Fluconazole

Class and Category

Pharmacologic class: Azole antifungal

Therapeutic class: Antifungal

Indications and Dosages

To treat oral and esophageal candidiasis

ORAL SUSPENSION, TABLETS, I.V. INFUSION

Adults and adolescents: 200 mg on day 1 followed by 100 mg daily for at least 2 (oral) or 3 (esophageal) wk after symptoms resolve. I.V. dosage infused at a rate no greater than 200 mg/hr.

Children: 6 mg/kg on day 1, followed by 3 mg/kg daily for at least 2 (oral) or 3 (esophageal) wk and then for 2 wk after esophageal symptoms resolve. I.V. dosage infused at a rate no greater than 200 mg/hr.

To treat systemic candidiasis

ORAL SUSPENSION, TABLETS, I.V. INFUSION

Adults and children: Highly individualized. Maximum: 400 mg daily (adults) and 12 mg/kg/day (children). I.V. dosage infused at a rate no greater than 200 mg/hr.

To treat cryptococcal meningitis

ORAL SUSPENSION, TABLETS, I.V. INFUSION

Adults and adolescents: 400 mg on day 1, followed by 200 to 400 mg daily based on patient’s response, and continued for 10 to 12 wk after CSF culture is negative. Maintenance: 200 mg daily to suppress relapse. I.V. dosage infused at a rate no greater than 200 mg/hr.

Children: 12 mg/kg on day 1, followed by 6 to 12 mg/kg daily and continued for 10 to 12 wk after CSF culture is negative. I.V. dosage infused at a rate no greater than 200 mg/hr.

To prevent candidiasis after bone marrow transplantation in patients who receive cytotoxic chemotherapy and/or radiation

ORAL SUSPENSION, TABLETS, I.V. INFUSION

Adults and adolescents: 400 mg daily starting several days before procedure if severe neutropenia is expected and continued for 7 days after absolute neutrophil count exceeds 1,000/mm3. I.V. dosage infused at a rate no greater than 200 mg/hr.

To treat vaginal candidiasis

ORAL SUSPENSION, TABLETS

Adults: 150 mg as a single dose.

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DOSAGE ADJUSTMENT 

After initial loading dose, dosage reduced for all indications by 50% for patients with creatinine clearance of 11 to 50 ml/min. For patient on hemodialysis, usual dosage given after each hemodialysis; on nondialysis days, dosage reduced according to the patient’s creatinine clearance.

Mechanism of Action

• It Damages fungal cells by interfering with a cytochrome P-450 enzyme needed to convert lanosterol to ergosterol, an essential part of the fungal cell membrane.
• Decreased ergosterol synthesis causes increased cell permeability, which allows cell contents to leak. Fluconazole also may inhibit endogenous respiration, interact with membrane phospholipids, inhibit transformation of yeasts to mycelial forms, inhibit purine uptake, and impair biosynthesis of triglycerides and phospholipids.

Incompatibilities

Don’t add fluconazole to I.V. container that contains any other drug.

Contraindications

Co-administration of drugs known to prolong QT interval and which are metabolized via the enzyme CYP3A4 (astemizole, cisapride, erythromycin, pimozide, or quinidine) or concurrent therapy with terfenadine (when multiple dosages reach or exceed 400 mg), hypersensitivity to fluconazole or its components

Interactions

DRUGS

alfentanil, amitriptyline, astemizole, celecoxib, cyclosporine, halofantrine, methadone, nortriptyline, olaparib, phenytoin, rifabutin, saquinavir, sirolimus, theopylline, tofacitiib, trizaolam, zidovudine: Increased blood levels of these drugs with possible increase in adverse reactions amiodarone, astemizole, cisapride, erythromycin, pimozide, quinidine: Increased risk of QT-interval prolongation possibly leading to torsades de pointes benzodiazepines (short-acting): Possibly increased benzodiazepine level and psychomotor effects.

calcium-channel blockers: Possibly increased systemic exposure of calcium channel blockers causing adverse effects

carbamazepine: Possibly increased risk of carbamazepine toxicity

cyclophosphamide: Increased serum bilirubin and creatinine levels

fentanyl: Possibly elevated fentanyl concentration that may lead to respiratory depression 

glipizide, glyburide, tolbutamide and other sulfonylurea oral hypoglycemic agents: Increased risk of hypoglycemia

