AHFS Class:

• Cardiotonic Agents 24:04.08

Generic Name(s):

• Ivabradine

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

Heart Failure

Ivabradine is used to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic, mild to severe chronic heart failure (New York Heart Association [NYHA] class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] of 35% or less), who are in sinus rhythm with a resting heart rate of 70 beats/minute or more 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 guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure.524,700,701,703 (See Uses: Heart Failure, in Enalapril 24:32.04 and in Sacubitril and Valsartan 24:32.92.) Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart-failure related hospitalizations.524,700 Experts recommend that all asymptomatic patients with reduced LVEF (i.e., American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and a β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality.524 In patients with prior or current symptoms of chronic heart failure with reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality.700 If a patient cannot tolerate a β-blocker or if increasing the dosage of the β-blocker is ineffective, experts suggest that ivabradine be considered in symptomatic patients as an alternative or additional treatment option to reduce heart failure-related hospitalizations.5,8,700,701 Unlike β-blockers, ivabradine selectively reduces heart rate without any adverse effects on myocardial contractility, left ventricular relaxation, and coronary tone.6,7,16 Ivabradine also has a use-dependent mechanism of action, in which the reduction in heart rate is greater at higher heart rates than at lower heart rates, minimizing the risk of severe bradycardia.7,38,40 (See Description.) Unlike β-blockers, ivabradine has not been shown to reduce cardiovascular mortality.1,2,8,15,20 Given the well-established mortality benefits of β-blocker therapy, it remains important to initiate and titrate the dosage of β-blockers upwards to optimal level, as tolerated, before assessing the resting heart rate for consideration of ivabradine therapy.700

Efficacy and safety of ivabradine as an adjunct to or a substitute for therapy with a β-blocker in the management of chronic heart failure has been established principally by the results of a randomized, double-blind, placebo-controlled trial (SHIFT) in patients with chronic heart failure receiving standard-of-care therapy at baseline, which included a β-blocker if tolerated.1,2 In this trial, ivabradine reduced the risk of the combined end point of hospitalization for worsening heart failure or cardiovascular death by 18% when added to guideline- and evidence-based treatment within 3 months.1,2 The trial was conducted in 6558 adults with stable NYHA class II-IV chronic heart failure with an LVEF of 35% or less, who were in sinus rhythm with a resting heart rate of 70 beats/minute or more and had been admitted to the hospital for worsening of heart failure within the previous 12 months.1,2 Patients received ivabradine or placebo in addition to standard-of-care therapy that included maximally tolerated dosages of β-blockers.1,2 Approximately 89% of enrolled patients received a β-blocker; 26% of patients were receiving guideline-defined target daily dosages of these drugs.1,2 The predominant reasons for patients not achieving target dosages of β-blockers were hypotension, fatigue, dyspnea, dizziness, cardiac decompensation, and excessive bradycardia.1,2,18 Approximately 11% of patients did not receive a β-blocker, principally because of chronic obstructive pulmonary disease (COPD), asthma, or hypotension.1,2,18 Most patients' baseline treatment regimens included an ACE inhibitor or angiotensin II receptor antagonist (91% of patients), diuretic (83%), and aldosterone antagonist (60%).1,2 The initial dosage of ivabradine was 5 mg twice daily.1,2 After a 14-day titration period, the dosage was increased to 7.5 mg twice daily unless the resting heart rate was 60 beats/minute or less.1,2 The dosage of ivabradine was adjusted throughout the trial (range: 2.5-7.5 mg twice daily) as tolerated to maintain a resting heart rate of 50-60 beats/minute.1,2 The primary end point of the trial was the composite of cardiovascular death or hospital admission for worsening heart failure.1,2

