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Corlanor

Generic Name: Ivabradine Hydrochloride
Class: Cardiac Drugs, Miscellaneous
Chemical Name: 3 - [3 - [[(7S) - 3,4 - dimethoxy - 7 - bicyclo[4.2.0]octa - 1,3,5 - trienyl]methyl - methylamino]propyl] - 7,8 - dimethoxy - 2,5 - dihydro - 1H - 3 - benzazepin - 4 - one;hydrochloride
Molecular Formula: C27H37ClN2O5
CAS Number: 148849-67-6

Introduction

Ivabradine hydrochloride, a hyperpolarization-activated cyclic nucleotide-gated channel blocker, is a cardiac drug.

Uses for Corlanor

Ivabradine hydrochloride has the following uses:

Ivabradine hydrochloride is a hyperpolarization-activated cyclic nucleotide-gated channel blocker 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. 1

Corlanor Dosage and Administration

General

Ivabradine hydrochloride is available in the following dosage form(s) and strength(s):

Tablets: 5 mg, 7.5 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • Starting dose is 5 mg twice daily. After 2 weeks of treatment, adjust dose based on heart rate. The maximum dose is 7.5 mg twice daily.1

  • In patients with conduction defects or in whom bradycardia could lead to hemodynamic compromise, initiate dosing at 2.5 mg twice daily.1

Cautions for Corlanor

Contraindications

  • Acute decompensated heart failure.1

  • Blood pressure less than 90/50 mmHg.1

  • Sick sinus syndrome, sinoatrial block or 3rd degree atrioventricular block, unless a functioning demand pacemaker is present.1

  • Resting heart rate less than 60 bpm prior to treatment.1

  • Severe hepatic impairment.1

  • Pacemaker dependence (heart rate maintained exclusively by the pacemaker).1

  • In combination with strong cytochrome CYP3A4 inhibitors.1

Warnings/Precautions

Fetal Toxicity

Ivabradine hydrochloride 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). Advise females to use effective contraception when taking ivabradine hydrochloride.1

Atrial Fibrillation

Ivabradine hydrochloride increases the risk of atrial fibrillation. In SHIFT, the rate of atrial fibrillation was 5% per patient-year in patients treated with ivabradine hydrochloride and 3.9% per patient-year in patients treated with placebo. Regularly monitor cardiac rhythm. Discontinue ivabradine hydrochloride if atrial fibrillation develops.1

Bradycardia and Conduction Disturbances

Bradycardia, sinus arrest, and heart block have occurred with ivabradine hydrochloride. The rate of bradycardia was 6% per patient-year in patients treated with ivabradine hydrochloride (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., 1st or 2nd 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 ivabradine hydrochloride exposure, may themselves contribute to heart rate lowering, and should be avoided. Avoid use of ivabradine hydrochloride in patients with 2nd degree atrioventricular block, unless a functioning demand pacemaker is present.1

Specific Populations

Pregnancy

Risk Summary: Based on findings in animals, ivabradine hydrochloride may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of ivabradine hydrochloride 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 (AUC0-24hr) 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 (AUC0-24hr) 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.1

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 ivabradine hydrochloride, especially during the first trimester, should be followed closely for destabilization of their congestive heart failure that could result from heart rate slowing.1

Monitor pregnant women with chronic heart failure in 3rd trimester of pregnancy for preterm birth.1

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 AUC0- 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 AUC0- 24 hr).1

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 AUC0- 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 AUC0- 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. 1

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 AUC0- 24 hr).1

Lactation

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. Because of the potential risk to breastfed infants from exposure to ivabradine hydrochloride, breastfeeding is not recommended.1

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.1

Females and Males of Reproductive Potential

Ivabradine hydrochloride may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during ivabradine hydrochloride treatment.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.1

Geriatric Use

No pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population. However, ivabradine hydrochloride has only been studied in a limited number of patients ≥ 75 years of age.1

Hepatic Impairment

No dose adjustment is required in patients with mild or moderate hepatic impairment. Ivabradine hydrochloride 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.1

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.1

Common Adverse Effects

Most common adverse reactions occurring in ≥ 1% of patients are bradycardia, hypertension, atrial fibrillation and luminous phenomena (phosphenes).1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • CYP3A4 inhibitors increase ivabradine hydrochloride plasma concentrations and CYP3A4 inducers decrease ivabradine hydrochloride plasma concentrations.1

  • Negative chronotropes: Increased risk of bradycardia; monitor heart rate.1

  • Pacemakers: Not recommended for use with demand pacemakers set to rates ≥ 60 beats per minute.1

Actions

Mechanism of Action

Ivabradine hydrochloride blocks the hyperpolarization-activated cyclic nucleotide-gated 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 on the surface ECG, as has PR interval prolongation. There was no effect on ventricular repolarization and no effects on myocardial contractility.1

Ivabradine hydrochloride can also inhibit the retinal current Ih. Ih is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of Ih by ivabradine hydrochloride 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.1

Advice to Patients

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling.1

Advise pregnant women of the potential risks to a fetus. Advise females of reproductive potential to use effective contraception and to notify their healthcare provider with a known or suspected pregnancy. 1

Advise patients to report significant decreases in heart rate or symptoms such as dizziness, fatigue, or hypotension.1

Advise patients to report symptoms of atrial fibrillation, such as heart palpitations or racing, chest pressure, or worsened shortness of breath.1

Advise patients about the possible occurrence of luminous phenomena (phosphenes). Advise patients to use caution if they are driving or using machines 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 ivabradine hydrochloride.1

Advise patients to avoid ingestion of grapefruit juice and St. John’s wort.1

Advise patients to take ivabradine hydrochloride twice daily with meals. 1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ivabradine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

5 mg

Corlanor

Amgen Inc

7.5 mg

Corlanor

Amgen Inc

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: September 09, 2016
Last reviewed: September 09, 2016
Date modified: October 12, 2016

References

1. Amgen Inc. Corlanor (ivabradine hydrochloride) ORAL prescribing information. 2015 Apr.

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