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Ivabradine Hydrochloride

Class: Cardiac Drugs, Miscellaneous
Chemical Name: 3-[3-[[[(7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]methylamino]propyl]-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one
Molecular Formula: C27H36N2O5
CAS Number: 155974-00-8
Brands: Corlanor

Introduction

A sinoatrial modulator; a hyperpolarization activated cyclic nucleotide-gated (HCN) channel (funny-channel [f-channel]) blocking agent.1 7 37 700

Uses for Ivabradine Hydrochloride

Heart Failure

Used to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic, mild to severe chronic heart failure (NYHA class II–IV) with reduced ejection fraction (LVEF ≤35%), who are in sinus rhythm with a resting heart rate ≥70 bpm and are either on maximally tolerated dosages of a β-adrenergic blocking agent (β-blocker) or have a contraindication to β-blocker use.1 5 700 701

Current heart failure guidelines generally recommend clinical trial-proven β-blockers (e.g., carvedilol, bisoprolol, extended-release metoprolol succinate) in conjunction with neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs]) to inhibit the renin-angiotensin-aldosterone (RAA) system in patients with heart failure and reduced LVEF due to favorable effects of these drugs on survival and disease progression.524 700 If patients cannot tolerate therapy with a β-blocker or if increasing the β-blocker dosage is ineffective, consider ivabradine in symptomatic patients as an alternative or additional treatment option to reduce heart failure-related hospitalizations.5 8 700 701

Initiate and titrate the dosage of β-blockers upwards to optimal level for prevention of cardiovascular mortality, as tolerated, before assessing resting heart rate for consideration of ivabradine therapy.700

No reduction in cardiovascular mortality demonstrated with ivabradine in patients with chronic heart failure.1 2 8 15 20

Not established whether ivabradine can improve cardiovascular outcomes when added to optimally managed heart failure therapies.17

Angina

Adjunct to or substitute for β-blocker therapy for treatment of chronic stable angina pectoris in patients with inadequately controlled symptoms or a contraindication or intolerance to β-blockers. 11 13 14 24

Reduces heart rate, improves exercise capacity, and decreases the number of anginal attacks.21 23 30 31 34

No benefit with ivabradine in terms of cardiovascular outcomes (e.g., MI, cardiovascular death) in patients with stable coronary artery disease with or without stable heart failure who are receiving guideline-based therapy for angina (e.g., aspirin, statins, ACE inhibitors, β-blockers).1 26

Some clinical trial data suggest ivabradine use was associated with possible increase in the risk of death from cardiovascular causes or nonfatal MI in patients with more severe forms of angina and no clinical heart failure; further study and experience needed.26 29 42

Ivabradine Hydrochloride Dosage and Administration

General

  • Individualize dosage according to patient's heart rate response and tolerance (target resting heart rate 50–60 bpm).1

Administration

Oral Administration

Administer twice daily with meals.1

If a dose is missed, take next dose at the regularly scheduled time; do not double the dose.1 (See Advice to Patients.)

Dosage

Available as ivabradine hydrochloride; dosage expressed in terms of ivabradine.1

Adults

Heart Failure
Oral

Initially, 5 mg twice daily.1

Initiate dosage of 2.5 mg twice daily in patients with history of conduction defects, or patients in whom bradycardia could lead to hemodynamic compromise.1

Allow 2 weeks to assess response to initial dosage.1 After initial adjustment period, adjust dosage as needed based on resting heart rate and tolerability to achieve resting heart rate of 50–60 beats/minute.1

If heart rate is >60 beats/minute, increase dosage by 2.5 mg (given twice daily) up to maximum of 7.5 mg twice daily.1

If heart rate is <50 beats/minute or patient is experiencing signs and symptoms of bradycardia, decrease dosage by 2.5 mg (given twice daily).1

Discontinue therapy if patient is receiving ivabradine 2.5 mg twice daily and heart rate is <50 beats/minute or patient is experiencing signs and symptoms of bradycardia.1

Angina
Oral

Dosages of 2.5–10 mg twice daily have been used.21 23 25 26 31 In clinical trials, ivabradine initiated at dosages of 5 or 7.5 mg twice daily and titrated after 2–4 weeks to a target heart rate of 50–60 beats/minute.25 26

In clinical trials, dosage was titrated downward in patients with resting heart rate <50 beats/minute or if signs or symptoms of bradycardia were present.25

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild or moderate hepatic impairment.1 40

Contraindicated in patients with severe hepatic impairment (Child-Pugh class C); safety and efficacy not established in this population but increase in systemic exposure expected.1 40 (See Contraindications under Cautions.)