The benefit of ivabradine in the SHIFT trial was attributable mainly to a reduction in the risk of hospitalization for worsening heart failure with ivabradine compared with placebo (15.6 versus 20.2%, respectively).1 Ivabradine did not have a favorable effect on the mortality component of the primary end point and did not substantially reduce cardiovascular death in the overall treatment population.1,2 The beneficial effect of ivabradine on the primary end point appeared to diminish as the dosage of β-blockers increased, with negligible benefit seen in patients taking guideline-defined target dosages of β-blockers.1,15,17 The composite end point of hospitalization for worsening heart failure or cardiovascular death was not substantially reduced by ivabradine in the subgroup of patients receiving at least 50% of the evidence-based target daily dosage of a β-blocker.2,15,17 Ivabradine therapy was associated with an average reduction in heart rate of 15 beats/minute (baseline value 80 beats/minute), which was generally maintained throughout the course of the trial.2 Patients with heart rates higher than the median were at increased risk of an end point event and exhibited greater event-reducing benefit from ivabradine than those with lower heart rates.2 A diminishing benefit of ivabradine was also seen in patients with lower baseline heart rates (less than 77 beats/minute).2,17 It has been suggested that this diminished benefit may be due to the lower risk of all end points in patients with lower heart rates and/or ivabradine's use-dependent mechanism of action, which may limit the heart rate reduction in patients with lower baseline heart rates.2,10,19 Whether ivabradine can improve patient outcomes when added to optimally managed heart failure therapies has not been established.17

Angina

Ivabradine also has been used for the treatment of chronic stable angina pectoris† in patients with normal sinus rhythm as an adjunct to, or a substitute for, β-blockers in patients whose symptoms are inadequately controlled by β-blockers or in those who have a contraindication or intolerance to the drugs.11,13,14,24 In some clinical trials in patients with chronic stable angina, ivabradine has reduced heart rate, improved exercise capacity, and decreased the number of anginal attacks.21,23,30,31,34 Evidence from randomized controlled trials using standard stress testing indicates that ivabradine may be as effective as atenolol or amlodipine in patients with stable coronary artery disease and that adding ivabradine to atenolol therapy may provide better control of heart rate and anginal symptoms.14,21,22,23,30 However, clinical trials (e.g., BEAUTIFUL, SIGNIFY) have not demonstrated any benefit of ivabradine in terms of cardiovascular outcomes (e.g., myocardial infarction [MI], cardiovascular death) among patients who have stable coronary artery disease with or without stable heart failure and are receiving guideline-based therapy for angina (e.g., including aspirin, statins, ACE inhibitors, β-blockers).1,26 Some clinical trial data suggest that ivabradine should be used with caution in patients with more severe forms of angina due to the possibility of an increased risk of death due to cardiovascular causes or nonfatal MI; however, further study and experience are needed to confirm these findings.26,29,42 Since ivabradine therapy has not been associated with a reduction in cardiovascular mortality, it is important to ensure that dosages of β-blockers (which do reduce cardiovascular mortality) are adjusted to clinically optimal levels before initiating ivabradine therapy.26,29

The BEAUTIFUL trial was a randomized, double-blind placebo-controlled trial evaluating the use of ivabradine in approximately 11,000 patients with coronary artery disease, LVEF less than 40%, and a heart rate of at least 60 beats/minute.1,25 Eligible patients had heart failure and/or angina with stable symptoms for at least 3 months and were receiving conventional drug therapy for these conditions at stable dosages for at least 1 month.1,25,27 Patients who received ivabradine were given an initial dosage of 5 mg twice daily, which was increased to 7.5 mg twice daily depending on resting heart rate and tolerability.1,25 The primary end point was the composite of time to cardiovascular death, hospitalization for acute MI, or hospitalization for new-onset or worsening heart failure.1,25 After a median follow-up of 19 months, the primary composite end point was not reduced with ivabradine therapy.1,25 However, in a post hoc analysis of a subgroup of patients with activity-limiting anginal symptoms (e.g., pain, fatigue, palpitations, dyspnea) and a heart rate of at least 70 beats/minute at the time of randomization, ivabradine therapy was associated with reductions in the primary composite end point of cardiovascular death or hospitalization for fatal and nonfatal MI or heart failure and in coronary revascularization; these reductions were observed despite almost all patients in the subgroup receiving concomitant β-blocker therapy.14,27,28

