Corlanor Oral Solution Generic Name & Formulations
Corlanor (ivabradine) oral solution is a colorless liquid supplied in an opaque, low density polyethylene (LDPE) plastic ampule. Each 5 mL ampule is individually packaged in a child-resistant foil pouch and supplied in cartons containing 28 foil pouches. Corlanor oral solution is supplied as 5 mg/5 mL (1 mg/mL).
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.
Mechanism of Action
Corlanor Oral Solution Indications
Corlanor Oral Solution Dosage and Administration
The recommended starting dose of Corlanor is 5 mg twice daily with food. Assess after 2 weeks and adjust dose based on resting heart rate and tolerability to achieve a resting heart rate between 50-60 beats per minute (bpm). The maximum dose is 7.5 mg twice daily. If unable to swallow tablets, Corlanor oral solution can be used.
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.
Dose Adjustment for Adults:
Heart rate (> 60 bpm): Increase 2.5 mg (given twice daily) up to a maximum dose of 7.5 mg twice daily.
Heart rate (50–60 bpm): Maintain dose.
Heart rate (< 50 bpm or signs and symptoms of bradycardia): Decrease 2.5 mg (given twice daily); if current dose is 2.5 mg twice daily, discontinue therapy.
Pediatric Patients 6 Months of Age and Older Weighing Less than 40 kg (Oral Solution)
The recommended starting dose of Corlanor oral solution in pediatric patients ≥6 months of age (weighing <40 kg) is 0.05 mg/kg twice daily with food.
Assess at 2-week intervals and adjust dose by 0.05 mg/kg to achieve a heart rate (HR) reduction of at least 20%, based on tolerability. The maximum dose for pediatric patients 6 months to less than 1 year old is 0.2 mg/kg twice daily, and the maximum dose for patients 1 year old and older is 0.3 mg/kg twice daily, up to a total of 7.5 mg twice daily.
Pediatric Patients Weighing 40 kg and Greater (Tablets)
The recommended starting dose of Corlanor tablets in pediatric patients weighing more than 40 kg is 2.5 mg twice daily with food.
Assess at 2-week intervals and adjust dose by 2.5 mg to target a heart rate (HR) reduction of at least 20%, based on tolerability. The maximum dose is 7.5 mg twice daily. In patients unable to swallow tablets, Corlanor oral solution can be used.
Dose Reduction for Bradycardia
If bradycardia develops, reduce the dose to the previous titration step.
If bradycardia develops at the recommended initial dosage, consider reducing the dose to 0.02 mg/kg twice daily.
Oral Solution Preparation and Administration
To administer Corlanor oral solution, empty the entire contents of the ampule(s) into a medication cup. Measure the prescribed dose of Corlanor using a calibrated oral syringe from the medication cup and administer the drug orally.
Discard the unused oral solution. Do not store or reuse any oral solution left in either the medication cup or an ampule.
Corlanor Oral Solution Contraindications
Corlanor Oral Solution Boxed Warnings
Corlanor Oral Solution Warnings/Precautions
Based on findings in animal studies, Corlanor may cause fetal toxicity.
Advise females of reproductive potential to use effective contraception when taking Corlanor.
Increased 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.
Monitor cardiac rhythm regularly. Discontinue if atrial fibrillation develops.
Bradycardia and Conduction Disturbances
Increased risk of bradycardia, sinus arrest, and heart block with Corlanor. 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).
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.
Avoid concurrent use with verapamil or diltiazem, which may contribute to heart rate lowering. Avoid use in patients with 2nd degree atrioventricular block unless a functioning demand pacemaker is present.
Bradycardia and first-degree heart block were observed in pediatric patients treated with Corlanor.
Pediatric patients with bradycardia were managed through dose titration but did not result in study drug discontinuation.
Based on findings in animals, Corlanor may cause fetal harm. Advise a pregnant woman of the potential risk to the fetus.
There are no adequate and well-controlled studies of Corlanor in pregnant women to inform any drug-associated risks.
Disease-associated Maternal and/or Embryo-fetal Risk:
Stroke volume and heart rate increase during pregnancy, increasing cardiac output (esp. during the first trimester).
