Itraconazole

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving)

Transient or permanent hearing loss has been reported. Quinidine (a contraindicated drug) was used concurrently in several of these cases. Hearing loss usually resolves after discontinuation, but may persist in some patients.

Negative inotropic effects have been observed following intravenous administration. Discontinue or reassess use if signs or symptoms of heart failure (HF) occur during treatment. CHF has been reported, particularly in patients receiving a total daily oral dose of 400 mg. Use with caution in patients with risk factors for HF (COPD, renal failure, edematous disorders, ischemic or valvular disease). Discontinue treatment if signs or symptoms of heart failure develop. In a scientific statement from the American Heart Association, itraconazole has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major); may consider use when treating life-threatening fungal infections (AHA [Page 2016]).

Rare cases of serious hepatotoxicity (including liver failure and death) have been reported (including some cases occurring within the first week of therapy); hepatotoxicity was reported in some patients without preexisting liver disease or risk factors. Discontinue treatment if signs or symptoms of hepatotoxicity develop.

Use caution in patients with a history of hypersensitivity to other azoles.

Discontinue if signs or symptoms of neuropathy occur during treatment. Disease-related concerns:

Large differences in itraconazole pharmacokinetic parameters have been observed in cystic fibrosis patients receiving the oral solution; if a patient with cystic fibrosis does not respond to therapy, alternate therapies should be considered.

Use with caution in patients with hepatic impairment; monitor liver function closely. Not recommended for use in patients with active liver disease, elevated liver enzymes, or prior hepatotoxic reactions to other drugs unless the expected benefit exceeds the risk of hepatotoxicity.

Use is contraindicated for treatment of onychomycosis in patients with ventricular dysfunction such as heart failure (HF) or a history of HF. Cases of HF, peripheral edema, and pulmonary edema have occurred in this patient population. Due to potential toxicity, the manufacturer recommends confirmation of diagnosis testing of nail specimens prior to treatment of onychomycosis.

Use with caution in patients with renal impairment; limited information is available; dosage adjustment may be needed. Concurrent drug therapy issues:

Additional potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients taking CYP 3A inhibitors such as cisapride, pimozide, methadone or quinidine. [US Boxed Warning]: Coadministration with itraconazole can cause elevated plasma concentrations of certain drugs and can lead to QT prolongation and ventricular tachyarrhythmias, including torsades de pointes. Coadministration with methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids, irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor and, in subjects with varying degrees of renal or hepatic impairment, colchicine, fesoterodine, and solifenacin is contraindicated. Coadministration with eliglustat is contraindicated in poor or intermediate metabolizers of CYP2D6 and in patients taking strong or moderate CYP2D6 inhibitors. Dosage form specific issues:

Absorption of itraconazole capsules is reduced when gastric acidity is reduced (eg, achlorhydria, acid suppressive therapy) administer capsules or tablets with an acidic beverage (eg, non-diet cola) in patients with reduced gastric acidity and separate administration from acid suppressive therapy (refer to drug interactions section). Monitor for response.

Only the oral solution has proven efficacy in oral/esophageal candidiasis; mucosal exposure may vary between the oral solution and capsules. Initiation of treatment with oral solution is not recommended in patients at immediate risk for systemic candidiasis (eg, patients with severe neutropenia).

Due to differences in bioavailability, oral capsules and oral solution cannot be used interchangeably.

Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures and respiratory depression; use caution (AAP 1997; Zar 2007). Other warnings/precautions:

Itraconazole should NOT be used for voriconazole-refractory aspergillosis because the same antifungal and/or resistance mechanism(s) may be shared by both agents.