harmacology ( 12.3 )] . avoid concomitant use of cyp3a4 inducers when using corlanor. examples of cyp3a4 inducers include st. john’s wort, rifampicin, barbiturates, and phenytoin [ s ee clinical pharmacology ( 12.3 )] . 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 in adults corlanor dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute in adults [see dos ag e 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 corlanor is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute.

ue to dilated cardiomyopathy (dcm) in pediatric patients aged 6 months and older, who are in sinus rhythm with an elevated heart rate.

e 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 )] .

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.

cebo. 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.

harmacology ( 12.3 )] . avoid concomitant use of cyp3a4 inducers when using corlanor. examples of cyp3a4 inducers include st. john’s wort, rifampicin, barbiturates, and phenytoin [ s ee clinical pharmacology ( 12.3 )] . 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 in adults corlanor dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute in adults [see dos ag e 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 corlanor is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute.

opulation 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 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 6-15) 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- 24 hr ). 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- 24 hr ). 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 auc 0- 24 hr ) 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- 24 hr ), 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- 24 hr ). 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 [ s ee data ] . because of the potential risk to breastfed infants from exposure to corlanor, breastfeeding is not recommended. 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 [ s ee use in specific populations ( 8.1 )] . 8.4 pediatric use the safety and effectiveness of corlanor have been established in pediatric patients (age 6 months to less than 18 years old) and are supported by pharmacokinetic and pharmacodynamic trials and evidence from adequate and well-controlled trials of corlanor in adult patients. the pediatric study included 116 patients in the following age groups: 17 patients in the 6 months to less than 12 months age group, 36 patients in the 1 year to less than 3 years age group, and 63 patients in the 3 years to less than 18 years age group [see dosage and administration ( 2.2 ), adverse reactions ( 6.1 ), clinical pharmacology ( 12.3 ) and clinical studies ( 14.2 )] . the safety and efficacy of corlanor have not been established in patients less than 6 months of age. animal data ivabradine given orally to juvenile rats from post-natal day (pnd) 7 until pnd 77 at 7.5, 15 and 30 mg/kg/day did not affect post-natal (pre-weaning) development and reproductive performance (post-weaning development). similar to adult animals, ivabradine decreased heart rate dose-dependently, and increased heart weights at the highest dose administered. ivabradine also decreased white blood cell counts (lymphocytes) at the highest dose administered. the decrease in white blood cell counts partially reversed within a 3-week recovery period. exposures in male and female rats at the no observed adverse effect level (noael) of 7.5 mg/kg/day, was approximately 3 and 8 times, respectively, steady state exposure associated with the highest received maintenance doses across age groups in pediatric patients (based on aucs). 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 )] .

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 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 6-15) 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- 24 hr ). 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- 24 hr ). 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 auc 0- 24 hr ) 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- 24 hr ), 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- 24 hr ).

lopment). similar to adult animals, ivabradine decreased heart rate dose-dependently, and increased heart weights at the highest dose administered. ivabradine also decreased white blood cell counts (lymphocytes) at the highest dose administered. the decrease in white blood cell counts partially reversed within a 3-week recovery period. exposures in male and female rats at the no observed adverse effect level (noael) of 7.5 mg/kg/day, was approximately 3 and 8 times, respectively, steady state exposure associated with the highest received maintenance doses across age groups in pediatric patients (based on aucs).

d area of the visual field [see a dverse r eactions ( 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 patients 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 patients 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 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 b ioavailability 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 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 corlanor 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 co a dministered 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 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 corlanor. 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 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 ivabradine and the major metabolite s 18982 were evaluated in 70 pediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure aged from 6 months to less than 18 years of age given ivabradine twice daily [see clinical studies ( 14.2 )] . ivabradine and s 18982 metabolite exposures were measured following weight-based dosing and dose titration designed to reach a dose that enables a 20% heart rate reduction without inducing bradycardia and/or signs or symptoms related to bradycardia. analyses showed the relationship between exposure and heart rate reduction was similar across pediatric age groups and adults. steady state exposures of ivabradine and s 18982 following maintenance doses in pediatric patients are similar to exposures achieved in adult heart failure patients given 5 mg bid.

jor 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. figure 2 . impact of co a dministered 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 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 corlanor. 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 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 ivabradine and the major metabolite s 18982 were evaluated in 70 pediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure aged from 6 months to less than 18 years of age given ivabradine twice daily [see clinical studies ( 14.2 )] . ivabradine and s 18982 metabolite exposures were measured following weight-based dosing and dose titration designed to reach a dose that enables a 20% heart rate reduction without inducing bradycardia and/or signs or symptoms related to bradycardia. analyses showed the relationship between exposure and heart rate reduction was similar across pediatric age groups and adults. steady state exposures of ivabradine and s 18982 following maintenance doses in pediatric patients are similar to exposures achieved in adult heart failure patients given 5 mg bid.

