Identification
- Summary
Ivabradine is a HCN channel blocker used to reduce the risk of hospitalization for worsening heart failure in adult patients and for treatment of stable symptomatic heart failure as a result of dilated cardiomyopathy in pediatric patients.
- Brand Names
- Corlanor, Lancora, Procoralan
- Generic Name
- Ivabradine
- DrugBank Accession Number
- DB09083
- Background
Ivabradine is a novel heart rate lowering medicine for the symptomatic management of stable angina pectoralis and symptomatic chronic heart failure. Ivabradine, brand name Corlanor, was approved by the FDA in April 2015 for the treatment of chronic heart failure in patients with an ejection fraction of ≤35%, in sinus rhythm with resting heart rate ≥70 beats per minute, who are not on beta-blockers due to contraindications or already receiving maximum beta-blocker dose. Recently a new indication was added to treat symptomatic heart failure from dilated cardiomyopathy for patients 6 months or more in ageLabel. Ivabradine acts by selectively inhibiting the "funny" channel pacemaker current (If) in the sinoatrial node in a dose-dependent fashion, resulting in a lower heart rate and thus more blood to flow to the myocardium. Although non-dihydropyridine calcium channel blockers and beta blockers also effectively lower heart rate, they exhibit adverse events due to their negative ionotropic effects. Therefore, as ivabradine is designed as a "pure" heart rate-lowering drug by selectively acting on the If channels, it may offer a more favorable side effect profile due to its lower likelihood of causing serious adverse effects.
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Ivabradine (DB09083)
- Weight
- Average: 468.594
Monoisotopic: 468.262422267 - Chemical Formula
- C27H36N2O5
- Synonyms
- 3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
- Ivabradin
- Ivabradina
- Ivabradine
- Ivabradinum
- External IDs
- S 16257
Pharmacology
- Indication
Ivabradine is indicated by the FDA to reduce the risk of hospitalization for worsening heart failure in adult patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use. It is also indicated for treatment of stable symptomatic heart failure as a result of dilated cardiomyopathy for pediatric patients 6 months of age or moreLabel.
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to manage Chronic heart failure (chf) Combination Product in combination with: Carvedilol (DB01136) •••••••••••• ••••• •••••••• •••••••••••• •••••••••• •• •••••••• •••• ••••••• ••••••• •••• •••••• Used in combination to manage Chronic stable angina pectoris Combination Product in combination with: Carvedilol (DB01136) •••••••••••• ••••• •••••••• •••••• ••••••• •••••• •••••••••• •• •••••••• •••• ••••••• ••••••• •••• •••••• Used in combination to manage Chronic stable angina pectoris Combination Product in combination with: Metoprolol (DB00264) •••••••••••• ••••• •••••••••• •• •••••••• •••• ••••••• ••••••• •••• •••••• Management of Left ventricular dysfunction •••••••••••• ••••• ••••••••• •••••• Treatment of Stable, symptomatic chronic heart failure •••••••••••• ••••••••• ••••••••• •••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
The funny channels (If) open during repolarization and close during depolarization, making ivabradine's activity dependent on heart rate or the closing and opening of the channels. Therefore ivabradine exhibits use-dependence and is more pharmacologically active at higher heart rates. Ivabradine exhibits a linear dose-dependent heart-rate lowering activity (bradycardic effect) until a maximum dose of 30-40mg. At higher doses, the concentration of ivabradine tends to plateau, reducing risk of serious sinus bradycardia. It has been shown that the metabolite of ivabradine lowers heart rate as well, contributing to ivabradine's overall effect.
- Mechanism of action
Ivabradine lowers heart rate by selectively inhibiting If channels ("funny channels") in the heart in a concentration-dependent manner without affecting any other cardiac ionic channels (including calcium or potassium). Ivabradine binds by entering and attaching to a site on the channel pore from the intracellular side and disrupts If ion current flow, which prolongs diastolic depolarization, lowering heart rate. The If currents are located in the sinoatrial node and are the home of all cardiac pacemaker activity. Ivabradine therefore lowers the pacemaker firing rate, consequently lowering heart rate and reducing myocardial oxygen demand. This allows for an improved oxygen supply and therefore mitigation of ischemia, allowing for a higher exercise capacity and reduction in angina episodes.
Target Actions Organism UPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 inhibitorHumans - Absorption
It is recommended to take ivabradine with food to reduce variability in systemic exposure. Administration with food slows absorption by 1 hour, but increases systemic absorption by 20-30%. Ivabradine's oral bioavailability is about 40%.
- Volume of distribution
~100 L.
- Protein binding
70% bound to plasma proteins.
- Metabolism
Ivabradine is extensively metabolized by oxidation in the gut and liver by cytochrome P450 3A4 enzyme. Its active metabolite, N-desmethylated derivative, is also metabolized by CYP 3A4. Ivabradine's affinity for CYP 3A4 is low, making it unlikely to affect the metabolism of other drugs; however potent inhibitors or inducers of CYP 3A4 may affect ivabradine's plasma concentration and pharmacodynamic effects and should not be co-administered.
