IVABRADINE ZYDUS 5 mg

1 INDICATIONS AND USAGE Ivabradine tablets are a hyperpolarization-activated cyclic nucleotide-gated channel blocker indicated: To reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with reduced left ventricular ejection fraction. ( 1.1 ) 1.1 Heart Failure in Adult Patients Ivabradine tablets are indicated to reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤ 35%, who are in sinus rhythm with resting heart rate ≥ 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

2 DOSAGE AND ADMINISTRATION Adult patients Starting dose is 2.5 (vulnerable adults) or 5 mg twice daily with food. After 2 weeks of treatment, adjust dose based on heart rate. The maximum dose is 7.5 mg twice daily. ( 2.1 ) 2.1 Adults The recommended starting dose of ivabradine tablets are 5 mg twice daily with food. Assess patient after two weeks and adjust dose to achieve a resting heart rate between 50 and 60 beats per minute (bpm) as shown in Table 1. Thereafter, adjust dose as needed based on resting heart rate and tolerability. The maximum dose is 7.5 mg twice daily. In adult patients unable to swallow tablets, Ivabradine oral solution can be used [see Clinical Pharmacology (12.3)] . In patients with a history of conduction defects or other patients in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg twice daily before increasing the dose based on heart rate [see Warnings and Precautions (5.3)] . Table 1. Dose Adjustment for Adults Heart Rate Dose Adjustment > 60 bpm Increase dose by 2.5 mg (given twice daily) up to maximum dose of 7.5 mg twice daily 50-60 bpm Maintain dose < 50 bpm or signs and symptoms of bradycardia Decrease dose by 2.5 mg (given twice daily); if current dose is 2.5 mg twice daily, discontinue therapy* * [see Warnings and Precautions (5.3)]

5 WARNINGS AND PRECAUTIONS • Fetal toxicity: Females should use effective contraception. ( 5.1 ) • Monitor patients for atrial fibrillation. ( 5.2 ) • Monitor heart rate decreases and bradycardia symptoms during treatment. ( 5.3 ) • Not recommended in patients with 2 nd degree AV block. ( 5.3 ) 5.1 Fetal Toxicity Ivabradine may cause fetal toxicity when administered to a pregnant woman based on findings in animal studies. Embryo-fetal toxicity and cardiac teratogenic effects were observed in fetuses of pregnant rats treated during organogenesis at exposures 1 to 3 times the human exposures (AUC 0-24hr ) at the maximum recommended human dose (MRHD) [ see Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception when taking ivabradine [ see Use in Specific Populations (8.3) ] . 5.2 Atrial Fibrillation Ivabradine increases the risk of atrial fibrillation. In the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), the rate of atrial fibrillation was 5.0% per patient-year in patients treated with ivabradine and 3.9% per patient-year in patients treated with placebo [ see Clinical Studies (14) ] . Regularly monitor cardiac rhythm. Discontinue ivabradine if atrial fibrillation develops. 5.3 Bradycardia and Conduction Disturbances Adult Patients Bradycardia, sinus arrest, and heart block have occurred with ivabradine. The rate of bradycardia was 6.0% per patient-year in patients treated with ivabradine (2.7% symptomatic; 3.4% asymptomatic) and 1.3% per patient-year in patients treated with placebo. Risk factors for bradycardia include sinus node dysfunction, conduction defects (e.g., 1 st or 2 nd degree atrioventricular block, bundle branch block), ventricular dyssynchrony, and use of other negative chronotropes (e.g., digoxin, diltiazem, verapamil, amiodarone). Bradycardia may increase the risk of QT prolongation which may lead to severe ventricular arrhythmias, including torsade de pointes, especially in patients with risk factors such as use of QTc prolonging drugs [see Adverse Reactions (6.2)] . Concurrent use of verapamil or diltiazem will increase ivabradine exposure, may themselves contribute to heart rate lowering, and should be avoided [see Clinical Pharmacology (12.3)] . Avoid use of ivabradine in patients with 2 nd degree atrioventricular block unless a functioning demand pacemaker is present [see Contraindications (4)] .

6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: • Atrial Fibrillation [ see Warnings and Precautions (5.2) ] • Bradycardia and Conduction Disturbances [ see Warnings and Precautions (5.3) ] Most common adverse reactions occurring in ≥ 1% of patients are bradycardia, hypertension, atrial fibrillation and luminous phenomena (phosphenes). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals, LLC at 1-855-668-2369 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 practice. Adult Patients with Heart Failure In SHIFT, safety was evaluated in 3,260 patients treated with ivabradine and 3,278 patients given placebo. The median duration of ivabradine exposure was 21.5 months. The most common adverse drug reactions in the SHIFT trial are shown in Table 2 [ see Warnings and Precautions (5.2) , ( 5.3 )] . Table 2. Adverse Drug Reactions with Rates ≥ 1.0% Higher on Ivabradine than Placebo occurring in > 1% on Ivabradine in SHIFT Ivabradine N = 3,260 Placebo N = 3,278 Bradycardia 10% 2.2% Hypertension, blood pressure increased 8.9% 7.8% Atrial fibrillation 8.3% 6.6% Phosphenes, visual brightness 2.8% 0.5% Luminous Phenomena (Phosphenes) Phosphenes are phenomena described as a transiently enhanced brightness in a limited area of the visual field, halos, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency). Phosphenes are usually triggered by sudden variations in light intensity. Ivabradine can cause phosphenes, thought to be mediated through ivabradine's effects on retinal photoreceptors [ see Clinical Pharmacology (12.1) ] . Onset is generally within the first 2 months of treatment, after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity and led to treatment discontinuation in < 1% of patients; most resolved during or after treatment. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. The following adverse reactions have been identified in adults during post-approval use of ivabradine: syncope, hypotension, torsade de pointes, ventricular fibrillation, ventricular tachycardia, angioedema, erythema, rash, pruritus, urticaria, vertigo, diplopia, and visual impairment.