Ivabradine

Registered South African indications:

• Chronic stable angina pectoris
  - For symptomatic treatment in patients with normal sinus rhythm and heart rate ≥70 bpm, as monotherapy or in combination with beta-blockers
• Chronic heart failure
  - In adults in sinus rhythm with mild to moderate (NYHA II & III class) symptomatic heart failure whose heart rate is ≥77 bpm to reduce cardiovascular events (cardiovascular mortality or hospitalisation for worsening heart failure), in combination with standard therapy including beta-blockers or when beta-blockers are contraindicated or not tolerated

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy 
• Breastfeeding
• 3rd degree AV Block
• Pacemaker dependent (heart rate imposed exclusively by the pacemaker)
• Resting heart rate below 70 bpm prior to treatment
• Severe hypotension (<90/50mmHg)
• Cardiogenic shock
• Unstable or acute heart failure
• Acute coronary syndrome
• Unstable angina pectoris
• Use in patients with congenital long QT syndrome or in patients treated with QT-prolonging medicines should be avoided
• In combination with strong cytochrome P450 inhibitors such as azole antifungals, macrolide antibiotics, HIV protease inhibitors
• Concomitant use of St John’s Wort
• Ivabradine is not recommended in patients with moderate liver dysfunction (limited data in these populations) and is contraindicated in severe liver dysfunction (no data)
• Combination with verapamil or diltiazem, which are moderate CYP3A4 inhibitors with heart-rate reducing properties
• Women of childbearing potential not using appropriate contraceptive measures
• Concomitant use of grapefruit juice is not recommended
• Concomitant use with QT-prolonging medicines: The concomitant use of cardiovascular (quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone) or non-cardiovascular (tricyclic antidepressant, antipsychotics, erythromycin IV, pentamidine, pimozide, mefloquine) QT-prolonging medicines with ivabradine should be avoided since QT-prolongation may be exacerbated by heart rate reduction
• Ivabradine has not been studied in patients with rapid conduction disorders i.e., WPW
• Cardiac dysrhythmias:
  • Sick sinus syndrome
  • Sino-atrial block
• Stroke: The use of ivabradine is not recommended immediately after a stroke since no data is available in these situations
• Use in patients with AV-block of 2nd degree: Ivabradine is not recommended in patients with AV-block of 2nd degree

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Women of childbearing potential not using appropriate contraceptive measures
• Severe hepatic impairment
• Resting heart rate <70 bpm before initiating treatment
• Cardiogenic shock
• Acute myocardial infarction
• Severe hypotension (< 90/50mmHg)
• Sick sinus syndrome
• Sino-atrial block
• Unstable or acute cardiac failure
• Pacemaker dependent (heart rate imposed exclusively by the pacemaker)
• Unstable angina
• AV-block of 3^rd degree
• Combination with strong cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone
• Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties

• Severe renal impairment (CrCl<15ml/min)
• Moderate hepatic impairment
• Elderly
• Atrial fibrillation
• Cardiac arrhythmias that interfere with sinus node function
• Cardiac failure with intraventricular conduction defects or ventricular dyssynchrony
• 2nd-degree atrioventricular block
• NYHA IV cardiac failure
• Stroke
• Retinitis pigmentosa
• Hypotension
• QT prolongation syndrome
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Chronic stable angina pectoris
- For symptomatic treatment in patients with normal sinus rhythm and heart rate ≥70 bpm, as monotherapy or in combination with beta-blockers
Chronic heart failure
- In adults in sinus rhythm with mild to moderate (NYHA II & III class) symptomatic heart failure whose heart rate is ≥77 bpm to reduce cardiovascular events (cardiovascular mortality or hospitalisation for worsening heart failure), in combination with standard therapy including beta-blockers or when beta-blockers are contraindicated or not tolerated

• Oral (fct, tab): Initial: Should not exceed 5mg, twice daily in patients <75 years; If patient is still symptomatic after 2-4 weeks of treatment (and initial dose is well tolerated and if resting heart rate remains above 60 bpm) increase to: Max: 7.5mg, twice daily depending on the therapeutic response

It is recommended that the decision to initiate or titrate treatment takes place using serial heart rate measurements, ECG or ambulatory 24-hour monitoring

If there is no improvement in symptoms of angina within 3 months after start of treatment, treatment of ivabradine should be discontinued. In addition, discontinuation of treatment should be considered if there is only limited symptomatic response and when there is no clinically relevant reduction in resting heart rate within 3 months

If, during treatment, heart rate decreases below 50 bpm at rest or the patient experiences symptoms related to bradycardia, such as dizziness, fatigue or hypotension, the dosage must be titrated downward including the lowest dose of 2.5mg twice daily (one half 5mg tablet twice daily). After dose reduction, heart rate should be monitored

 Treatment must be discontinued if the heart rate remains below 50 bpm or symptoms of bradycardia persist, despite dose reduction

Chronic heart failure
- In adults in sinus rhythm with mild to moderate (NYHA II & III class) symptomatic heart failure whose heart rate is ≥77 bpm to reduce cardiovascular events (cardiovascular mortality or hospitalisation for worsening heart failure), in combination with standard therapy including beta-blockers or when beta-blockers are contraindicated or not tolerated