The findings of the post hoc subgroup analysis in the BEAUTIFUL trial, which were generally considered hypothesis generating, were further evaluated in the SIGNIFY trial in which approximately 19,000 patients with stable coronary artery disease, no clinical heart failure (NYHA class I), and a heart rate of at least 70 beats/minute received ivabradine or placebo in addition to standard therapy.1,26 After a median follow-up of 24.1 months, ivabradine did not substantially affect the primary end point (first occurrence of either cardiovascular death or MI).1 However, in the prespecified subgroup of patients with angina of Canadian Cardiovascular Society (CCS) class II or higher in the SIGNIFY trial, ivabradine increased the absolute risk of the primary composite end point of death from cardiovascular causes or nonfatal MI (7.6 versus 6.5%) compared with placebo, despite improving angina symptoms.26,29 The use of β-blockers was not required for inclusion in the SIGNIFY trial, but approximately 83% of patients in the ivabradine and placebo groups received a β-blocker as a part of their therapy.26 Approximately 12,000 patients in the trial had activity-limiting (CSS Class II or greater) angina.26 Ivabradine was initiated at a dosage of 7.5 mg twice daily, which could be increased to 10 mg twice daily or decreased to 5 mg twice daily to achieve a target heart rate of 55-60 beats/minute.1,26 Further study is needed to evaluate the adverse effects seen in the subgroup analysis of SIGNIFY as these effects may be attributable to the high dosages of ivabradine (10 mg twice daily) used in the trial and potentially exacerbated by concurrent use of drugs that increase ivabradine plasma concentrations and have negative chronotropic actions (e.g., verapamil, diltiazem).42 However, some experts currently suggest that ivabradine not be used in patients with activity-limiting angina who do not have clinical heart failure.701

General

Dosage of ivabradine should be individualized according to the patient's heart rate response and tolerance to a target resting heart rate of 50-60 beats/minute.1

Administration

Ivabradine is administered orally twice daily with meals.1 If a dose is missed, the next dose should be taken at the usual time; the dose should not be doubled to make up for the missed dose.1 (See Advice to Patients.)

Dosage

Dosage of ivabradine hydrochloride is expressed in terms of ivabradine.1

Heart Failure

For the management of chronic symptomatic heart failure, the initial dosage of ivabradine is 5 mg twice daily.1 In patients with a history of conduction defects, or other patients in whom bradycardia could lead to hemodynamic compromise, therapy should be initiated at a dosage of 2.5 mg twice daily.1 Patients should be assessed 2 weeks after initiation of therapy and the dosage adjusted to achieve a resting heart rate of 50-60 beats/minute.1 After the initial adjustment period, the dosage may be adjusted as needed based on resting heart rate and tolerability.1 If the heart rate exceeds 60 beats/minute, the dosage should be increased by 2.5 mg (given twice daily) up to a maximum of 7.5 mg twice daily.1 If the heart rate is less than 50 beats/minute or if the patient is experiencing signs and symptoms of bradycardia, the dosage should be decreased by 2.5 mg (given twice daily).1 If a patient is receiving ivabradine 2.5 mg twice daily and their heart rate is less than 50 beats/minute or they are experiencing signs and symptoms of bradycardia, ivabradine therapy should be discontinued.1

Angina

For the treatment of chronic stable angina†, ivabradine dosages of 2.5-10 mg twice daily have been used.21,23,25,26,31 In 2 large clinical trials in patients with stable angina with or without heart failure, ivabradine was 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 the BEAUTIFUL trial, if the patient's resting heart rate was less than 50 beats/minute or if signs or symptoms of bradycardia were present, the dosage was titrated downward.25 In clinical trials, ivabradine was discontinued if the resting heart rate was less than 50 beats/minute or if signs or symptoms related to bradycardia were present despite reduction of ivabradine dosage.25,26

Special Populations

Hepatic Impairment

No dosage adjustment is required in patients with mild or moderate hepatic impairment.1,40 Ivabradine is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) as safety and efficacy have not been established in this population and an increase in systemic exposure is expected.1 (See Cautions: Contraindications.)

