Ivabradine

1. 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 adult patients with stable, symptomatic chronic heart failure with reduced left ventricular ejection fraction. ( 1.1 ) For the treatment of stable symptomatic heart failure due to dilated cardiomyopathy in pediatric patients ages 6 months and older. ( 1.2 ) 1.1 Heart Failure in Adult Patients Corlanor is 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. 1.2 Heart Failure in Pediatric Patients Corlanor is indicated for the treatment of stable symptomatic heart failure due to dilated cardiomyopathy (DCM) in pediatric patients aged 6 months and older, who are in sinus rhythm with an elevated heart rate.

2. DOSAGE AND ADMINIST R ATION Adult and pediatric patients greater than 40 kg Starting dose is 2.5 (pediatrics and 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 ) Pediatric patients less than 40 kg Starting dose is 0.05 mg/kg twice daily with food. Adjust dose at two-week intervals by 0.05 mg/kg based on heart rate. Maximum dose is 0.2 mg/kg (patients 6 months to less than 1 year old) or 0.3 mg/kg (patients 1 year old and older), up to a total of 7.5 mg twice daily. 2.1 Adults The recommended starting dose of Corlanor 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, Corlanor 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 50-60 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 )] 2.2 Pediatric Patients Recommended Dosage Pediatric Patients 6 Months of Age and Older Weighing Less than 40 kg (Oral Solution) The recommended starting dose of Corlanor oral solution in pediatric patients 6 months of age and older and weighing less than 40 kg is 0.05 mg/kg twice daily with food. Assess patient at two-week intervals and adjust dose by 0.05 mg/kg to target a heart rate (HR) reduction of at least 20%, based on tolerability. The maximum dose is 0.2 mg/kg twice daily for patients 6 months to less than 1 year old, and 0.3 mg/kg twice daily for patients 1 year old and older, up to a total of 7.5 mg twice daily. If a dose of Corlanor is missed or spit out, do not give another dose to make up for the missed or spit out dose. Give the next dose at the usual time. Pediatric Patients Weighing 40 kg and Greater (Tablets) The recommended starting dose of Corlanor tablets in pediatric patients weighing more than 40 kg is 2.5 mg twice daily with food. Assess patient at two-week intervals and adjust dose by 2.5 mg to target a heart rate (HR) reduction of at least 20%, based on tolerability. The maximum dose is 7.5 mg twice daily. In patients unable to swallow tablets, Corlanor oral solution can be used. Dose Reduction for Bradycardia If bradycardia develops, reduce the dose to the previous titration step. In patients who develop bradycardia at the recommended initial dosage, consider reducing the dosage to 0.02 mg/kg twice daily. Oral Solution Preparation and Administration To administer Corlanor oral solution, empty the entire contents of the ampule(s) into a medication cup. With a calibrated oral syringe, measure the prescribed dose of Corlanor from the medication cup and administer the drug orally. Corlanor oral solution is sterile and preservative-free. Discard the unused oral solution. Do not store or reuse any oral solution left in either the medication cup or an ampule.

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 Corlanor 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 Corlanor [see Use in Specific Populations ( 8.3 )] . 5.2 Atrial Fibrillation Corlanor 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 Corlanor and 3.9% per patient-year in patients treated with placebo [see Clinical Studies ( 14 )] . Regularly monitor cardiac rhythm. Discontinue Corlanor if atrial fibrillation develops. 5.3 Bradycardia and Conduction Disturbances Adult Patients Bradycardia, sinus arrest, and heart block have occurred with Corlanor. The rate of bradycardia was 6.0% per patient-year in patients treated with Corlanor (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 Corlanor exposure, may themselves contribute to heart rate lowering, and should be avoided [see Clinical Pharmacology ( 12.3 )] . Avoid use of Corlanor in patients with 2 nd degree atrioventricular block unless a functioning demand pacemaker is present [see Contraindications ( 4 ) ]. Pediatric Patients Bradycardia and first-degree heart block were observed in pediatric patients treated with Corlanor. Asymptomatic and symptomatic bradycardia were observed in 6.8% and 4.1% of pediatric patients treated with Corlanor, respectively. In the placebo treatment arm, 2.4% of pediatric patients had asymptomatic bradycardia, but none had symptomatic bradycardia. Bradycardia was managed through dose titration but did not result in study drug discontinuation [see Dosage and Administration ( 2.2 )] .

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 )

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 tablets. 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 tablets. 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 tablets 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 tablets with other negative chronotropes. 7.3 Pacemakers in Adults Ivabradine tablets 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 tablets 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 Amgen Medical Information at 1-800-772-6436 (1-800-77-AMGEN) 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 Corlanor and 3,278 patients given placebo. The median duration of Corlanor 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 P henomena (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. Corlanor can cause phosphenes, thought to be mediated through Corlanor’s effects on retinal photoreceptors [see Clinical Ph a rmacology ( 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. Pediatric Patients with Heart Failure The safety of Corlanor in pediatric patients 6 months to less than 18 years of age is based on a clinical trial [see Clinical Studies ( 14.2 )] in symptomatic heart failure patients with dilated cardiomyopathy and elevated heart rate. This trial provides experience in 73 patients treated with Corlanor for a median duration of 397 days, and 42 patients given placebo. Bradycardia (symptomatic and asymptomatic) occurred at rates similar to those in adults. Phosphenes were observed in pediatric patients treated with Corlanor. 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 Corlanor: syncope, hypotension, torsade de pointes, ventricular fibrillation, ventricular tachycardia, angioedema, erythema, rash, pruritus, urticaria, vertigo, and diplopia, and visual impairment.

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Ivabradine tablets blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I f 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 occurred as has PR interval prolongation. There was no effect on ventricular repolarization and no effects on myocardial contractility [see Clinical Pharmacology (12.2) ]. Ivabradine tablets can also inhibit the retinal current I h . I h is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of I h by ivabradine tablets 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 Ivabradine tablets 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). Ivabradine tablets 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 The peak concentration (C max ) and area under the plasma concentration time curve (AUC) are similar for ivabradine and S 18982 between oral solution and tablets for the same dose. Absorption and Bioavailability Following oral administration, peak plasma ivabradine concentrations are reached in approximately1 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%. Ivabradine tablets should be taken with food [see Dosage and Administration (2) ]. Ivabradine is approximately 70% plasma protein bound, and the volume of distribution at steady state is approximately 100 L. 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 ivabradine tablets were studied in several single-and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 2. Figure 2. Impact of Coadministered Drugs on the Pharmacokinetics of Ivabradine tablets 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 C max and AUC inf 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 ivabradine tablets. Specific Populations Age No pharmacokinetic differences (AUC or C max ) 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) ]. Hepatic impairment In patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, the pharmacokinetics of ivabradine tablets 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 ivabradine tablets. No data are available for patients with creatinine clearance below 15 mL/min. Image