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Details

Stereochemistry ABSOLUTE
Molecular Formula C27H36N2O5.H2O4S
Molecular Weight 566.664
Optical Activity UNSPECIFIED
Defined Stereocenters 1 / 1
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of IVABRADINE SULFATE

SMILES

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

InChI

InChIKey=BTPJWGWDKZFLCT-ZMBIFBSDSA-N
InChI=1S/C27H36N2O5.H2O4S/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;1-5(2,3)4/h12-14,16,21H,6-11,15,17H2,1-5H3;(H2,1,2,3,4)/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 H2O4S
Molecular Weight 98.078
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
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
Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation during exercise.
2002 Feb
Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology.
2003
Contributions of heart rate and contractility to myocardial oxygen balance during exercise.
2003 Feb
Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial.
2003 Feb 18
Effect of chronic heart rate reduction with ivabradine on carotid and aortic structure and function in normotensive and hypertensive rats.
2003 Jul-Aug
Heart rate reduction during exercise-induced myocardial ischaemia and stunning.
2004 Apr
Long-term heart rate reduction induced by the selective I(f) current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure.
2004 Apr 6
Drug insight: If inhibitors as specific heart-rate-reducing agents.
2004 Dec
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
If at first you don't succeed try ... a new target in the treatment of angina.
2005 Dec
Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina.
2005 Dec
Chronic heart rate reduction remodels ion channel transcripts in the mouse sinoatrial node but not in the ventricle.
2005 Dec 14
Cardiac pacemaker I(f) current and its inhibition by heart rate-reducing agents.
2005 Jul
New agent ivabradine (Procoralan) for treatment of chronic stable angina.
2005 Sep-Oct
[Why it is necessary to reduce heart rate in the treatment of stable angina?].
2006
Clinical perspectives of heart rate slowing for coronary event reduction and heart failure.
2006
Heart rate reduction by pharmacological If current inhibition.
2006
Evolving treatment strategies for chronic refractory angina.
2006 Feb
Funny channels in the control of cardiac rhythm and mode of action of selective blockers.
2006 May
Ivabradine: a selective If current inhibitor in the treatment of stable angina.
2006 Nov
Heart rate lowering by inhibition of the pacemaker current: a new therapeutic perspective in cardiovascular disease.
2006 Oct
Perspectives of I(f) inhibition by ivabradine in cardiology.
2007
Preclinical results with I(f) current inhibition by ivabradine.
2007
The funny current: cellular basis for the control of heart rate.
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
Conversion of post-systolic wall thickening into ejectional thickening by selective heart rate reduction during myocardial stunning.
2007 Apr
Symptom improvement in postural orthostatic tachycardia syndrome with the sinus node blocker ivabradine.
2007 Dec
Heart failure management. Interview with Karl Swedberg.
2007 Jan 9
Ivabradine: a new strategy for management of stable angina.
2007 Jun
Heart rate reduction after heart transplantation with beta-blocker versus the selective If channel antagonist ivabradine.
2007 Oct 27
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.
Substance Class Chemical
Created
by admin
on Thu Jul 06 20:30:49 UTC 2023
Edited
by admin
on Thu Jul 06 20:30:49 UTC 2023
Record UNII
HY3BQT704N
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
IVABRADINE SULFATE
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-, SULFATE (1:1)
Systematic Name English
IVABRADINE MONOSULFATE
Common Name English
Code System Code Type Description
CAS
1202000-62-1
Created by admin on Thu Jul 06 20:30:49 UTC 2023 , Edited by admin on Thu Jul 06 20:30:49 UTC 2023
PRIMARY
FDA UNII
HY3BQT704N
Created by admin on Thu Jul 06 20:30:49 UTC 2023 , Edited by admin on Thu Jul 06 20:30:49 UTC 2023
PRIMARY
PUBCHEM
44599367
Created by admin on Thu Jul 06 20:30:49 UTC 2023 , Edited by admin on Thu Jul 06 20:30:49 UTC 2023
PRIMARY
SMS_ID
300000002056
Created by admin on Thu Jul 06 20:30:49 UTC 2023 , Edited by admin on Thu Jul 06 20:30:49 UTC 2023
PRIMARY
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