- Route of elimination
Metabolites are equally excreted in feces and urine.
- Half-life
2 hours.
- Clearance
Total clearance is about 400ml/min; renal clearance about 70ml/min. About 4% is excreted unchanged in urine.
- Adverse Effects
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Ivabradine may cause fetal toxicity when administered to pregnant women. Animal studies in pregnant rats have shown embryo-fetal toxicity and cardiac teratogenic effects. Effective contraception in women is recommended while using ivabradine.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Ivabradine can be increased when it is combined with Abametapir. Acebutolol Acebutolol may increase the bradycardic activities of Ivabradine. Acrivastine The risk or severity of QTc prolongation can be increased when Acrivastine is combined with Ivabradine. Adagrasib The serum concentration of Ivabradine can be increased when it is combined with Adagrasib. Adenosine Ivabradine may increase the QTc-prolonging activities of Adenosine. - Food Interactions
- Avoid grapefruit products.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Ivabradine hydrochloride TP19837BZK 148849-67-6 HLUKNZUABFFNQS-ZMBIFBSDSA-N Ivabradine oxalate K6SGA5L3AB 1086026-42-7 BOHZBFAHOBOJOS-ZMBIFBSDSA-N - International/Other Brands
- Bradia (Biocon) / Ivabid
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Corlanor Tablet, film coated 7.5 mg/1 Oral AMGEN INC 2015-04-20 Not applicable US 
Corlanor Tablet, film coated 5 mg/1 Oral AMGEN INC 2015-04-20 Not applicable US Corlanor Tablet, film coated 5 mg/1 Oral REMEDYREPACK INC. 2021-12-24 Not applicable US Corlanor Solution 5 mg/5mL Oral AMGEN INC 2019-04-19 Not applicable US Corlentor Tablet, film coated 7.5 mg Oral Les Laboratoires Servier 2016-09-08 Not applicable EU 
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image IMPLICOR FILM-COATED TABLET 25 mg/5 mg Ivabradine hydrochloride (5 mg) + Metoprolol tartrate (25 mg) Tablet, film coated Oral SERVIER (S) PTE LTD 2017-10-19 Not applicable Singapore 
IMPLICOR FILM-COATED TABLET 25 mg/7.5 mg Ivabradine hydrochloride (7.5 mg) + Metoprolol tartrate (25 mg) Tablet, film coated Oral SERVIER (S) PTE LTD 2017-10-19 Not applicable Singapore IMPLICOR FILM-COATED TABLET 50 mg/5 mg Ivabradine hydrochloride (5 mg) + Metoprolol tartrate (50 mg) Tablet, film coated Oral SERVIER (S) PTE LTD 2017-10-19 Not applicable Singapore IMPLICOR FILM-COATED TABLET 50 mg/7.5 mg Ivabradine hydrochloride (7.5 mg) + Metoprolol tartrate (50 mg) Tablet, film coated Oral SERVIER (S) PTE LTD 2017-10-19 Not applicable Singapore
Categories
- ATC Codes
- C01EB17 — Ivabradine
- C01EB — Other cardiac preparations
- C01E — OTHER CARDIAC PREPARATIONS
- C01 — CARDIAC THERAPY
- C — CARDIOVASCULAR SYSTEM
- C07FX — Beta blocking agents, other combinations
- C07F — BETA BLOCKING AGENTS, OTHER COMBINATIONS
- C07 — BETA BLOCKING AGENTS
- C — CARDIOVASCULAR SYSTEM
- Drug Categories
- Benzazepines
- Bradycardia-Causing Agents
- Cardiac Therapy
- Cardiovascular Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Highest Risk QTc-Prolonging Agents
- Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists
- Hyperpolarization-activated Cyclic Nucleotide-gated Channel Blocker
- Miscellaneous Cardiac Drugs
- QTc Prolonging Agents
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as benzazepines. These are organic compounds containing a benzene ring fused to an azepine ring (unsaturated seven-membered heterocycle with one nitrogen atom replacing a carbon atom).
