IVABRADINE

1 INDICATIONS AND USAGE Ivabradine is 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 is 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 a maximum dose of 7.5 mg twice daily 50 to 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 )]

4 CONTRAINDICATIONS Ivabradine tablets are contraindicated in patients with: • Acute decompensated heart failure • Clinically significant hypotension • Sick sinus syndrome, sinoatrial block or 3 rd degree AV block, unless a functioning demand pacemaker is present • Clinically significant bradycardia [see Warnings and Precautions ( 5.3 )] • Severe hepatic impairment [see Use in Specific Populations ( 8.6 )] • Pacemaker dependence (heart rate maintained exclusively by the pacemaker) [see Drug Interactions ( 7.3 )] • Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors [see Drug Interactions ( 7.1 )] • Acute decompensated heart failure ( 4 ) • Clinically significant hypotension ( 4 ) • Sick sinus syndrome, sinoatrial block or 3 rd degree AV block, unless a functioning demand pacemaker is present ( 4 ) • Clinically significant bradycardia ( 4 ) • Severe hepatic impairment ( 4 ) • Heart rate maintained exclusively by the pacemaker ( 4 ) • In combination with strong cytochrome CYP3A4 inhibitors ( 4 )

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 to 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 I f 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 )].

7 DRUG INTERACTIONS • Avoid CYP3A4 inhibitors or inducers. ( 7.1 ) • Negative chronotropes increase risk of bradycardia; monitor heart rate. ( 7.2 ) 7.1 Cytochrome P450-Based Interactions Ivabradine is primarily metabolized by CYP3A4. Concomitant use of CYP3A4 inhibitors increases ivabradine plasma concentrations and use of CYP3A4 inducers decreases them. Increased plasma concentrations may exacerbate bradycardia and conduction disturbances. The concomitant use of strong CYP3A4 inhibitors is contraindicated [see Contraindications ( 4 ) and Clinical Pharmacology ( 12.3 )] . Examples of strong CYP3A4 inhibitors include azole antifungals (e.g., itraconazole), macrolide antibiotics (e.g., clarithromycin, telithromycin), HIV protease inhibitors (e.g., nelfinavir), and nefazodone. Avoid concomitant use of moderate CYP3A4 inhibitors when using ivabradine. Examples of moderate CYP3A4 inhibitors include diltiazem, verapamil, and grapefruit juice [see Warnings and Precautions ( 5.3 ) and Clinical Pharmacology ( 12.3 )]. Avoid concomitant use of CYP3A4 inducers when using ivabradine. Examples of CYP3A4 inducers include St. John's wort, rifampicin, barbiturates, and phenytoin [see Clinical Pharmacology ( 12.3 )]. 7.2 Negative Chronotropes Most patients receiving ivabradine will also be treated with a beta-blocker. The risk of bradycardia increases with concomitant administration of drugs that slow heart rate (e.g., digoxin, amiodarone, beta-blockers). Monitor heart rate in patients taking ivabradine with other negative chronotropes. 7.3 Pacemakers in Adults Ivabradine dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute in adults [see Dosage and Administration ( 2.1 )] . Patients with demand pacemakers set to a rate ≥ 60 beats per minute cannot achieve a target heart rate < 60 beats per minute, and these patients were excluded from clinical trials [see Clinical Studies ( 14.1 )] . The use of ivabradine is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute.

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 Annora Pharma Private Limited at 1-866-495-1995 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 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, and diplopia, and visual impairment.

8.1 Pregnancy Risk Summary Based on findings in animals, ivabradine may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of ivabradine in pregnant women to inform any drugassociated risks. In animal reproduction studies, oral administration of ivabradine to pregnant rats during organogenesis at a dosage providing 1 to 3 times the human exposure (AUC 0 to 24hr ) at the MRHD resulted in embryo-fetal toxicity and teratogenicity manifested as abnormal shape of the heart, interventricular septal defect, and complex anomalies of primary arteries. Increased post-natal mortality was associated with these teratogenic effects in rats. In pregnant rabbits, increased post-implantation loss was noted at an exposure (AUC 0 to 24hr ) 5 times the human exposure at the MRHD. Lower doses were not tested in rabbits. The background risk of major birth defects for the indicated population is unknown. The estimated background risk of major birth defects in the U.S. general population is 2 to 4%, however, and the estimated risk of miscarriage is 15 to 20% in clinically recognized pregnancies. Advise a pregnant woman of the potential risk to the fetus. Clinical Considerations Disease-associated Maternal and/or Embryo-fetal Risk Stroke volume and heart rate increase during pregnancy, increasing cardiac output, especially during the first trimester. Pregnant patients with left ventricular ejection fraction less than 35% on maximally tolerated doses of beta-blockers may be particularly heart rate dependent for augmenting cardiac output. Therefore, pregnant patients who are started on ivabradine, especially during the first trimester, should be followed closely for destabilization of their congestive heart failure that could result from heart rate slowing. Monitor pregnant women with chronic heart failure in 3 rd trimester of pregnancy for preterm birth. Data Animal Data In pregnant rats, oral administration of ivabradine during the period of organogenesis (gestation day 6 to 15) at doses of 2.3, 4.6, 9.3, or 19 mg/kg/day resulted in fetal toxicity and teratogenic effects. Increased intrauterine and post-natal mortality and cardiac malformations were observed at doses ≥ 2.3 mg/kg/day (equivalent to the human exposure at the MRHD based on AUC 0 to 24hr ). Teratogenic effects including interventricular septal defect and complex anomalies of major arteries were observed at doses ≥ 4.6 mg/kg/day (approximately 3 times the human exposure at the MRHD based on AUC 0 to 24hr ). In pregnant rabbits, oral administration of ivabradine during the period of organogenesis (gestation day 6 to 18) at doses of 7, 14, or 28 mg/kg/day resulted in fetal toxicity and teratogenicity. Treatment with all doses ≥ 7 mg/kg/day (equivalent to the human exposure at the MRHD based on AUC 0 to 24hr ) caused an increase in post-implantation loss. At the high dose of 28 mg/kg/day (approximately 15 times the human exposure at the MRHD based on AUC 0 to 24hr ), reduced fetal and placental weights were observed, and evidence of teratogenicity (ectrodactylia observed in 2 of 148 fetuses from 2 of 18 litters) was demonstrated. In the pre- and post-natal study, pregnant rats received oral administration of ivabradine at doses of 2.5, 7, or 20 mg/kg/day from gestation day 6 to lactation day 20. Increased post-natal mortality associated with cardiac teratogenic findings was observed in the F1 pups delivered by dams treated at the high dose (approximately 15 times the human exposure at the MRHD based on AUC 0 to 24hr ).