What is the information about Itraconazole (antifungal medication)?

From the Guidelines

Itraconazole is a broad-spectrum antifungal medication that should be used with caution due to its potential for liver toxicity and numerous drug interactions, and its use should be guided by therapeutic drug monitoring to ensure adequate plasma concentrations and minimize toxicity, as recommended by the most recent guidelines 1.

Key Considerations

• Itraconazole belongs to the triazole class of antifungals and works by inhibiting the synthesis of ergosterol, an essential component of fungal cell membranes.
• The typical adult dosage ranges from 100-400 mg daily, depending on the infection being treated, and it is available in capsule, oral solution, and intravenous forms.
• The medication should be taken with food to enhance absorption, and the capsules specifically should be taken with a full meal, while the oral solution is better absorbed on an empty stomach.
• Important considerations include numerous drug interactions due to itraconazole's inhibition of the CYP3A4 enzyme system, potential liver toxicity requiring monitoring of liver function, and contraindications in patients with heart failure or pregnancy.

Therapeutic Drug Monitoring

• Therapeutic drug monitoring (TDM) is recommended for itraconazole to ensure adequate plasma concentrations and minimize toxicity, with target trough concentrations between 1 and 2 mcg/mL for invasive infections and >0.5 mcg/mL for prophylaxis 1.
• TDM should be considered for patients receiving triazoles, and the NCCN panel recommends consideration of TDM in conjunction with involvement of an infectious disease expert.

Infections Treated with Itraconazole

• Itraconazole is commonly prescribed for infections such as blastomycosis, histoplasmosis, aspergillosis, onychomycosis (fungal nail infections), and certain types of candidiasis.
• For onychomycosis, a common regimen is 200 mg daily for 12 weeks, while systemic infections may require 200-400 mg daily for extended periods.

Side Effects and Contraindications

• Common side effects include nausea, abdominal pain, rash, headache, and elevated liver enzymes.
• Contraindications include patients with heart failure or pregnancy, and caution should be used in patients with liver disease or those taking medications that interact with itraconazole.

Recent Guidelines

• The most recent guidelines recommend the use of therapeutic drug monitoring to guide the use of itraconazole and other triazoles, and emphasize the importance of careful patient selection and monitoring to minimize toxicity and ensure effective treatment 1.

From the FDA Drug Label

Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction. Neuropathy If neuropathy occurs that may be attributable to SPORANOX ®Oral Solution, the treatment should be discontinued. Cystic Fibrosis If a patient with cystic fibrosis does not respond to SPORANOX ® Oral Solution, consideration should be given to switching to alternative therapy Hearing Loss Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole Several of these reports included concurrent administration of quinidine which is contraindicated The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Information for Patients Only SPORANOX Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. SPORANOX ® Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin which produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study The clinical relevance of these adenocarcinomas is unknown. Taking SPORANOX ® Oral Solution under fasted conditions improves the systemic availability of itraconazole. Instruct patients to take SPORANOX ® Oral Solution without food, if possible. SPORANOX ® Oral Solution should not be used interchangeably with SPORANOX ® Capsules Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during SPORANOX ® administration, they should discontinue SPORANOX ® and contact their healthcare provider immediately. Instruct patients to stop SPORANOX ® treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines. Drug Interactions Effect of SPORANOX ® on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP). Consequently, SPORANOX ® has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs. Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases Reduced concentrations of concomitant drugs may reduce their efficacy The table below lists examples of drugs that may have their concentrations affected by itraconazole, but it is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ® Although many of the clinical drug interactions in Table 1 below are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ®. Table 1: Drug Interactions with SPORANOX ® that Affect Concomitant Drug Concentrations Examples of Concomitant Drugs Within ClassPrevention or Management

• Based on clinical drug interaction information with itraconazole. † Based on 400 mg bedaquiline once daily for 2 weeks. ‡ CYP3A4 inhibitors (including itraconazole) may increase systemic contraceptive hormone concentrations § EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers Drug Interactions with SPORANOX ®that Increase Concomitant Drug Concentrations and May Increase Risk of Adverse Reactions Associated with the Concomitant Drug Alpha Blockers Alfuzosin Silodosin Tamsulosin Not recommended during and 2 weeks after SPORANOX ® treatment. Analgesics MethadoneContraindicated during and 2 weeks after SPORANOX ®treatment. FentanylNot recommended during and 2 weeks after SPORANOX ® treatment. Alfentanil Buprenorphine (IV and sublingual) Oxycodone * Sufentanil Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Antiarrhythmics Disopyramide Dofetilide Dronedarone Quinidine *Contraindicated during and 2 weeks after SPORANOX ® treatment. Digoxin *Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Antibacterials Bedaquiline †Concomitant SPORANOX ®not recommended for more than 2 weeks at any time during bedaquiline treatment. RifabutinNot recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment. See also Table 2. ClarithromycinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 2. TrimetrexateMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. Anticoagulants and Antiplatelets TicagrelorContraindicated during and 2 weeks after SPORANOX ®

Itraconazole is an azole antifungal agent used to treat various fungal infections.

