Corlanor® - Ivabradine Manufacturer: Amgen Inc FDA Approval Date: April 15, 2015

Corlanor® - Ivabradine Clinical Application Indications: 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

Corlanor® - Ivabradine Clinical Application Contraindications: Acute decompensated heart failure Blood pressure less than 90/50 mmHg Sick sinus syndrome, sinoatrial block or 3rd degree AV block, unless a functioning demand pacemaker is present Resting heart rate less than 60 bpm prior to treatment Severe hepatic impairment Pacemaker dependence (heart rate maintained exclusively by the pacemaker)

Corlanor® - Ivabradine Clinical Application Warnings & Precautions: Fetal toxicity: females should use effective contraception Monitor patients for atrial fibrillation Monitor heart rate decreases and bradycardia symptoms during treatment Not recommended in patients with 2nd degree AV block

Corlanor® - Ivabradine Clinical Application Pregnancy: Category D Lactation: Breastfeeding is not recommended

Corlanor® - Ivabradine Drug Facts Pharmacology: First-in-class to selectively and specifically inhibit hyperpolarization-activated cyclic nucleotide (HCN) gated (If current) channel within the SA node that lowers heart rate It causes a dose-dependent reduction in heart rate. Size of the effect is dependent on the baseline heart rate

Corlanor® - Ivabradine Drug Facts Pharmacokinetics: A Time to peak, plasma: ~1 hour (fasting); ~2 hours (with food) AUC increased 20% to 40% with food D 70% plasma protein bound; Vd: 100 L M Extensively metabolized by CYP3A4 Major metabolite is also metabolized by CYP3A4 E T1/2: 6 hours

Corlanor® - Ivabradine Drug Interactions Drug Interactions – Precipitant/Object Drugs: Any CYP3A4 inhibitors or inducers Moderate risk QTc-prolonging agents: Ivabradine may enhance the QTc prolonging effect Any agents that enhance the bradycardic effects

Corlanor® - Ivabradine Adverse Effects Common Adverse Effects: Ivabradine (N=3,260) Placebo (N=3,278) Bradycardia 10% 2.2% Atrial Fibrillation 8.3% 6.6% Phosphenes, visual brightness 2.8% 0.5% Hypertension, blood pressure increase 8.9% 7.8%

Corlanor® - Ivabradine Monitoring Parameters Efficacy Monitoring: Heart rate Cardiac rhythm

Corlanor® - Ivabradine Prescription Information Recommended starting dose 5mg tablet by mouth twice daily with meals or 2.5mg tablet by mouth twice daily for patients in whom bradycardia could lead to hemodynamic compromise or with a history of conduction defects After 2 weeks, check resting heart rate >60 bpm Increase dose by 2.5mg twice daily up to max of 7.5mg twice daily 50-60 bpm (target range) Maintain dose <50 bpm Decrease dose by 2.5mg twice daily *Discontinue therapy if current dose is 2.5mg twice daily

Corlanor® - Ivabradine Prescription Information Moderate to severe renal impairment (CrCl 15-60 mL/min): no dosage adjustment Mild or moderate hepatic impairment (Child-Pugh Class A or B): no dosage adjustment necessary Severe hepatic impairment (Child-Pugh Class C): Use is contraindicated

Corlanor® - Ivabradine Prescription Information Cost: $450 (AWP) for 30 day supply (60 tabs) of either 5mg or 7.5mg McKesson

Corlanor® - Ivabradine Literature Review The SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine) trial Randomized, double-blind, placebo-controlled, parallel group study in patients with systolic HF, NYHA class II, III, IV symptoms, in a stable condition for >4 weeks, on guideline-based medical therapy with unchanged HF medications and doses for >4 weeks, and with a documented hospital admission for worsening HF within the previous 12 months Swedberg K, et al. SHIFT Study. Journal of the American College of Cardiology 2012;59:1938-45.

Corlanor® - Ivabradine Literature Review Patients had to be in sinus rhythm with resting HR >70 bpm & LVEF <35% Patients were randomized to ivabradine 5mg BID (titrated to max 7.5mg BID) vs. matching placebo Primary composite endpoint: cardiovascular death or hospital admission for worsening heart failure Swedberg K, et al. SHIFT Study. Journal of the American College of Cardiology 2012;59:1938-45.

Corlanor® - Ivabradine Literature Review Patient Demographics (N=6,398) Age, years: 60.3 NYHA functional class: II: 48.6%, III: 49.6%, IV: 1.7% Male: 76.4% Ischemic heart failure: 67.2% Caucasian: 88.6% Asian: 8.3% Hx of: MI: 56.2%, DM: 30.3%, Stroke: 8%, A-fib: 8%, COPD: 11.3% Current smokers: 17.3% Use of: ACE: 78.6%, ARB: 14.3%, ACE/ARB: 91.1%, Diuretic: 83.2%, Anti-aldos: 60.7%, Statin: 58.3%, CCB: 8.1%, Digoxin: 21.8% BMI: 28 Resting heart rate: 79.9 bpm LVEF: 29% BP: 121/75 Swedberg K, et al. SHIFT Study. Journal of the American College of Cardiology 2012;59:1938-45.

Corlanor® - Ivabradine Literature Review 24% in the ivabradine group vs. 29% in the placebo group had a primary event (95% CI 0.75-0.90; p<0.0001; NNT=20) Cardiovascular deaths & all cause deaths were NOT significantly reduced with tx Deaths due to HF decreased significantly (3% ivabradine vs. 5% placebo; p=0.014) All cause hospitalization ↓ significantly (16% ivabradine vs. 21% placebo; p<0.0001) Swedberg K, et al. SHIFT Study. Journal of the American College of Cardiology 2012;59:1938-45.

Corlanor® - Ivabradine Literature Review Overall, there were fewer serious adverse events in the ivabradine group (p=0.025) Two side effects are noteworthy: Bradycardia was more common with ivabradine 5% vs. 1% with placebo Visual disturbances (phosphene) was 3% in the ivabradine group vs. < 1% placebo Swedberg K, et al. SHIFT Study. Journal of the American College of Cardiology 2012;59:1938-45.

Corlanor® - Ivabradine Summary First in-class Hyperpolarizing-activated Cyclic Nucleotide (HCN) channel blocker that lowers heart rate, indicated for patients with stable chronic HFref and heart rate ≥ 70 bpm Use in patients who are already on maximum tolerated dose of beta-blockers or are unable to use beta blockers Ivabradine reduces heart rate without reducing the heart’s contractility (no negative inotropic effects) No clinical benefit in the treatment of atrial fibrillation Potential drug interactions w/ CYP3A4 inhibitors/inducers Bradycardia is the most common adverse effect This trial confirms that heart rate plays an important part in the pathophysiology of heart failure and supports the concept that reduction in heart rate contributes significantly to beneficial outcomes in patients with heart failure. In patients of systolic heart failure, in sinus rhythm, and receiving the usual care and who have heart rates 70beats/min but are intolerant to higher doses of I-f blocker, ivabradine can improve clinical outcomes.

Corlanor® - Ivabradine References 1. www.Corlanor.com 2. Corlanor [ivabradine] package insert. Amgen Inc. April. 2015. 3. Ivabradine. UpToDate Drug Information. Accessed through UpToDate. Accessed on May 23, 2015. 4. Swedberg K, et al. SHIFT Study. Journal of the American College of Cardiology 2012;59:1938-45.