Consumer medicine information

Coralan

Ivabradine

BRAND INFORMATION

Brand name

Coralan

Active ingredient

Ivabradine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Coralan.

What is in this leaflet

This leaflet answers some common questions about CORALAN (Coh'-rah-lan).

It does not contain all the available information.

Reading this leaflet does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of taking CORALAN against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What CORALAN is

The name of your medicine is CORALAN. It contains the active ingredient ivabradine (I-vab'-rah-deen).

What CORALAN is used for

You may be prescribed CORALAN for:

  • symptomatic stable angina in adult patients whose heart rate is over or equal to 70 beats per minute (bpm) or
  • heart failure.

Stable angina:
Stable angina typically occurs when you exert yourself, and is usually relieved with medication or rest.

Angina is a pain or uncomfortable feeling in the chest. This pain or feeling can also spread to the arms and neck and sometimes also to the shoulders and back. Angina is caused by too little blood and oxygen getting to the heart.

CORALAN relieves stable angina by lowering the heart rate. CORALAN is not for the relief of a sudden attack of angina. Your doctor will have given you other medication to treat this.

Heart failure:
Heart failure means that the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body. Heart failure is not the same as heart attack and does not mean that the heart stops working.

Some people develop heart failure after having had a heart attack. However there are also other causes of heart failure.

Heart failure may start off with no symptoms, but as the condition progresses, you may feel short of breath or may get tired easily after light physical activity such as walking. You may wake up short of breath at night. Fluid may collect in different parts of the body, often first noticed as swollen ankles and feet. In severe heart failure, symptoms may occur even at rest.

CORALAN helps to treat heart failure. If you follow your doctor's advice, your ability to perform daily activities may improve. You may breath more easily, feel less tired, and have less swelling.

CORALAN can only be obtained with a doctor's prescription.

There is no evidence that CORALAN is addictive.

Ask your doctor if you have any questions about why CORALAN has been prescribed for you.

Before you take CORALAN

When you must not take it

There are some people who should not take CORALAN. Please read the lists below. If you think any of these situations apply to you, or you have any questions, please talk to your doctor or pharmacist.

Do not use CORALAN if you:

  • have an allergy to ivabradine hydrochloride, the active substance in CORALAN, or to any of the other ingredients listed at the end of this leaflet
  • have disturbances of heart rhythm; a "sick sinus syndrome" or sino-atrial block
  • have a certain type of artificial pacemaker
  • have 3rd degree Atrioventricular (AV) block
  • have a resting heart rate below 70 beats per minute prior to treatment
  • have unstable or acute heart failure
  • have very low blood pressure
  • have unstable angina
    Unstable angina is a pain or uncomfortable feeling in the chest that lasts longer than a few minutes or occurs with rest, and may not be relieved with medication
  • have cardiogenic shock
    Which is a sudden and severe drop in blood pressure and blood flow through the body because the heart is not pumping normally
  • are having a heart attack
  • are taking any of the following medications:
    - ketoconazole, an oral antifungal therapy
    - diltiazem or verapamil, used to treat high blood pressure or angina
    - antibiotics of the macrolide class, including azithromycin, clarithromycin, erythromycin and roxithromycin
    - cyclosporin, used to prevent rejection following transplants
    - gestodene and anti-retroviral drugs such as medicines to treat HIV infections.
  • have severe liver disease
  • suffer from Hypertrophic Cardiomyopathy (HOCM)
  • are pregnant, or trying to become pregnant
  • are of childbearing age and are not using reliable birth control
    CORALAN may affect your developing baby if you take it during pregnancy
  • are breastfeeding.

Do not give this medicine to anyone else.

Do not use CORALAN if the packaging is torn or shows signs of tampering. If the packaging is damaged when you first receive the product, return it to your pharmacist.

Do not take CORALAN if the expiry date (EXP) printed on the pack has passed. If you take it after the expiry date has passed, it may not work as well.

Tell your doctor if:

  • you are pregnant, or trying to become pregnant
  • you are of childbearing age and are not using reliable birth control
  • you are breastfeeding or plan to breast-feed as breastfeeding should be discontinued if you take CORALAN
  • you have or have had any medical conditions, especially the following:
    - an artificial pacemaker. People with a certain type of artificial pacemaker should not use CORALAN. Your doctor will be able to tell you whether you can use CORALAN with your pacemaker
    - a slow heart beat (less than 70 beats per minute)
    - a particular heart condition with an abnormal electrical signal called 'long QT syndrome'
    - symptoms of atrial fibrillation, a heart condition where the pulse at rest is unusually high (over 110 beats per minute) or irregular without any apparent reason
    - low blood pressure
    - a recent stroke
    - unstable heart failure
    - severe heart failure or heart failure with an abnormal electrical signal called 'bundle branch block'
    - allergies to any other medicines or any foods, dyes or preservatives
    - severe liver disease
    - moderate or severe kidney disease
    - an eye condition called 'retinitis pigmentosa', a condition that affects the light sensitive cells on the inner portion of the eye.

Your doctor may want to take special precautions if you have any of these conditions.

If you think any of these situations apply to you, or you have any doubts or questions about taking CORALAN talk to your doctor or pharmacist.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and foods can interfere with the action of CORALAN by increasing or decreasing its effect. You may need different amounts of your medication or to take different medicines. The medicines that interact with CORALAN include the following:

  • grapefruit and grapefruit juice
  • antibiotics of the macrolide class, including azithromycin, clarithromycin, erythromycin and roxithromycin
  • cyclosporin, used to prevent rejection following transplants
  • ketoconazole, an oral antifungal therapy
  • gestodene
  • medicines to treat HIV infections;
  • rifampicin (an antibiotic)
  • barbiturates (for difficulty sleeping or epilepsy)
  • phenytoin (for epilepsy)
  • beta-blockers (like atenolol, propranolol, metoprolol, etc, for high blood pressure, heart rhythm disorders, or angina pectoris)
  • quinidine, disopyramide, ibutilide, sotalol (to treat heart rhythm disorders)
  • certain types of medicines to treat depression (such as imipramine)
  • certain types of medicines to treat anxiety, schizophrenia or other psychoses (such as phenothiazines and thioridazine)
  • amiodarone (for heart rhythm disorders)
  • some medicines of the calcium channel blocker class, including diltiazem and verapamil
  • some herbal remedies such as St John's Wort
  • some types of 'fluid' or 'water tablets' (used to treat high blood pressure, or fluid retention) which may cause a decrease in blood potassium level, such as frusemide, hydrochlorothiazide, Indapamide.

Your doctor and pharmacist may have more information on medicines to be careful with or to avoid while taking CORALAN.