Renal Impairment

No dosage adjustment is required in patients with creatinine clearance 15-60 mL/minute.1,40 Data are lacking on use of ivabradine in patients with creatinine clearance less than 15 mL/minute.1

Contraindications

Acute decompensated heart failure.1

Blood pressure less than 90/50 mm Hg.1

Heart rate less than 60 beats/minute prior to treatment.1

Severe hepatic impairment.1,40 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

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

Concomitant use of potent cytochrome P-450 (CYP) isoenzyme 3A4 inhibitors.1,40 (See Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes.)

Sick sinus syndrome, sinoatrial (SA) block, or third-degree atrioventricular (AV) block (unless a functioning demand pacemaker is present).1

Warnings/Precautions

Fetal Toxicity

Based on findings in animal studies, ivabradine may cause fetal toxicity and teratogenicity when administered to pregnant women.1,7 Embryofetal toxicity and cardiac teratogenic effects (abnormal shape of the heart, interventricular septal defect, complex anomalies of primary arteries) were 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) were observed in pregnant rabbits treated with ivabradine during organogenesis at exposures 15 times the human exposures at the maximum recommended human dose.1

Women of childbearing potential should be advised to use effective contraception while taking ivabradine.1 (See Advice to Patients.)

Atrial Fibrillation

Ivabradine increases the risk of atrial fibrillation.1,2,41 In the SHIFT trial, the rate of atrial fibrillation was 5 versus 3.9% per patient-year in patients treated with ivabradine or placebo, respectively.1 Results of a meta-analysis evaluating clinical trial data from 11 studies indicated a 15% increase in the relative risk of atrial fibrillation with ivabradine therapy.41 Patients receiving ivabradine should receive regular cardiac rhythm monitoring and the drug should be discontinued if atrial fibrillation occurs.1

Bradycardia and Conduction Disturbances

Bradycardia, sinus arrest, and heart block have occurred with ivabradine therapy.1,2 The rate of bradycardia was 6% per patient-year with ivabradine (2.7% symptomatic; 3.4% asymptomatic) and 1.3% per patient-year with placebo.1 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 Concurrent use of verapamil or diltiazem can increase ivabradine exposure, may contribute to heart rate lowering, and should be avoided.1,42 (See Drug Interactions: Calcium-channel Blocking Agents.)

Ivabradine should be avoided in patients with second degree AV block, unless a functioning demand pacemaker is present.1 (See Cautions: Contraindications.) Patients with demand pacemakers set to a rate of 60 beats/minute or more cannot achieve a target heart rate less than 60 beats/minute, and these patients were excluded from clinical trials.1,43 The use of ivabradine is not recommended in patients with demand pacemakers set to rates of 60 beats/minute or higher.1

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions (e.g., angioedema, erythema, rash, pruritus, urticaria) have been reported during postmarketing experience in patients receiving ivabradine.1

Specific Populations

Pregnancy

There are no adequate and well-controlled studies of ivabradine in pregnant women.1 Studies in rats and rabbits indicate that ivabradine can cause fetal harm when administered to pregnant women.1,7 (See Fetal Toxicity under Cautions: Warnings/Precautions.) Increased postnatal mortality was associated with the teratogenic effects seen in rats.1 In pregnant rabbits, increased postimplantation loss was observed at an exposure 5 times the human exposure at the maximum recommended human dose.1,7 Pregnant women receiving ivabradine should be informed of the potential risk to the fetus.1

