Tolsura

1 INDICATIONS AND USAGE TOLSURA is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised adult 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, anti-fungal therapy should be adjusted accordingly TOLSURA is an azole antifungal indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised adult 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.

Limitations of Use: TOLSURA is not indicated for the treatment of onychomycosis TOLSURA is NOT interchangeable or substitutable with other itraconazole products Limitations of Use: TOLSURA is not indicated for the treatment of onychomycosis. TOLSURA is NOT interchangeable or substitutable with other itraconazole products due to the differences in the dosing between TOLSURA and other itraconazole products. Therefore, follow the specific dosage recommendations for TOLSURA .

2 DOSAGE AND ADMINISTRATION TOLSURA must be administered with food. TOLSURA capsules must be swallowed whole. Do not chew, crush or break TOLSURA capsules. Table 1 below describes the recommended dosage for TOLSURA. Table 1: Dosage and Administration of TOLSURA Indications Daily Dosing Treatment of Blastomycosis and Histoplasmosis Recommended dose 130 mg (2 × 65 mg capsules) once daily If no obvious improvement, or there is evidence of progressive fungal disease, the dose should be increased in 65 mg increments to a maximum of 260 mg/day (130 mg (2 × 65 mg capsules) twice daily).

Doses above 130 mg/day should be given in two divided doses. Treatment of Aspergillosis Recommended dose 130 mg (2 × 65 mg capsules) once daily 260 mg/day (130 mg (2 × 65 mg capsules) twice daily) Treatment in Life-Threatening Situations Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose should be used. A loading dose of 130 mg (2 × 65 mg capsules) three times daily (390 mg/day) is recommended to be given for the first 3 days, followed by the appropriate recommended dosing based on indication.

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. Blastomycosis and Histoplasmosis - 130 mg to 260 mg daily Aspergillosis - 130 mg to 260 mg daily See full prescribing information for additional dosing for life-threatening situations.

TOLSURA must be administered with food. Swallow whole. Do not chew crush or break.

Hepatotoxicity : Serious hepatotoxicity, including liver failure and death were reported with the use of itraconazole. Discontinue treatment if signs of liver dysfunction occur Cardiac Dysrhythmias : Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using certain drugs that are metabolized by human CYP450 enzymes concomitantly with oral itraconazole and/or other CYP3A4 inhibitors. ( 4 , 5.3 , 5.5 ) Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels and manage as necessary. Peripheral Neuropathy : This has been reported in patients on long-term therapy with itraconazole. Monitor and promptly evaluate neurologic symptoms. Hearing Loss : Reversible or permanent has been reported in patients. Discontinue treatment if hearing loss occurs

5.1Congestive Heart Failure

TOLSURA can cause or exacerbate congestive heart failure (CHF) . For patients with evidence of ventricular dysfunction such as CHF, history or risk factors for CHF, physicians should carefully review the risks and benefits of TOLSURA 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. Inform such patients of the signs and symptoms of CHF and monitor carefully for signs and symptoms of CHF during treatment.

If signs or symptoms of CHF appear or worsen during administration of TOLSURA, reassess the benefit-risk of continuing treatment. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was demonstrated. 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 CHF, peripheral edema, and pulmonary edema. In post-marketing experience, heart failure was more frequently reported in patients receiving higher total daily doses of itraconazole 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, when co-administering itraconazole and calcium channel blockers, monitor carefully for signs and symptoms of CHF during treatment due to an increased risk of CHF. Concomitant administration of TOLSURA and felodipine or nisoldipine is contraindicated

5.2Hepatotoxicity Itraconazole

has been associated with 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, discontinue treatment and perform testing for liver disease.

Continued TOLSURA use or reinstitution of treatment with TOLSURA is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk .

5.3Cardiac Dysrhythmias Life-threatening

cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as, pimozide, methadone, or quinidine concomitantly with oral itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with TOLSURA is contraindicated .

5.4Pseudoaldosteronism Pseudoaldosteronism,

manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevate 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 TOLSURA, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists.

5.5Drug Interaction Potential Itraconazole

has a potential for clinically important drug interactions . Co-administration of specific drugs with TOLSURA may result in changes in the efficacy of itraconazole and/or the co-administered drug, life-threatening effects and/or sudden death. .

5.6Peripheral Neuropathy Cases of

peripheral neuropathy have been reported in patients on long-term therapy with itraconazole. Monitor for and promptly evaluate neurologic symptoms. If neuropathy attributable to TOLSURA occurs, discontinue treatment.

5.7Hearing Loss Reversible 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 . The hearing loss usually resolves when treatment is stopped but can persist in some patients.