How to take CORALAN

Follow all directions given to you by your doctor and pharmacist carefully. These directions may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How to take it

Swallow your tablets with water, and with food. The usual dose is one tablet in the morning and one tablet in the evening. In some cases, for example if you are elderly, your doctor may prescribe half the dose i.e. one half of a CORALAN 5 mg tablet in the morning and one half of a CORALAN 5 mg tablet in the evening.

How much to take

For stable angina:
The starting dose should not exceed one tablet of CORALAN 5 mg taken twice a day. After three to four weeks of starting treatment, and during ongoing treatment, your doctor may review your dose and may adjust it depending on your condition. The maintenance dose should not exceed one tablet of CORALAN 7.5 mg taken twice daily.

For heart failure:
The usual starting dose is one tablet of CORALAN 5 mg taken twice a day. After two weeks of starting treatment, and during ongoing treatment, your doctor may review your dose and may adjust it depending on your condition. The maintenance dose should not exceed one tablet of CORALAN 7.5 mg taken twice daily.

Your doctor will tell you what dose to take.

When to take it

Take one tablet in the morning and one tablet at night.

How long to take it for

You should take CORALAN until your doctor tells you to stop taking it. If you are not sure how long to take it for, talk to your doctor.

The dose of CORALAN you need will be decided and adjusted by your doctor. In all cases, strictly follow your doctor's directions.

If you think that the effect of CORALAN is too strong or too weak, talk to your doctor or pharmacist.

If you forget to take CORALAN

If you forget to take a dose, take the next dose at your normal time.

Do not take a double dose next time, to make up for the dose that you missed.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take more CORALAN than you should (overdose)

If you think that you or anyone else may have taken too much CORALAN, immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to the Accident & Emergency Department at your nearest hospital. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

The general effects of taking an overdose of CORALAN is a very slow heartbeat. You may feel breathless or tired.

If you have this symptom when you take CORALAN, tell your doctor.

While you are taking CORALAN

Things you must do

Follow your doctor's instructions about how many tablets to take, and when to take them.

Avoid drinking grapefruit juice while you are taking CORALAN.

If you do not follow your doctor's instructions, you may not get the benefits from treating your angina or heart failure.

If you are taking Coralan for stable angina, tell your doctor if you continue to have angina attacks or if they become more frequent while you are using CORALAN.

Tell your doctor well in advance of any expected hospitalisation or surgery. If you go to hospital unexpectedly, tell the doctor who admits you that you are using CORALAN.

Tell all doctors, dentists or pharmacists who treat you that you are using CORALAN.

Tell your doctor or pharmacist that you are taking CORALAN if you are about to be started on any new medicines.

If you discover you are pregnant while taking CORALAN, tell your doctor immediately.

Things you must not do

Do not use CORALAN to treat any other complaints unless your doctor says to.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Things to be careful of

Be careful when driving or operating machinery in situations where there may be sudden changes in dim to bright lighting.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking CORALAN. CORALAN helps most people with symptoms of stable angina or heart failure, but it may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this explanation of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following side effects and if they worry you:

  • temporary visual symptoms (very common side effect). Some patients taking CORALAN may see bright spots of light, a halo, coloured flashes or multiple or distorted images. This may occur particularly when moving quickly between dim and bright lighting conditions.
    These visual symptoms are usually mild and appear in the first two months of treatment, and then disappear as treatment continues. Tell your doctor or pharmacist if they bother you.
    Be careful when driving or operating machinery in situations where there may be sudden changes in dim to bright lighting.
    Blurred vision, double vision or impaired vision may also occur.
  • Changes in heart function (symptoms are a slowing down of the heart rate) is a common side effect. It mainly occurs within the first 2 to 3 months of treatment initiation.
  • uncontrolled (e.g. low or high) blood pressure.
  • Feeling sick (nausea), constipation, diarrhoea, abdominal pain
  • headache
  • fainting (possibly related to slow heart rate)
  • spinning sensation (vertigo)
  • difficulty breathing (dyspnoea)
  • muscle cramps
  • feeling tired or weak
  • dizziness, light headedness (a symptom of low blood pressure possibly related to slow heart rate), generally feeling unwell
  • abnormal ECG heart tracing.

CORALAN may cause changes in laboratory tests including high blood levels of uric acid, an excess of eosinophils (a type of white blood cell) and elevated creatinine in blood (a breakdown product of muscle).

Tell your doctor if you notice anything else that makes you feel unwell.

If the following signs occur then tell your doctor immediately or go to the accident and emergency department at your nearest hospital:

  • difficulty in breathing
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • skin rash, redness of the skin, itching, itchy rash
  • Changes in heart rate (fast, dangerously fast or irregular), palpitations

These side effects are not common but can become serious.

After taking CORALAN

Storage

Keep this medicine where children cannot reach it. A locked cupboard at least one and-a-half metres above floor level is a good place to store medicines.

Heat and dampness can reduce the quality of medicines.

Keep CORALAN in a cool dry place where the temperature stays below 30 degrees C, but not in the fridge or freezer.

Do not store it, or any other medicine, in a bathroom or near a sink. Do not leave it in the car or on window sills.

Keep your tablets in their blister pack until it is time to take them. If you take the tablets out of the box or the blister pack they may not keep well.

Disposal

If your doctor tells you to stop taking CORALAN or the tablets have passed their expiry date, return the unused medicines to your pharmacist.

Product description

What it looks like

CORALAN 5mg:
Salmon-pink coloured, rod-shaped, film-coated tablet scored on both edges, engraved with "5" on one face and a company logo on the other.

CORALAN 7.5mg:
Salmon-pink coloured, triangular, film-coated tablet engraved with "7.5" on one face and a company logo on the other.

CORALAN 5mg and CORALAN 7.5mg tablets are supplied in a blister strip, in packs containing 14 or 56 tablets.

Ingredients

Each CORALAN 5mg tablet contains 5mg of ivabradine, as the hydrochloride salt.

Each CORALAN 7.5mg tablet contains 7.5mg of ivabradine, as the hydrochloride salt.

CORALAN also contains the following inactive ingredients:

Tablet Core:
Lactose, magnesium stearate, maize starch, maltodextrin, colloidal anhydrous silica.

Film-coating:
Hypromellose, titanium dioxide (E 171), macrogol 6000, glycerol, magnesium stearate, yellow iron oxide (E 172), red iron oxide (E 172).

Manufacturer and sponsor

CORALAN is a product discovered by Servier Research International.

It is distributed in Australia by:

Servier Laboratories (Aust.) Pty. Ltd.
Level 4, Building 9,
588A Swan Street
Burnley, 3121, Victoria
Telephone: 1800 153 590
Internet: www.servier.com.au

Australian Registration Number:

CORALAN 5mg tablet AUSTR: 107297

CORALAN 7.5mg tablet AUSTR: 107301

Date of preparation of this leaflet:
June 2022

Published by MIMS August 2022

BRAND INFORMATION

Brand name

Coralan

Active ingredient

Ivabradine

Schedule

S4

 

1 Name of Medicine

Ivabradine (as the hydrochloride).