• Mechanism of Action: Itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, a vital component of fungal cell membranes.
• Indications: Itraconazole is used to treat oral and/or esophageal candidiasis, and other fungal infections.
• Administration: Itraconazole should be taken without food, if possible, and should not be used interchangeably with itraconazole capsules.
• Contraindications: Itraconazole is contraindicated in patients with certain medical conditions, such as congestive heart failure, and in patients taking certain medications, such as quinidine.
• Adverse Reactions: Common adverse reactions to itraconazole include hearing loss, liver dysfunction, and neuropathy.
• Drug Interactions: Itraconazole has the potential to interact with many concomitant drugs, resulting in increased or decreased concentrations of the concomitant drugs.
• Precautions: Patients should be instructed to contact their physician before taking any concomitant medications with itraconazole, and to discontinue therapy and inform their physicians if any adverse reactions occur.
• Special Populations: Itraconazole has not been studied in patients with cystic fibrosis who do not respond to treatment, and consideration should be given to switching to alternative therapy in these patients 2.
• Pharmacokinetics: Itraconazole is a potent CYP3A4 inhibitor and has a high potential for drug interactions 2.
• Chemical Structure: Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64 2.

From the Research

Overview of Itraconazole

• Itraconazole is an orally administered triazole antifungal agent 3
• Its spectrum of activity includes dermatophyte, dimorphic and dematiaceous fungi, yeasts, and some moulds 3

Efficacy of Itraconazole

• Mycological cure was attained in approximately 70 to 80, > or = 70 and > or = 80% of patients with, respectively, fingernail and toenail onychomycosis, dermatophytosis, and vaginal candidiasis 3
• Itraconazole is highly effective for nonmeningeal, nonlife-threatening blastomycosis and histoplasmosis, with success rates of 90% and 81%, respectively 4
• Itraconazole is effective for the treatment of histoplasmosis and blastomycosis, and is considered the drug of choice for patients with mild to moderate disease without central nervous system involvement 5

Treatment Regimens and Dosage

• Standard regimens of itraconazole include 200 mg/day for 3 months for onychomycosis, 100 mg/day for 2 to 4 weeks for dermatophytosis, and 400 mg/day for 1 day or 200 mg/day for 3 days for vaginal candidiasis 3
• Intermittent regimens of itraconazole, such as 400 mg/day for 1 week per month for 3 to 4 months, appear to have similar efficacy to standard regimens in the treatment of onychomycosis 3
• Shorter, higher dosage itraconazole treatment regimens, such as 200 or 400 mg/day for 1 week, are also beneficial in dermatomycoses 3

Safety and Tolerability

• Itraconazole is generally well tolerated, with gastrointestinal disturbances, dizziness, and headache being the most common side effects 3
• Liver toxicity has been rarely described, and itraconazole toxicity necessitated stopping therapy in only 1 patient in a study of 85 patients with blastomycosis or histoplasmosis 4

Comparison to Other Antifungal Agents

• The efficacy of itraconazole appears to be greater than that of griseofulvin, but similar to or lower than that of terbinafine in patients with dermatophyte onychomycosis or cutaneous fungal infections 3
• Itraconazole may be similar to or lower than fluconazole in the treatment of cutaneous mycoses 3
• Itraconazole is at least as effective as intravaginal clotrimazole and oral fluconazole, and superior to intravaginal econazole, in the treatment of acute vaginal candidiasis 3

Clinical Experience and New Formulations

• The broad spectrum antifungal itraconazole is an effective and well-tolerated agent for the prophylaxis and treatment of systemic fungal infections 6
• New formulations of itraconazole, such as an oral solution and an intravenous solution, have increased the options for the use of this drug and increased the oral bioavailability in at-risk patients 6
• Itraconazole is recommended for primary therapy in mild-to-moderate blastomycosis and for step-down therapy after initial amphotericin B treatment 7