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

Details

Stereochemistry ABSOLUTE
Molecular Formula C27H36N2O5.ClH
Molecular Weight 505.046
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of IVABRADINE HYDROCHLORIDE

SMILES

Cl.COC1=C(OC)C=C2[C@@H](CN(C)CCCN3CCC4=CC(OC)=C(OC)C=C4CC3=O)CC2=C1

InChI

InChIKey=HLUKNZUABFFNQS-ZMBIFBSDSA-N
InChI=1S/C27H36N2O5.ClH/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;1H/t21-;/m1./s1

HIDE SMILES / InChI

Molecular Formula C27H36N2O5
Molecular Weight 468.5851
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 1 / 1
E/Z Centers 0
Optical Activity UNSPECIFIED

Molecular Formula ClH
Molecular Weight 36.461
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

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
Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and stunning.
2001 Dec
An identifiability analysis of a parent-metabolite pharmacokinetic model for ivabradine.
2001 Feb
Optimal design of a population pharmacodynamic experiment for ivabradine.
2001 Jan
Clinical trial simulation using therapeutic effect modeling: application to ivabradine efficacy in patients with angina pectoris.
2002 Aug
A single intravenous dose of ivabradine, a novel I(f) inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction.
2003
Effect of chronic heart rate reduction with ivabradine on carotid and aortic structure and function in normotensive and hypertensive rats.
2003 Jul-Aug
Pharmacokinetics-pharmacodynamics during drug development--an example from Servier: ivabradine.
2004 Mar-Apr
I(f) channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities.
2004 May
Current and future treatment strategies for refractory angina.
2004 Oct
Efficacy and safety of a metabolic modulator drug in chronic stable angina: review of evidence from clinical trials.
2004 Sep
Selective reduction of heart rate by ivabradine: effect on the visco-elastic arterial properties in rats.
2004 Sep
Heart rate reduction: a potential target for the treatment of myocardial ischaemia.
2004 Sep-Oct
[Heart rate and experimental myocardial ischaemia].
2004 Sep-Oct
[Selection and pharmacological characterisation of Procoralan, a selective inhibitor of the pacemaker If current].
2004 Sep-Oct
[From ischaemia to heart failure: heart rate--actor or stamper?].
2004 Sep-Oct
Chronic heart rate reduction remodels ion channel transcripts in the mouse sinoatrial node but not in the ventricle.
2005 Dec 14
[The best of clinical pharmacology in 2004].
2005 Jan
The murine HCN3 gene encodes a hyperpolarization-activated cation channel with slow kinetics and unique response to cyclic nucleotides.
2005 Jul 22
[Why it is necessary to reduce heart rate in the treatment of stable angina?].
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
Selective and specific I(f) inhibition: new perspectives for the treatment of stable angina.
2006 Jun
Anti-ischaemic effect of ivabradine.
2006 May
Therapeutic effects of I(f) blockade: evidence and perspective.
2006 May
[Ivabradine--a medical alternative for patients with chronic stable angina pectoris].
2006 Nov 13
The funny current: cellular basis for the control of heart rate.
2007
Conversion of post-systolic wall thickening into ejectional thickening by selective heart rate reduction during myocardial stunning.
2007 Apr
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
[Selective and specific reduction in the heart rate: a promising direction in the creation of new cardiovascular drugs].
2007 Jul-Aug
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.
Substance Class Chemical
Created
by admin
on Thu Jul 06 02:06:00 UTC 2023
Edited
by admin
on Thu Jul 06 02:06:00 UTC 2023
Record UNII
TP19837BZK
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
IVABRADINE HYDROCHLORIDE
EMA EPAR   MI   USAN   WHO-DD  
USAN  
Official Name English
IVABRADINE HYDROCHLORIDE [USAN]
Common Name English
IVABRADINE HYDROCHLORIDE [ORANGE BOOK]
Common Name English
S-16257-2
Code English
Ivabradine hydrochloride [WHO-DD]
Common Name English
2H-3-BENZAZEPIN-2-ONE, 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-, HYDROCHLORIDE (1:1)
Systematic Name English
IVABRADINE HYDROCHLORIDE [JAN]
Common Name English
AMG 998
Code English
CORLENTOR
Brand Name English
IVABRADINE HYDROCHLORIDE [EMA EPAR]
Common Name English
IVABRADINE HYDROCHLORIDE [MI]
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 HYDROCHLORIDE
Systematic Name English
PROCORALAN
Brand Name English
IVABRADINE HCL
Common Name English
CORLANOR
Brand Name English
AMG-998
Code English
Classification Tree Code System Code
EMA ASSESSMENT REPORTS PROCORALAN (AUTHORIZED: ANGINA PECTORIS)
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
NCI_THESAURUS C47793
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
EMA ASSESSMENT REPORTS CORLENTOR (AUTHORIZED: ANGINA PECTORIS)
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
Code System Code Type Description
CAS
148849-67-6
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
RXCUI
1649479
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY RxNorm
DAILYMED
TP19837BZK
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
SMS_ID
100000092729
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
EVMPD
SUB22933
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
WIKIPEDIA
Ivabradine hydrochloride
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
CHEBI
85969
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
ChEMBL
CHEMBL471737
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
NCI_THESAURUS
C148546
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
MESH
C088408
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
DRUG BANK
DBSALT001237
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
USAN
BC-98
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
EPA CompTox
DTXSID2046913
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
CHEBI
85966
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
PUBCHEM
3045381
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
MERCK INDEX
M6564
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY Merck Index
FDA UNII
TP19837BZK
Created by admin on Thu Jul 06 02:06:01 UTC 2023 , Edited by admin on Thu Jul 06 02:06:01 UTC 2023
PRIMARY
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