DRUG INTERACTIONS Cytochrome P450-Based Interactions Corlanor 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 Corlanor. 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 Corlanor. Examples of CYP3A4 inducers include St. John’s wort, rifampicin, barbiturates, and phenytoin [see Clinical Pharmacology (12.3)]. Reference ID: 3732763 7.2 Negative Chronotropes Most patients receiving Corlanor 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 Corlanor with other negative chronotropes. 7.3 Pacemakers

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use CORLANOR ® safely and effectively. See full prescribing information for CORLANOR. CORLANOR (ivabradine) tablets, for oral use Initial U.S. Approval: 2015 --------------------------- INDICATIONS AND USAGE---------------------------- Corlanor (ivabradine) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker indicated to reduce the risk of hospitalization for worsening heart failure in 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 betablockers or have a contraindication to beta-blocker use. (1) -----------------------DOSAGE AND ADMINISTRATION ----------------------­ • Starting dose is 5 mg twice daily. After 2 weeks of treatment, adjust dose based on heart rate. The maximum dose is 7.5 mg twice daily. (2) • In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, initiate dosing at 2.5 mg twice daily. (2) --------------------- DOSAGE FORMS AND STRENGTHS---------------------­ Tablets: 5 mg, 7.5 mg (3) ------------------------------ CONTRAINDICATIONS -----------------------------­ • Acute decompensated heart failure (4) • Blood pressure less than 90/50 mmHg (4) • Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present (4) • Resting heart rate less than 60 bpm prior to treatment (4) • Severe hepatic impairment (4) • Pacemaker dependence (heart rate maintained exclusively by the pacemaker) (4) • In combination with strong cytochrome CYP3A4 inhibitors (4) ----------------------- 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 2nd degree AV block. (5.3) ------------------------------ ADVERSE REACTIONS -----------------------------­ 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 Amgen Medical Information at 1-800-772-6436 (1-800-77-AMGEN) or FDA at 1­ 800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS------------------------------­ • CYP3A4 inhibitors increase Corlanor plasma concentrations and CYP3A4 inducers decrease Corlanor plasma concentrations. (7.1) • Negative chronotropes: Increased risk of bradycardia, monitor heart rate. (7.2) • Pacemakers: Not recommended for use with demand pacemakers set to rates = 60 beats per minute. (7.3) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ • Lactation: Breastfeeding not recommended. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 04/2015 FULL PRES

In combination with strong cytochrome CYP3A4 inhibitors (4) ----------------------- 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 2nd degree AV block. (5.3) ------------------------------ ADVERSE REACTIONS -----------------------------­ 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 Amgen Medical Information at 1-800-772-6436 (1-800-77-AMGEN) or FDA at 1­ 800-FDA-1088 or www.fda.gov/medwatch. ------------------------------ DRUG INTERACTIONS------------------------------­ • CYP3A4 inhibitors increase Corlanor plasma concentrations and CYP3A4 inducers decrease Corlanor plasma concentrations. (7.1) • Negative chronotropes: Increased risk of bradycardia, monitor heart rate. (7.2) • Pacemakers: Not recommended for use with demand pacemakers set to rates = 60 beats per minute. (7.3) ----------------------- USE IN SPECIFIC POPULATIONS ----------------------­ • Lactation: Breastfeeding not recommended. (8.2) See 17 for PATIENT C

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). • Fetal Toxicity Advise pregnant women of the potential risks to a fetus. Reference ID: 3732763 Advise females of reproductive potential to use effective contraception and to notify their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. • Low Heart Rate Advise patients to report significant decreases in heart rate or symptoms such as dizziness, fatigue, or hypotension [see Warnings and Precautions (5.3)]. • Atrial fibrillation Advise patients to report symptoms of atrial fibrillation, such as heart palpitations or racing, chest pressure, or worsened shortness of breath [see Warnings and Precautions (5.2)]. • Phosphenes Advise patients about the possible occurrence of luminous phenomena (phosphenes). Advise patients to use caution if they are driving or using machines in situations where sudden changes in light intensity may occur, especially when driving at night. Advise patients that phosphenes may subside spontaneously during continued treatment with Corlanor [see Adverse Reactions (6.1)]. • Drug Interactions Advise patients to avoid ingestion of grapefruit juice and St. John’s wort [see Drug Interactions (7.1)]. • Intake with Food Advise patients to take Corlanor twice daily with meals [see Dosage and Administration (2)].

