looking for [50:<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 Cl cr 15 60 mL/minute. 1 Data lacking on use in patients with Cl cr> <15 mL/minute. 1 7 16 Cautions for Corlanor 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 (Cl cr 15 60 mL/minute) has minimal effect on pharmacokinetics of ivabradine. 1 Data lacking on use in patients with Cl cr> <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 Corlanor 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 bradycardia 1 Monitor heart rate with concomitant use 1 Amiodarone Increases risk of bradycardia 1 Monitor heart rate with concomitant use 1 Antifungals, azoles (e.g., itraconazole, ketoconazole) Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances 1 7 16 Concomitant use contraindicated 1 16 Barbiturates Decreases plasma ivabradine concentrations 1 7 Avoid concomitant use 1 7 Calcium-channel blocking agents, nondihydropyridine (e.g., diltiazem, verapamil) Increases plasma ivabradine concentrations, and may exacerbate bradycardia and conduction disturbances; increases risk of bradycardia 1 7 16 42 Avoid concomitant use; monitor heart rate 1 7 16 42 Digoxin Increases risk of bradycardia; digoxin exposure unchanged 1 Monitor heart rate with concomitant use 1 Grapefruit juice Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances 1 7 Avoid concomitant use 1 7 HIV protease inhibitors (e.g., nelfinavir) Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances 1 16 Concomitant use contraindicated 1 16 Macrolides (e.g., clarithromycin, telithromycin) Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances 1 16 Concomitant use contraindicated 1 16 Metformin No effects on the pharmacokinetics of metformin 1 No dosage adjustment necessary 1 Nefazodone Increases plasma ivabradine concentrations; may exacerbate bradycardia and conduction disturbances 1 16 Concomitant use contraindicated 1 16 Phenytoin Decreases plasma ivabradine concentrations 1 7 16 Avoid concomitant use 1 7 16 Proton-pump inhibitors (e.g., lansoprazole, omeprazole) No effects on the pharmacokinetics of ivabradine 1 7 16 No dosage adjustment necessary 1 7 16 Rifampin Decreases plasma ivabradine concentrations 1 7 Avoid concomitant use 1 7 Sildenafil No effects on the pharmacokinetics of ivabradine 1 40 No dosage adjustment necessary 1 40 Simvastatin No effects on the pharmacokinetics of ivabradine 1 No dosage adjustment necessary 1 St. John's wort ( Hypericum perforatum ) Decreases plasma ivabradine concentrations 1 7 16 Avoid concomitant use 1 7 16 Warfarin No effects on the pharmacokinetics of ivabradine 1 7 No dosage adjustment necessary 1 7 Corlanor 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 ( I f ) 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 I f , 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 ( I h ), which closely resemble the I f 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 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] 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] 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] 9. Fox K, Borer JS, Camm AJ et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol . 2007; 50:823-30. [PubMed 17719466] 10. Böhm M, Swedberg K, Komajda M et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet . 2010; 376:886-94. [PubMed 20801495] 11. Custodis F, Reil JC, Laufs U et al. Heart rate: a global target for cardiovascular disease and therapy along the cardiovascular disease continuum. J Cardiol . 2013; 62:183-7. [PubMed 23806547] 12. Reil JC, Böhm M. Heart rate and heart failure: the role of ivabradine therapy. Curr Opin Cardiol . 2013; 28:326-31. [PubMed 23549235] 13. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol . 2012; 60:e44-e164. [PubMed 23182125] 14. Task Force Members, Montalescot G, Sechtem U et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J . 2013; 34:2949-3003. [PubMed 23996286] 15. Schuster A, Tang WH. Ivabradine in heart failure: to SHIFT or not to SHIFT. Curr Heart Fail Rep . 2011; 8:1-3. [PubMed 21057902] 16. Perry CM. Ivabradine: in adults with chronic heart failure with reduced left ventricular ejection fraction. Am J Cardiovasc Drugs . 2012; 12:415-26. [PubMed 23181944] 17. Teerlink JR. Ivabradine in heart failure--no paradigm SHIFT yet. Lancet . 2010; 376:847-9. [PubMed 20801501] 18. Swedberg K, Komajda M, Böhm M et al. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study. J Am Coll Cardiol . 