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Benzazepines
- Sub Class
- Not Available
- Direct Parent
- Benzazepines
- Alternative Parents
- Anisoles / Azepines / Aralkylamines / Alkyl aryl ethers / Tertiary carboxylic acid amides / Trialkylamines / Lactams / Amino acids and derivatives / Azacyclic compounds / Organopnictogen compounds show 3 more
- Substituents
- Alkyl aryl ether / Amine / Amino acid or derivatives / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Azepine / Benzazepine / Benzenoid show 15 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- tertiary amino compound, aromatic ether, benzazepine, carbobicyclic compound (CHEBI:85966)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 3H48L0LPZQ
- CAS number
- 155974-00-8
- InChI Key
- ACRHBAYQBXXRTO-OAQYLSRUSA-N
- InChI
- InChI=1S/C27H36N2O5/c1-28(17-21-11-20-14-25(33-4)26(34-5)16-22(20)21)8-6-9-29-10-7-18-12-23(31-2)24(32-3)13-19(18)15-27(29)30/h12-14,16,21H,6-11,15,17H2,1-5H3/t21-/m1/s1
- IUPAC Name
- 3-[3-({[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino)propyl]-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one
- SMILES
- COC1=C(OC)C=C2[C@@H](CN(C)CCCN3CCC4=CC(OC)=C(OC)C=C4CC3=O)CC2=C1
References
- General References
- DiFrancesco D: The role of the funny current in pacemaker activity. Circ Res. 2010 Feb 19;106(3):434-46. doi: 10.1161/CIRCRESAHA.109.208041. [Article]
- 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 Feb;60(2):222-8. [Article]
- DiFrancesco D, Camm JA: Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16):1757-65. [Article]
- Nawarskas JJ, Bowman BN, Anderson JR: Ivabradine: A Unique and Intriguing Medication for Treating Cardiovascular Disease. Cardiol Rev. 2015 Jul-Aug;23(4):201-11. doi: 10.1097/CRD.0000000000000070. [Article]
- Rosa GM, Ferrero S, Ghione P, Valbusa A, Brunelli C: An evaluation of the pharmacokinetics and pharmacodynamics of ivabradine for the treatment of heart failure. Expert Opin Drug Metab Toxicol. 2014 Feb;10(2):279-91. doi: 10.1517/17425255.2014.876005. Epub 2013 Dec 31. [Article]
- hERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes [Link]
- FDA Approved Drug Products: CORLANOR (ivabradine) oral [Link]
- External Links
- KEGG Drug
- D07165
- PubChem Compound
- 132999
- PubChem Substance
- 310265010
- ChemSpider
- 117373
- BindingDB
- 50326992
- 1649480
- ChEBI
- 85966
- ChEMBL
- CHEMBL471737
- ZINC
- ZINC000003805768
- PharmGKB
- PA166123415
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Ivabradine
- FDA label
- Download (1.43 MB)
- MSDS
- Download (23.8 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Basic Science Aortic Blood Pressure 1 4 Completed Basic Science Dilated Cardiomyopathies, Idiopathic / Electrical Remodeling / Hearth Failure With Reduced Ejection Fraction (HFrEF) / Ventricular Remodelling 1 4 Completed Other Myocardial Injury / Myocardial Ischemia 1 4 Completed Treatment Acute Coronary Syndrome (ACS) 1 4 Completed Treatment Asthma-chronic obstructive pulmonary disease overlap syndrome 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet, coated Oral 5 mg Tablet, film coated Oral 5 mg Tablet, film coated Oral 7.5 mg Tablet, coated Oral 7.5 mg Solution Oral 5 mg/5mL Tablet, film coated Oral 5 mg/1 Tablet, film coated Oral 7.5 mg/1 Tablet, film coated Oral Tablet, film coated Oral 5 mg Tablet, film coated Oral 7.5 mg Tablet, film coated Oral Tablet, film coated Oral 2.5 MG Tablet Oral 5 mg Tablet Oral 7.5 mg Tablet Oral 5.39000 mg Tablet Oral 8.085 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7879842 Yes 2011-02-01 2026-08-22 US US7361650 Yes 2008-04-22 2026-08-22 US US7867996 Yes 2011-01-11 2026-08-22 US US7361649 Yes 2008-04-22 2026-08-22 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0202 mg/mL ALOGPS logP 3.17 ALOGPS logP 2.72 Chemaxon logS -4.4 ALOGPS pKa (Strongest Basic) 9.37 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 6 Chemaxon Hydrogen Donor Count 0 Chemaxon Polar Surface Area 60.47 Å2 Chemaxon Rotatable Bond Count 10 Chemaxon Refractivity 133.51 m3·mol-1 Chemaxon Polarizability 54.56 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-0000900000-03ca5deccd6b39beb343 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0000900000-31f9a3b5b64e8d7b0450 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-0131900000-6d3ccc0351f75f81d1d8 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-014i-0010900000-a797e752779013045001 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-0400-0951500000-ec1bb5c38ab9f4f02df2 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0ht9-0242900000-bff20c42b68274b872ad Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 208.75462 predictedDeepCCS 1.0 (2019) [M+H]+ 211.1502 predictedDeepCCS 1.0 (2019) [M+Na]+ 217.16338 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Voltage-gated sodium channel activity
- Specific Function
- Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Can also transpor...
- Gene Name
- HCN2
- Uniprot ID
- Q9UL51
- Uniprot Name
- Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
- Molecular Weight
- 96949.43 Da
References
- hERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes [Link]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Rosa GM, Ferrero S, Ghione P, Valbusa A, Brunelli C: An evaluation of the pharmacokinetics and pharmacodynamics of ivabradine for the treatment of heart failure. Expert Opin Drug Metab Toxicol. 2014 Feb;10(2):279-91. doi: 10.1517/17425255.2014.876005. Epub 2013 Dec 31. [Article]
Drug created at September 14, 2015 15:24 / Updated at February 20, 2024 23:54