2 Qualitative and Quantitative Composition

Each Coralan 5 mg film-coated tablet contains 5 mg of ivabradine (as the hydrochloride).
Each Coralan 7.5 mg film-coated tablet contains 7.5 mg of ivabradine (as the hydrochloride).
The active component of Coralan is ivabradine which has the chemical name (3-(3-{[((7S)-3,4-dimethoxybicyclo[4,2,0]octa-1,3,5-trien-7-yl) methyl] methylamino}propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one, hydrochloride).
It contains two rings: one benzazepinone and one benzocyclobutane linked with an azapentane chain. The structural form of ivabradine includes one asymmetric carbon and ivabradine corresponds to the S enantiomer. The hydrochloride salt is a white hygroscopic powder, soluble in water (50 mg/mL) and in 0.9% saline solution (14 mg/mL). The pH is 5.1 - 5.4 in aqueous solutions at concentration of 10 mg/mL.

Excipients with known effect.

Each Coralan 5 mg tablet contains 63.91 mg of lactose. Each Coralan 7.5 mg tablet contains 61.215 mg of lactose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Coralan 5 mg.

Salmon-pink coloured, rod-shaped, film-coated tablet scored on both edges, engraved with "5" on one face and the company logo on the other.

Coralan 7.5 mg.

Salmon-pink coloured, triangular, film-coated tablet engraved with "7.5" on one face and the company logo on the other.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of chronic stable angina.

Symptomatic treatment of chronic stable angina due to atherosclerotic coronary artery disease in patients with normal sinus rhythm and heart rate at or above 70 bpm, who are unable to tolerate or have a contraindication to the use of beta-blockers, or in combination with atenolol 50 mg once daily when angina is inadequately controlled.

Treatment of chronic heart failure.

Treatment of symptomatic chronic heart failure of NYHA classes II or III and with documented left ventricular ejection fraction (LVEF) ≤ 35% in adult patients in sinus rhythm and with heart rate at or above 77 bpm, in combination with optimal standard chronic heart failure treatment.

4.2 Dose and Method of Administration

Dosage (dose and interval).

Symptomatic treatment of chronic stable angina.

It is recommended that the decision to initiate or titrate treatment takes place with the availability of serial heart rate measurements, ECG or ambulatory 24 hour monitoring.
The starting dose of ivabradine for patients with stable angina, alone or in combination with atenolol 50 mg, should not exceed 5 mg twice daily (BD) in patients aged below 75 years when heart rate is at or above 70 bpm.
After three to four weeks of treatment, if the patient is still symptomatic, if the initial dose is well tolerated and if 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 in accordance with Table 1 if necessary. The maintenance dose should not exceed 7.5 mg twice daily.
If there is no improvement in symptoms of angina 3 months after start of treatment, ivabradine should be discontinued. Discontinuation of treatment should also be considered if there is only limited symptomatic response and when there is no clinically relevant reduction in resting heart rate within three 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 dose must be titrated downward to the lowest dose (2.5 mg twice daily - one half 5 mg tablet twice daily). After dose reduction, heart rate should be monitored (see Section 4.4 Special Warnings and Precautions for Use).
Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist despite dose reduction (see Section 4.4 Special Warnings and Precautions for Use).

Chronic heart failure (CHF).

The recommended starting dose for patients with heart failure is ivabradine 5 mg twice daily (BD) when heart rate is at or above 77 bpm.
After two weeks of treatment, and during ongoing treatment the dose should be reviewed and depending on the heart rate, adjusted according to Table 1 if necessary.
Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist (see Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

Ivabradine should be taken once in the morning and once in the evening during meals (see Section 5.2 Pharmacokinetic Properties).
If a dose is missed, the next scheduled dose should be taken at the usual time without doubling it.

Dosage adjustment.

Elderly.

In patients aged 75 years or more, a lower starting dose (2.5 mg twice daily) should be considered before up titration if necessary.

Renal insufficiency.

No dose adjustment is required in patients with renal insufficiency and creatinine clearance above 15 mL/min (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

No dose adjustment is required in patients with mild hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use). Caution should be exercised when using ivabradine in patients with moderate hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use). Ivabradine is contraindicated in patients with severe hepatic insufficiency (see Section 4.3 Contraindications).

Concomitant use with cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.

Potent CYP3A4 inhibitors such as ketoconazole, macrolide antibiotics, cyclosporin, gestodene and anti-retroviral drugs.

Ivabradine is contraindicated (see Section 4.3 Contraindications).

Moderate CYP 3A4 inhibitors.

The concomitant use of ivabradine with verapamil or diltiazem is not recommended.

Other moderate CYP3A4 inhibitors (see Section 4.4 Special Warnings and Precautions for Use).

Ivabradine treatment should be initiated at the starting dose of 2.5 mg twice daily if resting heart rate is at or above 60 bpm, with monitoring of heart rate.

CYP3A4 inducers.

Ivabradine treatment can be initiated at the usual recommended dose of 5 mg twice daily. In the event of prolonged concomitant use, the dose of ivabradine may need to be titrated upward.

4.3 Contraindications

Coralan (ivabradine) is contraindicated in the following circumstances:
Known hypersensitivity to ivabradine or any of the excipients listed in Section 6.1.
Conditions in which the sinus node is no longer the cardiac pacemaker, e.g. artificial pacemaker, sick sinus syndrome.
3rd degree atrioventricular (AV) block.
Unstable or acute heart failure.
Resting heart rate below 70 bpm prior to treatment.
Severe hypotension (< 90/50 mmHg) (see Section 4.4 Special Warnings and Precautions for Use).
Unstable angina.
Cardiogenic shock.
Acute myocardial infarction.
Sino-atrial block.
Patients with hypertrophic cardiomyopathy (HOCM) unless co-existing coronary artery disease (CAD) is proven (see Section 4.4 Special Warnings and Precautions for Use).
Combination with potent cytochrome P450 3A4 (CYP 3A4) inhibitors such as ketoconazole, macrolide antibiotics, cyclosporin, gestodene and anti-retroviral drugs (see Section 5.2 Pharmacokinetic Properties; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Severe hepatic insufficiency (see Section 4.4 Special Warnings and Precautions for Use).
Pregnancy, lactation, and women of childbearing potential not using appropriate contraceptive measures (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Lack of benefit on clinical outcomes in patients with symptomatic chronic stable angina pectoris.

Ivabradine is indicated only for symptomatic treatment of chronic stable angina because ivabradine has no benefits on cardiovascular outcomes, e.g. myocardial infarction or cardiovascular death (see Section 5.1 Pharmacodynamic Properties).

Measurement of heart rate.