ed that ivabradine did not affect fertility in male or female rats at exposures 46 to 133 times the human exposure (auc 0-24hr ) at the mrhd. 13.2 animal toxicology and/or pharmacology reversible changes in retinal function were observed in dogs administered oral ivabradine at total doses of 2, 7, or 24 mg/kg/day (approximately 0.6 to 50 times the human exposure at the mrhd based on auc 0- 24 hr ) for 52 weeks. retinal function assessed by electroretinography demonstrated reductions in cone system responses, which reversed within a week post-dosing, and were not associated with damage to ocular structures as evaluated by light microscopy. these data are consistent with the pharmacological effect of ivabradine related to its interaction with hyperpolarization-activated i h currents in the retina, which share homology with the cardiac pacemaker i f current.

affect fertility in male or female rats at exposures 46 to 133 times the human exposure (auc 0-24hr ) at the mrhd.

8% of patients. at baseline, approximately 49% of randomized patients were nyha class ii, 50% were nyha class iii, and 2% were nyha class iv. the mean left ventricular ejection fraction was 29%. all patients were initiated on corlanor 5 mg (or matching placebo) twice daily and the dose was increased to 7.5 mg twice daily or decreased to 2.5 mg twice daily to maintain the resting heart rate between 50 and 60 bpm, as tolerated. the primary endpoint was a composite of the first occurrence of either hospitalization for worsening heart failure or cardiovascular death. most patients (89%) were taking beta-blockers, with 26% on guideline-defined target daily doses. the main reasons for not receiving the target beta-blocker doses at baseline were hypotension (45% of patients not at target), fatigue (32%), dyspnea (14%), dizziness (12%), history of cardiac decompensation (9%), and bradycardia (6%). for the 11% of patients not receiving any beta-blocker at baseline, the main reasons were chronic obstructive pulmonary disease, hypotension, and asthma. most patients were also taking ace inhibitors and/or angiotensin ii antagonists (91%), diuretics (83%), and anti-aldosterone agents (60%). few patients had an implantable cardioverter-defibrillator (icd) (3.2%) or a cardiac resynchronization therapy (crt) device (1.1%). median follow-up was 22.9 months. at 1 month, 63%, 26%, and 8% of corlanor-treated patients were taking 7.5, 5, and 2.5 mg bid, whereas 3% had withdrawn from the drug, primarily for bradycardia. shift demonstrated that corlanor reduced the risk of the combined endpoint of hospitalization for worsening heart failure or cardiovascular death based on a time-to-event analysis (hazard ratio: 0.82, 95% confidence interval [ci]: 0.75, 0.90, p < 0.0001) (table 3). the treatment effect reflected only a reduction in the risk of hospitalization for worsening heart failure; there was no favorable effect on the mortality component of the primary endpoint. in the overall treatment population, corlanor had no statistically significant benefit on cardiovascular death. table 3. shift – incidence of the primary composite endpoint and components corlanor (n = 3,241) placebo (n = 3,264) endpoint n % % py n % % py hazard ratio [95% ci] p-value primary composite endpoint: time to first hospitalization for worsening heart failure or cardiovascular death a 793 24.5 14.5 937 28.7 17.7 0.82 [0.75, 0.90] < 0.0001 hospitalization for worsening heart failure 505 15.6 9.2 660 20.2 12.5 cardiovascular death as first event 288 8.9 4.8 277 8.5 4.7 patients with events at any time hospitalization for worsening heart failure b 514 15.9 9.4 672 20.6 12.7 0.74 [0.66, 0.83] cardiovascular death b 449 13.9 7.5 491 15.0 8.3 0.91 [0.80, 1.03] a patients who died on the same calendar day as their first hospitalization for worsening heart failure are counted under cardiovascular death. b analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity. n: number of patients at risk; n: number of patients having experienced the endpoint; %: incidence rate = (n/n) × 100; % py: annual incidence rate = (n/number of patient-years) × 100; ci: confidence interval the hazard ratio between treatment groups (ivabradine/placebo) was estimated based on an adjusted cox proportional hazards model with beta-blocker intake at randomization (yes/no) as a covariate; p-value: wald test the kaplan-meier curve (figure 3) shows time to first occurrence of the primary composite endpoint of hospitalization for worsening heart failure or cardiovascular death in the overall study. figure 3. shift: time to first event of primary composite endpoint a wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. many of these results are shown in figure 4. such analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. most of the results show effects consistent with the overall study result. corlanor’s benefit on the primary endpoint in shift appeared to decrease as the dose of beta-blockers increased, with little if any benefit demonstrated in patients taking guideline-defined target doses of beta-blockers. figu re 4 . effect of t reatment on primary composite e ndpoint in s ubgroups note: the figure above presents effects in various subgroups, all