Renal Impairment

No dosage adjustment required for patients with Clcr 15–60 mL/minute.1

Data lacking on use in patients with Clcr <15 mL/minute.1 7 16

Cautions for 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

Pregnancy

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

Lactation

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

Pediatric Use

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

Geriatric Use

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

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

Hepatic Impairment

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

Interactions for Ivabradine Hydrochloride

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

Drug or Food

Interaction

Comments

β-Adrenergic blocking agents (β-blockers)

Increases risk of bradycardia1

Monitor heart rate with concomitant use1

Amiodarone

Increases risk of bradycardia1

Monitor heart rate with concomitant use1

Antifungals, azoles (e.g., itraconazole, ketoconazole)

Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 7 16

Concomitant use contraindicated1 16

Barbiturates

Decreases plasma ivabradine concentrations1 7

Avoid concomitant use1 7

Calcium-channel blocking agents, nondihydropyridine (e.g., diltiazem, verapamil)

Increases plasma ivabradine concentrations, and may exacerbate bradycardia and conduction disturbances; increases risk of bradycardia1 7 16 42

Avoid concomitant use; monitor heart rate1 7 16 42

Digoxin

Increases risk of bradycardia; digoxin exposure unchanged1

Monitor heart rate with concomitant use1

Grapefruit juice

Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 7

Avoid concomitant use1 7

HIV protease inhibitors (e.g., nelfinavir)

Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 16

Concomitant use contraindicated1 16

Macrolides (e.g., clarithromycin, telithromycin)

Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 16

Concomitant use contraindicated1 16

Metformin

No effects on the pharmacokinetics of metformin1

No dosage adjustment necessary1

Nefazodone

Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances1 16

Concomitant use contraindicated1 16

Phenytoin

Decreases plasma ivabradine concentrations1 7 16

Avoid concomitant use1 7 16

Proton-pump inhibitors (e.g., lansoprazole, omeprazole)

No effects on the pharmacokinetics of ivabradine1 7 16

No dosage adjustment necessary1 7 16

Rifampin

Decreases plasma ivabradine concentrations1 7

Avoid concomitant use1 7

Sildenafil

No effects on the pharmacokinetics of ivabradine1 40

No dosage adjustment necessary1 40

Simvastatin

No effects on the pharmacokinetics of ivabradine1

No dosage adjustment necessary1

St. John's wort (Hypericum perforatum)

Decreases plasma ivabradine concentrations1 7 16

Avoid concomitant use1 7 16

Warfarin

No effects on the pharmacokinetics of ivabradine1 7

No dosage adjustment necessary1 7

Ivabradine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability approximately 40%.1 7 16 38 40

Following oral administration, peak plasma concentrations occur within 1 hour under fasting conditions.1 7 16 38 40

Food

Food delays absorption by approximately 1 hour and increases plasma exposure by 20–40%.1 7 16 38 40

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1 7

Plasma Protein Binding

Approximately 70%.1 7 16 38 40

Elimination

Metabolism

Undergoes first-pass metabolism in gut and liver via CYP3A4-mediated oxidation.1 7 16 38 40 Major metabolite is N-desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations approximately 40% that of ivabradine; also metabolized by CYP3A4.1 7 16 38

Elimination Route

Equally excreted in feces and urine as metabolites;1 approximately 4% of an oral dose eliminated in urine as unchanged drug.1 16 38 40

Half-life

Distribution half-life of 2 hours and effective half-life of approximately 6 hours.1

Special Populations

Increased systemic exposure anticipated in severe hepatic impairment (Child-Pugh class C).1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • 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.)

Advice to Patients

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ivabradine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets (film-coated)

5 mg (of ivabradine)

Corlanor

Amgen

7.5 mg (of ivabradine)

Corlanor

Amgen

AHFS DI Essentials. © Copyright 2017, Selected Revisions January 19, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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