Itraconazole 100 mg Capsule, 28-count — NDC 13668-463-37 (Billing 13668-0463-37)

WARNINGS Hepatic Effects: Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed.

Continued itraconazole use or reinstitution of treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.) Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated.

(See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.) Cardiac Disease: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy.

These risk factors 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. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole capsules, discontinue administration.

Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

Itraconazole has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg although there were also cases reported among those receiving lower total daily doses. Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.

In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Postmarketing Experience for more information.) Pseudoaldosteronism: Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has been reported with itraconazole use in the postmarketing setting.

Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldos… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition.

If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of itraconazole use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.) Adverse Events in the Treatment of Systemic Fungal Infections Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications.

Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients.

Table 3: Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1% *Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea Vomiting Diarrhea Abdominal Pain Anorexia 11 5 3 2 1 Body as a Whole Edema Fatigue Fever Malaise 4 3 3 1 Skin and Appendages Rash* Pruritus 9 3 Central/Peripheral Nervous System Headache Dizziness 4 2 Psychiatric Libido Decreased Somnolence 1 1 Cardiovascular Hypertension 3 Metabolic/Nutritional Hypokalemia 2 Urinary System Albuminuria 1 Liver and Biliary System Hepatic Function Abnormal 3 Reproductive System, Male Impotence 1 Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain.

Adverse Events Reported in Toenail Onychomycosis Clinical Trials Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks. The following adverse events led to temporary or permanent discontinuation of therapy. Table 4: Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=112) Elevated Liver Enzymes (greater than twice the upper limit of normal) 4 Gastrointestinal Disorders 4 Rash 3 Hypertension 2 Orthostatic Hypotension 1 Headache 1 Malaise 1 Myalgia 1 Vasculitis 1 Vertigo 1 The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache: 10%; rhinitis: 9%; upper respiratory tract infection: 8%; sinusitis, injury: 7%; diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash: 4%; cystitis, urinary tract infection, liver function abnormality, myalgia, nausea: 3%; appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming: 2%.

Adverse Events Reported in Fingernail Onychomycosis Clinical Trials Patients in these trials were on a dosing regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug. The following adverse events led to temporary or permanent discontinuation of therapy. Table 5: Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy Adverse Event Incidence (%) Itraconazole (N=37) Rash/Pruritus 3 Hypertriglyceridemia 3 The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache:… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General: Itraconazole capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism). Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity.

The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a non-diet cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown.

(See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism). Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving itraconazole.

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 itraconazole capsules, the treatment should be discontinued. Immunocompromised Patients: In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of itraconazole capsules may be decreased.

Therefore, the dose should be adjusted based on the clinical response in these patients. Cystic Fibrosis: If a cystic fibrosis patient does not respond to itraconazole capsules, consideration should be given to switching to alternative therapy. For more information concerning the use of itraconazole in cystic fibrosis patients see the prescribing information for itraconazole oral solution.

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 (See BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Information for Patients: The topical effects of mucosal exposure may be different between the itraconazole capsules and oral solution. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Itraconazole capsules should not be used interchangeably with itraconazole oral solution.

Instruct patients to take itraconazole capsules with a full meal. Itraconazole capsules must be swallowed whole. Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during itraconazole administration, they should discontinue itraconazole and contact their healthcare provider immediately.

Instruct patients to stop itraconazole 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 Itraconazole Capsules on Other Drugs Itraconazole and its major metabolite, hydroxy-itraconazole, are potent… [Excerpted — this section continues on DailyMed.]