Corlanor Drug Information

2. DOSAGE AND ADMINIST R ATION 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.

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. In adult patients 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. If a dose of Corlanor is missed or spit out, do not give another dose to make up for the missed or spit out dose. Give the next dose at the usual time.

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 patient at two-week intervals and adjust dose by 2.5 mg to target a heart rate (HR) reduction of at least 20%, based on tolerability. Dose Reduction for Bradycardia If bradycardia develops, reduce the dose to the previous titration step.

In patients who develop bradycardia at the recommended initial dosage, consider reducing the dosage 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. With a calibrated oral syringe, measure the prescribed dose of Corlanor from the medication cup and administer the drug orally.

Corlanor oral solution is sterile and preservative-free. Discard the unused oral solution. Do not store or reuse any oral solution left in either the medication cup or an ampule.

6. ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Atrial Fibrillation Bradycardia and Conduction Disturbances Most common adverse reactions occurring in ≥ 1% of patients are bradycardia, hypertension, atrial fibrillation and luminous phenomena (phosphenes). To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-772-6436 (1-800-77-AMGEN) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Patients with Heart Failure In SHIFT, safety was evaluated in 3,260 patients treated with Corlanor and 3,278 patients given placebo. The median duration of Corlanor exposure was 21.5 months. The most common adverse drug reactions in the SHIFT trial are shown in Table 2.

Table 2. Adverse Drug Reactions with Rates ≥ 1.0% Higher on Ivabradine than Placebo occurring in > 1% on Ivabradine in SHIFT Luminous P henomena (Phosphenes) Phosphenes are phenomena described as a transiently enhanced brightness in a limited area of the visual field, halos, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency). Phosphenes are usually triggered by sudden variations in light intensity.

Corlanor can cause phosphenes, thought to be mediated through Corlanor’s effects on retinal photoreceptors. Onset is generally within the first 2 months of treatment, after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity and led to treatment discontinuation in < 1% of patients; most resolved during or after treatment.

Pediatric Patients with Heart Failure The safety of Corlanor in pediatric patients 6 months to less than 18 years of age is based on a clinical trial in symptomatic heart failure patients with dilated cardiomyopathy and elevated heart rate. This trial provides experience in 73 patients treated with Corlanor for a median duration of 397 days, and 42 patients given placebo. Bradycardia (symptomatic and asymptomatic) occurred at rates similar to those in adults.

Phosphenes were observed in pediatric patients treated with Corlanor. 6.2 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. The following adverse reactions have been identified in adults during post-approval use of Corlanor: syncope, hypotension, torsade de pointes, ventricular fibrillation, ventricular tachycardia, angioedema, erythema, rash, pruritus, urticaria, vertigo, and diplopia, and visual impairment.

7. DRUG INTERACTIONS Avoid CYP3A4 inhibitors or inducers. Negative chronotropes increase risk of bradycardia; monitor heart rate. 7.1 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. 7.2 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. 7.3 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.

Pregnancy Risk Summary 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. In animal reproduction studies, oral administration of ivabradine to pregnant rats during organogenesis at a dosage providing 1 to 3 times the human exposure (AUC 0-24hr ) 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 post-natal mortality was associated with these teratogenic effects in rats. In pregnant rabbits, increased post-implantation loss was noted at an exposure (AUC 0-24hr ) 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. Advise a pregnant woman of the potential risk to the fetus. Clinical Considerations 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 Corlanor, especially during the first trimester, should be followed closely for destabilization of their congestive heart failure that could result from heart rate slowing. Monitor pregnant women with chronic heart failure in 3 rd trimester of pregnancy for preterm birth.

Data Animal Data In pregnant rats, oral administration of ivabradine during the period of organogenesis (gestation day 6-15) at doses of 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 AUC 0- 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 AUC 0- 24 hr ).

Treatment with all doses ≥ 7 mg/kg/day (equivalent to the human exposure at the MRHD based on AUC 0- 24 hr ) caused an increase in post-implantation loss. Increased post-natal 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 AUC 0- 24 hr ).

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 safety and efficacy of Corlanor have not been established in patients less than 6 months of age. Animal Data Ivabradine given orally to juvenile rats from post-natal day (PND) 7 until PND mg/kg/day did not affect post-natal (pre-weaning) development and reproductive performance (post-weaning development).

Similar to adult animals, ivabradine decreased heart rate dose-dependently, and increased heart weights at the highest dose administered. Ivabradine also decreased white blood cell counts (lymphocytes) at the highest dose administered. The decrease in white blood cell counts partially reversed within a 3-week recovery period.

Exposures in male and female rats at the No Observed Adverse Effect Level (NOAEL) of 7.5 mg/kg/day, was approximately 3 and 8 times, respectively, steady state exposure associated with the highest received maintenance doses across age groups in pediatric patients (based on AUCs).

• 4. CONTRAINDICATIONS Corlanor is contraindicated in patients with:
• Acute decompensated heart failure
• Clinically significant hypotension
• Sick sinus syndrome, sinoatrial block or 3 rd degree AV block, unless a functioning demand pacemaker is present
• Clinically significant bradycardia
• Severe hepatic impairment
• Pacemaker dependence (heart rate maintained exclusively by the pacemaker)
• Concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors Acute decompensated heart failure Clinically significant hypotension Sick sinus syndrome, sinoatrial block or 3 rd 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

10. 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.