Ivabradine

Pharmacologic Category

Cardiovascular Agent, Miscellaneous

Dosing: Adult

Heart failure: Oral: Initial: 5 mg twice daily or 2.5 mg twice daily in patients with a history of conduction defects or who may experience hemodynamic compromise due to bradycardia. After 2 weeks, adjust dose to achieve a resting heart rate between 50 and 60 beats per minute (bpm). Thereafter, adjust dose as needed based on resting heart rate and tolerability. Maximum dose: 7.5 mg twice daily.

Dosage adjustment based on resting heart rate:

If heart rate >60 bpm: Increase dose by 2.5 mg twice daily (maximum dose: 7.5 mg twice daily)

If heart rate 50 to 60 bpm: Maintain dose

If heart rate <50 bpm or signs and symptoms of bradycardia: Decrease dose by 2.5 mg twice daily; if current dose is 2.5 mg twice daily, discontinue therapy

Inappropriate sinus tachycardia (off-label use): Oral: Initial: 5 mg twice daily; maintenance: 7.5 mg twice daily (ACC/AHA/HRS [Page 2015]; Cappato 2012). May also use in combination with a beta-blocker (eg, metoprolol) in patients who are refractory to monotherapy (Ptaszynski 2013).

Stable angina (off-label use): Adults <75 years: Oral: Initial: 2.5 to 5 mg twice daily; titrate up in increments of 2.5 mg after 3 to 4 weeks if symptoms persist and heart rate is greater than 60 bpm to a maximum dose of 7.5 mg twice daily. Discontinue therapy if angina symptoms do not improve within 3 months of initiation. Also consider discontinuation if improvement of angina symptoms is limited and no clinically significant heart rate reduction occurs in the first 3 months. If heart rate is lower than 50 bpm at rest or patient experiences symptomatic bradycardia (eg, dizziness, fatigue, hypotension) during therapy, decrease dose by 2.5 mg per dose, or discontinue if already at the minimum dose of 2.5 mg twice daily. Monitor heart rate carefully after dosage reduction. If heart rate continues to be lower than 50 bpm or symptoms of bradycardia persist, discontinue ivabradine (Corlentor 2015).

If symptoms are not controlled on beta-blocker or calcium channel blocker monotherapy, addition of ivabradine can be considered. If combined with a calcium channel blocker, use of a dihydropyridine (such as slow-release nifedipine, amlodipine, or felodipine) is suggested (Montalescot 2013; NICE 2012).

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Heart failure: Refer to adult dosing.

Stable angina (off-label use): Adults ≥75 years: Initial: Oral: Consider 2.5 mg twice daily. Titration and maintenance: Refer to adult dosing.

Dosing: Renal Impairment: Adult

CrCl ≥15 mL/minute: No dosage adjustment necessary.

CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): Use is contraindicated (has not been studied; increase in systemic exposure anticipated).

Dosing: Pediatric

Heart failure, dilated cardiomyopathy:

Infants ≥6 months, Children, and Adolescents <18 years:

<40 kg: Oral: Initial: 0.05 mg/kg/dose twice daily; may increase dose every 2 weeks by 0.05 mg/kg/dose as tolerated to achieve a 20% reduction in heart rate without inducing bradycardia.

Maximum dose: Age-dependent:

≥6 months to <1 year: 0.2 mg/kg/dose twice daily.

≥1 year: 0.3 mg/kg/dose twice daily, not to exceed 7.5 mg/dose twice daily.

Dosage adjustment for bradycardia:

Initial dose: Decrease dose to 0.02 mg/kg/dose twice daily.

During titration: Decrease dose to previous dose.

≥40 kg: Oral: Initial: 2.5 mg twice daily; may increase dose every 2 weeks by 2.5 mg as tolerated to achieve a 20% reduction in heart rate without inducing bradycardia; maximum dose: 7.5 mg/dose twice daily.

Dosage adjustment for bradycardia: Decrease dose to previous dose.