of which are baseline characteristics. the 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. apparent homogeneity or heterogeneity among groups should not be over-interpreted. beautiful and signify: no benefit in stable coronary artery disease with or without stable heart failure the morbidity-mortality evaluation of the i f inhibitor ivabradine in patients with coronary disease and left ventricular dysfunction trial (beautiful) was a randomized, double-blind, placebo-controlled trial in 10,917 adult patients with coronary artery disease, impaired left ventricular systolic function (ejection fraction < 40%) and resting heart rate ≥ 60 bpm. patients had stable symptoms of heart failure and/or angina for at least 3 months and were receiving conventional cardiovascular medications at stable doses for at least 1 month. beta-blocker therapy was not required, nor was there a protocol mandate to achieve any specific dosing targets for patients who were taking beta-blockers. patients were randomized 1:1 to corlanor or placebo at an initial dose of 5 mg twice daily with the dose increased to 7.5 mg twice daily depending on resting heart rate and tolerability. the primary endpoint was the composite of time to first cardiovascular death, hospitalization for acute myocardial infarction, or hospitalization for new-onset or worsening heart failure. most patients were nyha class ii (61.4%) or class iii (23.2%) - none were class iv. through a median follow-up of 19 months, corlanor did not significantly affect the primary composite endpoint (hr 1.00, 95% ci = 0.91, 1.10). the study assessing the morbi-mortality benefits of the i f inhibitor ivabradine in patients with coronary artery disease trial (signify) was a randomized, double-blind trial administering corlanor or placebo to 19,102 adult patients with stable coronary artery disease but without clinically evident heart failure (nyha class i). beta-blocker therapy was not required. corlanor was initiated at a dose of 7.5 mg twice daily and the dose could be increased to as high as 10 mg twice daily or down-titrated to 5.0 mg twice daily to achieve a target heart rate of 55 to 60 bpm. the primary endpoint was a composite of the first occurrence of either cardiovascular death or myocardial infarction. through a median follow-up of 24.1 months, corlanor did not significantly affect the primary composite endpoint (hr 1.08, 95% ci = 0.96, 1.20). 14.2 heart failure in pediatric patients because corlanor was effective in improving outcomes in patients with dilated cardiomyopathy (dcm) in shift, the effect on heart rate was considered a reasonable basis to infer clinical benefits in pediatric patients with dcm. thus, corlanor was evaluated for its effect on heart rate in a multi-center, randomized, double-blind, placebo-controlled trial in children with symptomatic dcm. the study collected data from 116 patients aged 6 months to less than 18 years with dcm in sinus rhythm, nyha/ross class ii to iv heart failure, and left ventricular ejection fraction ≤ 45%. patients had to be clinically stable for at least 4 weeks and on optimized medical therapy with a resting heart rate (hr) complying with the following criteria: hr ≥ 105 bpm in the age-subset 6–12 months. hr ≥ 95 bpm in the age-subset 1–3 years. hr ≥ 75 bpm in the age-subset 3–5 years. hr ≥ 70 bpm in the age-subset 5–18 years. patients were randomized in a 2:1 ratio to receive corlanor or placebo. doses of study medication were titrated over a 2- to 8-week period to achieve a 20% heart rate reduction without inducing bradycardia. the target heart rate reduction was obtained at the end of the titration period in a significantly higher proportion of patients with corlanor vs. placebo (72% vs. 16% respectively; odds ratio = 15; 95% ci = [5; 47]). a statistically significant reduction in hr was observed with corlanor compared to placebo at the end of the titration period (-23 ± 11 bpm vs. -2 ± 12 bpm respectively).

rlanor tablets and oral solution at 25°c (77°f); excursions permitted to 15°c - 30°c (59°f - 86°f) [see usp controlled room temperature] . protect corlanor ampule from light by storing in the foil pouch until use.

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 i nteractions ( 7.1 )] . intake with food advise patients to take corlanor twice daily with food [ see dosage and administration ( 2 )] . oral solution advise parents/caregivers on preparation and administration instructions including the use of a calibrated oral syringe and a medicine cup (provided by the pharmacy) to avoid dosing errors [see dosage and administration ( 2.2 )] . advise parents/caregivers that the oral solution should not be administered by the child. advise parents/caregivers to not double up doses (e.g., if patient spits out the drug or caregiver forgets to give the drug at the prescribed time). advise parents/caregivers to throw away the unused product remaining in the cup immediately after drawing up the prescribed dose in the syringe. corlanor ® (ivabradine) manufactured by : amgen inc. one amgen center drive thousand oaks, california 91320-1799 patent: http://pat.amgen.com/corlanor/ © 2015, 2017, 2019, 2021 amgen inc. all rights reserved. [part number] v5