Stroke volume and heart rate increase during pregnancy, which increases cardiac output, especially during the first trimester.1,35 Pregnant patients with left ventricular ejection fraction (LVEF) less than 35% on maximally tolerated dosages of β-adrenergic blocking agents (β-blockers) may be particularly dependent on increases in heart rate for augmentation of cardiac output.1 Therefore, pregnant patients taking ivabradine, especially during the first trimester, should be closely monitored for destabilization of their heart failure that could result from heart rate slowing.1 Pregnant women with chronic heart failure in their third trimester of pregnancy should be monitored for preterm birth.1

Lactation

Ivabradine is distributed into milk in rats; it is not known whether ivabradine is distributed into human milk.1,7 Because of the potential risk to breast-fed infants from exposure to ivabradine, breast-feeding is not recommended.1,7

Pediatric Use

Safety and efficacy have not been established in patients younger than 18 years of age.1

Geriatric Use

No pharmacokinetic differences with ivabradine have been observed in patients 65 years of age or older compared with the overall population.1 However, there is limited experience with ivabradine in patients 75 years of age or older.1

Renal Impairment

Renal impairment (creatinine clearance 15-60 mL/minute) has minimal effect on the pharmacokinetics of ivabradine.1 Data are lacking on use of ivabradine in patients with creatinine clearance less than 15 mL/minute.1

Hepatic Impairment

In patients with mild or moderate hepatic impairment, the pharmacokinetics of ivabradine were similar to that in patients with normal hepatic function.1 Safety and efficacy have not been established in patients with severe hepatic impairment (Child-Pugh class C); use is contraindicated in these patients as increased systemic exposure is anticipated.1 (See Cautions: Contraindications.)

Common Adverse Effects

Adverse effects reported in more than 1% of patients receiving ivabradine in the SHIFT trial and occurring at least 1% more frequently with ivabradine than with placebo include bradycardia, hypertension, atrial fibrillation, and phosphenes/visual brightness.1,2 Phosphenes are described as a transiently enhanced brightness in a limited area of the visual field, or as halos, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency).1,7 Phosphenes generally are triggered by sudden changes in light intensity.1,7 Phosphenes generally become apparent within the first 2 months of treatment, after which they may occur repeatedly.1 This phenomenon generally has been of mild to moderate intensity and usually has resolved during or after ivabradine treatment.1,7

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Ivabradine is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4.1,7,16 The major metabolite of ivabradine is the N -desmethylated derivative (S 18982), which is also metabolized by CYP3A4.1,7,16 Drugs that inhibit or induce CYP3A4 can increase or decrease, respectively, ivabradine plasma concentrations; increased concentrations may exacerbate bradycardia and conduction disturbances.1,16 Concomitant use of potent CYP3A4 inhibitors such as azole antifungal agents, macrolide antibiotics, HIV protease inhibitors, and nefazodone is contraindicated.1,16,40 (See Cautions: Contraindications.) The concomitant use of moderate CYP3A4 inhibitors such as diltiazem, verapamil, and grapefruit juice should be avoided.1 Inducers of CYP3A4 such as St. John's wort ( Hypericum perforatum ), rifampin, barbiturates, and phenytoin also should be avoided during ivabradine therapy.1

Azole Antifungal Agents

Concomitant use of ivabradine and potent CYP3A4 inhibitors such as azole antifungal agents (e.g., itraconazole, ketoconazole) increases the plasma concentrations of ivabradine and is contraindicated.1,16 (See Cautions: Contraindications.)

Calcium-channel Blocking Agents

Concomitant use of ivabradine and moderate CYP3A4 inhibitors such as diltiazem and verapamil increases plasma ivabradine concentrations and should be avoided.1,7,16,42 Calcium-channel blocking agents such as diltiazem and verapamil that act as negative chronotropes also may increase the risk of bradycardia.1 Heart rate should be monitored in patients taking ivabradine with other negative chronotropes.1

HIV Protease Inhibitors

Concomitant use of ivabradine and potent CYP3A4 inhibitors such as HIV protease inhibitors (e.g., nelfinavir) increases plasma concentrations of ivabradine and is contraindicated.1,16 (See Cautions: Contraindications.)

