INDICATIONS & USAGE Itraconazole capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 1.

Blastomycosis, pulmonary and extrapulmonary 2.

Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and 3.

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: 1.

Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium), and 2.

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 itraconazole capsules) in which patients with onychomycosis of the toenails received 200 mg of itraconazole capsules once daily for 12 consecutive weeks.

Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients.

Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity).

The mean time to overall success was approximately 10 months.

Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the fingernail: Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given itraconazole capsules) in which patients with onychomycosis of the fingernails received a 1-week course of 200 mg of itraconazole capsules b.i.d., followed by a 3-week period without itraconazole, which was followed by a second 1-week course of 200 mg of itraconazole capsules b.i.d.

Results demonstrated mycologic cure in 61% of patients.

Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure.

The mean time to overall success was approximately 5 months.

None of the patients who achieved overall success relapsed.

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 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 itraconazole 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 discontinuation of itraconazole, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists.

Interaction Potential: Itraconazole has a potential for clinically important drug interactions.

Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.

Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability: Itraconazole capsules and itraconazole oral solution should not be used interchangeably.

This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given.

In addition, the topical effects of mucosal exposure may be different between the two formulations.

Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

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% 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 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 course 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 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%.

Adverse Events Reported from Other Clinical Trials In addition, the following adverse drug reaction was reported in patients who participated in itraconazole capsules clinical trials: Hepatobiliary Disorders : hyperbilirubinemia.

The following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of itraconazole oral solution and itraconazole IV excluding the adverse reaction term “Injection site inflammation” which is specific to the injection route of administration: Cardiac Disorders : cardiac failure, left ventricular failure, tachycardia; General Disorders and Administration Site Conditions : face edema, chest pain, chills; Hepatobiliary Disorders: hepatic failure, jaundice; Investigations : alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gamma-glutamyltransferase increased, urine analysis abnormal; Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia, hypomagnesemia; Psychiatric Disorders: confusional state; Renal and Urinary Disorders : renal impairment; Respiratory, Thoracic and Mediastinal Disorders: dysphonia, cough; Skin and Subcutaneous Tissue Disorders: rash erythematous, hyperhidrosis; Vascular Disorders: hypotension Postmarketing Experience Adverse drug reactions that have been first identified during postmarketing experience with itraconazole (all formulations) are listed in the table below.

Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Table 6: Postmarketing Reports of Adverse Drug Reactions There is limited information on the use of itraconazole 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 postmarketing experience.

A causal relationship with itraconazole has not been established.

(See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc.

at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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