Identification

Name
Ivabradine
Accession Number
DB09083
Description

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
Thumb
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

Pharmacology
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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.

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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.

TargetActionsOrganism
UPotassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2
inhibitor
Humans
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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Toxicity

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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of Ivabradine can be increased when it is combined with Abametapir.
AbirateroneThe metabolism of Ivabradine can be decreased when combined with Abiraterone.
AcebutololAcebutolol may increase the bradycardic activities of Ivabradine.
AcrivastineThe risk or severity of QTc prolongation can be increased when Acrivastine is combined with Ivabradine.
AdenosineIvabradine may increase the QTc-prolonging activities of Adenosine.
AjmalineThe risk or severity of QTc prolongation can be increased when Ajmaline is combined with Ivabradine.
AlfentanilAlfentanil may increase the bradycardic activities of Ivabradine.
AlfuzosinThe risk or severity of QTc prolongation can be increased when Alfuzosin is combined with Ivabradine.
AlimemazineThe risk or severity of QTc prolongation can be increased when Alimemazine is combined with Ivabradine.
AmantadineThe risk or severity of QTc prolongation can be increased when Amantadine is combined with Ivabradine.
Interactions
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Food Interactions
  • Avoid grapefruit products.

Products

Products
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Product Ingredients
IngredientUNIICASInChI Key
Ivabradine hydrochlorideTP19837BZK148849-67-6HLUKNZUABFFNQS-ZMBIFBSDSA-N
Ivabradine oxalateK6SGA5L3AB1086026-42-7BOHZBFAHOBOJOS-ZMBIFBSDSA-N
International/Other Brands
Bradia (Biocon) / Ivabid
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
CorlanorTablet, film coated5 mg/1OralAMGEN INC2015-04-20Not applicableUS flag
CorlanorSolution5 mg/5mLOralAMGEN INC2019-04-19Not applicableUS flag
CorlanorTablet, film coated7.5 mg/1OralAMGEN INC2015-04-20Not applicableUS flag
CorlentorTablet, film coated5 mgOralLes Laboratoires Servier2016-09-08Not applicableEU flag
CorlentorTablet, film coated5 mgOralLes Laboratoires Servier2016-09-08Not applicableEU flag
CorlentorTablet, film coated7.5 mgOralLes Laboratoires Servier2016-09-08Not applicableEU flag
CorlentorTablet, film coated5 mgOralLes Laboratoires Servier2016-09-08Not applicableEU flag
CorlentorTablet, film coated7.5 mgOralLes Laboratoires Servier2016-09-08Not applicableEU flag
CorlentorTablet, film coated5 mgOralLes Laboratoires Servier2016-09-08Not applicableEU flag
CorlentorTablet, film coated7.5 mgOralLes Laboratoires Servier2016-09-08Not applicableEU flag

Categories

ATC Codes
C01EB17 — IvabradineC07FX05 — Metoprolol and ivabradineC07FX06 — Carvedilol and ivabradine
Drug Categories
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)

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
  1. 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. [PubMed:20167941]
  2. 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. [PubMed:16451297]
  3. 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. [PubMed:15301560]
  4. 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. [PubMed:25839989]
  5. 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. [PubMed:24377458]
  6. hERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes [Link]
KEGG Drug
D07165
PubChem Compound
132999
PubChem Substance
310265010
ChemSpider
117373
BindingDB
50326992
RxNav
1649480
ChEBI
85966
ChEMBL
CHEMBL471737
ZINC
ZINC000003805768
PharmGKB
PA166123415
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ivabradine
AHFS Codes
  • 24:04.92 — Miscellaneous Cardiac Drugs
FDA label
Download (1.43 MB)
MSDS
Download (23.8 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceAortic Blood Pressure1
4CompletedTreatmentAcute Coronary Syndrome (ACS)1
4CompletedTreatmentAsthma-chronic obstructive pulmonary disease overlap syndrome1
4CompletedTreatmentCardiac Failure1
4CompletedTreatmentChronic Stable Angina Pectoris1
4CompletedTreatmentCongestive Heart Failure (CHF)1
4CompletedTreatmentCoronary Artery Disease (CAD)1
4CompletedTreatmentHeart Failure3
4RecruitingBasic ScienceDilated Cardiomyopathies, Idiopathic / Electrical Remodeling / Heart Failure, Systolic / Ventricular Remodelling1
4RecruitingOtherMyocardial Injury / Myocardial Ischemia1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, coatedOral
SolutionOral5 mg/5mL
Tablet, film coatedOral5 mg/1
Tablet, film coatedOral7.5 mg/1
Tablet, film coatedOral5 mg
Tablet, film coatedOral7.5 mg
Tablet, film coatedOral
Tablet, film coatedOral
TabletOral
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7879842Yes2011-02-012026-08-22US flag
US7361650Yes2008-04-222026-08-22US flag
US7867996Yes2011-01-112026-08-22US flag
US7361649Yes2008-04-222026-08-22US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0202 mg/mLALOGPS
logP3.17ALOGPS
logP2.72ChemAxon
logS-4.4ALOGPS
pKa (Strongest Basic)9.37ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area60.47 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity133.51 m3·mol-1ChemAxon
Polarizability54.56 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets
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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
  1. 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
Yes
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
  1. 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. [PubMed:24377458]

Drug created on September 14, 2015 15:24 / Updated on April 17, 2021 10:37