U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ABSOLUTE
Molecular Formula C27H36N2O5
Molecular Weight 468.5862
Optical Activity ( + )
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of IVABRADINE

SMILES

CN(CCCN1CCc2cc(c(cc2CC1=O)OC)OC)C[C@@]3([H])Cc4cc(c(cc43)OC)OC

InChI

InChIKey=ACRHBAYQBXXRTO-OAQYLSRUSA-N
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

HIDE SMILES / InChI

Description
Curator's Comment:: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/16451297

Ivabradine (CORLANOR®) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker that reduces the spontaneous pacemaker activity of the cardiac sinus node by selectively inhibiting the If-current, resulting in heart rate reduction at concentrations that do not affect other cardiac ionic currents. Specific heart-rate lowering with ivabradine (CORLANOR®) reduces myocardial oxygen demand, simultaneously improving oxygen supply. It has no negative inotropic or lusitropic effects, preserving ventricular contractility, and does not change any major electrophysiological parameters unrelated to heart rate.

CNS Activity

Curator's Comment:: Ivabradine (CORLANOR®) can also inhibit the retinal current Ih. Ih is involved in curtailing retinal responses to bright light stimuli. Under triggering circumstances (e.g., rapid changes in luminosity), partial inhibition of Ih by ivabradine (CORLANOR®) may underlie the luminous phenomena experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field.

Approval Year

TargetsConditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Palliative
CORLANOR

Approved Use

Corlanor is indicated to reduce the risk of hospitalization for worsening heart failure in 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. Corlanor (ivabradine) is a hyperpolarization-activated cyclic nucleotide-gated channel blocker indicated to reduce the risk of hospitalization for worsening heart failure in 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.

Launch Date

1.429056E12
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
35.98 ng/mL
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
IVABRADINE blood
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
171.19 μg × h/mL
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
IVABRADINE blood
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
5.03 h
5 mg single, oral
dose: 5 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
IVABRADINE blood
Homo sapiens
population: HEALTHY
age: UNKNOWN
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
10 mg 2 times / day steady, oral
Highest studied dose
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
unhealthy, 18–70 years
n = 9
Health Status: unhealthy
Condition: asthma
Age Group: 18–70 years
Sex: M+F
Population Size: 9
Sources:
Other AEs: Nausea, Vision disorders...
Other AEs:
Nausea (1 patient)
Vision disorders (2 patients)
Abdominal pain (1 patient)
Leg pain (1 patient)
Fatigue (1 patient)
Sources:
150 mg single, oral
Overdose
Dose: 150 mg
Route: oral
Route: single
Dose: 150 mg
Sources:
unhealthy, 19 years
n = 1
Health Status: unhealthy
Age Group: 19 years
Sex: F
Population Size: 1
Sources:
Other AEs: Dizziness, Nausea...
Other AEs:
Dizziness (1 patient)
Nausea (1 patient)
Vomiting (1 patient)
Sources:
250 mg single, oral
Overdose
Dose: 250 mg
Route: oral
Route: single
Dose: 250 mg
Sources:
unknown, 26 years
n = 1
Health Status: unknown
Age Group: 26 years
Sex: F
Population Size: 1
Sources:
10 mg 2 times / day steady, oral
Highest studied dose
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
healthy, 27.7 years
n = 9
Health Status: healthy
Age Group: 27.7 years
Sex: M
Population Size: 9
Sources:
280 mg single, oral
Overdose
Dose: 280 mg
Route: oral
Route: single
Dose: 280 mg
Sources:
unhealthy, 47 years
n = 1
Health Status: unhealthy
Age Group: 47 years
Sex: M
Population Size: 1
Sources:
Other AEs: Drowsiness...
Other AEs:
Drowsiness (1 patient)
Sources:
10 mg 1 times / day multiple, intravenous
Dose: 10 mg, 1 times / day
Route: intravenous
Route: multiple
Dose: 10 mg, 1 times / day
Sources:
unhealthy, 61 years (range: 59 - 67 years)
n = 14
Health Status: unhealthy
Condition: low cardiac output syndrome
Age Group: 61 years (range: 59 - 67 years)
Sex: M+F
Population Size: 14
Sources:
Disc. AE: Bradyarrhythmia, Heart rate decreased...
Other AEs: Pulmonary capillary wedge pressure, Sustained ventricular tachycardia...
AEs leading to
discontinuation/dose reduction:
Bradyarrhythmia (1 patient)
Heart rate decreased (3 patients)
Other AEs:
Pulmonary capillary wedge pressure (5 patients)
Sustained ventricular tachycardia (1 patient)
Sources:
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources: Page: p. 171
unhealthy, adult
n = 5477
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 5477
Sources: Page: p. 171
Disc. AE: Atrial fibrillation, Heart rate increased...
AEs leading to
discontinuation/dose reduction:
Atrial fibrillation (2.5%)
Heart rate increased (0.5%)
Bradycardia (0.4%)
Sources: Page: p. 171
AEs

