hypersensitivity to any component of the product.

Dosage and Administration

Candidemia and Disseminated Candida Infections
Children

PO / IV 6 to 12 mg/kg/day.

Cryptococcal meningitis

12 mg/kg on first day, followed by 6 mg/kg/day (or 12 mg/kg/day based on medical judgment of patient's response). Recommended duration is 10 to 12 wk after CSF becomes culture negative.

Newborns

Experience is limited to pharmacokinetic studies in premature newborns. Prolonged half-life has been noted. These children, in the first 2 wk of life, should receive the same mg/kg dosage as other children, but administered every 72 h. After the first 2 wk, dose every day.

Cryptococcal Meningitis
Adults

PO / IV 400 mg first day, followed by 200 mg every day thereafter (400 mg may be used) for 10 to 12 wk after CSF culture is negative for initial meningitis; 200 mg ever day for suppression of relapse of cryptococcal meningitis.

Oropharyngeal or Esophageal Candidiasis
Adults

PO / IV 200 mg first day, followed by 100 mg every day thereafter for minimum of 2 wk for oropharyngeal candidiasis, or for 3 wk and at least 2 wk following resolution of symptoms for esophageal candidiasis.

Children

PO / IV 6 mg/kg on first day, followed by 3 mg/kg every day thereafter for minimum of 2 wk for oropharyngeal candidiasis or 3 wk (at least 2 wk after symptom resolution) for esophageal candidiasis.

Prevention of Candidiasis in Bone Marrow Transplant
Adults

PO / IV 400 mg every day; in patients with anticipated severe granulocytopenia (less than 500 neutrophils/mm 3 ), start fluconazole several days before anticipated onset and continue 7 days after neutrophil count rises more than 1,000 cells/mm 3 .

Systemic Candida Infections
Adults

Optimal therapeutic dosage and duration not established; however, in noncomparative studies of small numbers of patients, doses up to 400 mg/day have been used.

UTIs and Peritonitis
Adults

Daily doses of 50 to 200 mg have been used in open, noncomparative studies of small numbers of patients.

Vaginal Candidiasis
Adults

PO 150 mg single dose.

Drug Interactions

Alfentanil, benzodiazepines (eg, midazolam), buspirone, corticosteroids (eg, prednisone), losartan, nisoldipine, sulfonylureas (eg, glyburide), tacrolimus, theophylline, tricyclic antidepressants, vinca alkaloids (eg, vincristine), zidovudine, zolpidem

Levels may be elevated by fluconazole, increasing the risk of adverse reactions and toxicity.

Anticoagulants (eg, warfarin)

Anticoagulant effect may be increased.

Cimetidine, rifamycins (eg, rifampin)

Fluconazole plasma levels may be reduced, decreasing therapeutic effects.

Cisapride

Contraindicated; increased cisapride plasma levels with cardiotoxicity may occur.

Cyclosporine

Increased cyclosporine concentrations.

Hydantoins (eg, phenytoin)

Increased hydantoin levels.

Hydrochlorothiazide

May increase fluconazole levels, increasing adverse reactions.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

QT prolongation (including torsades de pointes).

CNS

Headache (2%).

Dermatologic

Skin rash (2%); exfoliative skin disorders (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

GI

Nausea (4% [children 2%]); vomiting (2% [children 5%]); abdominal pain (2% [children 3%]); diarrhea (2%).

Hematologic

Leukopenia (including neutropenia and agranulocytosis); thrombocytopenia.

Hepatic

Hepatitis; cholestasis; fulminant hepatitis.

Precautions

Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

An open-label, randomized, controlled trial has shown fluconazole to be effective in children 6 mo to 13 y of age. Efficacy has not been established in infants younger than 6 mo of age.

Renal Function

Dosage reduction based on CrCl may be necessary.

Anaphylaxis

Anaphylaxis occurred rarely.

Dermatologic changes

Exfoliative skin disorders reported.

Hepatic injury

Monitor patients with abnormal LFT results for development of more severe hepatic injury.

Immunocompromised patients

To prevent relapse, patients with AIDS and cryptococcal meningitis usually require maintenance therapy.

Overdosage

Symptoms

Hallucinations, paranoid behavior.

Patient Information

  • Advise patient to read patient information leaflet before starting therapy and with each refill.
  • Review dosing schedule and prescribed length of therapy with patient. Advise patient that treatment may be prolonged (eg, several wk or mo) and to continue medication until advised to stop using by health care provider.
  • Tablets and Suspension
  • Advise patient that tablets can be taken with a full glass of water without regard to meals but to take with food if GI upset occurs.
  • Advise patient using suspension that the suspension can be taken without regard to meals but to take with food if GI upset occurs.
  • Advise patient or caregiver to shake suspension well before measuring dose and to measure prescribed dose of suspension using dosing cup, spoon, or syringe.
  • Advise patient that if a dose is missed, to take as soon as remembered. However, if it is nearing the time for the next dose, to skip the dose and take the next dose at the regularly scheduled time.
  • Remind patient to complete entire course of therapy, even if symptoms of infection have disappeared.
  • Advise patient to inform health care provider if infection does not improve or worsens.
  • Advise patient to contact health care provider immediately if skin rash, persistent nausea or vomiting, dark urine, or yellowing of skin or eyes occur.
  • Injection
  • Advise patient that medication will be prepared and administered by a health care professional in a health care setting when oral therapy is not feasible, but that the patient will be switched to oral therapy when health care provider believes it is appropriate.

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