Corlanor ® ( ivabradine )
BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information
1 . INDICATIONS AND USAGE Corlanor is 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 beta-blockers or have a contraindication to beta-blocker use .
4 . CONTRAINDICATIONS Corlanor is contraindicated in patients with :
• Acute decompensated heart failure
• Blood pressure less than 90 / 50 mmHg
• Sick sinus syndrome , sinoatrial block , or 3 rd degree AV block , unless a functioning demand pacemaker is present
• Resting heart rate less than 60 bpm prior to treatment [ 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 )]
5 . WARNINGS AND PRECAUTIONS 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 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 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 Bradycardia , sinus arrest , and heart block have occurred with Corlanor . The rate of bradycardia was 6.0 % per patientyear 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 ). 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 ) and Dosage and Administration ( 2 )].
6 . ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include :
• Fetal Toxicity [ see Warnings and Precautions ( 5.1 )]
• Atrial Fibrillation [ see Warnings and Precautions ( 5.2 )]
• Bradycardia and Conduction Disturbances [ see Warnings and Precautions ( 5.3 )]
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 . In the Systolic Heart failure treatment with the I f inhibitor ivabradine Trial ( SHIFT ), safety was evaluated in 3260 patients treated with Corlanor and 3278 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 also 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 = 3260
Placebo N = 3278
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 . Corlanor can cause phosphenes , thought to be mediated through Corlanor ’ 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 during post-approval use of Corlanor : syncope , hypotension , angioedema , erythema , rash , pruritus , urticaria , vertigo , diplopia , and visual impairment .
7 . DRUG INTERACTIONS 7.1 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 )].
7.2 Negative Chronotropes Most patients receiving Corlanor will also be treated with a betablocker . 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 Corlanor dosing is based on heart rate reduction , targeting a heart rate of 50 to 60 beats per minute [ see Dosage and Administration ( 2 )]. 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 )]. The use of Corlanor is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute .
8 . USE IN SPECIFIC POPULATIONS 8.1 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 ( AUC 0-24hr ) 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 ( AUC 0-24hr ) 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 followed closely for destabilization of their congestive heart failure that could result from heart rate slowing .
© 2015 Amgen Inc . All rights reserved . Not for reproduction . USA-998-115485 , v2 11 / 15
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 0-24hr ). 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 0-24hr ).
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 AUC 0-24hr ) 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 0-24hr ), 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 AUC 0-24hr ).
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 .
Data Lactating rats received daily oral doses of [ 14 C ] -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 [ 14 C ] - 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 betastimulating agents such as isoproterenol , may be considered .
This Brief Summary is based on the Corlanor ® Prescribing Information v1 , 04 / 15
Corlanor ® ( ivabradine ) Manufactured for : Amgen Inc . One Amgen Center Drive Thousand Oaks , California 91320-1799 Patent : http :// pat . amgen . com / Corlanor /