itraconazole
Sporanox

Available forms
Available by prescription only
Capsules: 100 mg
Injection: 10 mg/ml
Oral solution: 10 mg/ml

Indications and dosages
 Treatment of blastomycosis (pulmonary and extrapulmonary), histoplasmosis (including chronic cavitary pulmonary disease and disseminated nonmeningeal histoplasmosis). Adults: 200 mg P.O. once daily. If condition doesn’t improve or shows evidence of progressive fungal disease, increase dose in 100-mg increments to maximum of 400 mg daily. Give doses of more than 200 mg daily in two divided doses. Or, 200 mg I.V. b.i.d. for four doses, then decrease to 200 mg I.V. once daily for up to 14 days.
 Aspergillosis (pulmonary and extrapulmonary) in patients who are intolerant of or refractory to amphotericin B therapy. Adults: 200 to 400 mg P.O. daily, or 200 mg I.V. b.i.d. for four doses; then decrease to 200 mg I.V. daily for up to 14 days.
 Oropharyngeal candidiasis. Adults: 200 mg (20 ml) oral solution P.O. daily for 1 to 2 weeks.
 Esophageal candidiasis. Adults: 100 mg (10 ml) oral solution P.O. daily for at least 3 weeks. Should be continued for 2 weeks after symptoms resolve.
 Superficial mycoses (dermatophytoses, pityriasis versicolor, sebopsoriasis, candidiasis [vaginal, oral, or chronic mucocutaneous], onychomycosis) ◇, leishmaniasis ◇, fungal keratitis ◇, alternariatoxicosis ◇, zygomycosis ◇, and systemic mycoses (candidiasis, cryptococcal infections [meningitis, disseminated], dimorphic infections [paracoccidioidomycosis, coccidioidomycosis]) ◇, subcutaneous mycoses (sporotrichosis, cutaneous chromomycosis) ◇. Adults: 50 to 400 mg P.O. daily. Duration of therapy varies from 1 day to more than 6 months, depending on the condition and mycologic response.
 Onychomycosis. Adults: For toenail involvement, with or without fingernail involvement, 200 mg P.O. daily for 12 weeks. For fingernail involvement only, 200 mg P.O. b.i.d. for 1 week, followed by a 3-week rest period, then another week of 200 mg b.i.d. for 1 week.

Pharmacodynamics
Antifungal action: Itraconazole is a synthetic triazole antifungal agent. In vitro, itraconazole inhibits the cytochrome P-450 dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Pharmacokinetics
Absorption: Oral bioavailability of drug is maximal when taken with food.
Distribution: Plasma protein-binding of drug is 99.8%; 99.5% for its metabolite.
Metabolism: Extensively metabolized by the liver.
Excretion: Fecal excretion of parent drug varies between 3% and 18% of the dose. Renal excretion of parent drug is less than 0.03% of dose. About 40% of dose is excreted as inactive metabolites in the urine. Drug isn’t removed by hemodialysis.

Contraindications and precautions
Contraindicated in patients with ventricular dysfunction or history of heart failure. If signs and symptoms of heart failure occur, discontinue itraconazole. Also contraindicated in patients hypersensitive to drug and in breast-feeding women.
  Use cautiously in patients with hypochlorhydria or HIV infection and in those receiving drugs that are highly protein-bound.

Interactions
Drug-drug. Benzodiazepines (midazolam, triazolam): Increases plasma levels of these drugs, which may prolong hypnotic and sedative effects. Avoid use together.
Calcium channel blockers: May cause edema. Adjust dosage as needed.
Cyclosporine, tacrolimus: May increase cyclosporine or tacrolimus plasma levels. Reduce dosages of these drugs by 50% when using itraconazole doses greater than 100 mg daily. Monitor cyclosporine or tacrolimus levels.
Digoxin: Increases digoxin levels. Monitor digoxin levels.
Dofetilide, pimozide, quinidine: May increase plasma levels of these drugs by CYP-3A4 metabolism, causing serious CV events, including torsades de pointes, QT prolongation, ventricular tachycardia, cardiac arrest, and sudden death. Don’t use together.
H₂-receptor antagonists, isoniazid, phenytoin, rifampin: May reduce plasma itraconazole levels. Monitor patient for drug effect.
HMG-CoA reductase inhibitors: Contraindicated during treatment with itraconazole. Don’t use together.
Indinavir, ritonavir: Alters plasma levels of either drug. Use together cautiously.
Nonsedating antihistamines: May rarely cause life-threatening arrhythmias and death. Don’t use together.
Oral hypoglycemics: May cause severe hypoglycemia. Monitor blood glucose level carefully.
Phenytoin: Alters phenytoin metabolism. Monitor phenytoin levels.
Sulfonylureas: May cause hypoglycemia. Monitor serum glucose levels.
Warfarin: Enhances anticoagulant effect. Monitor PT.
Drug-food. Grapefruit juice: Decreases plasma levels and therapeutic effect of itraconazole. Tell patient to take drug with liquid other than grapefruit juice.

Adverse reactions
CNS: malaise, fatigue, headache, dizziness, somnolence, fever, asthenia, pain, abnormal dreaming, anxiety, depression.
CV: edema, hypertension, orthostatic hypotension, heart failure.
EENT: rhinitis, sinusitis, pharyngitis.
GI: nausea, vomiting, diarrhea, abdominal pain, anorexia, dyspepsia, flatulence, increased appetite, constipation, gastritis, gastroenteritis, ulcerative stomatitis, gingivitis.
GU: impotence, cystitis, UTI, albuminuria.
Metabolic: hypokalemia, hypertriglyceridemia.
Musculoskeletal: myalgia.
Respiratory: upper respiratory tract infection, pulmonary embolism.
Skin: rash, pruritus.
Other: decreased libido, injury, herpes zoster, hypersensitivity reactions.

Effects on lab test results
• May increase alkaline phosphatase, ALT, AST, bilirubin, and GGT levels. May decrease potassium level.

Overdose and treatment
In overdose, employ supportive measures, including gastric lavage with sodium bicarbonate. Itraconazole isn’t removed by dialysis.

Special considerations
• In life-threatening situations, the recommended loading dose is 200 mg three times daily (600 mg daily) for first 3 days. Continue treatment for minimum of 3 months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.
 ALERT Hypersensitivity reactions can include angioedema and Stevens-Johnson syndrome.
• Obtain specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) before therapy to isolate and identify causative organisms. Therapy may be instituted before results of cultures and other laboratory studies are known; once results become available, adjust anti-infective therapy accordingly.
• The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Because hypochlorhydria has occurred in HIV-infected patients, absorption of itraconazole may be decreased.
• Don’t give itraconazole to patient with creatinine clearance of less than 30 ml/minute.
• Before initiating treatment, obtain appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) to confirm the diagnosis of onychomycosis.
• Discontinue drug if signs and symptoms develop that are consistent with liver disease and may be attributable to itraconazole.
Pregnant patients
• Don’t give drug to pregnant women because of risk to fetus.
Breast-feeding patients
• Contraindicated in breast-feeding women.
Pediatric patients
• Safety and efficacy in children haven’t been established.

Patient education
• Instruct patient to take drug with food to enhance absorption.
• Tell patient to swish oral solution vigorously before swallowing.
• Tell patient to report signs and symptoms that may suggest liver dysfunction (jaundice, unusual fatigue, anorexia, nausea, vomiting, dark urine, pale stool) so appropriate laboratory tests can be performed.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use