SPORANOX

INDICATIONS AND USAGE SPORANOX ® (itraconazole) Capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly. SPORANOX ® Capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients: Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , WARNINGS , and ADVERSE REACTIONS: Postmarketing Experience for more information.) Description of Clinical Studies Blastomycosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis compared with the natural history of untreated cases. Histoplasmosis Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of histoplasmosis, compared with the natural history of untreated cases. Histoplasmosis in HIV-infected patients Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse. Aspergillosis Analyses were conducted on data from an open-label, "single-patient-use" protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy. Onychomycosis of the toenail Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given SPORANOX ® Capsules) in which patients with onychomycosis of the toenails received 200 mg of SPORANOX ® Capsules once daily for 12 consecutive we…

DOSAGE AND ADMINISTRATION SPORANOX ® (itraconazole) Capsules should be taken with a full meal to ensure maximal absorption. SPORANOX ® (itraconazole) Capsules must be swallowed whole. SPORANOX ® Capsules is a different preparation than SPORANOX ® Oral Solution and should not be used interchangeably. Treatment of Blastomycosis and Histoplasmosis The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 100-mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses. Treatment of Aspergillosis A daily dose of 200 to 400 mg is recommended. Treatment in Life-Threatening Situations In life-threatening situations, a loading dose should be used. Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment. Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection. SPORANOX ® Capsules and SPORANOX ® Oral Solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Treatment of Onychomycosis Toenails with or without fingernail involvement The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks. Treatment of Onychomycosis Fingernails only The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without SPORANOX ® . Use in Patients with Renal Impairment Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS .) Use in Patients with Hepatic Impairment Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY: Special Populations , WARNINGS , and PRECAUTIONS .)

WARNINGS Hepatic Effects 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, 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 SPORANOX ® use or reinstitution of treatment with SPORANOX ® 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 SPORANOX ® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX ® is contraindicated. (See BOXED WARNING , CONTRAINDICATIONS , and PRECAUTIONS: Drug Interactions .) Cardiac Disease SPORANOX ® 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. SPORANOX ® 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 SPORANOX ® 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 SPORANOX ® 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. SPORANOX ® has been associated with reports of congestive heart failure. In postmarketing 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 SPORANOX ® and felodipine or nisoldipine is contraindicated. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the postmarketing 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 pseudoaldosteronism may include …

CONTRAINDICATIONS Congestive Heart Failure SPORANOX ® (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. (See BOXED WARNING , WARNINGS , PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, ADVERSE REACTIONS: Postmarketing Experience , and CLINICAL PHARMACOLOGY: Special Populations .) Drug Interactions Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX ® . Some examples of drugs for which plasma concentrations increase are: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin. In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. (See PRECAUTIONS: Drug Interactions Section for specific examples.) This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Some specific examples are listed in PRECAUTIONS: Drug Interactions. Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome. SPORANOX ® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX ® is contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing SPORANOX ® to patients with hypersensitivity to other azoles.

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 (e.g., QT prolongation, torsade de pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism). Reduced concentrations of concomitant drugs may reduce their efficacy. Table 1 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 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 Class Prevention or Management 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 Methadone Contraindicated during and 2 weeks after SPORANOX ® treatment. Fentanyl Not recommended during and 2 weeks after SPORANOX ® treatment. Alfentanil Buprenorphine (IV and sublingual) Oxycodone Based on clinical drug interaction information with itraconazole. 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 Based on 400 mg bedaquiline once daily for 2 weeks. Concomitant SPORANOX ® not recommended for more than 2 weeks at any time during bedaquiline treatment. Rifabutin Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment. See also Table 2 . Clarithromycin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 2 . Trimetrexate Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Anticoagulants and Antiplatelets Ticagrelor Contraindicated during and 2 weeks after SPORANOX ® treatment. Apixaban Rivaroxaban Vorapaxar Not recommended during and 2 weeks after SPORANOX ® treatment. Cilostazol Dabigatran Warfarin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Anticonvulsants Carbamazepine Not recommended 2 weeks before, during, and 2 weeks after SPORANOX ® treatment. See also Table 2 . Antidiabetic Drugs Repaglinide Saxagliptin Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Antihelminthics, Antifungals and Antiprotozoals Isavuconazonium Contraindicated during and 2 weeks after SPORANOX ® treatment. Praziquantel Monitor for adverse reactions. Concomitant drug dose reduction may be necessary. Artemether-lumefantrine Quinine Monitor for adverse reactions. Antimigraine Drugs Ergot alkaloids (e.g., dihydroergotamine, ergotamine) Contraindicated during and 2 weeks after SPORANOX ® treatment. Eletriptan Monitor for adverse reactions. Concomitant drug dose reduction may b…

Pregnancy Teratogenic Effects Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (1-4 times the MRHD based on body surface area comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (1 time the MRHD based on body surface area comparisons). Itraconazole has been shown to cross the placenta in a rat model. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia. There are no studies in pregnant women. SPORANOX ® should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. SPORANOX ® should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. SPORANOX ® should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Highly effective contraception should be continued throughout SPORANOX ® therapy and for 2 months following the end of treatment. During postmarketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS: Postmarketing Experience .)

Nursing Mothers Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX ® therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

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. 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: 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% Body System/Adverse Event Incidence (%) (N=602) Gastrointestinal Nausea 11 Vomiting 5 Diarrhea 3 Abdominal Pain 2 Anorexia 1 Body as a Whole Edema 4 Fatigue 3 Fever 3 Malaise 1 Skin and Appendages Rash Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications. 9 Pruritus 3 Central/Peripheral Nervous System Headache 4 Dizziness 2 Psychiatric Libido Decreased 1 Somnolence 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 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. 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: 8%; pr…