Given that heart rate may fluctuate considerably over time, serial heart rate measurements, ECG or ambulatory 24 hour monitoring should be considered when determining resting heart rate before initiation of ivabradine treatment and in patients on treatment with ivabradine when titration is considered. This also applies to patients with a low heart rate, in particular when heart rate decreases below 50 bpm, or after dose reduction (see Section 4.2 Dose and Method of Administration).

Pulse rate monitoring.

Where heart rate monitoring is recommended, estimation of pulse rate by radial, brachial or carotid pulse palpation will usually be sufficient.

Low heart rate.

Ivabradine must not be initiated in patients with a pre-treatment resting heart rate below 70 beats per minute (see Section 4.3 Contraindications).
If, during treatment, resting heart rate decreases persistently below 50 bpm or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward (see Section 4.2 Dose and Method of Administration). If heart rate remains below 50 bpm or symptoms of bradycardia persist, treatment with ivabradine should be discontinued.

Congenital QT syndrome or treatment with QT prolonging medicines.

The use of ivabradine in patients with QT prolongation, congenital QT syndrome or treated with QT prolonging medicinal products should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If the combination appears necessary, close cardiac monitoring is needed.
Heart rate reduction with ivabradine may exacerbate QT prolongation, which may give rise to severe arrhythmias in particular torsades de pointes.

Cardiac arrhythmias.

Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its efficacy when a tachyarrhythmia occurs (e.g. ventricular or supraventricular tachycardia). Ivabradine is not recommended in patients with atrial fibrillation or with other cardiac arrhythmias that interfere with sinus node function.
In patients treated with ivabradine the risk of developing atrial fibrillation is increased (see Section 4.8 Adverse Effects (Undesirable Effects)). Atrial fibrillation has been more common in patients taking amiodarone or potent class I anti-arrhythmics concomitantly.
It is recommended to regularly monitor ivabradine treated patients for the occurrence of atrial fibrillation (sustained or paroxysmal), including ECG monitoring if clinically indicated (e.g. in case of exacerbated angina, palpitations, irregular pulse).
Patients should be informed of signs and symptoms of atrial fibrillation and be advised to contact their physician if these occur.
If atrial fibrillation develops during treatment, the balance of benefits and risks of continued ivabradine treatment should be carefully reconsidered.
Chronic heart failure patients with intraventricular conduction defects (bundle branch block left, bundle branch block right) and ventricular dyssynchrony should be monitored closely.
There is no evidence of risk of (excessive) bradycardia on return to sinus rhythm when pharmacological cardioversion is initiated in patients treated with ivabradine. However, in the absence of extensive data, non-urgent DC cardioversion should be considered 24 hours after the last dose of ivabradine.

Combination with calcium channel blockers.

Concomitant use of ivabradine with heart rate reducing calcium channel blockers such as verapamil or diltiazem is contraindicated (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). No safety issue has been raised on the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers such as amlodipine. Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been established.

Aortic stenosis.

Experience with the use of ivabradine in patients with aortic stenosis is limited and should be used with caution in this patient population. A low initiation dose, slow dose titration and patient monitoring are recommended.

Patients with 2nd degree AV block.

Ivabradine should be used with caution in patients with 2nd degree AV block.

Patients with hypotension.

Limited data are available in patients with mild to moderate hypotension, and ivabradine should therefore be used with caution in these patients. Ivabradine is contraindicated in patients with severe hypotension (blood pressure < 90/50 mmHg).

Blood pressure treatment modification.

Blood pressure should be monitored in ivabradine treated chronic heart failure patients, following blood pressure treatment modification.
In the SHIFT trial, of the patients receiving concomitant blood pressure treatments, those treated with ivabradine experienced episodes of transient increased blood pressure (ivabradine 7.1%, placebo 6.1%) (see Section 4.8 Adverse Effects (Undesirable Effects)). These episodes occurred most frequently shortly after blood pressure treatment was modified. This did not affect the treatment effect of ivabradine.

Stroke.

The use of ivabradine is not recommended immediately after a stroke since no data is available in these situations.

Wolff-Parkinson-White syndrome.

Ivabradine has not been studied in patients with Wolff-Parkinson-White syndrome.

Heart failure.

Caution is needed in asymptomatic left ventricular dysfunction due to the limited number of patients studied. Heart failure must be stable before considering ivabradine treatment. Ivabradine should also be used with caution in patients with NYHA class IV severe functional status due to limited number of patients studied (n = 111 (1.7%) (ivabradine n = 50 (1.5%), placebo n = 61 (1.9%)).

Hypertrophic cardiomyopathy.

Ivabradine should be used with caution in patients with HOCM and coexisting CAD due to limited data in this patient population.

Cardiac and non-cardiac surgery.

Ivabradine should not be commenced peri-operatively due to limited safety data available in this population.

Visual effects.

Changes in retinal function were observed in dogs at ivabradine exposures similar to or higher (i.e. about 1 to 46 times) than those in patients treated with 7.5 mg ivabradine twice daily, based on AUC. These changes were reversible after cessation of treatment, and were not associated with any damage to ocular structures. These data are consistent with the pharmacological effect of ivabradine related to its interaction with hyperpolarisation activated Ih currents in the retina, which share extensive homology with the cardiac pacemaker If current.
Ivabradine influences retinal function in humans. There is no evidence of a toxic effect of long-term ivabradine treatment on the retina. Studies of long-term ivabradine therapy detected only mild reversible effects on the cone system (see Section 5.1 Pharmacodynamic Properties). A previous study has detected effects on the combined rod/cone response (i.e. 3RC) at supra-therapeutic doses. Cessation of treatment should be considered if any unexpected deterioration in visual function occurs. Caution should be exercised in patients with retinitis pigmentosa.

Lactose intolerance.

Ivabradine tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use in hepatic impairment.

Studies in patients with mild hepatic insufficiency (AST/ALT 1.5 to 2 times ULN or Child Pugh score up to 7) support the use of ivabradine in this patient population. Caution should be exercised when using ivabradine in patients with moderate hepatic insufficiency. The use of ivabradine in patients with severe hepatic insufficiency is contraindicated as it has not been studied in this population and a large increase in systemic exposure is expected.

Use in renal impairment.

There are no data available in patients with creatinine clearance below 15 mL/min therefore ivabradine should be used with caution in patients with end stage renal disease. There is limited safety data in patients with a creatinine clearance of 15 to 30 mL/min. As with any new drug given over prolonged periods, laboratory parameters should be monitored at regular intervals in patients with renal insufficiency, particularly following a dose increase.

Use in the elderly.

No pharmacokinetic differences (AUC and Cmax) have been observed between elderly (≥ 65 years) or very elderly patients (≥ 75 years) and the overall population. However, since ivabradine has been studied in a limited number of patients aged ≥ 75 years, a lower starting dose should be considered before up titration if necessary in this population (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Ivabradine is not recommended in children and adolescents, as efficacy and safety have not been studied in these populations.