Pregnant patients treated with Corlanor (esp. during the first trimester) should be followed closely for destabilization of their congestive heart failure which may result from heart rate slowing.
Monitor pregnant women with chronic heart failure in 3rd trimester of pregnancy for preterm birth.
Nursing Mother Considerations
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.
Breastfeeding is not recommended due to the potential risk to breastfed infants from exposure to Corlanor.
Safety and efficacy has not been established in patients <6 months of age.
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.
Renal Impairment Considerations
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.
Hepatic Impairment Considerations
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.
Other Considerations for Specific Populations
Females: Corlanor may cause fetal harm, based on animal data. Advise females of reproductive potential to use effective contraception during Corlanor treatment.
Corlanor Oral Solution Pharmacokinetics
Peak plasma ivabradine concentrations are reached in approximately 1 hour under fasting conditions. The absolute oral bioavailability of ivabradine is approximately 40%.
Corlanor should be taken with food. The absorption of ivabradine is delayed by approximately 1 hour when taken with food, and food increases plasma exposure by 20% to 40%.
Approximately 70% plasma protein bound. Volume of distribution at steady state is approximately 100 L.
Plasma levels decline with a distribution half-life of 2 hours and an effective half-life of approximately 6 hours. The excretion of metabolites occurs to a similar extent via feces and urine.
Corlanor Oral Solution Interactions
Corlanor Oral Solution Adverse Reactions
Corlanor Oral Solution Clinical Trials
Heart Failure in Adult Patients: SHIFT
The randomized, double-blind Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT) compared the efficacy of Corlanor to placebo in 6558 adult patients with stable New York Heart Association (NYHA) class II to IV heart failure, left ventricular ejection fraction ≤ 35%, and resting heart rate ≥ 70 bpm. Eligible patients included the following:
Clinically stable for at least 4 weeks on an optimized and stable clinical regimen, which included maximally tolerated doses of beta-blockers and, in most cases, ACE inhibitors or ARBs, spironolactone, and diuretics, with fluid retention and symptoms of congestion minimized.
Hospitalized for heart failure within 12 months prior to study entry.
Patients were randomly assigned to receive Corlanor 5 mg (or matching placebo) twice daily, followed by either an increase to 7.5 mg twice daily or decrease to 2.5 mg twice daily to maintain the resting heart rate between 50 and 60 bpm, as tolerated. The primary endpoint was a composite of the first occurrence of either hospitalization for worsening heart failure or cardiovascular death.
Most patients (89%) were taking beta-blockers, with 26% on guideline-defined target daily doses. Most patients were also taking ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and anti-aldosterone agents (60%). Few patients had an implantable cardioverter-defibrillator (ICD) (3.2%) or a cardiac resynchronization therapy (CRT) device (1.1%). Median follow-up was 22.9 months. At 1 month, 63%, 26%, and 8% of Corlanor-treated patients were taking 7.5, 5, and 2.5 mg BID, whereas 3% had withdrawn from the drug, primarily for bradycardia.
Results from SHIFT showed that Corlanor reduced the risk of the combined endpoint of hospitalization for worsening heart failure or cardiovascular death based on a time-to-event analysis (hazard ratio: 0.82; 95% CI, 0.75-0.90; P < 0.0001). The incidence of the primary composite endpoint occurred in 24.5% of patients in the Corlanor group vs 28.7% of patients in the placebo group. The treatment effect reflected only a reduction in the risk of hospitalization for worsening heart failure (15.6% for Corlanor vs 20.2% for placebo); there was no favorable effect on the mortality component of the primary endpoint. In the overall treatment population, Corlanor had no statistically significant benefit on cardiovascular death.
Most of the results show effects consistent with the overall study result. Corlanor’s benefit on the primary endpoint in SHIFT appeared to decrease as the dose of beta-blockers increased, with little if any benefit demonstrated in patients taking guideline-defined target doses of beta-blockers.