Macrolide Antibiotics

Concomitant use of ivabradine and potent CYP3A4 inhibitors such as macrolide antibiotics (e.g., clarithromycin, telithromycin) increases plasma concentrations of ivabradine and is contraindicated.1,16 (See Cautions: Contraindications.)

Metformin

Ivabradine (10 mg twice daily dosed to steady state) did not affect the pharmacokinetics of concomitantly administered metformin, an organic cation transporter (OCT2) sensitive substrate.1 No dosage adjustment is required for metformin when administered with ivabradine.1

Nefazodone

Concomitant use of ivabradine and potent CYP3A4 inhibitors such as nefazodone increases plasma concentrations of ivabradine and is contraindicated.1,16 (See Cautions: Contraindications.)

Negative Chronotropes

The risk of bradycardia increases with concomitant administration of drugs that slow heart rate (e.g., digoxin, amiodarone, β-adrenergic blocking agents [β-blockers]).1 Heart rate should be monitored in patients taking ivabradine with other negative chronotropes.1 Digoxin exposure did not change when used concomitantly with ivabradine.1

Proton-pump Inhibitors

Concomitant administration of lansoprazole (60 mg daily) or omeprazole (40 mg daily) did not have a clinically important effect on the pharmacokinetics of ivabradine; no dosage adjustment is required.1,7,16

Sildenafil

Sildenafil (100 mg) did not have a clinically important effect on the pharmacokinetics of ivabradine; no dosage adjustment is required.1,40

Simvastatin

Simvastatin (20 mg daily) did not have a clinically important effect on the pharmacokinetics of ivabradine; no dosage adjustment is required.1

Warfarin

Warfarin (1-5 mg daily) did not have a clinically important effect on the pharmacokinetics of ivabradine; no dosage adjustment is required.1,7

Description

Ivabradine is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel (funny-channel [f-channel]) blocking agent that reduces the spontaneous pacemaker activity of the sinoatrial (SA) node by selectively inhibiting the funny-current ( I _f) in pacemaker cells, resulting in heart rate reduction with no effect on ventricular repolarization or myocardial contractility.1,7,36,37

The f-channels are part of the HCN channel family, which is comprised of many distinct isoforms (HCN 1-4), and are expressed in the heart and nervous system.36,38,39 The HCN4 channel is found in the heart and is active in the pacemaker cells of the SA node.7,38,39 The 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 These channels open and close in response to ambient voltage and local intracellular cyclic adenosine monophosphate (cAMP) concentrations.7,34,37,38 Adrenergic agonists activate adenylate cyclase, which causes an increase in intracellular cAMP, whereas cholinergic transmitters decrease local cAMP by inhibiting adenylate cyclase.7,34,37,38 Intracellular cAMP acts as a second messenger and favors f-channel opening by direct binding to the c-terminus of the channel, which induces a depolarizing shift of the activation curve, leading to an increase in the number of open f-channels.7,36,40 The I _f current, which is a mixed sodium-potassium current, is able to move across open f-channels;40 this causes a deeper slope of diastolic depolarization and a reduction in diastolic duration, leading to an elevation in heart rate.36,38