• Intake with Food Advise patients to take Corlanor twice daily with meals [see Dosage and Administration (2)].

Corlanor® (ivabradine) Manufactured for: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799

CLINICAL PHARMACOLOGY Mechanism of Action Corlanor blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker If current, which regulates heart rate. In clinical electrophysiology studies, the cardiac effects were most pronounced in the sinoatrial (SA) node, but prolongation of the AH interval has Reference ID: 3732763 occurred on the surface ECG, as has PR interval prolongation. There was no effect on ventricular repolarization and no effects on myocardial contractility [see Clinical Pharmacology (12.2)]. Corlanor can also inhibit the retinal current Ih. Ih is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of Ih by Corlanor may underlie the luminous phenomena experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field [see Adverse Reactions (6.1)]. 12.2 Pharmacodynamics Corlanor causes a dose-dependent reduction in heart rate. The size of the effect is dependent on the baseline heart rate (i.e., greater heart rate reduction occurs in subjects with higher baseline heart rate). At recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise. Analysis of heart rate reduction vs. dose indicates a plateau effect at doses > 20 mg twice daily. In a study of subjects with preexisting conduction system disease (first-or second-degree AV block or left or right bundle branch block) requiring electrophysiologic study, IV ivabradine (0.20 mg/kg) administration slowed the overall heart rate by approximately 15 bpm, increased the PR interval (29 msec), and increased the AH interval (27 msec). Corlanor does not have negative inotropic effects. Ivabradine increases the uncorrected QT interval with heart rate slowing but does not cause rate-corrected prolongation of QT. 12.3 Pharmacokinetics Absorption and Bioavailability Following oral administration, peak plasma ivabradine concentrations are reached in approximately 1 hour under fasting conditions. The absolute oral bioavailability of ivabradine is approximately 40% because of first-pass elimination in the gut and liver. Food delays absorption by approximately 1 hour and increases plasma exposure by 20% to 40%. Corlanor should be taken with meals [see Dosage and Administration (2)]. Ivabradine is approximately 70% plasma protein bound, and the volume of distribution at steady state is approximately 100 L. Reference ID: 3732763 Metabolism and Excretion The pharmacokinetics of ivabradine are linear over an oral dose range of 0.5 mg to 24 mg. Ivabradine is extensively metabolized in the liver and intestines by CYP3A4-mediated oxidation. The major metabolite is the N-desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations approximately 40% that of ivabradine. The N-desmethylated derivative is also metabolized by CYP3A4. Ivabradine plasma levels decline with a distribution half-life of 2 hours and an effective half-life of approximately 6 hours. The total clearance of ivabradine is 24 L/h, and renal clearance is approximately 4.2 L/h, with ~ 4% of an oral dose excreted unchanged in urine. The excretion of metabolites occurs to a similar extent via feces and urine.

