Oral Chronic stable angina pectoris in coronary artery disease patients with normal sinus rhythm
Adult: Initially, should not exceed 5 mg bid. Increase if necessary to 7.5 mg bid after 3-4 wk. Titrate downward to as low as 2.5 mg bid, if patient develops bradycardia symptoms (e.g. dizziness, fatigue) or resting heart rate is persistently <50 beats/min. Elderly: ≥75 yr Initiate treatment at 2.5 mg bid. Titrate up if necessary.
Oral Chronic heart failure
Adult: Initially, 5 mg bid. After 2 wk, increase to 7.5 mg bid if resting heart rate is persistently >60 beats/min or decrease to 2.5 mg bid if resting heart rate is persistently <50 beats/min. If heart rate is between 50-60 beats/min, maintain 5 mg bid. Max: 7.5 mg bid. Elderly: ≥75 yr Initiate treatment at 2.5 mg bid. Titrate up if necessary.
Renal Impairment
CrCl (mL/min)
Dosage
<15
Use w/ caution.
Hepatic Impairment
Severe: Contraindicated.
Administration
Should be taken with food. Avoid excessive consumption of grapefruit juice.
Contraindications
Resting heart rate <70 beats/min prior to treatment, cardiogenic shock, acute MI, severe hypotension (<90/50 mmHg), sick sinus syndrome, SA block, unstable or acute heart failure, pacemaker dependent, unstable angina, 3rd degree AV block. Severe hepatic impairment. Pregnancy and lactation. Concurrent use w/ potent CYP3A4 inhibitors (e.g. azole antifungals, macrolides, HIV protease inhibitors or nefazodone), moderate CYP3A4 inhibitors (e.g. verapamil or diltiazem).
Special Precautions
Patient w/ retinitis pigmentosa, 2nd degree AV block, congenital QT prolongation, AF or other cardiac arrhythmias that interfere w/ sinus node function. Severe renal impairment (CrCl <15 mL/min).
Adverse Reactions
Luminous phenomena in the visual field (phosphenes), blurred vision, bradycardia, other cardiac arrhythmias, syncope, hypotension, asthenia, fatigue, headache, dizziness, nausea, constipation, diarrhoea, dyspnoea, muscle cramps, skin reactions, angioedema, hyperuricaemia, eosinophilia, elevated blood-creatinine concentrations.
Monitoring Parameters
Monitor heart rate prior to initiation of treatment, prior to increasing dose or after decreasing dose; BP, cardiac rhythm.
Overdosage
Symptoms: Severe and prolonged bradycardia. Management: Treat severe bradycardia symptomatically. In case of bradycardia w/ poor haemodynamic tolerance, IV β-stimulating medicines e.g. isoprenaline may be used. If necessary, may institute temporary cardiac electrical pacing.
Drug Interactions
QT prolongation may be exacerbated by heart rate reduction w/ QT-prolonging drugs (e.g. quinidine, disopyramide, pimozide, ziprasidone). Concentration may be reduced w/ CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin) and may require ivabradine dose adjustment. Potentially Fatal: Increased serum concentration w/ potent CYP3A4 inhibitors (e.g. azole antifungals, macrolides, HIV protease inhibitors or nefazodone), moderate CYP3A4 inhibitors (e.g. verapamil or diltiazem).
Food Interaction
Food delays absorption but increases exposure by 20-30%. Increased serum concentration w/ grapefruit juice. Decreased serum concentration w/ St John's wort.
Action
Description: Ivabradine is a heart rate lowering agent that works through selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. Pharmacokinetics: Absorption: Almost completely absorbed from GI tract. Food delays absorption by approx 1 hr and increases exposure by 20-30%. Absolute bioavailability: Approx 40%. Time to peak plasma concentration: Approx 1 hr. Distribution: Volume of distribution: Approx 100 L. Plasma protein binding: Approx 70%. Metabolism: Extensively metabolised in the liver and gut via oxidation by CYP3A4 isoenzyme to form major active metabolite N-desmethyl-ivabradine (S-18982). Excretion: Approx 4% as unchanged drug via urine; metabolites are excreted to a similar extent via urine and faeces. Plasma elimination half-life: 2 hr.
Chemical Structure
Ivabradine Source: National Center for Biotechnology Information. PubChem Database. Ivabradine, CID=132999, https://pubchem.ncbi.nlm.nih.gov/compound/Ivabradine (accessed on Jan. 21, 2020)
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