AEs

AESignificanceDosePopulation
Abdominal pain 1 patient
10 mg 2 times / day steady, oral
Highest studied dose
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
unhealthy, 18–70 years
n = 9
Health Status: unhealthy
Condition: asthma
Age Group: 18–70 years
Sex: M+F
Population Size: 9
Sources:
Fatigue 1 patient
10 mg 2 times / day steady, oral
Highest studied dose
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
unhealthy, 18–70 years
n = 9
Health Status: unhealthy
Condition: asthma
Age Group: 18–70 years
Sex: M+F
Population Size: 9
Sources:
Leg pain 1 patient
10 mg 2 times / day steady, oral
Highest studied dose
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
unhealthy, 18–70 years
n = 9
Health Status: unhealthy
Condition: asthma
Age Group: 18–70 years
Sex: M+F
Population Size: 9
Sources:
Nausea 1 patient
10 mg 2 times / day steady, oral
Highest studied dose
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
unhealthy, 18–70 years
n = 9
Health Status: unhealthy
Condition: asthma
Age Group: 18–70 years
Sex: M+F
Population Size: 9
Sources:
Vision disorders 2 patients
10 mg 2 times / day steady, oral
Highest studied dose
Dose: 10 mg, 2 times / day
Route: oral
Route: steady
Dose: 10 mg, 2 times / day
Sources:
unhealthy, 18–70 years
n = 9
Health Status: unhealthy
Condition: asthma
Age Group: 18–70 years
Sex: M+F
Population Size: 9
Sources:
Dizziness 1 patient
150 mg single, oral
Overdose
Dose: 150 mg
Route: oral
Route: single
Dose: 150 mg
Sources:
unhealthy, 19 years
n = 1
Health Status: unhealthy
Age Group: 19 years
Sex: F
Population Size: 1
Sources:
Nausea 1 patient
150 mg single, oral
Overdose
Dose: 150 mg
Route: oral
Route: single
Dose: 150 mg
Sources:
unhealthy, 19 years
n = 1
Health Status: unhealthy
Age Group: 19 years
Sex: F
Population Size: 1
Sources:
Vomiting 1 patient
150 mg single, oral
Overdose
Dose: 150 mg
Route: oral
Route: single
Dose: 150 mg
Sources:
unhealthy, 19 years
n = 1
Health Status: unhealthy
Age Group: 19 years
Sex: F
Population Size: 1
Sources:
Drowsiness 1 patient
280 mg single, oral
Overdose
Dose: 280 mg
Route: oral
Route: single
Dose: 280 mg
Sources:
unhealthy, 47 years
n = 1
Health Status: unhealthy
Age Group: 47 years
Sex: M
Population Size: 1
Sources:
Sustained ventricular tachycardia 1 patient
10 mg 1 times / day multiple, intravenous
Dose: 10 mg, 1 times / day
Route: intravenous
Route: multiple
Dose: 10 mg, 1 times / day
Sources:
unhealthy, 61 years (range: 59 - 67 years)
n = 14
Health Status: unhealthy
Condition: low cardiac output syndrome
Age Group: 61 years (range: 59 - 67 years)
Sex: M+F
Population Size: 14
Sources:
Bradyarrhythmia 1 patient
Disc. AE
10 mg 1 times / day multiple, intravenous
Dose: 10 mg, 1 times / day
Route: intravenous
Route: multiple
Dose: 10 mg, 1 times / day
Sources:
unhealthy, 61 years (range: 59 - 67 years)
n = 14
Health Status: unhealthy
Condition: low cardiac output syndrome
Age Group: 61 years (range: 59 - 67 years)
Sex: M+F
Population Size: 14
Sources:
Heart rate decreased 3 patients
Disc. AE
10 mg 1 times / day multiple, intravenous
Dose: 10 mg, 1 times / day
Route: intravenous
Route: multiple
Dose: 10 mg, 1 times / day
Sources:
unhealthy, 61 years (range: 59 - 67 years)
n = 14
Health Status: unhealthy
Condition: low cardiac output syndrome
Age Group: 61 years (range: 59 - 67 years)
Sex: M+F
Population Size: 14
Sources:
Pulmonary capillary wedge pressure 5 patients
10 mg 1 times / day multiple, intravenous
Dose: 10 mg, 1 times / day
Route: intravenous
Route: multiple
Dose: 10 mg, 1 times / day
Sources:
unhealthy, 61 years (range: 59 - 67 years)
n = 14
Health Status: unhealthy
Condition: low cardiac output syndrome
Age Group: 61 years (range: 59 - 67 years)
Sex: M+F
Population Size: 14
Sources:
Bradycardia 0.4%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources: Page: p. 171
unhealthy, adult
n = 5477
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 5477
Sources: Page: p. 171
Heart rate increased 0.5%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources: Page: p. 171
unhealthy, adult
n = 5477
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 5477
Sources: Page: p. 171
Atrial fibrillation 2.5%
Disc. AE
5 mg 2 times / day steady, oral
Recommended
Dose: 5 mg, 2 times / day
Route: oral
Route: steady
Dose: 5 mg, 2 times / day
Sources: Page: p. 171
unhealthy, adult
n = 5477
Health Status: unhealthy
Age Group: adult
Sex: M+F
Population Size: 5477
Sources: Page: p. 171
OverviewDrug as perpetrator​Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
no [Km 310 uM]
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
yes
yes
yes
yes (co-administration study)
Comment: After coadministration of ivabradine with the CYP3A4 inducer St. John’s Wort (Hypericum perforatum) peak and total systemic exposures were reduced ~2-fold.
Page: 6.0
Tox targets
PubMed