Drug Interactions The effects of coadministered drugs (CYP3A4 inhibitors, substrates, inducers, and other concomitantly administered drugs) on the pharmacokinetics of Corlanor were studied in several single- and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 2. Reference ID: 3732763 Figure 2. Impact of Coadministered Drugs on the Pharmacokinetics of Corlanor Digoxin exposure did not change when concomitantly administered with ivabradine. No dose adjustment is required when ivabradine is concomitantly administered with digoxin. Effect of Ivabradine on Metformin Pharmacokinetics Ivabradine, dosed at 10 mg twice daily to steady state, did not affect the pharmacokinetics of metformin (an organic cation transporter [OCT2] sensitive substrate). The geometric mean (90% confidence interval [CI]) ratios of Cmax and AUCinf of metformin, with and without ivabradine were 0.98 [0.83–1.15] and 1.02 [0.86–1.22], respectively. No dose adjustment is required for metformin when administered with Corlanor. Specific Populations Age No pharmacokinetic differences (AUC or Cmax) have been observed between elderly (= 65 years) or very elderly (= 75 years) patients and the overall patient population [see Use in Specific Populations (8.5)]. Reference ID: 3732763 Hepatic Impairment In patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of Corlanor were similar to that in patients with normal hepatic function. No data are available in patients with severe hepatic impairment (Child-Pugh C) [see Contraindications (4)].

Renal Impairment Renal impairment (creatinine clearance from 15 to 60 mL/min) has minimal effect on the pharmacokinetics of Corlanor. No data are available for patients with creatinine clearance below 15 mL/min. Pediatrics The pharmacokinetics of Corlan

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on findings in animals, Corlanor may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Corlanor in pregnant women to inform any drug associated 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 (AUC0-24hr) 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 postnatal mortality was associated with these teratogenic effects in rats. In pregnant rabbits, increased post-implantation loss was noted at an exposure (AUC0-24hr) 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 Corlanor, especially during the first trimester, should be Reference ID: 3732763 followed closely for destabilization of their congestive heart failure that could result from heart rate slowing. Monitor pregnant women with chronic heart failure in 3rd trimester of pregnancy for preterm birth. Data Animal Data In pregnant rats, oral administration of ivabradine during the period of organogenesis (gestation day 6-15) 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 AUC0-24hr). 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 AUC0-24hr). In pregnant rabbits, oral administration of ivabradine during the period of organogenesis (gestation day 6 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 AUC0-24hr) 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 AUC0-24hr), 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 postnatal 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 postnatal 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 AUC0-24hr). 8.2 Lactation Risk Summary There is no information regarding the presence of ivabradine in human milk, the effects of ivabradine on the breastfed infant, or the effects of the drug on milk production. Animal studies have shown, however, that ivabradine is present in rat milk [see Data]. Because of the potential risk to breastfed infants from exposure to Corlanor, breastfeeding is not recommended. Reference ID: 3732763 Data Lactating rats received daily oral doses of [14C]-ivabradine (7 mg/kg) on post-parturition days 10 to 14; milk and maternal plasma were collected at 0.5 and 2.5 hours post-dose on day 14. The ratios of total radioactivity associated with [14C]-ivabradine or its metabolites in milk vs. plasma were 1.5 and 1.8, respectively, indicating that ivabradine is transferred to milk after oral administration. 8.3 Females and Males of Reproductive Potential Contraception Females Corlanor may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during Corlanor treatment [see Use in Specific Populations (8.1)]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use No pharmacokinetic differences have been observed in elderly (= 65 years) or very elderly (= 75 years) patients compared to the overall population. However, Corlanor has only been studied in a limited number of patients = 75 years of age. 8.6 Hepatic Impairment No dose adjustment is required in patients with mild or moderate hepatic impairment. Corlanor is contraindicated in patients with severe hepatic impairment (Child-Pugh C) as it has not been studied in this population and an increase in systemic exposure is anticipated [see Contraindications (4) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dosage adjustment is required for patients with creatinine clearance 15 to 60 mL/min. No data are available for patients with creatinine clearance below 15 mL/min [see Clinical Pharmacology (12.3)].

10. OVERDOSAGE Overdose may lead to severe and prolonged bradycardia. In the event of bradycardia with poor hemodynamic tolerance, temporary cardiac pacing may be required. Supportive treatment, including intravenous (IV) fluids, atropine, and intravenous beta-stimulating agents such as isoproterenol, may be considered.