Bolardi

INDICATIONS AND USAGE 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. Itraconazole 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: Post-marketing 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…

DOSAGE AND ADMINISTRATION Itraconazole capsules should be taken with a full meal to ensure maximal absorption. Itraconazole capsules must be swallowed whole. Itraconazole capsules is a different preparation than itraconazole 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 mg 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. Itraconazole capsules and itraconazole 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 itraconazole. Use in Patients with Renal Impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be…

CLINICAL PHARMACOLOGY Pharmacokinetics and Metabolism: General Pharmacokinetic Characteristics Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with C max values of 0.5 mcg/mL, 1.1 mcg/mL and 2 mcg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism. Absorption Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%. The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H 2 -receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (See PRECAUTIONS: Drug Interactions.) Absorption of itraconazole under fasted conditions in these subjects is increased when itraconazole capsules are administered with an acidic beverage (such as a non-diet cola). When itraconazole capsules were administered as a single 200 mg dose under fasted…

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% 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* 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 * Rash tends to occur more frequently in immunocompromised patients receiving…

CONTRAINDICATIONS Congestive Heart Failure: 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 : Post-marketing Experience, and CLINICAL PHARMACOLOGY : Special Populations.) Drug Interactions: Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole. Plasma concentrations increase for the following drugs: 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. 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. Specific examples are listed in PRECAUTIONS : Drug Interactions. Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole…

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…