IVATERO 5

Indications

• Stable angina
• Patients inadequately controlled or intolerant of first-line antianginal therapies

Dosage

Children: null

Adults: Initially 375 mg twice daily for 2–4 weeks, then increased to 500 mg twice daily if necessary. For patients aged 18–74 years, initial dosage can be 2.5–5 mg twice daily, increased to 7.5 mg twice daily based on response. For those aged 75 years and over, start at 2.5 mg twice daily, increasing as necessary up to 7.5 mg twice daily.

Mechanism of action

Ivabradine lowers heart rate by selectively inhibiting If channels (funny channels) in a concentration-dependent manner. It binds to a site on the channel pore from the intracellular side, disrupting If ion current flow, which prolongs diastolic depolarization and lowers the pacemaker firing rate in the sinoatrial node, leading to decreased heart rate and reduced myocardial oxygen demand.

Pharmacodynamics

Ivabradine's activity is dependent on heart rate, exhibiting use-dependence. It is more pharmacologically active at higher heart rates, showing a linear dose-dependent bradycardic effect until a maximum dose of 30-40 mg, where the effect plateaus. Its metabolite also contributes to heart rate lowering, enhancing its overall efficacy.

Pharmacokinetics

Ivabradine is absorbed after oral administration and undergoes extensive first-pass metabolism. It has a half-life of approximately 2 hours, but due to its active metabolite, the overall effect on heart rate may last longer. The drug is primarily eliminated via hepatic metabolism and renal excretion of metabolites.

Contra-indications

• Severe hepatic impairment
• Acute myocardial infarction
• Cardiogenic shock
• Severe hypotension
• Sick sinus syndrome
• Pacemaker dependence
• Hypersensitivity to ivabradine or any excipient

Adverse effects

• Bradycardia
• Visual disturbances (luminous phenomena)
• Headache
• Dizziness
• Fatigue
• Nausea
• Diarrhea
• Abdominal pain

Interactions

• Grapefruit juice: increases exposure to ivabradine
• St. John's wort: decreases exposure to ivabradine
• Clarithromycin: increases exposure to ivabradine
• Erythromycin: increases exposure to ivabradine
• Mitotane: decreases exposure to ivabradine
• Rifampicin: decreases exposure to ivabradine
• Dronedarone: increases exposure to ivabradine (unknown mechanism)
• Azole antifungals: increases exposure to ivabradine (unknown mechanism)
• Cobicistat: increases exposure to ivabradine (unknown mechanism)
• Crizotinib: increases exposure to ivabradine (unknown mechanism)

Precautions

• Monitor heart rate; should not fall below 50 beats per minute
• Caution in patients with body weight less than 60 kg
• Caution in the elderly
• Caution in patients with moderate to severe congestive heart failure
• QT interval prolongation requires monitoring

Pregnancy

Manufacturer advises avoiding use unless essential; no information available.

Breast-feeding

Manufacturer advises avoiding use; no information available.

Storage

Store in a cool, dry place below 25°C. Protect from light.

Formulations

• Ivabradine 2.5 mg modified-release tablet
• Ivabradine 5 mg modified-release tablet
• Ivabradine 7.5 mg modified-release tablet

Mechanism of action

Ivabradine lowers heart rate by selectively inhibiting If channels ("funny channels") in the heart in a concentration-dependent manner without affecting any other cardiac ionic channels (including calcium or potassium). Ivabradine binds by entering and attaching to a site on the channel pore from the intracellular side and disrupts If ion current flow, which prolongs diastolic depolarization, lowering heart rate. The If currents are located in the sinoatrial node and are the home of all cardiac pacemaker activity. Ivabradine therefore lowers the pacemaker firing rate, consequently lowering heart rate and reducing myocardial oxygen demand. This allows for an improved oxygen supply and therefore mitigation of ischemia, allowing for a higher exercise capacity and reduction in angina episodes.

Pharmacodynamics

The funny channels (If) open during repolarization and close during depolarization, making ivabradine's activity dependent on heart rate or the closing and opening of the channels. Therefore ivabradine exhibits use-dependence and is more pharmacologically active at higher heart rates. Ivabradine exhibits a linear dose-dependent heart-rate lowering activity (bradycardic effect) until a maximum dose of 30-40mg. At higher doses, the concentration of ivabradine tends to plateau, reducing risk of serious sinus bradycardia. It has been shown that the metabolite of ivabradine lowers heart rate as well, contributing to ivabradine's overall effect.