ITRACONAZOLE CONTRAINDICATED IN CHF PATIENTS

Itraconazole (Sporanox) Contraindicated in CHF Patients

On March 3, the FDA approved safety labeling revisions for itraconazole (Sporanox injection and oral solution; Johnson & Johnson Pharmaceutical Research and Development) to warn against its use in patients with congestive heart failure (CHF) and advise caution with concomitant use of certain drugs that rely on the hepatic cytochrome P 450 isoenzyme 3A4 (CYP 3A4) for metabolism.

Itraconazole should not be used in patients with evidence of left ventricular dysfunction unless life-threatening or other serious infection is suspected and the potential benefit outweighs the risk of therapy, the FDA emphasized.

Risk factors to be considered include cardiac disease such as ischemic and valvular disease, significant pulmonary disease such as chronic obstructive pulmonary disease, and renal failure and other edematous disorders. If signs or symptoms of CHF occur during treatment, alternative therapies and discontinuation of itraconazole may be required.

Itraconazole has been shown to have a dose-related negative inotropic effect; in healthy volunteers, symptoms resolved before the next intravenous dose 12 hours later. CHF has been reported during clinical studies of the drug, particularly in patients receiving a total daily dose of 400 mg.

The FDA notes that coadministration of calcium channel blockers yields additive inotropic effects, particularly because itraconazole also inhibits the metabolism of calcium channel blockers. Dose reductions may be required for dihydropyridines such as nifedipine and felodipine. Because the significant increases in nisoldipine plasma levels cannot be managed by dose reduction, use of this drug combination is contraindicated.

The agency also advised of other drug interactions with itraconazole.

Itraconazole and its metabolite, hydroxyitraconazole, are inhibitors of the hepatic metabolic CYP 3A4 enzyme. Use of the antifungal can decrease the elimination of drugs metabolized by this enzyme, leading to elevated plasma concentrations that can increase or prolong both therapeutic and adverse events.

Cilostazol and eletriptan are CYP 3A4–metabolized drugs that should be used with caution when coadministered with itraconazole. Itraconazole also enhances the anticoagulant effect of coumarin-like drugs (eg, warfarin) and can increase or prolong fentanyl plasma concentrations, leading to potentially fatal respiratory depression.

Caution is advised with concomitant use of halofantrine because high plasma concentrations of the drug have the potential to prolong the QT interval.

Concurrent administration of itraconazole decreases glucosteroid metabolism, thereby potentially increasing serum levels of budesonide, dexamethasone, fluticasone, and methylprednisolone.

Itraconazole is indicated as empiric therapy for suspected fungal infections in patients with febrile neutropenia. The oral formulation may also be used for the treatment of oropharyngeal and esophageal candidiasis; additional indications for intravenous itraconazole include blastomyocosis, histoplasmosis, and aspertillosis.