WARNING: CONGESTIVE HEART FAILURE, CARDIAC EFFECTS, AND DRUG INTERACTIONS Do not administer ONMEL for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur during administration of ONMEL, discontinue administration. [See Contraindications (4) , Warnings and Precautions (5) , Drug Interactions (7) , and Clinical Pharmacology (12) ] Drug Interactions: Co-administration of cisapride, pimozide, quinidine, dofetilide, levacetylmethadol (levomethadyl), felodipine, oral midazolam, nisoldipine, triazolam, lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with ONMEL is contraindicated. ONMEL, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. [See Contraindications (4) , Warnings and Precautions (5) , and Drug Interactions (7) ] WARNING: CONGESTIVE HEART FAILURE, CARDIAC EFFECTS AND DRUG INTERACTIONS See full prescribing information for complete boxed warning. Do not administer for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF ( 4 ). If signs or symptoms of congestive heart failure occur during administration, discontinue administration. ( 4 ) Negative inotropic effects were seen when itraconazole was administered intravenously to dogs and healthy human volunteers. ( 5.3 ) Drug Interactions: Co-administration of certain drugs is contraindicated. See complete boxed warning. ( 7 ) May increase plasma concentrations of drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) pathway. ( 7 ) Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using certain drugs. See complete boxed warning. ( 5.2 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Cases of CHF, peripheral edema, and pulmonary edema have been reported with itraconazole administration among patients being treated for onychomycosis and/or systemic fungal infections. ( 5.5 ) Cardiac Dysrhythmias: ( 5.2 ) Cardiac Disease : ( 5.3 ) Hepatic Effects: ( 5.4 ) Calcium Channel Blockers : ( 5.5 ) Neuropathy: ( 5.6 ) Hearing Loss: ( 5.7 ) 5.1 Congestive Heart Failure, Peripheral Edema, and Pulmonary Edema Cases of CHF, peripheral edema, and pulmonary edema have been reported with itraconazole administration among patients being treated for onychomycosis and/or systemic fungal infections. [ See Contraindications (4) , Warnings and Precautions (5) , and Clinical Pharmacology (12) .] 5.2 Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with ONMEL is contraindicated. [See Boxed Warning , Contraindications (4) , Warnings and Precautions (5) , and Drug Interactions (7) .] 5.3 Cardiac Disease ONMEL should not be administered in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. 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 injection, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of ONMEL 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 ONMEL, discontinue administration. 5.4 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 hepatotoxicity, treatment should be discontinued immediately and liver function testing performed. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is not recommended. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving ONMEL. 5.5 Calcium Channel Blockers 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 ONMEL and nisoldipine is contraindicated. 5.6 Neuropathy If neuropathy occurs that may be attributable to ONMEL, the treatment should be discontinued. 5.7 Hearing Loss Transient 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 , Warnings and Precautions (5) , and Drug Interactions (7) .] The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
6 ADVERSE REACTIONS Most common adverse reactions observed in the treatment phase of the onychomycosis clinical trial (>1%) are upper respiratory tract infections, increased hepatic enzymes, hypoacusis, headache, abdominal pain, diarrhea, nausea, fatigue, arrhythmia, cough, sore throat and back pain. ( 6.1 ) Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merz Pharmaceuticals, LLC at 1-877-743-8454 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, the adverse reaction rate 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. Patients in the trial for toenail onychomycosis were treated with a dosing regimen of 200 mg once daily for 12 consecutive weeks. The most commonly reported adverse reaction leading to discontinuation of ONMEL was increased hepatic enzyme (6 subjects, 1.0%), followed by dizziness (3 subjects, 0.5%). No other adverse reaction leading to discontinuation occurred in more than one subject. The table below lists all adverse reactions reported by at least 1% of patients who received ONMEL during 12 weeks of treatment: Table 1: Adverse Reactions Occurring at Frequencies ≥ 1% in the Onychomycosis Clinical Trial Incidence (%) Incidence (%) BODY SYSTEM/ADVERSE REACTION ONMEL Placebo tablet (N = 582) (N = 191) INFECTIONS AND INFESTATIONS Upper respiratory tract infections 6.0% 7.3% Bacteriuria 1.4% 1.6% Urinary tract infection 1.0% 0.5% I NVESTIGATIONS Hepatic enzymes increased 2.9% 0.0% Electrocardiogram abnormal 1.4% 1.6% EAR AND LABYRINTH DISORDERS Hypoacusis 3.3% 3.1% NERVOUS SYSTEM DISORDERS Headache 2.2% 1.6% Dizziness 1.2% 0.0% GASTROINTESTINAL DISORDERS Abdominal pain or discomfort 1.7% 2.6% Diarrhea 1.7% 3.1% Nausea 1.7% 1.6% GENERAL DISORDERS OF ADMINISTRATION SITE CONDITIONS Fatigue 1.5% 2.6% CARDIAC DISORDERS Sinus Bradycardia 1.0% 0.0% RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Cough 1.2% 0.0% Pharyngolaryngeal pain 1.0% 0.5% MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Back pain 1.2% 2.1% 6.2 Post Marketing Experience The following adverse reactions have been identified during post-approval use of itraconazole (all formulations) and are listed in Table 2 below. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establishing a causal relationship to drug exposure. Table 2: Postmarketing Reports of Adverse Reactions for Itraconazole Blood and lymphatic system disorders: Leukopenia, neutropenia, thrombocytopenia Immune system disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Metabolism and nutritional disorders: Hypertriglyceridemia, hypokalemia Nervous system disorders: Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness Eye disorders: Visual disturbances, including vision blurred and diplopia Ear and labyrinth disorders: Transient or permanent hearing loss, tinnitus Cardiac disorders: Congestive heart failure Respiratory, thoracic and mediastinal disorders: Pulmonary edema Gastrointestinal disorders: Abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia Hepato-biliary disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, leukocytoclastic vasculitis, erythema multiforme, alopecia, photosensitivity, rash, urticaria, pruritus Musculoskeletal and connective tissue disorders: Myalgia, arthralgia Renal and urinary disorders: Urinary incontinence, pollakiuria Reproductive system and breast disorders: Menstrual disorders, erectile dysfunction General disorders and administration site conditions: Peripheral edema