HMG-CoA reductase inhibitors: Increased risk of myopathy and rhabdomyolysis

hydrochlorothiazide: Increased fluconazole level from decreased excretion

losartan: Possibly decreased hypotensive effect of losartan

NSAIDs: Increased systemic exposure of NSAIDs

oral anticoagulants: Increased anticoagulant effects

prednisone: Possibly increased risk of acute adrenal cortex insufficiency

rifampin: Decreased serum fluconazole level

tacrolimus: Increased tacrolimus levels, possibly leading to nephrotoxicity

terfenadine: Increased risk of serious cardiac arrhythmias; increased terfenadine levels when dosage of terfenadine is 400 mg/day or greater.

vinca alkaloids: Possibly increased plasma vinca alkaloids, which may lead to neurotoxicity

vitamin A: Possible adverse CNS effects

voriconazole: Increased risk of toxicity

Adverse Reactions

CNS: Chills, dizziness, drowsiness, fever, headache, seizures

CV: Prolonged QT interval, torsades de pointes

ENDO: Adrenal insufficiency

GI: Abdominal pain, anorexia, constipation, diarrhea, hepatic failure, nausea, vomiting

HEME: Agranulocytosis, leukopenia, thrombocytopenia

SKIN: Acute generalized exanthematous pustulosis, alopecia, diaphoresis, drug eruption, exfoliative dermatitis, photosensitivity, pruritus, rash, Stevens- Johnson syndrome, toxic epidermal necrolysis

Other: Anaphylaxis, angioedema, drug reaction with eosinophilia an sytemic symptoms (DRESS).

Childbearing Considerations

PREGNANCY

• Drug can cause fetal harm such as distinct congenital anomalies in infants exposed in utero to high doses of the drug (400 to 800 mg per day) during most or all of the first trimester. Spontaneous abortions and congenital abnormalities may be potential risks even with 150 mg of the drug given as a single or repeated dose during the first trimester.
• Drug should be avoided in pregnancy except in patients with severe or potentially life-threatening fungal infections in whom the beneficial use of the drug outweighs the potential risk to the fetus.

LACTATION

• Drug is present in breast milk.
• Patient should check with prescriber before breastfeeding.

REPRODUCTION

• Advise women of child bearing age to use effective contraceptive measures during drug therapy and for about 1 week after the final dose when prescribed 400 to 800 mg of the drug daily.

Nursing Considerations

• Use fluconazole cautiously in patients with potentially proarrhythmic conditions because drug may prolong the QT interval, which can lead to life-threatening torsades de pointes.
• Expect to obtain BUN and serum creatinine levels, as well as culture, sensitivity, and liver enzymes, as ordered, before therapy starts.
• Refrigerate, but don’t freeze, fluconazole oral suspension. Shake well before administering.

• Discard I.V. solution that’s cloudy or contains precipitate. Don’t infuse more than 200 mg/hr or add supplemental drugs to infusion.
• Monitor hepatic and renal function periodically during therapy, and notify prescriber if you detect signs of dysfunction.
• Assess for rash every 8 hours during therapy, and notify prescriber if rash occurs.
• Monitor coagulation test results and assess patient for bleeding if patient is receiving an oral anticoagulant.
• Monitor patient for symptoms of overdose, such as hallucinations and paranoia. If they occur, provide supportive treatment, gastric lavage, and, possibly, hemodialysis, which can reduce blood fluconazole level by half after about 3 hours.

PATIENT TEACHING

• Instruct patient to take fluconazole tablets or oral suspension 30 minutes before or 2 hours after meals. Inform her that tablets may be crushed for easier swallowing if needed.
• Advise patient to complete entire course of therapy, even if she feels better.
• Tell patient to inform all prescribers of fluconazole use and not to take any over-the-counter preparations, including herbal preparations, without consulting prescriber first, as drug can interact with many other drugs and substances.
• Urge patient to monitor blood glucose level often if she takes an oral antidiabetic drug, because of increased risk of hypoglycemia.
• Alert patient that fluconazole may change the taste of food.
• Encourage patient to notify prescriber immediately about diarrhea, headache, nausea, rash, rightupper-quadrant abdominal pain, yellow skin or whites of eyes, or vomiting. Also tell patient to notify prescriber of fever, skin rash, swollen glands, or other persistent, severe, or unusual adverse reactions such as chronic fatigue, loss of appetite, muscle weakness, or weight loss.
• Urge women of childbearing age to notify prescriber immediately if pregnancy is suspected or known, as drug may need to be discontinued.

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