5.8Hypersensitivity Reactions

TOLSURA is contraindicated in patients with a known hypersensitivity to itraconazole . Hypersensitivity reactions have been reported with the use of itraconazole . Due to the limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal drugs, careful enquiry about previous hypersensitivity to other azole antifungal drugs should be made when prescribing TOLSURA. If hypersensitivity reactions to TOLSURA occurs, discontinue the drug and institute appropriate therapy.

Co-administration with certain drugs that either affect metabolism of itraconazole or whose metabolism is affected by itraconazole. Hypersensitivity to itraconazole

4.1Drug Interactions Co-administration of

certain drugs that are metabolized by human CYP3A4 substrates are contraindicated with TOLSURA because plasma concentrations of such drugs are increased, which may also increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs . Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment. Co-administration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors . Increased plasma concentrations of some of these drugs due to co-administration of TOLSURA can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes , a potentially fatal arrhythmia .

4.2Hypersensitivity

TOLSURA is contraindicated in patients with known hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents .

8.1Pregnancy Risk Summary There

are no data on exposure to itraconazole during pregnancy for the approved indications. Published epidemiologic studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy have reported no risk of major birth defects overall and inconclusive findings on the risk of miscarriage . In animal reproduction studies, itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately (6-25 times the maximum recommended human dose [MRHD] of 390 mg/day based on mg/kg comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (12 times the MRHD). All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Human Data Published prospective and retrospective cohort studies of women exposed to short courses of treatment with itraconazole in the first trimester of pregnancy (sample size 198-687) have reported no increase in the rate of major birth defects.

The most important methodological limitation of these studies is the short duration of exposure in pregnancy (mean duration 6.9 to 8.5 days), or the lack of information on treatment duration. The risk of prolonged exposure in pregnancy is not known. Published prospective and retrospective cohort studies of pregnant women exposed to itraconazole (sample size 131-198) have reported inconsistent findings on the risk of miscarriage.

Available data are inconclusive and limited by possible bias due to earlier enrollment and possible residual confounding in the exposed group compared to the unexposed group. Animal Data Itraconazole has been shown to cross the placenta in a rat model. In animal reproduction studies, itraconazole administration to rats and mice during organogenesis resulted in maternal toxicity, embryotoxicity and teratogenicity at and above 40 and 80 mg/kg respectively (doses equivalent to 6- and 12-times the MRHD of 390 mg/day, based on mg/kg comparisons).

In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

The following clinically significant adverse reactions are described elsewhere in the labeling: Congestive Heart Failure Hepatotoxicity Cardiac Dysrhythmias Pseudoaldosteronism Peripheral Neuropathy Hearing Loss Hypersensitivity Reactions Most common adverse reactions (incidence ≥ 1%) are nausea, rash, vomiting, edema, headache, diarrhea, fatigue, fever, pruritus, hypertension, abnormal hepatic function, abdominal pain, dizziness, hypokalemia, anorexia, malaise, decreased libido, somnolence, albuminuria, impotence To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience 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. Adverse Reactions in the Treatment of Systemic Fungal Infections Safety data with itraconazole capsules 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). Table 2 lists adverse reactions reported by at least 1% of patients. Table 2: Clinical Trials of Systemic Fungal Infections: Adverse Reactions Occurring with an Incidence of ≥1% Body System/Adverse Reaction 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 reactions reported at a rate of <1% included: constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia, and male breast pain.

Adverse Reactions Reported from Other Clinical Trials In addition, the following adverse reactions were reported in itraconazole-treated patients who participated in clinical trials: Hepatobiliary Disorders: hyperbilirubinemia; 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, gammaglutamyltransferase 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: hyperhidrosis; Vascular Disorders: hypotension

6.2Postmarketing Experience Adverse

reactions that have been identified during post-marketing experience with itraconazole are listed in Table 3. 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 3: Postmarketing Reports of Adverse Drug Reactions Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocytopenia Immune System Disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Endocrine Disorders: Pseudoaldosteronism Nervous System Disorders: Peripheral neuropathy, paresthesia, hypoesthesia, tremor Eye Disorders: Visual disturbances, including blurred vision and diplopia Ear and Labyrinth Disorders: Transientor permanent hearing loss Respiratory, Thoracic and Mediastinal Disorders: Pulmonary edema, dyspnea Gastrointestinal Disorders: Pancreatitis, dysgeusia Hepatobiliary Disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria Musculoskeletal and Connective Tissue Disorders: Arthralgia Renal and Urinary Disorders: Urinary incontinence, pollakiuria Reproductive System and Breast Disorders: Erectile dysfunction General Disorders and Administration Site Conditions: Peripheral edema Investigations: Blood creatine phosphokinase increased