PubMed

TitleDatePubMed
[Ivabradin (coraxan). One more new approach to fighting myocardial ischemia in patients with ischemic heart disease].
2006
[Why it is necessary to reduce heart rate in the treatment of stable angina?].
2006
[Ivabradine--the first selective and specific I(f) inhibitor, novel preparation for treatment of stable angina].
2006
Future directions: what data do we need?
2006
Heart rate slowing for myocardial dysfunction/heart failure.
2006
Novel If current inhibitor ivabradine: safety considerations.
2006
Heart rate slowing versus other pharmacological antianginal strategies.
2006
Clinical effect of 'pure' heart rate slowing with a prototype If current inhibitor: placebo-controlled experience with ivabradine.
2006
Clinical perspectives of heart rate slowing for coronary event reduction and heart failure.
2006
Heart rate reduction by pharmacological If current inhibition.
2006
If current inhibition: cellular basis and physiology.
2006
[A new medicine for treatment of stable angina pectoris].
2006
[Heart rate reduction as a therapeutic strategy: novel options].
2006 Dec
Comparison of a beta-blocker and an If current inhibitor in rabbits with myocardial infarction.
2006 Dec
[New drugs; ivabradine].
2006 Dec 2
Ivabradine: a selective If current inhibitor in the treatment of stable angina.
2006 Nov
Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the I(f) inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study.
2006 Nov
[Ivabradine--a medical alternative for patients with chronic stable angina pectoris].
2006 Nov 13
Heart rate lowering by inhibition of the pacemaker current: a new therapeutic perspective in cardiovascular disease.
2006 Oct
Lack of pharmacokinetic interaction between omeprazole or lansoprazole and ivabradine in healthy volunteers: an open-label, randomized, crossover, pharmacokinetic interaction clinical trial.
2006 Oct
Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers: an open-label, pharmacokinetic interaction clinical trial.
2006 Oct
Perspectives of I(f) inhibition by ivabradine in cardiology.
2007
Clinical results of I(f) current inhibition by ivabradine.
2007
Preclinical results with I(f) current inhibition by ivabradine.
2007
The funny current: cellular basis for the control of heart rate.
2007
If inhibition by Ivabradine. Foreword.
2007
Long-term safety and efficacy of ivabradine in patients with chronic stable angina.
2007
Molecular regulation and pharmacology of pacemaker channels.
2007
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.
2007
I(f) current and heart rate control.
2007 Apr
Ivabradine: new drug. Best avoided in stable angina.
2007 Apr
Conversion of post-systolic wall thickening into ejectional thickening by selective heart rate reduction during myocardial stunning.
2007 Apr
Selective inhibition of the pacemaker channel I(f) improves symptoms in severe dilated cardiomyopathy.
2007 Apr
Heart rate reduction via selective 'funny' channel blockers.
2007 Apr
Symptom improvement in postural orthostatic tachycardia syndrome with the sinus node blocker ivabradine.
2007 Dec
Cellular mechanisms underlying the pharmacological induction of phosphenes.
2007 Feb
Heart rate reduction by inhibition of If or by beta-blockade has different effects on postsystolic wall thickening.
2007 Feb
Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity.
2007 Jan
Heart failure management. Interview with Karl Swedberg.
2007 Jan 9
Modulation of rate by autonomic agonists in SAN cells involves changes in diastolic depolarization and the pacemaker current.
2007 Jul
Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen.
2007 Jul
[Selective and specific reduction in the heart rate: a promising direction in the creation of new cardiovascular drugs].
2007 Jul-Aug
Ivabradine: a new strategy for management of stable angina.
2007 Jun
[Heart rate as a cardiovascular risk factor: potential clinical benefit with ivabradine].
2007 May 30
The heart rate-lowering agent ivabradine inhibits the pacemaker current I(f) in human atrial myocytes.
2007 Nov
Heart rate reduction after heart transplantation with beta-blocker versus the selective If channel antagonist ivabradine.
2007 Oct 27
I f inhibition with ivabradine : electrophysiological effects and safety.
2008
Ivabradine as an alternative therapeutic trial in the therapy of inappropriate sinus tachycardia: a case report.
2008
Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents.
2008 Apr
Effect of long-term heart rate reduction by If current inhibition on pressure overload-induced heart failure in rats.
2008 Jan
Patents

