Ivapace

Uses

Symptomatic treatment of chronic stable angina pectoris in coronary artery disease patients with normal sinus rhythm. Ivapace is used for:

• In patients unable to tolerate or with a contra-indication to the use of beta-blockers or
• In combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose and whose heart rate is > 60 bpm.

Ivapace is also used to associated treatment for these conditions: Chronic Heart Failure (CHF), Chronic Stable Angina Pectoris, Left Ventricular Dysfunction, Chronic, stable, symptomatic Heart Failure

How Ivapace works

Ivapace 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). Ivapace 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. Ivapace 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.

Dosage

Ivapace dosage

Adult: The usual recommended starting dose of Ivapace is 5 mg twice daily which may be increased after 3-4 weeks of treatment to 7.5 mg twice daily, depending on therapeutic response. Usual dose is 1 tablet in the morning and 1 tablet in the evening during meals.

If the heart rate decreases persistently below 50 bpm at rest or if symptoms related to bradycardia, the dose must be adjusted downwards to 2.5 mg twice daily (one half of the 5 mg tablet twice daily). Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist.

Elderly: Consider a lower starting dose (2.5 mg twice daily i.e. one half 5 mg tablet twice daily).

Children and adolescents: Not recommended.

Side Effects

Visual symptoms, blurred vision, bradycardia, 1st degree AV block, ventricular extrasystoles, headaches, and dizziness.

Toxicity

Ivapace may cause fetal toxicity when administered to pregnant women. Animal studies in pregnant rats have shown embryo-fetal toxicity and cardiac teratogenic effects. Effective contraception in women is recommended while using ivabradine.

Precaution

Mild to moderate hypotension, atrial fibrillation, patients with congenital QT syndrome or treated with QT wave prolonging medicinal products, Moderate hepatic insufficiency, severe renal insufficiency.

Interaction

QT wave prolonging medicinal products is not recommended. Cardiovascular QT wave prolonging medicinal products (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone). Non cardiovascular QT wave prolonging medicinal products (e.g. pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin).

The concomitant use of cardiovascular and non cardiovascular QT wave prolonging medicinal products with ivabradine should be avoided since QT wave prolongation may be exacerbated by heart rate reduction. If the combination appears necessary, close cardiac monitoring is needed.

Food Interaction

• Avoid grapefruit products.

[Major] GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of ivabradine.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

According to the product labeling, administration with grapefruit juice (quantity unknown) resulted in an approximately twofold increase in ivabradine systemic exposure (AUC).

Elevated plasma levels of ivabradine may increase the risk of excessive bradycardia and conduction disturbances.

ADJUST DOSING INTERVAL: Food delays the absorption of ivabradine by approximately 1 hour and increases plasma exposure by 20% to 40% compared to fasting conditions.

MANAGEMENT: Patients treated with ivabradine should avoid or limit consumption of grapefruit or grapefruit juice.

The manufacturer recommends taking ivabradine with meals to reduce variability in exposure.

Ivapace Drug Interaction

Major: ondansetron, sertralineModerate: metoprolol, metoprolol, albuterolUnknown: aspirin, aspirin, diphenhydramine, duloxetine, sacubitril / valsartan, furosemide, pregabalin, acetaminophen, clopidogrel, montelukast, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, cetirizine

Ivapace Disease Interaction

Major: conduction disturbances, heart failure, hepatic impairment, hypotensionModerate: renal impairment

Volume of Distribution

~100 L.

Elimination Route

It is recommended to take ivabradine with food to reduce variability in systemic exposure. Administration with food slows absorption by 1 hour, but increases systemic absorption by 20-30%. Ivapace's oral bioavailability is about 40%.

Half Life

2 hours.

Clearance

Total clearance is about 400ml/min; renal clearance about 70ml/min. About 4% is excreted unchanged in urine.

Elimination Route

Metabolites are equally excreted in feces and urine.

Pregnancy & Breastfeeding use

Fertility: Studies in rats have shown no effect on fertility in males and females

Pregnancy: There are no or limited amount of data from the use of ivabradine in pregnant women. Therefore, ivabradine is contra indicated during pregnancy.

Breast-feeding: Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contra-indicated during breast-feeding.

Contraindication

History of hypersensitivity to Ivapace or any of the excipients, resting heart rate below 60 bpm before treatment, cardiogenic shock, acute myocardial infarction, severe hypotension (< 90/50 mmHg), severe hepatic insufficiency, sick sinus syndrome, sino- atrial block, heart failure, pacemaker dependent, unstable angina, 3 rd degree AV block, combination with strong cytochrome P-450 3A4 inhibitors (such as azole antifungals, macrolide antibiotics, HIV protease inhibitors).

Special Warning

Renal insufficiency: Use with caution in patients with creatinine clearance

Hepatic impairment: Use with caution in patients with moderate hepatic impairment; Contraindicated in severe hepatic impairment.

Storage Condition

Store at cool and dry place, protect from light and moisture.

Innovators Monograph

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