Itraconazole and other azoles can interact with many drugs by virtue of their effects on CYP3A4 (Table 48—1); these interactions can cause serious toxicity from the companion drug, including fatal cardiac arrhythmias, and may decrease itraconazole concentrations below therapeutic levels.
Itraconazole rarely has led to hepatic failure and death. If symptoms of hepatotoxicity occur, the drug should be discontinued and liver function assessed. Itraconazole can lead to congestive heart failure in patients with impaired ventricular function. In the absence of interacting drugs, itraconazole capsules are well tolerated at 200 mg daily. GI distress occasionally prevents use of 400 mg/day. In patients receiving 50-400 mg/day, nausea and vomiting, hypertriglyceridemia, hypokalemia, elevated serum aminotransferases, and rash occurred in between 2-10% of patients. Occasionally, rash necessitates drug discontinuation, but most other adverse effects
Interactions of Itraconazole and other Triazoles with Other Drugs
Alfentanil Alprazolam Amprenavir Atorvastatin Buspirone Busulfan Cisapride
Cyclophosphamide Cyclosporine Delavirdine Diazepam Digoxin
channel blockers Docetaxel Felodipine Haloperidol Indinavir Loratidine Lovastatin Methylprednisolone Midazolam Nisoldipine Phenytoin Pimozide Quinidine Ritonavir Saquinavir Sildenafil Simvastatin Sirolimus
Sulfonylureas (glyburide, others)
Vinca alkaloids (vincristine, vinblastine) Warfarin
Drugs that decrease gastric acidity H2-receptor blockers Proton pump blockers Simultaneous antacids (includes didanosine buffer) Carbamazepine Isoniazid Nevirapine Phenobarbital Phenytoin Rifampin, rifabutin St. John's wort
Itraconazole Concentration Increased
Ritonavir can be handled with dose reduction. Doses of300 mg twice daily have led to adrenal insufficiency, lower limb edema, hypertension, and rhabdomyolysis; therefore, doses above 400 mg/day are not recommended for long-term use.
Relative to capsules, the oral solution of itraconazole more frequently causes diarrhea, abdominal cramps, anorexia, and nausea. GI side effects are common, but adherence generally is unimpaired. Anaphylaxis and severe rash have rarely occurred.
Intravenous itraconazole has all the adverse effects of capsules but generally is well tolerated. Due to chemical phlebitis, a dedicated catheter port is required, and infusion durations <1 hour are not recommended. The intravenous formulation is contraindicated in patients with a creati-nine clearance <30 mL/min.
DOSAGE For deep mycoses, a loading dose of 200 mg of itraconazole is administered three times daily for 3 days. Thereafter, two 100-mg capsules are given twice daily with food. Divided doses allegedly increase the plasma AUC. For maintenance therapy of HIV-infected patients with disseminated histoplasmosis, 200 mg once daily is used. Onychomycosis can be treated with either 200 mg once daily for 12 weeks or with pulse therapy (200 mg twice daily for 1 week out of each month). A loading dose of itraconazole is given as a 200-mg intravenous infusion over 1 hour twice daily for 2 days, followed by 200 mg once daily for 12 days. Itraconazole oral solution should be taken fasting in a dose of 100 mg once daily and swished vigorously in the mouth before swallowing to optimize topical effect. Patients with oropharyngeal or esophageal candidiasis are given 100 mg of the solution twice a day for 2-4 weeks.
absorption, distribution, and excretion Fluconazole is almost completely absorbed from the GI tract irrespective of food or gastric acidity. Only 10% of drug in circulation is protein bound. Renal excretion accounts for >90% of elimination, with a t1/2 of ~25 hours. Fluconazole readily diffuses into body fluids, including breast milk, sputum, saliva, and CSF. The dosage interval should be increased from 24-48 hours for a creatinine clearance of 21-40 mL/min and to 72 hours at 10-20 mL/min. In renal failure, a dose of 100-200 mg is given after hemodialysis.
Fluconazole inhibits CYP3A4 and CYP2C9 and thus significantly increases plasma concentrations of amprenavir, cisapride, cyclosporine, phenytoin, sulfonylureas, tacrolimus, theophylline, telithromycin, and warfarin. Patients receiving >400 mg daily or azotemic patients may experience additional drug interactions. Rifampin decreases the fluconazole AUC by ~25%.
therapeutic uses Candidiasis
Fluconazole, 200 mg on the first day and then 100 mg daily for at least 2 weeks, is effective in oropharyngeal candidiasis. Esophageal candidiasis responds to 100—200 mg/day, which also is used to decrease candiduria in high-risk patients. A single dose of 150 mg is effective in uncomplicated vaginal candidiasis. A dose of 400 mg daily decreases the incidence of deep candidiasis in allogeneic bone marrow transplant recipients and is useful in treating candidemia of immuno-competent patients. Fluconazole is not proven to be effective treatment for deep candidiasis in profoundly neutropenic patients.
Fluconazole, 400 mg/day, is used for the initial 8 weeks in the treatment of cryptococcal meningitis in patients with AIDS after the patient has been stabilized with intravenous amphotericin B. Thereafter, the dose is decreased to 200 mg daily and continued indefinitely. If the patient responds to HAART, maintains a CD4 count >200/mm3 for at least 6 months, and has no meningeal symptoms, it is reasonable to discontinue fluconazole as long as the CD4 count is maintained and CSF culture and cryptococcal antigen are negative. For AIDS patients with cryptococcal meningitis and favorable prognostic signs, initial therapy with 400 mg daily may be considered. Fluconazole 400 mg/day has been recommended as continuation therapy in non-AIDS patients with cryptococcal meningitis who have responded to an initial course of C-AMB or ambisome and for patients with pulmonary cryptococcosis.
Fluconazole is the drug of choice for coccidioidal meningitis and is comparable to itraconazole for other forms of coccidioidomycosis. Fluconazole is less active than itraconazole against
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