Tolsura

WARNING: CONGESTIVE HEART FAILURE and DRUG INTERACTIONS WARNING: CONGESTIVE HEART FAILURE and DRUG INTERACTIONS See full prescribing information for complete boxed warning. Congestive Heart Failure TOLSURA can cause or exacerbate congestive heart failure (CHF). When itraconazole was administered intravenously to healthy human volunteers and dogs, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur or worsen during administration of TOLSURA, reassess the benefit-risk of continuing treatment. ( 5.1 , 6 ). Drug Interactions Co-administration of certain drugs that are metabolized by human CYP3A4 enzymes are contraindicated with TOLSURA because plasma concentrations of such drugs are increased. ( 4.1 , 5.5 , 7.1 ) Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment. ( 4.1 , 7.1 ) Co-administration with eliglustat is contraindicated in poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. ( 4.1 , 7.1 ) Increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. ( 4.1 , 5.5 , 7.1 ) Congestive Heart Failure TOLSURA can cause or exacerbate congestive heart failure (CHF). When itraconazole was administered intravenously to healthy human volunteers and dogs, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur or worsen during administration of TOLSURA, reassess the benefit and risk of continuing treatment [ see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] . Drug Interactions Co-administration of certain drugs that are metabolized by human CYP3A4 enzymes 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 [see Contraindications (4.1) and Drug Interactions (7.1) ] Co-administration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and 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 caused by co-administration with TOLSURA can lead to QT prolongation and/or ventricular tachyarrhythmias, including occurrences of torsades de pointes , a potentially fatal arrhythmia [see Contraindications (4.1) , Warnings and Precautions (5.5) and Drug Interactions (7.1) ] .

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Serious hepatotoxicity, including liver failure and death were reported with the use of itraconazole. Discontinue treatment if signs of liver dysfunction occur ( 5.2 ) 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 ( 5.4 ). Peripheral Neuropathy : This has been reported in patients on long-term therapy with itraconazole. Monitor and promptly evaluate neurologic symptoms. ( 5.6 ) Hearing Loss : Reversible or permanent has been reported in patients. Discontinue treatment if hearing loss occurs ( 5.7 ) 5.1 Congestive Heart Failure TOLSURA can cause or exacerbate congestive heart failure (CHF) [see Boxed Warning and Adverse Reactions (6.1) ]. 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 [see Adverse Reactions (6.2) ] . 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 [see Contraindications (4.1) , Drug Interactions (7.1) and Adverse Reactions (6.2) ] 5.2 Hepatotoxicity 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 [ see Adverse Reactions (6.1) ]. 5.3 Cardiac 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 [see Boxed Warning , Contraindications (4) and Drug Interactions (7) ]. 5.4 Pseudoaldosteronism 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. 5.5 Drug Interaction Potential Itraconazole has a potential for clinically important drug interactions [see Drug Interactions (7.1 , 7.2) ] . 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. [see Boxed Warning , Contraindications (4.1) and Drug Interactions (7.1 , 7.2) ]. 5.6 Peripheral 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. 5.7 Hearing 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 [see Boxed Warning , Contraindications (4.2) and Drug Interactions (7) ] . The hearing loss usually resolves when treatment is stopped but can persist in some patients. 5.8 Hypersensitivity Reactions TOLSURA is contraindicated in patients with a known hypersensitivity to itraconazole [see Contraindications (4.2) ]. Hypersensitivity reactions have been reported with the use of itraconazole [see Adverse Reactions (6.2) ] . 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Congestive Heart Failure [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Cardiac Dysrhythmias [see Warnings and Precautions (5.3) ] Pseudoaldosteronism [see Warnings and Precautions (5.4) ] Peripheral Neuropathy [see Warnings and Precautions (5.6) ] Hearing Loss [see Warnings and Precautions (5.7) ] Hypersensitivity Reactions [see Warnings and Precautions (5.8) ] 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 ( 6.1 ) 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 . 6.1 Clinical 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 6.2 Postmarketing 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

<table width="75%"><caption>Table 2: Clinical Trials of Systemic Fungal Infections: Adverse Reactions Occurring with an Incidence of &#x2265;1%</caption><col width="60%" align="left" valign="top"/><col width="40%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule">Body System/Adverse Reaction</th><th styleCode="Rrule">Incidence (%) (N=602)</th></tr></thead><tbody><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal</content></td><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">11</td></tr><tr><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">5</td></tr><tr><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule">Abdominal Pain</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anorexia</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Body as a Whole</content></td><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Edema</td><td styleCode="Rrule">4</td></tr><tr><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule">Fever</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Malaise</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Skin and Appendages</content></td><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Rash<footnote ID="foot21">Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications.</footnote></td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Central/Peripheral Nervous System</content></td><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Psychiatric</content></td><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Libido Decreased</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Somnolence</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Cardiovascular</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Metabolic/Nutritional</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Urinary System</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Albuminuria</td><td styleCode="Rrule">1</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Liver and Biliary System</content></td><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hepatic Function Abnormal</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Reproductive System, Male</content></td><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Impotence</td><td styleCode="Rrule">1</td></tr></tbody></table>

<table width="90%"><caption>Table 3: Postmarketing Reports of Adverse Drug Reactions</caption><col width="50%" align="left" valign="top"/><col width="50%" align="left" valign="top"/><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Blood and Lymphatic System Disorders:</content></td><td styleCode="Rrule">Leukopenia, neutropenia, thrombocytopenia</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Immune System Disorders:</content></td><td styleCode="Rrule">Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Endocrine Disorders:</content></td><td styleCode="Rrule">Pseudoaldosteronism</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Nervous System Disorders:</content></td><td styleCode="Rrule">Peripheral neuropathy, paresthesia, hypoesthesia, tremor</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Eye Disorders:</content></td><td styleCode="Rrule">Visual disturbances, including blurred vision and diplopia</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Ear and Labyrinth Disorders:</content></td><td styleCode="Rrule">Transientor permanent hearing loss</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders:</content></td><td styleCode="Rrule">Pulmonary edema, dyspnea</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders:</content></td><td styleCode="Rrule">Pancreatitis, dysgeusia</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Hepatobiliary Disorders:</content></td><td styleCode="Rrule">Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders:</content></td><td styleCode="Rrule">Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders:</content></td><td styleCode="Rrule">Arthralgia</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Renal and Urinary Disorders:</content></td><td styleCode="Rrule">Urinary incontinence, pollakiuria</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Reproductive System and Breast Disorders:</content></td><td styleCode="Rrule">Erectile dysfunction</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions:</content></td><td styleCode="Rrule">Peripheral edema</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Investigations:</content></td><td styleCode="Rrule">Blood creatine phosphokinase increased</td></tr></tbody></table>