Corlanor
(Ivabradine)Corlanor Prescribing Information
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 Heart Failure in Adult PatientsCorlanor 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.
- For the treatment of stable symptomatic heart failure due to dilated cardiomyopathy in pediatric patients ages 6 months and older. ()
1.2 Heart Failure in Pediatric PatientsCorlanor 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.
- 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 AdultsThe 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 RateDoseAdjustment> 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* *
[seeWarnings and Precautions (5.3)]
- 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.
5 mg: salmon-colored, oval-shaped, film-coated tablet, functionally scored on both edges, debossed with “5” on one face and bisected on the other face. The tablet is scored and can be divided into equal halves to provide a 2.5 mg dose.
7.5 mg: salmon-colored, triangular-shaped, film-coated tablet debossed with “7.5” on one face and plain on the other face.
Corlanor 5 mg/5 mL (1 mg/mL) oral solution is a colorless liquid in an opaque, plastic, ampule containing 5 mg of Corlanor in 5 mL of liquid.
- Lactation: Breastfeeding not recommended. ()
8.2 LactationRisk SummaryThere 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
[seeData]. Because of the potential risk to breastfed infants from exposure to Corlanor, breastfeeding is not recommended.DataLactating 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.
Corlanor is contraindicated in patients with:
• Acute decompensated heart failure
• Clinically significant hypotension
• Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present
• Clinically significant bradycardia
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., 1stor 2nddegree 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
Concurrent use of verapamil or diltiazem will increase Corlanor exposure, may themselves contribute to heart rate lowering, and should be avoided
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
• Severe 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
• Pacemaker dependence (heart rate maintained exclusively by the pacemaker)
Corlanor dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute in adults
• Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors
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
Avoid concomitant use of moderate CYP3A4 inhibitors when using Corlanor. Examples of moderate CYP3A4 inhibitors include diltiazem, verapamil, and grapefruit juice
Avoid concomitant use of CYP3A4 inducers when using Corlanor. Examples of CYP3A4 inducers include St. John’s wort, rifampicin, barbiturates, and phenytoin
- Fetal toxicity: Females should use effective contraception. ()
5.1 Fetal ToxicityCorlanor 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 (AUC0-24hr) 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[seeUse in Specific Populations(8.3)]. - Monitor patients for atrial fibrillation. ()
5.2 Atrial FibrillationCorlanor increases the risk of atrial fibrillation. In the Systolic Heart Failure Treatment with the IfInhibitor 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. - Monitor heart rate decreases and bradycardia symptoms during treatment. ()
5.3 Bradycardia and Conduction DisturbancesAdult PatientsBradycardia, 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., 1stor 2nddegree 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 2nddegree atrioventricular block unless a functioning demand pacemaker is present[seeContraindications (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)]. - Not recommended in patients with 2nd degree AV block. ()
5.3 Bradycardia and Conduction DisturbancesAdult PatientsBradycardia, 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., 1stor 2nddegree 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 2nddegree atrioventricular block unless a functioning demand pacemaker is present[seeContraindications (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)].