Adolescents ≥18 years: Oral: Initial: 5 mg twice daily or 2.5 mg twice daily in patients with a history of conduction defects or who may experience hemodynamic compromise due to bradycardia; after 2 weeks, adjust dose to achieve a resting heart rate between 50 and 60 beats per minute (bpm); adjust dose as needed based on resting heart rate and tolerability; maximum dose: 7.5 mg/dose twice daily.

Dosage adjustment based on resting heart rate:

If heart rate >60 bpm: Increase dose by 2.5 mg twice daily; maximum dose: 7.5 mg/dose twice daily.

If heart rate 50 to 60 bpm: Maintain dose.

If heart rate <50 bpm or signs and symptoms of bradycardia: Decrease dose by 2.5 mg twice daily; if current dose is 2.5 mg twice daily, discontinue therapy.

Dosing: Renal Impairment: Pediatric

Infants ≥6 months, Children, and Adolescents:

CrCl ≥15 mL/minute: No dosage adjustment necessary.

CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Pediatric

Infants ≥6 months, Children, and Adolescents:

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment: Use is contraindicated (has not been studied; increase in systemic exposure anticipated).

Use: Labeled Indications

Heart failure: To reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic (NYHA class II to III according to the ACC/AHA/HFSA heart failure guidelines [Yancy 2016]) chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute (bpm) and either are on maximally tolerated doses of beta blockers or have a contraindication to beta-blocker use.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Inappropriate sinus tachycardiaLevel of Evidence [C, G]

Data from a small, prospective, randomized, placebo-controlled, crossover trial demonstrated that ivabradine significantly reduced daytime heart rate and improved exercise tolerance and symptoms in patients with inappropriate sinus tachycardia (IST) ^Ref. In addition, ivabradine may be combined with beta-blocker therapy in patients who are refractory to monotherapy ^Ref. Additional data may be necessary to further define the role of ivabradine in this condition.

Based on the American College of Cardiology/American Heart Association/Heart Rhythm Society guidelines for the management of patients with supraventricular arrhythmias, ivabradine may be a reasonable treatment option for ongoing management of symptomatic IST.

Stable anginaLevel of Evidence [B, G]

A multicenter, placebo-controlled trial evaluating the addition of ivabradine to current stable angina therapy demonstrated no significant differences in the incidence of primary end points (composite of death from cardiovascular events or nonfatal myocardial infarction) or incidence of primary end point components. In a single-center, placebo-controlled trial, ivabradine in combination with atenolol significantly improved total exercise endurance compared with atenolol alone in patients with stable angina. The long-term clinical and cost effectiveness of adding ivabradine to beta-blocker or calcium channel blocker therapy is unknown.

According to European and UK guidelines, ivabradine is recommended as second-line therapy (or as first-line therapy in select patients) for treatment of adults with chronic stable angina. Ivabradine is approved in Europe for symptomatic treatment of patients with chronic stable angina, normal sinus rhythm, and a heart rate of at least 70 bpm, specifically as monotherapy in cases unresponsive to or intolerant of beta-blockers, or as add-on therapy in cases uncontrolled by beta-blockers alone. US guidelines provide pharmacology and evidence for ivabradine; however, because ivabradine was not approved in the United States when the guidelines were published, no specific recommendation was made regarding its use. Access Full Off-Label Monograph

Level of Evidence Definitions

Level of Evidence Scale

Comparative Efficacy

• IVABRADINE

Clinical Practice Guidelines

Arrhythmias:

ACC/AHA/HRS, “Guideline for the Management of Adult Patients With Supraventricular Tachycardia,” 2015

Heart Failure:

ACC/AHA/HFSA, “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure,” May 2016

ACCF/AHA, “2013 ACCF/AHA Guideline for the Management of Heart Failure,” June 2013

Administration: Oral

Administer with food. Oral solution can be used for adults unable to swallow tablets. For oral solution, empty entire contents of ampule(s) into a medication cup; use a calibrated oral syringe to measure prescribed dose from the medication cup. Discard any unused oral solution.