Effects on laboratory tests.

Ivabradine has no clinically relevant effects on blood chemistry or haematology.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Concomitant use not recommended.

Concomitant use with QT prolonging medicines.

The concomitant use of cardiovascular (e.g. quinidine, disopyramide, sotalol, amiodarone) or noncardiovascular (e.g. tricyclic antidepressants, antipsychotics, erythromycin IV, pentamidine, pimozide, mefloquine) QT prolonging medicines with ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction. If the combination appears necessary, close cardiac monitoring is needed (see Section 4.4 Special Warnings and Precautions for Use).
Concomitant use with precaution.

Potassium depleting diuretics (thiazide diuretics and loop diuretics).

Hypokalemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting combination of hypokalemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, particularly in patients with long QT syndrome, whether congenital or substance induced.

Pharmacokinetic interactions.

Combinations that are contraindicated.

Concomitant use with cytochrome P450 3A4 (CYP3A4) inhibitors or inducers.

Ivabradine is metabolised by CYP3A4 only and is a very weak inhibitor of this cytochrome. Ivabradine is therefore unlikely to influence the metabolism and plasma concentrations of other CYP3A4 substrates. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine may be associated with a risk of excessive bradycardia (see Section 4.4 Special Warnings and Precautions for Use).

Potent CYP3A4 inhibitors (e.g. ketoconazole, macrolide antibiotics, cyclosporin, gestodene and anti-retroviral drugs).

Concomitant use with ivabradine is contraindicated (see Section 4.3 Contraindications). Specific clinical interaction studies have shown that the concomitant use of ivabradine (10 mg twice daily) and ketoconazole (200 mg once daily) produced 7 to 8-fold increases in ivabradine mean plasma exposure.

Moderate CYP3A4 inhibitors (e.g. diltiazem, verapamil) with heart rate reducing properties.

Concomitant use of ivabradine with diltiazem or verapamil is contraindicated due to the potential for additive heart rate lowering effects (see Section 4.3 Contraindications). Specific interaction studies in healthy volunteers and patients have shown that the combination of ivabradine with diltiazem or verapamil resulted in an increase in ivabradine exposure (2 to 3-fold increase in AUC) with an additional heart rate reduction of 5 bpm.
Combinations that are not recommended.

Grapefruit juice.

As ivabradine exposure was increased by 2-fold following co-administration with grapefruit juice the intake of grapefruit juice should be avoided.
Concomitant use with precautions.

CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, St John's wort (Hypericum perforatum)).

Prolonged concomitant use of these agents with ivabradine may decrease ivabradine exposure and therefore require an adjustment of the ivabradine dose depending on the therapeutic response (see Section 4.2 Dose and Method of Administration). In this case, heart rate monitoring is recommended when discontinuing CYP3A4 inducers.
The combination of ivabradine 10 mg twice daily with St John's wort was shown to reduce ivabradine AUC by half. The intake of St John's wort should be restricted during the treatment with ivabradine.

Other moderate CYP3A4 inhibitors.

Concomitant use with ivabradine can be used with caution if resting heart rate is at or above 70 bpm, and heart rate is carefully monitored (see Section 4.2 Dose and Method of Administration).
Concomitant use with heart rate reducing anti-anginal therapies.

Beta-blockers.

In patients with CAD, receiving ivabradine (10 mg twice daily) on top of atenolol (50 mg once daily), heart rate reducing effects of the two medicines were additive. There was no pharmacokinetic interaction.
On the basis of long-term safety data from the BEAUTIFUL study and efficacy data from a 12 week randomised placebo controlled study (see Section 5.1 Pharmacodynamic Properties), ivabradine can be used in combination with atenolol 50 mg once daily if resting heart rate is at or above 70 bpm, and heart rate is monitored (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).

Non-dihydropyridine calcium channel blockers.

In view of the potential for additive heart rate lowering effects, the concomitant use of ivabradine with heart rate reducing calcium channel blockers such as diltiazem or verapamil is contraindicated.

Other anti anginal therapies.

No safety issue has been raised on the combination of ivabradine with nitrates and the dihydropyridine calcium channel blocker amlodipine. Specific drug interaction studies with other dihydropyridine calcium channel blockers (i.e. nifedipine, felodipine and lercanidipine) have not been conducted, however in vitro data have indicated a very weak CYP3A4 inhibition with these medicines. Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been established (see Section 5.1 Pharmacodynamic Properties).

Concomitant use with other medicines.

Specific drug-drug interaction studies have shown no clinically significant pharmacokinetic or pharmacodynamic interactions between ivabradine and any of the following: digoxin, HMG-CoA reductase inhibitors (simvastatin), sildenafil, proton pump inhibitors (omeprazole, lansoprazole), dihydropyridine calcium channel blockers (amlodipine), aspirin and warfarin.
In pivotal phase III clinical trials the following drugs were routinely combined with ivabradine with no evidence of safety concerns: angiotensin converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, aldosterone antagonists, short and long acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin and other anti-platelet agents.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Reproductive toxicity studies showed no effect of ivabradine on fertility in male and female rats at oral doses up to 175 mg/kg/day, which result in plasma ivabradine levels approximately 50 to 110 times the average clinical levels at 7.5 mg twice daily based on AUC.
(Category D)
There are no adequate data concerning the use of ivabradine in pregnant women. Animal reproduction studies have shown embryotoxic and teratogenic effects (cardiac defects in rats and ectrodactylia) at exposures (based on AUC) close to the clinical exposure at 7.5 mg twice daily. Ivabradine is contraindicated during pregnancy as the potential risk for humans is unknown (see Section 4.3 Contraindications). Women of childbearing potential should use appropriate contraceptive measures during treatment with ivabradine (see Section 4.3 Contraindications).
 Animal studies indicate that ivabradine is excreted in milk. Treatment of dams during gestation and lactation resulted in postnatal mortalities and enlarged heart in the offspring from exposures (based on AUC) 3.1 times the expected clinical exposure at 7.5 mg twice daily. Therefore, ivabradine is contraindicated in breast-feeding women (see Section 4.3 Contraindications). If treatment with ivabradine is deemed necessary, then breast-feeding should be discontinued.

