Ivabradine Hydrochloride

Contraindications

• Acute decompensated heart failure.1

• BP <90/50 mm Hg.1

• Resting heart rate <60 bpm prior to treatment.1

• Severe hepatic impairment.1 40 (See Hepatic Impairment under Cautions.)

• Pacemaker dependence (heart rate maintained exclusively by pacemaker).1

• Concomitant use of potent CYP3A4 inhibitors.1 40 (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)

• Sick sinus syndrome, SA block, or third degree AV block, unless a functioning demand pacemaker is present.1

Warnings/Precautions

Fetal Toxicity

May cause fetal toxicity and teratogenicity when administered to pregnant women based on findings in animals.1

Embryofetal toxicity and cardiac teratogenic effects (abnormal shape of the heart, interventricular septal defect, complex anomalies of primary arteries) observed in fetuses of pregnant rats treated with ivabradine during organogenesis at exposures 1–3 times the human exposures at the maximum recommended human dose.1

Reduced fetal and placental weights and teratogenic effects (ectrodactylia) observed in pregnant rabbits treated with ivabradine during organogenesis at exposures 15 times the human exposure at the maximum recommended human dose.1

Advise women of childbearing potential to use effective contraception while taking ivabradine.1 (See Advice to Patients.)

Atrial Fibrillation

Increases risk of atrial fibrillation.1 2 41

In pivotal clinical trial, rate of atrial fibrillation was 5% per patient-year with ivabradine and 3.9% per patient-year with placebo.1

Regularly monitor cardiac rhythm and discontinue ivabradine if atrial fibrillation occurs.1 (See Advice to Patients.)

Bradycardia and Conduction Disturbances

Bradycardia, sinus arrest, and heart block reported with ivabradine use.1 2 Risk factors for bradycardia include sinus node dysfunction, conduction defects (e.g., first or second degree AV block, bundle branch block), ventricular dyssynchrony, and the use of other negative chronotropes (e.g., digoxin, diltiazem, verapamil, amiodarone).1 Avoid concurrent use of verapamil and diltiazem; increases ivabradine exposure and contributes to heart rate lowering.1 42 (See Calcium-channel Blocking Agents under Interactions.)

Avoid in patients with second degree AV block, unless a functioning demand pacemaker is present.1 (See Contraindications under Cautions.)

Patients with demand pacemakers set to a rate ≥60 bpm cannot achieve target heart rate <60 bpm and were excluded from clinical trials.1 43 Not recommended in patients with demand pacemakers set to rates ≥60 bpm.1

Sensitivity Reactions

Hypersensitivity reactions (e.g., angioedema, erythema, rash, pruritus, urticaria) reported during postmarketing experience.1 (See Contraindications under Cautions.)

Specific Populations

May cause fetal harm.1 (See Fetal Toxicity under Cautions.)

Monitor pregnant women taking ivabradine, especially during the first trimester, for destabilization of heart failure that could result from heart rate slowing.1

Monitor pregnant women with chronic heart failure in their third trimester for preterm birth.1

Distributed into milk in rats; not known whether ivabradine is distributed into human milk.1 Breast-feeding is not recommended.1

Safety and efficacy not established in patients <18 years of age.1

No pharmacokinetic differences observed in patients ≥65 years of age compared with the overall population.1 Ivabradine studied in only a limited number of patients ≥75 years of age.1

Renal impairment (Clcr 15–60 mL/minute) has minimal effect on pharmacokinetics of ivabradine.1

Data lacking on use in patients with Clcr <15 mL/minute.1

Pharmacokinetics of ivabradine similar in patients with mild and moderate hepatic impairment compared with that in patients with normal hepatic function.1 7

Contraindicated in patients with severe hepatic impairment (Child Pugh class C); increased systemic exposure expected.1 (See Contraindications under Cautions.)

Common Adverse Effects

Bradycardia, hypertension, atrial fibrillation, luminous visual phenomena (phosphenes).1 2

Metabolized principally by CYP3A4; does not modify CYP3A4 substrate metabolism or plasma concentrations.1 7 16 38 40

Drugs and Foods Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Increase plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances.1 16 Concomitant use of potent CY3A4 inhibitors (e.g., azole antifungal agents, macrolide antibiotics, HIV protease inhibitors, nefazodone) contraindicated.1 16 40 (See Contraindications under Cautions.) Avoid use of moderate CYP3A4 inhibitors.1

CYP3A4 inducers: Decrease plasma ivabradine concentrations; avoid concomitant use.1

Specific Drugs and Foods

Storage

Oral

25°C (may be exposed to 15–30°C).1

• Inhibits the funny-current (If) by blocking the funny-channel (f-channel) in the cardiac SA node, which is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel.1 7 36 37 These f-channels, unlike other voltage-gated ion channels, open with hyperpolarization rather than depolarization and have a mixed permeability to sodium and potassium ions.37 38 39 40

• Enters cardiac pacemaker cells and blocks the f-channel from the cytoplasmic side of the membrane preferentially when the channel is in an open state (state-dependent) and is more efficient at depolarized than hyperpolarized voltages.7 37 40

• Interaction between ivabradine and the f-channel binding is dependent upon the rate of opening and closing of the channels in response to repolarization and depolarization (i.e., related to heart rate); this use-dependent property makes ivabradine's heart rate reduction effect more pronounced at elevated heart rates.6 7 10 40

• Ivabradine is drawn to and dissociates from the binding domain of the f-channel by the electrostatic forces generated by depolarization and repolarization (current-dependent). 6 37

• Blockade of the f-channels by ivabradine inhibits the If, leading to a reduction in the slow diastolic depolarization phase of the SA node action potential and thereby a reduction in heart rate.7 34 40

• Adverse effects on vision (e.g., phosphenes) caused by interaction of ivabradine with retinal ion channels (Ih), which closely resemble the If channels in the SA node.7 38 40 (See Common Adverse Effects under Cautions.)

• Importance of advising patients to read the manufacturer's patient labeling (medication guide).1

• Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinician advising females of reproductive potential to use effective contraception and to notify their healthcare provider about a known or suspected pregnancy.1 Importance of informing pregnant women about the potential risks to the fetus.1

• Importance of advising patients to report substantial decreases in heart rate or symptoms such as dizziness, fatigue, or hypotension.1

• Importance of advising patients to report symptoms of atrial fibrillation, such as heart palpitations or racing pulse, chest pressure, or worsened shortness of breath.1 Importance of patients receiving regular cardiac rhythm monitoring.1

• Importance of advising patients about the possible occurrence of luminous phenomena (phosphenes).1 Importance of advising patients to use caution if they are driving or using machines in situations where sudden changes in light intensity may occur, especially when driving at night.1 Importance of informing patients that phosphenes may subside spontaneously during continued treatment with ivabradine.1

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 Importance of advising patients to avoid ingestion of grapefruit juice or St. John's wort.1

• Importance of advising patients to take ivabradine twice daily with meals.1 If a dose is missed, the next dose should be taken at the usual time; the missed dose should not be doubled.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)