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

2. 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

3. 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)

4. 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

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

6. 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

7. 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

8. 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

9. 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%

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

11. 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

12. Corlanor® - Ivabradine Prescription Information
Moderate to severe renal impairment (CrCl 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

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

14. 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:

15. 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:

16. 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:

17. Corlanor® - Ivabradine Literature Review
24% in the ivabradine group vs. 29% in the placebo group had a primary event (95% CI ; 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:

18. 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:

19. 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.

20. Corlanor® - Ivabradine References1.
2. Corlanor [ivabradine] package insert. Amgen Inc. April
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: