Brand Name: IVADIN
Generic Name: Ivabradine
Preparations: 5/ 7.5 mg Tablets
Pharmacological Category: Funny current inhibitor

Pharmacokinetics
Absorption: Almost completely absorbed after oral doses
Bioavailability: About 40% because of first pass metabolism
Peak Plasma Concentration: About 1 hour in fasting but delayed by 1 hour by food
Protein binding: 70%
Metabolism: Extensively in the liver and gut; active metabolite: N-desmethyl-ivabradine (S-18982)
Plasma Elimination Half-life: 2 hours
Excretion: Urine and feaces

Mechanism of action (MOA)
IVADIN is a heart-rate-lowering agent that selectively and specifically inhibits funny current (If), a mixed sodium-potassium inward current that controls the spontaneous diastolic depolarization in the SA node. This leads to prolongation of diastolic depolarization slowing firing in the SA node, and 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.
The cardiac effects of IVADIN are specific to the SA node, and the drug has no effect on blood pressure, intracardiac conduction, myocardial contractility, or ventricular repolarization.
IVADIN also inhibits the retinal current (Ih), the properties of which are similar to that of cardiac If. Ih participates in the temporal resolution of the visual system by curtailing retinal responses to bright light stimuli. Under triggering circumstances, such as rapid changes in luminosity, partial inhibition phenomena (phosphenes) is experienced by patients.

Indications and Dosage
• Symptomatic treatment of chronic stable angina pectoris
IVADIN is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal sinus rhythm and heart rate ≥70 bpm. IVADIN is indicated:
• In adults 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: Should not exceed 5 mg twice daily with meal in patient aged below 75 years.
After three to four weeks of treatment, if the patient is still symptomatic, the initial dose is well tolerated and resting heart rate remains above 60 bpm, the dose may be increased to the next higher dose in patients receiving 2.5 mg twice daily or 5 mg twice daily. The maintenance dose should not exceed 7.5 mg twice daily.
If there is no improvement in symptoms of angina within 3 months after start of treatment, treatment of IVADIN should be discontinued.

• Treatment of chronic heart failure
IVADIN is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with LVEF ≤35%, who are in sinus rhythm with restingheart rate ≥70 bpm and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.
Dose: 5 mg BID with meals
After 2 weeks, assess patient and adjust dose to achieve a resting heart rate of 50-60 bpm; not to exceed 7.5 mg BID
Dose adjustment
• HR >60 bpm: Increase dose by 2.5 mg (given BID) up to a maximum dose of 7.5 mg BID
• HR 50-60 bpm: Maintain dose
• HR <50 bpm or signs and symptoms of bradycardia: Decrease dose by 2.5 mg (given twice daily); if current dose is 2.5 mg BID, discontinue therapy

Side Effects
VERY COMMON: Luminous phenomena (phosphenes)
COMMON: Headache (generally during the first month of treatment), blurred vision, bradycardia, AV 1st degree block, ventricular extrasystoles, atrial fibrillation and uncontrolled blood pressure
UNCOMMON: Hyperuricemia, eosinophilia, syncope, diplopia, visual impairment, vertigo, palpitations, supraventricular extrasystoles, hypotension, dyspnoea, nausea, constipation, diarrhoea, abdominal pain, angioedema, rash, muscle spasm, asthenia, fatigue, elevated creatinine in blood and ECG prolonged QT interval
RARE: Erythema, pruritus, urticaria and malaise
VERY RARE: AV 2nd degree block, AV 3rd degree block and sick sinus syndrome

Contraindications
Hypersensitivity, resting heart rate below 70 bpm prior to treatment, cardiogenic shock, acute myocardial infarction, severe hypotension (<90/50 mmHg), severe hepatic insufficiency, sick sinus syndrome, sino-atrial block, unstable or acute heart failure, pacemaker dependent (heart rate imposed exclusively by the pacemaker), unstable angina, AV-block of 3rd degree, combination with strong cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone, combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties, pregnancy, lactation and women of child-bearing potential not using appropriate contraceptive measures.

Warnings/ Precautions
• Before starting the therapy, heart failure shouldbe stable; caution in severe heart failure.
• If resting heart rate falls below 50bpm, the dose should be reduced; treatment shouldbe stopped if this rate persists.
• Cautionin severe renal impairment (creatinine clearance of less than15 mL/minute).
• If unexpected deterioration in visual function occurs,treatment should be stopped.
• Caution is advisablein patients with retinitis pigmentosa.
• Embryotoxic and teratogenic have been observed during animal studies, and distribution into breastmilk occurs.

Interactions
• Should not generally be used with drugs thatprolong the QT interval.
• Metabolism by the cytochrome P450isoenzyme CYP3A4 occurs, and should not be used with potentinhibitors of this enzyme, including azole antifungals such as ketoconazole and itraconazole, macrolide antibacterial such as clarithromycin, HIV-protease inhibitors such as nelfinavir and ritonavir, and nefazodone.
• Use with themoderate CYP3A4 inhibitors diltiazem and verapamil is alsonot recommended as the increase in exposure to the therapymay cause an additional reduction in heart rate.
• May be used cautiously with other moderate inhibitors,such as fluconazole, at a lower starting dose of 2.5 mg twice daily, with monitoring of the heart rate.
• Consumptionof grapefruit juice should be restricted.
• Use with CYP3A4 inducers, such as rifampicin andphenytoin, may require an increase in the dose of the therapy.
• St John’s wort reduces the exposure tothe therapy by half and its use should be restricted.

Pregnancy Category: IVADIN may cause fetal toxicity when administered to a pregnant woman, based on findings in animal studies. There are no adequate and well-controlled studies in pregnant women to inform any drug-associated risks.

Presentations
IVADIN 5: 10 X 10’s
IVADIN 7.5: 10 X 10’s