FDA Approves CORLANOR (Ivabradine) Oral Solution to Reduce the Risk of Hospitalization for Worsening Heart Failure in Adult Patients with Chronic Heart Failure and for the Treatment of Heart Failure due to Dilated Cardiomyopathy in Pediatric Patients Aged 6 Months and Older.
On April 22, 2019, the U.S. Food and Drug Administration (FDA) approved CORLANOR (ivabradine) oral solution 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 and for the treatment of stable symptomatic heart failure due to dilated cardiomyopathy (DCM) in pediatric patients aged 6 months and older. CORLANOR is also available as a tablet for oral use.
The approved recommended dosage of CORLANOR for adult and pediatric patients is as follows:
Adult and Pediatric Patients Weighing Greater than 40 kg:
- The recommended starting dose of CORLANOR tablets is 5 mg twice daily with food in adults. A starting dose of 2.5 mg twice daily with food is recommended in adult patients with a history of conduction defects or in whom bradycardia could lead to hemodynamic compromise or in pediatric patients weighing > 40 kg. After 2 weeks of treatment, adjust dose based on heart rate with a maximum dose of 7.5 mg twice daily. In patients unable to swallow tablets, CORLANOR oral solution can be used.
Pediatric Patients 6 Months of Age and Older Weighing Less than 40 kg:
- Starting dose of CORLANOR oral solution is 0.05 mg/kg twice daily with food. Adjust the dose at two-week intervals by 0.05 mg/kg based on heart rate. The maximum approved recommended dosage 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.
CORLANOR is contraindicated in 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, severe hepatic impairment, heart rate maintained exclusively by the pacemaker, and in combination with strong CYP3A4 inhibitors. The use of CORLANOR in patients with demand pacemakers set to rates ≥ 60 beats per minute is not recommended.
Additional information regarding monitoring, dose titration, dose modifications for pediatric patients who develop bradycardia, and warnings and precautions are described in the full prescribing information linked below.
Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
- MOA: Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker.
- General PK: Ivabradine pharmacokinetics are linear over an oral dose range of 0.5 mg to 24 mg. The peak concentration (Cmax) and area under the plasma concentration time curve (AUC) are similar for ivabradine and its major metabolite, N-desmethylated derivative (S 18982) between oral solution and tablets for the same dose.
- Absorption: Following oral administration, ivabradine Tmax is 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%.
- Distribution: The plasma protein binding of ivabradine is approximately 70% and the volume of distribution at steady state is approximately 100 L.
- Elimination: 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.
- Metabolism: Ivabradine is extensively metabolized in the liver and intestines by CYP3A4-mediated oxidation. The major metabolite S 18982 is equipotent to ivabradine, circulates at concentrations approximately 40% that of ivabradine, and is also metabolized by CYP3A4.
- Excretion: Approximately 4% of an oral dose of ivabradine is excreted unchanged in urine. The excretion of metabolites occurs to a similar extent in feces and urine.
- PD/Cardiac Electrophysiology: 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. In 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, the relationship between exposure and heart rate reduction was similar to adults. 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.
- The concomitant use of strong CYP3A4 inhibitors with CORLANOR is contraindicated. Avoid concomitant use of moderate CYP3A4 inhibitors or CYP34A inducers when using CORLANOR.
- Monitor heart rate in patients taking CORLANOR with other negative chronotropes, as negative chronotropes increase risk of bradycardia.
Use in Specific Populations
No clinically significant differences in the pharmacokinetics of ivabradine were observed based on age (6 months to < 18 years old and ≥ 65 years), mild hepatic impairment (Child-Pugh A), moderate hepatic impairment (Child-Pugh B), and renal impairment (creatinine clearance 15 to 60 mL/min). 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.
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 twice daily.
Efficacy and Safety
Efficacy of CORLANOR was demonstrated in a randomized, double-blind trial comparing CORLANOR and placebo in adult patients with stable NYHA class II to IV heart failure, left ventricular ejection fraction ≤ 35%, and resting heart rate ≥ 70 bpm. Efficacy of CORLANOR in heart failure in pediatric patients was demonstrated in a multicenter, randomized, double-blind, placebo-controlled trial in children (6 months to less than 18 years old) with DCM and symptomatic chronic heart failure. Additional information regarding efficacy trials can be found in the full prescribing information linked below.
The most common adverse reactions occurring in ≥ 1% of patients are bradycardia, hypertension, atrial fibrillation, and luminous phenomena (phosphenes).
Full prescribing information is available at https://go.usa.gov/xmyPs.
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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.