SPORANOX® 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 SPORANOX® use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: General 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.

Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 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.

Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy

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 pulse 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.

Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy

The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache: 8%; pruritus, nausea, rhinitis: 5%; rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury: 3%.

Post-marketing Experience

Worldwide post-marketing experiences with the use of SPORANOX® include adverse events of gastrointestinal origin, such as dyspepsia, nausea, vomiting, diarrhea, abdominal pain and constipation. Other reported adverse events include peripheral edema, congestive heart failure and pulmonary edema, headache, dizziness, peripheral neuropathy, menstrual disorders, reversible increases in hepatic enzymes, hepatitis, liver failure, hypokalemia, hypertriglyceridemia, alopecia, allergic reactions (such as pruritus, rash, urticaria, angioedema, anaphylaxis), Stevens-Johnson syndrome, anaphylactic, anaphylactoid and allergic reactions, photosensitivity and neutropenia. There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX® has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: DRUG INTERACTIONS for more information).

Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1 below and the following drug class subheadings that follow):

1. SPORANOX® may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX®. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX® therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX® may not be effective in patients concomitantly taking SPORANOX® and one of these drugs. Therefore, administration of these drugs with SPORANOX® is not recommended.
3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX®.

Table 1: Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by SPORANOX®¹

Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX® may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and disopyramide are administered concomitantly.

Concomitant administration of digoxin and SPORANOX® has led to increased plasma concentrations of digoxin.

Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when SPORANOX® was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX® and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine.

Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX® could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.

Antineoplastics: SPORANOX® may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.

Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

Benzodiazepines: Concomitant administration of SPORANOX® and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX® and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.

Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving SPORANOX® and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.

Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS : Post-marketing Experience for more information).

Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when SPORANOX® Capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, SPORANOX® should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of SPORANOX® Capsules. In a clinical study, when SPORANOX® Capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced.

Gastrointestinal Motility Agents: Coadministration of SPORANOX® with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that SPORANOX® inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX® with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.)

Immunosuppressants: Concomitant administration of SPORANOX® and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® and sirolimus could increase plasma concentrations of sirolimus.

Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC_0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively.

Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and nevirapine is not recommended.

In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX® Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.

Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® and oral hypoglycemic agents are coadministered.

Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.

Protease Inhibitors: Concomitant administration of SPORANOX® and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX® and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX® and protease inhibitors must be given concomitantly.

Other:

• Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with SPORANOX® could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® and levacetylmethadol is contraindicated.
• Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with SPORANOX® is contraindicated.
• Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when SPORANOX® and halofantrine are administered concomitantly.
• In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX® may increase plasma concentrations of alfentanil.
• Human pharmacokinetic data suggest that concomitant administration of SPORANOX® and buspirone results in significant increases in plasma concentrations of buspirone.
• SPORANOX® may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone and methylprednisolone.
• In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and trimetrexate may inhibit the metabolism of trimetrexate.
• SPORANOX® enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.
• Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with SPORANOX®.

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