Administration: Pediatric

Oral: Administer with food. For oral solution, empty entire contents of ampule(s) into a medication cup; use a calibrated oral syringe to measure prescribed dose from the medication cup. Discard any unused oral solution. Rinse oral syringe and medicine cup with warm, running water after use and air dry.

If a dose is missed or spit out, do not administer another dose; administer next dose at usual time.

Hazardous Drugs Handling Considerations

This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Ivabradine may cause teratogenicity. Assess risk to determine appropriate containment strategy (USP-NF 2017).

Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016).

Storage/Stability

Store at 25ºC (77ºF); excursions are permitted between 15ºC and 30ºC (59ºF and 86ºF). To protect from light, keep oral solution ampules in original foil pouches until use.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat heart failure (weak heart).

• It is used in certain patients with heart failure to lower the chance of having to go to the hospital for heart failure that gets worse.

• It may be given to you for other reasons. Talk with the doctor.

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Slow heartbeat

• Abnormal heartbeat

• Dizziness

• Passing out

• Chest pain

• Shortness of breath

• Loss of strength and energy

• Vision changes

• Severe headache

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Corlanor: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/206143s007lbl.pdf#page=24

Contraindications

Acute decompensated heart failure; clinically significant hypotension; sick sinus syndrome, sinoatrial block, or third-degree AV block (unless a functioning demand pacemaker is present); clinically significant bradycardia; severe hepatic impairment; pacemaker dependence (heart rate maintained exclusively by the pacemaker); concomitant use with strong CYP3A4 inhibitors

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to ivabradine or any component of the formulation; resting heart rate <70 bpm prior to treatment; prolonged QT interval (eg, congenital long QT syndrome); cardiogenic shock; acute myocardial infarction; concomitant use of verapamil or diltiazem; pregnancy, breastfeeding, or women of child-bearing potential not using appropriate contraception; hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp lactase deficiency

Warnings/Precautions

Concerns related to adverse events:

• Atrial fibrillation: Use increases the risk of atrial fibrillation; monitor cardiac rhythm. Discontinue if atrial fibrillation develops.

• Bradycardia and conduction disturbances: Bradycardia, sinus arrest, and heart block may occur; monitor heart rate prior to initiation and with any dosage adjustment. Bradycardia may increase the risk of QT prolongation, which may lead to severe ventricular arrhythmias, including torsade de pointes, especially in patients with risk factors such as use of QTc prolonging drugs. 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, digoxin, diltiazem, verapamil, amiodarone). Avoid concurrent use with verapamil and diltiazem. Avoid use in patients with second-degree AV block (unless a functioning demand pacemaker is present). Use is contraindicated in patients with sick sinus syndrome, sinoatrial block, third-degree AV block (unless a functioning demand pacemaker is present), or pacemaker dependence. Decrease dose or discontinue use if heart rate <50 bpm persists during therapy or signs and symptoms of bradycardia occur. Use is contraindicated in patients with clinically significant bradycardia. In patients with history of conduction defects or in whom bradycardia could lead to hemodynamic compromise, initial dosage reduction is recommended. Heart rate reduction may prolong the uncorrected QT interval while QTc interval remains unchanged (Camm 2003; Murat 2009). At concentrations slightly higher than that achieved with therapeutic dosing, ivabradine prolonged ventricular repolarization in perfused guinea-pig hearts (Melgari 2015). Torsades de pointes has been reported when used with other drugs that produce bradycardia or prolong the QT interval (Cocco 2015; Mittal 2014).

• Visual function: Phosphenes (described as transient enhanced brightness in a limited area of the visual field, halos, image decomposition, colored bright lights, or multiple images) may occur with use. Onset is generally within the first 2 months of therapy and is reported to be of mild to moderate intensity; most cases resolve during or after treatment discontinuation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

An abstract of a study of 106 elderly patients (75 to 85 years of age) with NYHA class II or class III heart failure and preserved left ventricular ejection fraction (EF >50%) treated with ivabradine (up to 7.5 twice daily) demonstrated that the ivabradine was safe and efficacious in this population. The study showed improvement in symptoms and echocardiographic diastolic function with a significant reduction of heart rate. No specific dose recommendations based upon age were made (Cice 2013).