4.7 Effects on Ability to Drive and Use Machines

A specific study to assess the possible influence of ivabradine on driving performance has been performed in healthy volunteers where there was no evidence of alteration to driving performance. In post-marketing experience, cases of impaired driving ability due to visual symptoms have been reported. Ivabradine may cause transient luminous phenomena consisting mainly of phosphenes. The possible occurrence of such luminous phenomena should be taken into account when driving or using machines in situations where sudden variations in light intensity may occur, especially when driving at night. Ivabradine has no influence on the ability to operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Ivabradine has been studied in two broadly distinct adult populations, i.e. anginal/ ischaemic (nearly 37,200 patients) and CHF (about 6,800 patients), in clinical trials involving a total of nearly 44,000 patients.
Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field. Phosphenes may also be described as a halo, image decomposition (stroboscopic or kaleidoscopic effects), coloured bright lights, or multiple image (retinal persistency). They are usually triggered by sudden variations in light intensity and occur within the first 2 months of treatment. In clinical trials they were well tolerated, usually reported as mild to moderate (97%) in intensity. Phosphenes resolved spontaneously during treatment in 77.5% of patients, or were reversible when treatment ceased. Fewer than 1% of patients changed their daily routine or discontinued the treatment in relation with phosphenes.
In the SIGNIFY study atrial fibrillation was observed in 5.3% of patients taking ivabradine compared to 3.8% in the placebo group. In a pooled analysis including more than 40,000 patients from all the phase II/III double blind controlled clinical trials (whatever the indication) with a duration of at least 3 months, the incidence of atrial fibrillation was 4.86% in ivabradine treated patients compared to 4.08% in controls, corresponding to an odds ratio of 1.26, 95% CI [1.15-1.39].
The frequency of emergent adverse effects reported by patients treated in double blind studies, and from spontaneous reports in the anginal/ ischaemic, and CHF populations are summarised hereafter:

Anginal/ ischaemic population.

See Table 2.
The following events reported by > 1% of patients during clinical trials in the anginal/ ischaemic population were of similar incidence to comparators and/or possibly related to the underlying disease: unstable angina (2%), angina pectoris aggravated (2%) and myocardial ischaemia (1.2%).
Uncommon adverse effects (reported by ≤ 1%, > 0.1% of patients) with ivabradine in the anginal/ ischaemic population.

Blood and lymphatic system disorders.

Eosinophilia.

Cardiac disorders.

Palpitations, supraventricular extrasystoles. The following events reported by ≤ 1%, > 0.1% of ivabradine patients during clinical trials were of similar incidence to comparators and/or possibly related to the underlying disease: sinus arrhythmia, atrial fibrillation, myocardial infarction and ventricular tachycardia.

Ear and labyrinth disorders.

Vertigo.

Eye disorders.

Diplopia1, visual impairment1.

Gastrointestinal disorders.

Nausea, constipation, diarrhoea, abdominal pain1.

General disorders and administration site condition.

Asthenia1 (possibly related to bradycardia), fatigue1 (possibly related to bradycardia).

Investigations.

Elevated creatinine in blood, ECG prolonged QT interval.

Metabolism and nutrition disorders.

Hyperuricaemia.

Musculoskeletal and connective tissue disorders.

Muscle cramps.

Nervous system disorders.

Syncope1 (possibly linked to bradycardia).

Respiratory, thoracic and mediastinal disorders.

Dyspnoea.

Vascular disorders.

Hypotension (possibly related to bradycardia).

Skin and subcutaneous tissue disorders.

Angioedema1, rash1.
Rare adverse effects (reported by ≥ 0.01%, < 0.1% of patients) with ivabradine in the anginal/ischaemic population.

General disorders and administration site condition.

Malaise1 (possibly related to bradycardia).

Skin and subcutaneous tissue disorders.

Erythema1, pruritus1, urticaria1.

Cardiac disorders.

Ventricular fibrillation1
Post-marketing adverse effects (frequency unknown) with ivabradine in the anginal/ischaemic population.

Cardiac disorders.

Torsades de pointes.
Ivabradine in combination with atenolol 50 mg once daily in the anginal/ischaemic population. In a randomised, double blind, placebo controlled, parallel group study ASSOCIATE, the profile of the adverse effects reported was similar to the above. The incidence of treatment related emergent adverse events with ivabradine in combination with atenolol 50 mg (ivabradine) was 9.1% versus 2.7% with atenolol 50 mg alone (placebo). This difference was mainly due to bradycardia (ivabradine 4.2% versus placebo 0.5%), mostly asymptomatic (ivabradine 3.1% versus placebo 0.5%) (see Section 4.4 Special Warnings and Precautions for Use).

Principal emergent adverse events (EAEs) in the BEAUTIFUL study.

In the large outcome study, BEAUTIFUL (see Section 5.1 Pharmacodynamic Properties), the overall incidence of EAEs was similar in the ivabradine and placebo groups (55.7% versus 55.5%). The most frequent EAEs included (ivabradine versus placebo), atrial fibrillation (5.2% versus 4.9%), symptomatic bradycardia (3.8% versus 1.0%), asymptomatic bradycardia (3.1% versus 0.6%), phosphenes (3.8% versus 0.9%), blood pressure inadequately controlled (3.6% versus 3.5%), ventricular extrasystoles (2.0% versus 1.9%).
Serious adverse events (SAEs) and discontinuation in the anginal/ ischaemic population. In the Overall Safety Set (N = 2,907), the most frequently reported SAEs with ivabradine were cardiac disorders, where the only SAE reported with a ≥ 1% incidence was unstable angina (1.5%).
No serious adverse event nor events leading to treatment discontinuation were reported with a ≥ 1% incidence. Unstable angina was reported as serious in 0.4% (with ivabradine in combination with atenolol 50 mg od) vs 0.2% (with atenolol 50 mg od) and led to treatment discontinuation in 0.2% vs 0.2%.
1Adverse effect detected from spontaneous reports. Frequency is calculated from adverse event in clinical trials.

Chronic heart failure population.

See Table 3.
The incidence of adverse drug reactions related to ivabradine (reported by > 1.0% of patients in the ivabradine group, N = 3,232) in the SHIFT study were:

Cardiac disorders.

Bradycardia symptomatic, bradycardia asymptomatic.

Eye disorders.

Phosphenes.

Additional adverse effects reported with ivabradine in the CHF population.

Common (reported by > 1% to ≤ 10% of patients) in the CHF population.

Vascular disorders.

Blood pressure inadequately controlled (see Section 4.4 Special Warnings and Precautions for Use), atrial fibrillation.

Cardiac disorders.

Ventricular tachycardia.
Uncommon (reported by > 0.1% to ≤ 1% of patients) in the CHF population.

Investigations.

ECG prolonged QT interval.

Eye disorders.

Diplopia1, visual impairment1.

Gastrointestinal disorders.

Abdominal pain1.

Cardiac disorders.

Ventricular fibrillation1.
Rare (reported by > 0.01% to ≤ 0.1% of patients) in the CHF population.

Cardiac disorders.

Torsades de pointes 1.
Very rare (reported by < 0.0001% of patients) in the CHF population.

Cardiac disorders.