Ivabradine has a unique mechanism of action in that it displays state-dependent, use-dependent, and current-dependent properties.6 Ivabradine 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-dependence) and is more efficient at depolarized than hyperpolarized voltages.7,37,40 Therefore, the interaction between ivabradine and the f-channel binding site is dependent upon the rate of opening and closing of the channels in response to repolarization and depolarization (i.e., related to heart rate).6 As a result of this use-dependent inhibition, the reduction in pacemaker activity by ivabradine is more pronounced at higher firing rates in the SA node.7,10,40 Ivabradine also displays a current-dependence property by which ivabradine is drawn to the binding site of the f-channel by the electrostatic forces generated by the depolarization process and dissociates from the binding site in response to the inward current generated from the repolarization process.6,37 The blockade of f-channels by ivabradine inhibits the I _f current, which leads to a reduction in the slow diastolic depolarization phase of the SA node action potential, thereby reducing heart rate.7,34,40 The selective binding of ivabradine to f-channels makes it a pure heart-rate-reducing agent.7,40 Reduction in heart rate with ivabradine decreases myocardial oxygen consumption and increases oxygen supply due to prolongation of diastolic perfusion time.6,36

The adverse effects of ivabradine on vision are due to interaction of ivabradine with retinal ion channels ( I _h current), which closely resemble the I _f channels in the SA node.7,38,40 The I _h current is involved in curtailing retinal responses to bright light stimuli.1,5 Under circumstances that trigger these I _h channels (e.g., rapid changes in luminosity), partial inhibition of the I _h current by ivabradine may cause the luminous phenomena experienced by some patients.1,7,38 (See Cautions: Common Adverse Effects.)

Following oral administration, peak plasma concentrations of ivabradine are reached in approximately 1 hour under fasting conditions.1,7,16,38,40 Food delays absorption by approximately 1 hour and increases plasma ivabradine exposure by 20-40%; therefore, it is recommended that the drug be taken with meals to reduce individual variability in systemic exposure.1,7,16,38,40 (See Dosage and Administration: Administration.) The absolute oral bioavailability of ivabradine is approximately 40% due to first-pass elimination in gut and liver via cytochrome P-450 (CYP) isoenzyme 3A4-mediated oxidation.1,7,16,38,40 The major metabolite of ivabradine is the N -desmethylated derivative (S 18982), which is equipotent to ivabradine and circulates at concentrations approximately 40% that of ivabradine and is also metabolized by CYP3A4.1,7,16,38 Ivabradine has a low affinity for CYP3A4 and does not modify CYP3A4 substrate metabolism or plasma concentrations.7,16,38,40 Conversely, potent inhibitors and inducers may substantially affect ivabradine's bioavailability and plasma concentrations.1,7,16,38,40 (See Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes.) Ivabradine is approximately 70% bound to plasma proteins.1,7,16,38,40 Ivabradine plasma concentrations decline with a distribution half-life of 2 hours and an effective half-life of approximately 6 hours.1

Advice to Patients

Importance of advising patients to read the FDA-approved patient labeling (medication guide).1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of 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) in the field of vision.1 Importance of advising patients to use caution if they are driving or using machines in situations where sudden changes in light intensity could 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 diseases.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 dose should not be doubled to make up for the missed dose.1

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

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Amgen Inc. Corlanor^® (ivabradine) tablets prescribing information. Thousand Oaks, CA; 2015 Apr.

2. Swedberg K, Komajda M, Böhm M et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet . 2010; 376:875-85. [PubMed 20801500]

5. Urbanek I, Kaczmarek K, Cygankiewicz I et al. Risk-benefit assessment of ivabradine in the treatment of chronic heart failure. Drug Healthc Patient Saf . 2014; 6:47-54. [PubMed 24855390][PubMedCentral]

6. Scicchitano P, Cortese F, Ricci G et al. Ivabradine, coronary artery disease, and heart failure: beyond rhythm control. Drug Des Devel Ther . 2014; 8:689-700. [PubMed 24940047][PubMedCentral]

7. Parakh N, Bhargava B. Rate control with ivabradine: angina pectoris and beyond. Am J Cardiovasc Drugs . 2011; 11:1-12. [PubMed 21090826]

8. Di Franco A, Sarullo FM, Salerno Y et al. Beta-blockers and ivabradine in chronic heart failure: from clinical trials to clinical practice. Am J Cardiovasc Drugs . 2014; 14:101-10. [PubMed 24327100]

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