CORLANOR® (ivabradine)

CORLANOR® (ivabradine) tablets & oral solution

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CORLANOR® (ivabradine)

Corlanor (ivabradine) tablets and oral solution contains ivabradine as the active pharmaceutical ingredient. Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If current, resulting in heart rate reduction with no effect on ventricular repolarization and no effects on myocardial contractility.

The chemical name for ivabradine hydrochloride is 3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl] methyl amino} propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one, hydrochloride. The molecular formula is C27H36N2O5HCl, and the molecular weight (free base + HCl) is 505.1 (468.6 + 36.5).

Tablets

Corlanor tablets are supplied in 5 mg and 7.5 mg tablets for oral administration. The tablets contain 5 mg and 7.5 mg of ivabradine, as the active ingredient, equivalent to 5.39 mg and 8.09 mg of ivabradine hydrochloride, respectively. The tablets contain the following inactive ingredients: colloidal silicon dioxide, glycerol, hypromellose, lactose monohydrate, magnesium stearate, maize starch, maltodextrin, polyethylene glycol 6000, red iron oxide, titanium dioxide, and yellow iron oxide.

Oral Solution

Corlanor 5 mg/5 mL (1 mg/mL) oral solution is formulated as a sterile, preservative-free, colorless solution for oral administration. Each 5 mL ampule contains 5 mg of ivabradine, equivalent to 5.39 mg ivabradine hydrochloride, as the active ingredient. The solution contains the following inactive ingredients: maltitol and water.

Indications and usage

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.
  • For the treatment of stable symptomatic heart failure due to dilated cardiomyopathy in pediatric patients ages 6 months and older.

Dosage and administration

Adult and pediatric patients greater than 40 kg

  • 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.

Pediatric patients less than 40 kg

  • 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.

Mechanism of Action

Corlanor blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker If 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 as has PR interval prolongation. There was no effect on ventricular repolarization and no effects on myocardial contractility.

Corlanor 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 Corlanor 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

Contraindications

  • 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
  • In combination with strong cytochrome CYP3A4 inhibitors

Adverse reactions

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

Warnings and precautions

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 (AUC0-24hr) at the maximum recommended human dose (MRHD). Advise females of reproductive potential to use effective contraception when taking Corlanor.

Atrial Fibrillation: Corlanor increases the risk of atrial fibrillation. In the Systolic Heart Failure Treatment with the If Inhibitor 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. Regularly monitor cardiac rhythm. Discontinue Corlanor if atrial fibrillation develops.

Bradycardia and Conduction Disturbances: Concurrent use of verapamil or diltiazem will increase Corlanor exposure, may themselves contribute to heart rate lowering, and should be avoided. Avoid use of Corlanor in patients with 2nd degree atrioventricular block unless a functioning demand pacemaker is present.

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Drug interactions

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. 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.

Avoid concomitant use of CYP3A4 inducers when using Corlanor. Examples of CYP3A4 inducers include St. John’s wort, rifampicin, barbiturates, and phenytoin.

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.

Pacemakers in Adults

Corlanor dosing is based on heart rate reduction, targeting a heart rate of 50 to 60 beats per minute in adults. 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. The use of Corlanor is not recommended in patients with demand pacemakers set to rates ≥ 60 beats per minute.

Use in specific populations

Pregnancy: 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.

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 Corlanor, breastfeeding is not recommended.

Contraception: Corlanor may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during Corlanor treatment.

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.

The safety and efficacy of Corlanor have not been established in patients less than 6 months of age.

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.

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.

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.

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 beta-stimulating agents such as isoproterenol, may be considered.

Storage

Store Corlanor 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.

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