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Corlanor® - Ivabradine
Manufacturer: Amgen Inc
FDA Approval Date: April 15, 2015
Rashmi Patel, PharmD Candidate
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 hyperpolarizationactivated 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. Lancet 2010;376:875-85.
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. Lancet 2010;376:875-85.
Corlanor® - Ivabradine
Literature Review
Patient Demographics (N=6,398)
Age, years: 60.4
NYHA functional class:
II: 49%, III: 50%, IV: 2%
Male: 76.5%
Ischemic heart failure: 67.5%
Caucasian: 89%
Asian: 8%
Other: 3%
History of:
MI: 56%, DM: 30.5%, Stroke: 8%, A-fib: 8%
Current smokers: 17.5%
Use of:
Beta blockers: 89.5%, ACE: 78.5%, ARB: 14%,
Diuretic: 83.5%, Anti-aldosterone agent: 60%,
Digoxin: 22%
BMI: 28
Resting heart rate: 79.9 bpm
LVEF: 29%
BP: 121/75
Swedberg K, et al. SHIFT Study. Lancet 2010;376:875-85.
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 in the
ivabradine group (p=0.128) but deaths due
to HF (3% ivabradine vs. 5% placebo;
p=0.014) & hospital admissions for
worsening heart failure decreased
significantly (16% ivabradine vs. 21%
placebo; p<0.0001)
Swedberg K, et al. SHIFT Study. Lancet 2010;376:875-85.
Corlanor® - Ivabradine
Literature Review
• Overall, there were fewer serious
adverse events in the ivabradine group
(45% ivabradine vs. 48% placebo;
p=0.025)
• 5% experienced bradycardia in the
ivabradine group vs. 1% in the placebo
group
• 3% experienced visual disturbances
(phosphene) in the ivabradine group vs.
1% in the placebo group
Swedberg K, et al. SHIFT Study. Lancet 2010;376:875-85.
Corlanor® - Ivabradine
Conclusion
• These results show that ivabradine substantially and
significantly reduced major risks associated with heart
failure when added to standard of care treatment
• In patients treated with ivabradine, the relative risk of
the primary endpoint fell by 18% compared to placebo
• Heart rate modulation plays an important part in the
pathophysiology of heart failure and the progression
of the disease
• These findings reflect the good tolerability of
ivabradine in patients with chronic heart failure
Swedberg K, et al. SHIFT Study. Lancet 2010;376:875-85.
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
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. Lancet
2010;376:875-85.