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies, and fetal harm may occur if ivabradine is administered to pregnant women. Effective contraception is recommended in women of reproductive potential. If treatment is needed during pregnancy, closely monitor for destabilization of heart failure that could potentially result from heart rate slowing caused by ivabradine, especially during the first trimester. Pregnant women with chronic heart failure should also be monitored for preterm birth.

Breast-Feeding Considerations

It is not known if ivabradine is present in breast milk. Due to the potential risk from exposure in the breastfed infant, breastfeeding is not recommended by the manufacturer.

Briggs' Drugs in Pregnancy & Lactation

• Ivabradine

Adverse Reactions

1% to 10%:

Cardiovascular: Bradycardia (4% to 10%), hypertension (9%), atrial fibrillation (8%)

Central nervous system: Phosphene (3%)

Frequency not defined: Cardiovascular: Heart block, sinoatrial arrest

<1%, postmarketing, and/or case reports: Angioedema, diplopia, erythema, hypotension, pruritus, skin rash, syncope, torsades de pointes, urticaria, ventricular fibrillation, ventricular tachycardia, vertigo, visual impairment

* See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Effects

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions Open Interactions

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the bradycardic effect of Ivabradine. Ivabradine may enhance the QTc-prolonging effect of Calcium Channel Blockers (Nondihydropyridine). Specifically, the QTc prolonging effects of bepridil may be enhanced. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Ivabradine. Specifically, verapamil or diltiazem may increase serum ivabradine concentrations. Risk X: Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ivabradine. Risk X: Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Ivabradine. Risk X: Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ivabradine. Risk X: Avoid combination

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fexinidazole [INT]: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole [INT]. Risk X: Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Grapefruit Juice: May increase the serum concentration of Ivabradine. Risk X: Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Loop Diuretics: May enhance the arrhythmogenic effect of Ivabradine. Risk C: Monitor therapy

Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Regorafenib: May enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Risk C: Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. Risk D: Consider therapy modification

St John's Wort: May decrease the serum concentration of Ivabradine. Risk X: Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Risk D: Consider therapy modification

Terlipressin: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Thiazide and Thiazide-Like Diuretics: May enhance the arrhythmogenic effect of Ivabradine. Risk C: Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy

Food Interactions

Food: Absorption delayed by 1 hour and AUC increased by 20% to 40% when taken with food. Management: Take with food to reduce variability in exposure.

Grapefruit juice: Exposure increased twofold after ingestion of grapefruit juice. Management: Avoid consumption of grapefruit juice (Nawarskas 2015).

Genes of Interest

• Cytochrome P450 3A4

Monitoring Parameters

Heart rate (prior to initiation, prior to increasing dose, or after decreasing dose); monitor heart rate more closely if receiving other negative chronotropes (eg, amiodarone, beta-blockers, digoxin); blood pressure; regularly monitor cardiac rhythm (assessing for atrial fibrillation)

Advanced Practitioners Physical Assessment/Monitoring

Obtain heart rate (prior to initiation, prior to increasing dose, or after decreasing dose); monitor heart rate more closely if receiving other negative chronotropes (eg, amiodarone, beta-blockers, digoxin); blood pressure; and regularly monitor cardiac rhythm (assessing for atrial fibrillation).

Nursing Physical Assessment/Monitoring

Check blood pressure and heart rate. Monitor patients for signs of atrial fibrillation, decreased heart and symptomatic bradycardia.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Oral [preservative free]:

Corlanor: 5 mg/5 mL (5 mL)

Tablet, Oral:

Corlanor: 5 mg [scored]

Corlanor: 7.5 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Lancora: 5 mg, 7.5 mg [contains corn starch]

Anatomic Therapeutic Chemical (ATC) Classification

• C01EB17

Generic Available (US)

No

Pricing: US

Solution (Corlanor Oral)

5 mg/5 mL (per mL): $1.86

Tablets (Corlanor Oral)

5 mg (per each): $9.28

7.5 mg (per each): $9.28

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

Selective and specific inhibition of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (f-channels) within the sinoatrial (SA) node of cardiac tissue resulting in disruption of I_f ion current flow prolonging diastolic depolarization, slowing firing in the SA node, and ultimately reducing heart rate. Has not demonstrated effects on myocardial contractility or relaxation, ventricular repolarization, or conduction apart from the sinus node effects. Partial inhibition of the retinal I_h current (similar to the cardiac I_f current) may explain visual disturbances (eg, phosphenes) (Nawarskas 2015).