2012; 59:1938-45. [PubMed 22617188] 19. Böhm M, Borer J, Ford I et al. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol . 2013; 102:11-22. [PubMed 22575988] 20. Borer JS, Böhm M, Ford I et al. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J . 2012; 33:2813-20. [PubMed 22927555] 21. Tardif JC, Ford I, Tendera M et al. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J . 2005; 26:2529-36. [PubMed 16214830] 22. Saha M, Marber MS. If at first you don't succeed try ... a new target in the treatment of angina. Eur Heart J . 2005; 26:2482-3. [PubMed 16219649] 23. Tardif JC, Ponikowski P, Kahan T et al. Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur Heart J . 2009; 30:540-8. [PubMed 19136486] 24. Sajadieh A. A new combination therapy in stable angina pectoris. Eur Heart J . 2009; 30:524-5. [PubMed 19193673] 25. Fox K, Ford I, Steg PG et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet . 2008; 372:807-16. [PubMed 18757088] 26. Fox K, Ford I, Steg PG et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med . 2014; 371:1091-9. [PubMed 25176136] 27. Fox K, Ford I, Steg PG et al. Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J . 2009; 30:2337-45. [PubMed 19720635] 28. Heusch G. A BEAUTIFUL lesson--ivabradine protects from ischaemia, but not from heart failure: through heart rate reduction or more?. Eur Heart J . 2009; 30:2300-1. [PubMed 19720636] 29. Ohman EM, Alexander KP. The challenges with chronic angina. N Engl J Med . 2014; 371:1152-3. [PubMed 25176137] 30. Ruzyllo W, Tendera M, Ford I et al. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs . 2007; 67:393-405. [PubMed 17335297] 31. Borer JS, Fox K, Jaillon P et al. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation . 2003; 107:817-23. [PubMed 12591750] 33. Jones DA, Timmis A, Wragg A. Novel drugs for treating angina. BMJ . 2013; 347:f4726. [PubMed 24018101] 34. Sulfi S, Timmis AD. Ivabradine -- the first selective sinus node I(f) channel inhibitor in the treatment of stable angina. Int J Clin Pract . 2006; 60:222-8. [PubMed 16451297] 35. Ruys TP, Cornette J, Roos-Hesselink JW. Pregnancy and delivery in cardiac disease. J Cardiol . 2013; 61:107-12. [PubMed 23290155] 36. Thollon C, Vilaine JP. I(f) inhibition in cardiovascular diseases. Adv Pharmacol . 2010; 59:53-92. [PubMed 20933199] 37. DiFrancesco D. Funny channels in the control of cardiac rhythm and mode of action of selective blockers. Pharmacol Res . 2006; 53:399-406. [PubMed 16638640] 38. Rosa GM, Ferrero S, Ghione P et al. An evaluation of the pharmacokinetics and pharmacodynamics of ivabradine for the treatment of heart failure. Expert Opin Drug Metab Toxicol . 2014; 10:279-91. [PubMed 24377458] 39. Murray KT. It's a funny thing . J Cardiovasc Electrophysiol . 2013; 24:1401-2. [PubMed 24033556] 40. Deedwania P. Selective and specific inhibition of If with ivabradine for the treatment of coronary artery disease or heart failure. Drugs . 2013; 73:1569-86. [PubMed 24065301] 41. Martin RI, Pogoryelova O, Koref MS et al. Atrial fibrillation associated with ivabradine treatment: meta-analysis of randomised controlled trials. Heart . 2014; 100:1506-10. [PubMed 24951486] 42. Beltrame JF. Ivabradine and the SIGNIFY conundrum. Eur Heart J . 2015; :. 43. Swedberg K, Komajda M, Böhm M et al. Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail . 2010; 12:75-81. [PubMed 19892778] 524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327. 700. Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation . 2016; :. 701. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J . 2016; :. 703. Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. J Clin Pharm Ther . 2016; 41:119-27. [PubMed 26992459] Next Interactions Print this page Add to My Med List More about Corlanor (ivabradine) Side Effects During Pregnancy Dosage Information Drug Interactions Support Group Pricing & Coupons En Español 1 Review Add your own review/rating Drug class: miscellaneous cardiovascular agents Consumer resources Corlanor Corlanor (Advanced Reading) Professional resources Corlanor (FDA) Ivabradine Hydrochloride (AHFS Monograph) Related treatment guides Heart Failure> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only N Pregnancy Category Not classified N/A CSA Schedule Not a controlled drug 2 years Approval History FDA approved 2015 Manufacturer Amgen Inc. 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