New Release: Alpha testing version has been released.

Ivabradine

C01E - Other cardiac preparations ATC C01EB17 Small molecule approved 2005 Oral First-in-class Natural product

JFDA label: Procoralan

Mechanism of Action

Blocker of Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 — Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 blocker

TargetActionGene / class
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 efficacy BLOCKER HCN4

Indications

Approved

  • Heart failure

Off-label

  • Inappropriate sinus tachycardia
  • Stable angina

Contraindications

Source: Lexicomp

  • Acute decompensated heart failure Absolute
  • Additional contraindications (not in US labeling): Hypersensitivity to ivabradine or any component of the formulation Absolute
  • blood pressure Absolute
  • resting heart rate Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (3)

Common atrial fibrillation · Bradycardia · hypertension

Nervous system disorders (1)

Common Phosphene

Other (2)

Not Known Cardiovascular: Heart block · sinoatrial arrest

Dosing

Source: Lexicomp

Heart failure: Oral: Initial: 5 mg twice daily or 2.5 mg twice daily in patients with a history of conduction defects or who may experience hemodynamic compromise due to bradycardia. After 2 weeks, adjust dose to achieve a resting heart rate between 50 and 60 beats per minute (bpm). Thereafter, adjust dose as needed based on resting heart rate and tolerability. Maximum dose: 7.5 mg twice daily. Dosage adjustment based on resting heart rate: If heart rate >60 bpm: Increase dose by 2.5 mg twice daily (maximum dose: 7.5 mg twice daily) If heart rate 50 to 60 bpm: Maintain dose If heart rate Inappropriate sinus tachycardia (off-label use): Oral: Initial: 5 mg twice daily; maintenance: 7.5 mg twice daily (ACC/AHA/HRS [Page 2015]; Cappato 2012). May also use in combination with a beta-blocker (eg, metoprolol) in patients who are refractory to monotherapy (Ptaszynski 2013). Stable angina (off-label use): Adults If symptoms are not controlled on beta-blocker or calcium channel blocker monotherapy, addition of ivabradine can be considered. If combined with a calcium channel blocker, use of a dihydropyridine (such as slow-release nifedipine, amlodipine, or felodipine) is suggested (Montalescot 2013; NICE 2012).
Heart failure: Refer to adult dosing. Stable angina (off-label use): Adults ≥75 years: Initial: Oral: Consider 2.5 mg twice daily. Titration and maintenance: Refer to adult dosing.
CrCl ≥15 mL/minute: No dosage adjustment necessary. CrCl
Mild or moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary. Severe impairment (Child-Pugh class C): Use is contraindicated (has not been studied; increase in systemic exposure anticipated).

Warnings & Precautions

Source: Lexicomp

Atrial fibrillation

Use increases the risk of atrial fibrillation; monitor cardiac rhythm. Discontinue if atrial fibrillation develops.

Bradycardia and conduction disturbances

Bradycardia, sinus arrest, and heart block may occur; monitor heart rate prior to initiation and with any dosage adjustment. Bradycardia may increase the risk of QT prolongation, which may lead to severe ventricular arrhythmias, including torsade de pointes, especially in patients with risk factors such as use of QTc prolonging drugs. Risk factors for bradycardia include sinus node dysfunction, conduction defects (eg, first- or second-degree AV block, bundle branch block), ventricular dyssynchrony, and use of other negative chronotropes (eg, digoxin, diltiazem, verapamil, amiodarone). Avoid concurrent use with verapamil and diltiazem. Avoid use in patients with second-degree AV block (unless a functioning demand pacemaker is present). Use is contraindicated in patients with sick sinus syndrome, sinoatrial block, third-degree AV block (unless a functioning demand pacemaker is present), or pacemaker dependence. Decrease dose or discontinue use if heart rate • Visual function: Phosphenes (described as transient enhanced brightness in a limited area of the visual field, halos, image decomposition, colored bright lights, or multiple images) may occur with use. Onset is generally within the first 2 months of therapy and is reported to be of mild to moderate intensity; most cases resolve during or after treatment discontinuation. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy & Lactation

Pregnancy

Adverse events have been observed in animal reproduction studies, and fetal harm may occur if ivabradine is administered to pregnant women. Effective contraception is recommended in women of reproductive potential. If treatment is needed during pregnancy, closely monitor for destabilization of heart failure that could potentially result from heart rate slowing caused by ivabradine, especially during the first trimester. Pregnant women with chronic heart failure should also be monitored for preterm birth.

Lactation

Avoid

It is not known if ivabradine is excreted in breast milk. Due to the potential risk from exposure in the nursing infant, breast-feeding is not recommended by the manufacturer.

Monitoring

Clinical pearlHeart rate (prior to initiation, prior to increasing dose, or after decreasing dose); monitor heart rate more closely if receiving other negative chronotropes (eg, amiodarone, beta-blockers, digoxin); blood pressure; regularly monitor cardiac rhythm (assessing for atrial fibrillation)

Chemistry & Properties

2D structure
FormulaC27H36N2O5
Molecular weight468.59 g/mol
IUPAC name3-[3-[[(7S)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]methyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one
CAS155974-00-8
PubChem CID132999
InChIKeyACRHBAYQBXXRTO-OAQYLSRUSA-N
logP3.31 (XLogP 2.4)
Polar surface area60.47 Ų
H-bond acceptors / donors6 / 0
Drug-likeness (QED)0.53
Lipinski violations0
SMILESCOc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability10.0%
Half-life2.152 h
Volume of distribution1.539 L/kg
Protein binding62.2%
BBB penetrantYes

Enzyme interactions

EnzymeRoleDetail
CYP1A2Substrate
CYP2C19Substrate
CYP2D6Substrate
CYP3A4Inhibitor
CYP3A4Substrate

Receptor binding (top 3)

TargetActionAffinity
HCN1 (HCN1) Channel blocker pIC50 5.7
HCN3 (HCN3) Channel blocker pIC50 5.7
HCN4 (HCN4) Channel blocker pIC50 5.7

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCT2 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)OATP1B1 (Substrate)OATP1B3 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drugSeverityManagement
Abarelix major
Abiraterone major
Alimemazine major
Anagrelide major
Apalutamide major
Aprepitant major
Arsenic trioxide major
Astemizole major
Bicalutamide major
Bosutinib major
Cabozantinib major
Ceritinib major
Chloroquine major
Cilostazol major
Cisapride major
Clarithromycin major
Clotrimazole major
Cobicistat major
Crizotinib major
Dasatinib major
Daunorubicin major
Daunorubicin (liposomal) major
Degarelix major
Dolasetron major
Doxepin major
Doxepin (topical) major
Doxorubicin major
Doxorubicin (liposomal) major
Encorafenib major
Entrectinib major
Enzalutamide major
Epirubicin major
Eribulin major
Erythromycin major
Fedratinib major
Fluconazole major
Flutamide major
Gilteritinib major
Glasdegib major
Goserelin major

Showing 40 of 100+.

Registered Products (6)

BrandForm / strengthPackAgentCitizen (JOD)
Ivanor Tablet 5 mg 30 tab JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN 7.250
Ivanor Tablet 7.5 mg 30 tab JORDAN RIVER PHARMA.IND(JORIVER)/JORDAN 7.250
Procoralan Tablet 7.5 mg 56 tab The Jordan Drugstore Co 16.400
Procoralan Tablet 5 mg 56 tab The Jordan Drugstore Co 16.400
Tevader Tablet 5 mg 60 tab UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN 16.570
Tevader Tablet 7.5 mg 60 tab UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN 16.570