Pharmacodynamics/Kinetics

Note: Pharmacokinetic data (drug exposure) in pediatric patients 6 months to <18 years of age were observed to be similar to adults.

Distribution: V_d: ~100 L

Protein binding: ~70%

Metabolism: Extensively intestinal and hepatic via CYP3A4; major active metabolite equipotent to ivabradine is the N-desmethylated derivative (S 18982) which is also metabolized by CYP3A4

Bioavailability: ~40%; AUC increased 20% to 40% with food

Half-life elimination: Distribution: 2 hours; Effective: ~6 hours

Time to peak, plasma: ~1 hour (fasting); ~2 hours (with food)

Excretion: Feces and urine (~4% as unchanged drug)

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Related Information

• Safe Handling of Hazardous Drugs

Index Terms

Ivabradine HCl; Ivabradine Hydrochloride

FDA Approval Date

April 15, 2015

References

<800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopeia and National Formulary (USP 40-NF 35). Rockville, MD: United States Pharmacopeia Convention; 2017:83-102.

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Cappato R, Castelvecchio S, Ricci C, Bianco E, Vitali-Serdoz L, et al. Clinical efficacy of ivabradine in patients with inappropriate sinus tachycardia: a prospective, randomized, placebo-controlled, double-blind, crossover evaluation. J Am Coll Cardiol. 2012;60(15):1323-1329. doi: 10.1016/j.jacc.2012.06.031.[PubMed 22981555]

Cice G, D'Lsaa S, D'Andrea A, et al. Elderly patients with heart failure and preserved ejection fraction: effects of ivabradine [abstract]. Eur Heart J. 2013;34(suppl 1). http://eurheartj.oxfordjournals.org/content/34/suppl_1/P3329

Cocco G, Jerie P. Torsades de pointes induced by the concomitant use of ivabradine and azithromycin: an unexpected dangerous interaction. Cardiovasc Toxicol. 2015;15(1):104-106. doi: 10.1007/s12012-014-9274-y.[PubMed 25158669]

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Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med. 2014;371(12):1091-1099. doi: 10.1056/NEJMoa1406430.[PubMed 25176136]

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National Institute for Health and Care Excellence. Management of stable angina (NICE clinical guideline 126). http://guidance.nice.org.uk/cg126. Published July 2011. Updated December 2012. Accessed June 3, 2015.

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Page RL, Joglar JA, Caldwell MA, et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2015. pii: S0735-1097(15)05840-4. doi: 10.1016/j.jacc.2015.08.856.[PubMed 26409259]

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Brand Names: International

Apredonav (BG); Bixebra (CZ, DK, HR, HU, LT, LV, PL, SK); Bradipect (EG); Bredinal (EE); Brediwal (NL); Corabid (BD); Coralan (AU, HK, ID, IL, IN, MY, PH, SG, TH, VN); Coraxan (RU, UA); Corlentor (BE, CZ, DK, EE, ES, HR, HU, LT, LV, MT, NL, PL, PT, RO, SK); Ilibrift (CZ); Inevica (BG, HU); Ivabenor (BG); Ivacard (BD); Ivanor (BD, LK); Procoralan (AE, AR, AT, BE, BH, BR, CH, CL, CO, CR, CY, CZ, DE, DK, DO, EC, EE, EG, ES, FR, GB, GR, GT, HN, HR, HU, IS, IT, JO, KR, KW, LB, LT, LU, LV, MT, MX, NI, NL, NO, PA, PL, PT, QA, RO, SA, SE, SI, SK, SV, TR, UY); Raenom (HU); Savapran (EG); Siftus (LK)

Last Updated 2/20/20