Heart Failure in Adult Patients: BEAUTIFUL and SIGNIFY: No benefit in stable coronary artery disease with or without stable heart failure
The randomized, double-blind, placebo-controlled Morbidity-mortality Evaluation of the If Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction Trial (BEAUTIFUL) evaluated the effects of ivabradine in 10,917 adults with coronary artery disease, impaired left ventricular systolic function (ejection fraction < 40%) and resting heart rate ≥ 60 bpm. Patients had stable symptoms of heart failure and/or angina for at least 3 months and were receiving conventional cardiovascular medications at stable doses for at least 1 month. Beta-blocker therapy was not required, nor was there a protocol mandate to achieve any specific dosing targets for patients who were taking beta-blockers.
Patients were randomly assigned 1:1 to receive Corlanor or placebo at an initial dose of 5 mg twice daily with the dose increased to 7.5 mg twice daily depending on resting heart rate and tolerability. The primary endpoint was the composite of time to first cardiovascular death, hospitalization for acute myocardial infarction, or hospitalization for new-onset or worsening heart failure. Most patients were NYHA class II (61.4%) or class III (23.2%) - none were class IV. Through a median follow-up of 19 months, Corlanor did not significantly affect the primary composite endpoint (HR 1.00; 95% CI, 0.91-1.10).
The randomized, double-blind Study Assessing the Morbi-mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease Trial (SIGNIFY) compared Corlanor to placebo in 19,102 adults with stable coronary artery disease but without clinically evident heart failure (NYHA class I). Beta-blocker therapy was not required. Patients were initiated at Corlanor 7.5 mg twice daily and the dose could be increased to as high as 10 mg twice daily or down-titrated to 5.0 mg twice daily to achieve a target heart rate of 55 to 60 bpm. The primary endpoint was a composite of the first occurrence of either cardiovascular death or myocardial infarction. Results showed that treatment with Corlanor did not significantly affect the primary composite endpoint through a median follow-up of 24.1 months (HR 1.08; 95% CI, 0.96-1.20).
Heart Failure in Pediatric Patients
Corlanor was evaluated for its effect on heart rate in a multi-center, randomized, double-blind, placebo-controlled trial in 116 children aged 6 months to less than 18 years with symptomatic DCM who were in sinus rhythm, NYHA/Ross class II to IV heart failure, and left ventricular ejection fraction ≤ 45%. Patients were required to be clinically stable for at least 4 weeks and on optimized medical therapy with a resting heart rate (HR) complying with the following criteria:
HR ≥ 105 bpm in the age-subset 6–12 months.
HR ≥ 95 bpm in the age-subset 1–3 years.
HR ≥ 75 bpm in the age-subset 3–5 years.
HR ≥ 70 bpm in the age-subset 5–18 years.
Patients were randomly assigned 2:1 to receive Corlanor or placebo. Patients received dose titration of Corlanor over a 2- to 8-week period to achieve a 20% heart rate reduction without inducing bradycardia.
At the end of the titration period, a significantly higher proportion of patients treated with Corlanor achieved the target heart rate reduction vs. placebo (72% vs. 16% respectively; Odds Ratio = 15; 95% CI, 5-47). A statistically significant reduction in HR was observed with Corlanor compared to placebo at the end of the titration period (-23 ± 11 bpm vs. -2 ± 12 bpm respectively).
Corlanor Oral Solution Note
Corlanor Oral Solution Patient Counseling
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.
Low Heart Rate
Advise patients to report significant decreases in heart rate or symptoms such as dizziness, fatigue, or hypotension.
Advise patients to report symptoms of atrial fibrillation, such as heart palpitations or racing, chest pressure, or worsened shortness of breath.
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 Corlanor.
Advise patients to avoid ingestion of grapefruit juice and St. John’s wort.
Intake with Food
Advise patients to take Corlanor twice daily with food.
Advise parents/caregivers on preparation and administration instructions including the use of a calibrated oral syringe and a medicine cup (provided by the pharmacy) to avoid dosing errors.
Advise parents/caregivers that the oral solution should not be administered by the child.
Advise parents/caregivers to not double up doses (e.g., if patient spits out the drug or caregiver forgets to give the drug at the prescribed time).
Advise parents/caregivers to throw away the unused product remaining in the cup immediately after drawing up the prescribed dose in the syringe.
Cost Savings Program
Corlanor Patient Resources and Support: https://www.corlanor.com/chronichf-treatment-support