Dosing and uses of Corlanor (ivabradine)
Adult dosage forms and strengths
tablet
- 5mg (scored and can be divided into equal halves to provide a 2.5-mg dose)
- 7.5mg
Heart Failure
Indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with LVEF ≤35%, who are in sinus rhythm with resting heart rate ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use
Initial: 5 mg PO BID with meals (all see Dosage modifications)
After 2 weeks, assess patient and adjust dose to achieve a resting heart rate of 50-60 bpm (see dose adjustment section below)
Thereafter, adjust dose prn based on resting heart rate and tolerability; not to exceed 7.5 mg BId
Dose adjustment
- HR >60 bpm: Increase dose by 2.5 mg (given twice daily) up to a maximum dose of 7.5 mg BID
- HR 50-60 bpm: Maintain dose
- HR <50 bpm or signs and symptoms of bradycardia: Decrease dose by 2.5 mg (given twice daily); if current dose is 2.5 mg BID, discontinue therapy
Dosage modifications
History of conduction defects or patients in whom bradycardia could lead to hemodynamic compromise: Decrease initial dose to 2.5 mg PO BID; may increase dose based on heart rate
Hepatic impairment
- Mild or moderate (Child-Pugh A or B): No dose adjustment required
- Severe (Child-Pugh C): Contraindicated
Renal impairment
- CrCl 15-60 mL/min: No dose adjustment required
- CrCl <15 mL/min: No data are available
Pediatric dosage forms and strengths
Safety and efficacy not established
Cardiomyopathy (Orphan)
Orphan designation for treatment of pediatric patients with dilated cardiomyopathy
Sponsor
- Amgen, Inc; 1 Amgen Center Drive; Thousand Oaks, California 91320
Corlanor (ivabradine) adverse (side) effects
1-10%
Bradycardia (10%)
Hypertension or increased blood pressure (8.9%)
Atrial fibrillation (8.3%)
Luminous phenomena (phosphenes) or visual brightness (2.8%)
Postmarketing Reports
Syncope, hypotension
Angioedema, erythema, rash, pruritus, urticaria
Vertigo, diplopia, visual impairment
Warnings
Contraindications
Acute decompensated heart failure
Blood pressure <90/50 mmHg
Sick sinus syndrome, sinoatrial block, or third-degree AV block (unless a functioning demand pacemaker is present)
Resting heart rate <60 bpm prior to treatment
Severe hepatic impairment
Pacemaker dependence (heart rate maintained exclusively by the pacemaker)
Concomitant use of strong CYP3A4 inhibitors
Cautions
Increases the risk of atrial fibrillation; regularly monitor cardiac rhythm and discontinue drug if atrial fibrillation develops
May cause fetal toxicity when administered to a pregnant woman; inform women of childbearing potential to use effective contraception
Coadministration with CYP3A4 inhibitors and inducers
- Ivabradine is primarily metabolized by CYP3A4
- Coadministration of CYP3A4 inhibitors increases ivabradine plasma concentrations
- Increased plasma concentrations may exacerbate bradycardia and conduction disturbances
- Contraindicated with strong CYP3A4 inhibitors
- Avoid use with moderate CYP3A4 inhibitors
- Avoid use with CYP3A4 inducers; coadministration may decrease ivabradine plasma concentrations
Bradycardia and conduction disturbances
- Bradycardia, sinus arrest, and heart block reported
- Risk factors for bradycardia include sinus node dysfunction, conduction defects (eg, first or second degree AV block, bundle-branch block), ventricular dyssynchrony, and use of other negative chronotropes (eg, beta-blockers, clonidine, digoxin, diltiazem, verapamil, amiodarone)
- Also, concurrent use of verapamil or diltiazem increases ivabradine systemic exposure and should be avoided
- Avoid use in patients with second-degree AV block unless a functioning demand pacemaker is present
Pacemakers
- Dosing is based on heart rate reduction, targeting a heart rate of 50-60 bpm
- Patients with demand pacemakers set to a rate ≥60 bpm cannot achieve a target heart rate <60 bpm, and these patients were excluded from clinical trials
- Not recommended in patients with demand pacemakers set to rates ≥60 bpm
Pregnancy and lactation
Pregnancy
May cause fetal toxicity when administered to a pregnant woman, based on findings in animal studies
Advise females of childbearing potential to use effective contraception
Embryo-fetal toxicity and cardiac teratogenic effects were observed in fetuses of pregnant rats treated during organogenesis at exposures 1-3 times the human exposures (AUC 0-24hr) at the maximum recommended human dose
In pregnant rabbits, oral administration of ivabradine during the period of organogenesis (gestation day 618) at doses of 7, 14, or 28 mg/kg/day resulted in fetal toxicity and teratogenicity
Treatment with all doses ≥7 mg/kg/day (equivalent to human exposure) caused an increase in post implantation loss
Lactation
Unknown if distributed in human breast milk
Animal studies have shown, however, that ivabradine is present in rat milk
Because of the potential risk to breastfed infants, breastfeeding is not recommended
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Corlanor (ivabradine)
Mechanism of action
Blocks the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel responsible for the cardiac pacemaker I(f) ‘funny’ current, which regulates heart rate
In clinical electrophysiology studies, the cardiac effects were most pronounced in the sinoatrial (SA) node, but prolongation of the AH interval has occurred on the surface ECG, as has PR interval prolongation
There was no effect on ventricular repolarization and no effects on myocardial contractility
Absorption
Bioavailability: ~40% (because of first-pass elimination in the gut and liver)
Peak plasma time: 1 hr (fasting)
Food delays absorption by ~1 hr and increases plasma exposure by 20-40%
Ivabradine should be taken with meals
Distribution
Protein bound: 70%
Vd: 100 L
Metabolism
Extensively metabolized in the liver and intestines by CYP3A4-mediated oxidation
Major metabolite: N-desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations ~40% that of ivabradine
The N-desmethylated derivative is also metabolized by CYP3A4
Elimination
Distribution half-life: 2 hr
Effective half-life: ~6 hr
Total clearance: 24 L/hr
Renal clearance: 4.2 L/hr
Excretion: 4% unchanged in urine; excretion of metabolites occurs to a similar extent via feces and urine
Administration
Instructions
Take with meals to increase plasma concentration