AV 2nd degree block, AV 3rd degree block, sick sinus syndrome.
1Adverse effect detected from spontaneous reports. Frequency is calculated from adverse event in clinical trials.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
Overdose may lead to symptomatic bradycardia.
Severe bradycardia should be treated symptomatically in a specialised environment. In the event of bradycardia with poor haemodynamic tolerance, supportive treatment including intravenous beta-stimulating agents such as isoprenaline may be considered. Temporary cardiac electrical pacing may be instituted if required.
Due to ivabradine's rapid absorption, activated charcoal is unlikely to be of benefit in overdose. Neither haemodialysis nor peritoneal dialysis is likely to significantly affect the pharmacokinetics of ivabradine so their use is not recommended in overdose.

5 Pharmacological Properties

Pharmacotherapeutic group: cardiovascular system - heart rate reducing agents. ATC code: C01EB17.

5.1 Pharmacodynamic Properties

Mechanism of action.

Ivabradine is a heart rate lowering agent, acting by selective inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate.
The cardiac effects are relatively specific to the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, myocardial contractility or ventricular repolarisation in humans at the therapeutic dose. In experimental models the adaptability of myocardial contractility, cardiac output, mean coronary blood flow velocity and vascular resistance observed during exercise are preserved.
In animal models used to mimic exercise induced ischaemia that causes angina pectoris in humans, ivabradine significantly reduces myocardial ischaemia and myocardial contractility dysfunction induced by stunning.
Ivabradine can also interact with the retinal current Ih which closely resembles cardiac If. It participates in the temporal resolution of the visual system by curtailing the retinal response to bright light stimuli. Under triggering circumstances (e.g. rapid changes in luminosity), partial inhibition of Ih by ivabradine underlies the luminous phenomena that may be occasionally experienced by patients. Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visual field. Phosphenes may also be described as a halo, image decomposition (stroboscopic or kaleidoscopic effects), coloured bright lights, or multiple image (retinal persistency).
The main pharmacodynamic property of ivabradine in humans is a specific dose dependent reduction in heart rate. At usual recommended doses, heart rate reduction is approximately 10 beats per minute (bpm) at rest and during exercise. This leads to a reduction in cardiac workload and myocardial oxygen consumption. Analysis of heart rate reduction indicates a trend towards a plateau effect at doses over 20 mg twice daily.
Ivabradine does not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular repolarisation:
In clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricular conduction times or corrected QT intervals;
In specific studies including over 100 patients with left ventricular dysfunction, ivabradine was shown to preserve myocardial contractility.

Clinical trials.