• Oral (fct, tab): Initial: 5mg, twice daily in patients <75 years; If resting heart rate is persistently above 60 bpm: Increase to 7.5mg, twice daily after 2 weeks; If resting heart rate is persistently below 50 bpm or in case of symptoms related to bradycardia such as dizziness, fatigue or hypotension: Decrease to 2.5mg, twice daily after 2 weeks; If heart rate is between 50 and 60 bpm: 5mg, twice daily should be maintained

If during treatment, the heart rate decreases persistently to below 50 beats per minute (bpm) at rest or the patient experiences symptoms related to bradycardia, the dose must be titrated downward to the next lower dose in patients receiving 7.5mg twice daily or 5mg twice daily. Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist

Ivabradine tablets must be taken orally twice daily, i.e. once in the morning and once in the evening. Ivabradine tablets should be taken with food

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Animal reproduction studies have shown embryotoxic and teratogenic effects at doses similar to those used in humans. Therefore, ivabradine is contraindicated during pregnancy
• Women of childbearing potential:  Women of childbearing potential should use appropriate contraceptive measures during treatment

Recommendations in other jurisdictions

• Contraindicated
• There are no or limited amount of data from the use of ivabradine in pregnant women
• Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects. The potential risk for humans is unknown. Therefore, ivabradine is contraindicated during pregnancy
• Women of childbearing potential should use appropriate contraceptive measures during treatment

Breastfeeding

South African recommendations

• Contraindicated
• Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated during lactation

Recommendations in other jurisdictions

• Contraindicated
• Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated during breastfeeding
• Women that need treatment with ivabradine should stop breastfeeding, and choose another way of feeding their child

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

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

Recommendations below are applicable to South Africa and other jurisdictions

• CrCl>15ml/min: No dose adjustment recommended
• CrCl<15ml/min: Caution; no information available
  No data are available in patients with creatinine clearance below 15ml/min. Ivabradine should therefore be used with precaution in this population

South African recommendations

• Mild: No dose adjustment recommended
• Moderate: Caution; not recommended
  Ivabradine is not recommended in patients with moderate hepatic insufficiency, since there is limited data
• Severe: Contraindicated
  Ivabradine is contraindicated for use in patients with severe hepatic insufficiency, since it has not been studied in this population

Recommendations in other jurisdictions

• Mild: No dose adjustment recommended
• Moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated
  Ivabradine is contraindicated for use in patients with severe hepatic impairment, since it has not been studied in this population and a large increase in systemic exposure is anticipated

Recommendations below are applicable to South Africa and other jurisdictions

• >75 years: Caution; dose adjustment recommended
  In patients aged 75 years or more, a lower starting dose should be considered.  (2.5mg twice daily i.e. one half 5mg tablet twice daily) before up-titration if necessary

Central Nervous System Disorders

• Headache
• Dizziness
• Syncope
• Fatigue

Cardiovascular Disorders

• Bradycardia
• 1st, 2nd and 3rd degree atrioventricular block
• Prolonged QT interval
• Ventricular extrasystoles
• Atrial fibrillation
• Palpitations
• Supraventricular extrasystoles
• Sick sinus syndrome
• Uncontrolled blood pressure
• Hypotension

Respiratory Disorders

• Dyspnoea

Gastrointestinal Disorders

• Nausea
• Constipation
• Diarrhoea
• Abdominal pain

Genitourinary Disorders

• Increased creatinine

Endocrine and Metabolic Disorders

• Hyperuricaemia

Musculoskeletal Disorders

• Muscle cramps

Skin and Subcutaneous Tissue Disorders

• Angioedema
• Rash
• Erythema
• Pruritus
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Eosinophilia

Sensory Disorders

• Luminous phenomena
• Blurred vision
• Diplopia
• Visual impairment
• Vertigo

• CYP3A4 inhibitors
• Azole antifungals
• Ketoconazole
• Itraconazole
• Macrolide antibiotics
• Erythromycin
• Clarithromycin
• Josamycin
• Telithromycin
• HIV protease inhibitors
• Nelfinavir
• Ritonavir
• Nefazodone
• Verapamil
• Diltiazem
• QT prolonging agents
• Quinidine
• Disopyramide
• Bepridil
• Sotalol
• Ibutilide
• Amiodarone
• Tricyclic antidepressants
• Antipsychotics
• Pentamidine
• Pimozide
• Mefloquine
• CYP3A4 inducers
• Class I antiarrhythmics
• Potassium depleting agents
• Proton pump inhibitors

Other interactions

• Grapefruit juice
• St John’s Wort

• ECG
• Blood pressure

Ivabradine acts by selective and specific inhibition of the hyperpolarization-activated cyclic nucleotide-gated channels (f-channels) within the sinoatrial (SA) node of cardiac tissue. The cardiac effects are specific to the sinus node with no effect on other parts of the heart. Inhibition of these f-channels results in decreased heart rate.

Tablet 5mg

• Coralan (Servier) originator
• Ivabradine 5 Unicorn (Cipla Medpro)
• Ivacor 5 (Forrester Pharma)
• Ivolan 5mg (Pharma Dynamics)

Tablet 7.5mg 

• Coralan (Servier) originator
• Ivabradine 7.5 Unicorn (Cipla Medpro)
• Ivacor 7.5 (Forrester Pharma)