Sample Use Guides

The recommended starting dose of CORLANOR® is 5 mg twice daily with meals.
Route of Administration: Oral
The potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cyclic nucleotide-gated cation (HCN) channels was tested. All three substances blocked the slow inward current through HCN1, HCN2, HCN3, and HCN4 human channels. There was no subtype-specificity for the steady-state block, with mean IC50 values of 0.99, 2.25, and 1.96 microM for cilobradine, ivabradine, and zatebradine, respectively.
Name Type Language
IVABRADINE
DASH   EMA EPAR   INN   MART.   MI   USAN   WHO-DD  
INN   USAN  
Official Name English
S-16257
Code English
IVABRADINE [MI]
Common Name English
IVABRADINE [EMA EPAR]
Common Name English
IVABRADINE [MART.]
Common Name English
IVABRADINE [WHO-DD]
Common Name English
IVABRADINE [ORANGE BOOK]
Common Name English
3-(3-((((7S)-3,4-DIMETHOXYBICYCLO(4.2.0)OCTA-1,3,5-TRIEN-7-YL)METHYL)METHYLAMINO)PROPYL)-1,3,4,5-TETRAHYDRO-7,8-DIMETHOXY-2H-3-BENZAZEPIN-2-ONE
Systematic Name English
IVABRADINE [USAN]
Common Name English
IVABRADINE [INN]
Common Name English
Classification Tree Code System Code
WHO-ATC C07FX06
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
NCI_THESAURUS C47793
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
WHO-ATC C07FX05
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
FDA ORPHAN DRUG 631818
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
WHO-VATC QC01EB17
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
WHO-ATC C01EB17
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
NDF-RT N0000191544
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
FDA ORPHAN DRUG 511915
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
Code System Code Type Description
IUPHAR
2357
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
NCI_THESAURUS
C65995
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
EPA CompTox
155974-00-8
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
ChEMBL
CHEMBL471737
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
PUBCHEM
132999
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
NDF-RT
N0000191546
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY Hyperpolarization-activated Cyclic Nucleotide-gated Channel Antagonists [MoA]
CAS
155974-00-8
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
DRUG BANK
DB09083
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
EVMPD
SUB08357MIG
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
INN
7523
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
MERCK INDEX
M6564
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY Merck Index
FDA UNII
3H48L0LPZQ
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
WIKIPEDIA
IVABRADINE
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
DRUG CENTRAL
3312
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY
RXCUI
1649480
Created by admin on Fri Jun 25 21:38:02 UTC 2021 , Edited by admin on Fri Jun 25 21:38:02 UTC 2021
PRIMARY RxNorm