The anti-anginal and anti-ischaemic efficacy of ivabradine was demonstrated in five double blind randomised trials (three versus placebo, and one each versus atenolol and amlodipine). These trials included a total of 4,111 patients with coronary artery disease (CAD) and chronic stable angina pectoris, of whom 2,617 received ivabradine.
Stable angina - monotherapy. Ivabradine 5 mg twice daily was shown to be effective on exercise test parameters within 3 to 4 weeks of treatment (Table 4). Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over 5 mg twice daily was established in a reference controlled study versus atenolol: total exercise duration at trough was increased by about 1 minute after one month of treatment with 5 mg twice daily and further improved by almost 25 seconds after an additional 3 month period with forced titration to 7.5 mg twice daily. In this study, the anti-anginal and anti-ischaemic benefits of ivabradine were also confirmed in patients aged 65 years or more. The efficacy of 5 and 7.5 mg twice daily was consistent across studies on exercise test parameters (total exercise duration, time to limiting angina, time to angina onset and time to 1 mm ST segment depression) and was associated with a decrease of about 70% in the rate of angina attacks. The twice daily dosing regimen of ivabradine showed uniform efficacy over 24 hours.
Stable angina, combination therapy. In a 725 patient randomised placebo controlled study, ivabradine did not show additional efficacy on top of amlodipine at the trough of drug activity (12 hours after oral intake) while additional efficacy was shown at peak (3 to 4 hours after oral intake).
Ivabradine efficacy was fully maintained throughout the 3 or 4 month treatment periods in the efficacy trials. There is no evidence of pharmacological tolerance (loss of efficacy) developing during treatment or of rebound phenomena after abrupt treatment discontinuation.
A sustained reduction of heart rate was demonstrated in patients treated with ivabradine for at least one year. No influence on glucose or lipid metabolism was observed. The anti-anginal and anti-ischaemic efficacy of ivabradine was preserved in diabetic patients (n = 457) with a similar safety profile as compared to the overall population.
The anti-anginal and anti-ischaemic effects of ivabradine were associated with dose dependent reductions in heart rate and with a significant decrease in rate pressure product (heart rate x systolic blood pressure) at rest and during exercise. No clinically relevant effect on blood pressure was observed.
The efficacy of ivabradine versus placebo on top of a background therapy with atenolol 50 mg once daily in patients with stable angina was demonstrated in a randomised, double blind, placebo controlled, parallel group, international multicentre study. The ASSOCIATE study involved 219 centres in 20 countries with a diversity of results across different countries. The analysis in the intention to treat (ITT) population is presented below.
Patients included in the study were aged between 18 and 75 years, with a history of stable chronic effort angina pectoris for at least 3 months prior to pre-selection, with no angina at rest and no angina of class IV, with clinical stability, and with documented CAD. Overall, 58% of patients received atenolol 50 mg once daily within the 3 months before inclusion in the study, and 42% received another beta-blocker (i.e. metoprolol, bisoprolol, carvedilol, propranolol) at an equivalent dose. Patients on a different beta-blocker to atenolol 50 mg were switched to atenolol 50 mg once daily at the start of the run-in period, so that during the run-in period all patients received atenolol 50 mg once daily.
Three Exercise Tolerance Tests (ETTs) were performed during the 6-8 week run-in period (the first two at selection visits SEL1 and SEL2 and the third prior to the inclusion visit M0). In accordance with the requirements for patient inclusion outlined in the relevant TGA guideline, patients eligible for inclusion into the study were required to have a positive ETT result at the SEL1 visit and two positive stable ETTs at SEL2 and M0 visits. Patients selected for SEL2 were required to have had a positive result at the SEL1 visit. Stability was defined as time to 1 mm ST segment depression (TST) within ± 20%, or ± 1 min at the two visits.
Of the 2681 patients screened, a total of 889 patients met the inclusion criteria, and were thus included and randomised to the study. A total of 1792 patients failed to meet either pre-selection, selection or inclusion criteria. The majority of those not included in the study (1508/1792; 84.2%) did not produce a positive ETT result at SEL1 or did not meet the stability criteria.
After a run-in period lasting 6 to 8 weeks on atenolol (50 mg once daily) and placebo (twice daily), 889 patients complying with inclusion criteria were randomised to receive either ivabradine 5 mg twice daily then 7.5 mg twice daily given orally for 2 months each (n = 449) or placebo (n = 440), in combination with atenolol (50 mg once daily). The treatments compared were ivabradine with atenolol 50 mg once daily versus placebo with atenolol 50 mg once daily.
The primary efficacy endpoint was the improvement between baseline and end of 4 months of treatment (M4) in TED on a treadmill ETT according to the standard Bruce protocol at the trough of ivabradine and atenolol activity (i.e. 12 ± 1 hours and 24 ± 2 hours post-dosing, respectively) on centralised reading values.
Statistically, the between group difference in TED over the 4 month period was significant in favour of a greater increase in the ivabradine group (16.3 s (95% CI [7.9; 24.7]). An improvement was also observed over the 2 month period (8.2 s (95% CI [0.6; 15.7]). The improvement in TED of 16.3 s (p < 0.001) was achieved, most commonly, during the third stage of the standard Bruce protocol, where the functional capacity of an individual is approximately nine Metabolic Equivalents (METs) corresponding to activities considered to be of high intensity, i.e. cycling at ~ 25 km/h, jogging at ~ 9 km/h, cross country skiing at ~ 8 km/h.
Of the 875 patients in the full analysis set, 69.1% of ivabradine treated patients had an improvement in TED compared with 54.0% of placebo treated patients. The proportion of patients in whom the improvement was > 30 s was 48.5% in the ivabradine group and 33.8% in the placebo group. 0.9% and 0.5% of patients in the ivabradine and placebo groups respectively, had no change in TED. The proportion of patients who experienced a worsening in TED was considerably smaller in the ivabradine group, 29.9% compared to the placebo group 45.2%.
There were a number of secondary endpoints, parameters measured included: Time to 1 mm ST segment depression (TST, s), time to angina onset (TAO, s), time to limiting angina (TLA, s), heart rate (HR) at rest and at peak of exercise (bpm), rate pressure product (RPP) at rest and at peak of exercise (bpm x mmHg), and reason for stopping exercise. Adding ivabradine to atenolol 50 mg once daily increased TAO of 25.5 s, TST of 28.5 s and TLA of 16.3 s, relative to placebo. These results were statistically significant and consistent with the primary endpoint. No between group differences were observed in the number of angina attacks or short acting nitrates (SAN) over the 4 months of the study.
Mean change resting HR was -10.8 ± 10.8 bpm in ivabradine group versus -2.2 ± 10.1 bpm in placebo group (diff of -8.8 bpm; 95% CI: [-10.0; -7.6]). At the peak of exercise this was -11.3 ± 13.2 bpm versus -0.9 ± 12.3 bpm, respectively (difference of -10.8 bpm; 95% CI: [-12.4 ; -9.1]). The overall evolution in heart rate at rest in supine position observed in the ivabradine group was 67.0 ± 6.9 bpm at baseline to 58.4 ± 8.7 bpm at month 4. In the ivabradine group, 20.2% (89/441) of patients experienced a reduction in HR of more than 20 bpm. This was only experienced in patients with a high resting HR at baseline, i.e. patients with HR > 70 bpm at baseline.
Coronary artery disease (CAD) with left ventricular dysfunction (LVD). A large outcome study, BEAUTIFUL, studied the use of ivabradine compared with placebo in patients with CAD and left ventricular dysfunction (LVD) receiving treatment appropriate to their cardiovascular condition. A total of 10,917 patients with left ventricular ejection fractions (LVEF) between > 20% and < 40% were randomised with 87% receiving beta-blockers, most commonly carvedilol, metoprolol succinate/ tartrate, and bisoprolol. Angina was the main limiting factor for 14% of randomised patients. The main efficacy criterion was the composite of cardiovascular death, hospitalisation for acute MI or hospitalisation for new onset or worsening heart failure (HF). The study showed no difference in the primary composite endpoint (relative risk 1.00, p = 0.945).
The SIGNIFY study. A large outcome study, SIGNIFY, was performed in 19,102 patients with coronary artery disease and without clinical heart failure (LVEF > 40%), on top of optimal background therapy. A dose regimen higher than the approved dosage was used (starting dose 7.5 mg b.i.d. (5 mg b.i.d, if age ≥ 75 years) and titration up to 10 mg b.i.d). The main efficacy criterion was the composite of cardiovascular death or non-fatal MI. The study showed no difference in the rate of the primary composite endpoint (PCE) in the ivabradine group by comparison to the placebo group (relative risk ivabradine/ placebo 1.08, p = 0.197). Bradycardia was reported by 17.9% of patients in the ivabradine group (2.1% in the placebo group). Verapamil, diltiazem or strong CYP 3A4 inhibitors were received by 7.1% of patients during the study.
A small statistically significant increase in the PCE was observed in a pre-specified subgroup of patients with angina patients in CCS class II or higher at baseline (n = 12,049) (annual rates 3.4% versus 2.9%, relative risk ivabradine/ placebo 1.18, p = 0.018).
The higher than approved dose used in the study did not fully explain these findings.
Chronic heart failure. A large outcome study, SHIFT, was performed in 6,505 adult patients with moderate to severe symptoms of chronic heart failure (CHF), with a reduced left ventricular ejection fraction (LVEF ≤ 35%).
The SHIFT study was a multi-centre, international, randomised double blind placebo controlled trial. The trial population included patients with systolic chronic heart failure with NYHA class II to IV and in stable condition for ≥ 4 weeks. Patients had documented hospital admission for worsening heart failure within 12 months prior to selection, and were in sinus rhythm at selection with resting heart rate ≥ 70 bpm. Main exclusion criteria included recent (< 2 months) myocardial infarction, ventricular or atrioventricular pacing operative for 40% or more of the day, sustained atrial fibrillation or flutter, and symptomatic hypotension. The average age of the trial population was 60.4 (SD 11.4) years. Elderly patients, i.e. those aged > 65 years, comprised 38% (N = 2,474) of the overall population.
Ivabradine should be used with caution in patients with NYHA class IV due to limited number of patients studied (1.7%, N = 111 of the overall population) (see Section 4.4 Special Warnings and Precautions for Use).
In the trial, patients received optimised background therapy in accordance with guidelines for treatment of heart failure. Background treatment included beta-blockers (89%), ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and anti-aldosterone agents (60%). Approximately 10% of patients were not able to take beta-blockers due to contraindications. Those able to tolerate beta-blockers were required to be on a maximally tolerated daily beta-blocker dose at randomisation as part of the study protocol. Due to intolerances 56% of patients were administered at least half the target daily dose. 26% of patients on beta-blockers were at target doses at randomisation. The relative effects of ivabradine are therefore applicable to those treated with ivabradine in combination with optimal standard chronic heart failure treatment.
In the ivabradine group, 67% of patients were treated with 7.5 mg twice a day. The median follow-up duration was 22.9 months. After 4 weeks of treatment and from a mean baseline heart rate value of 80 bpm, patients randomised to ivabradine had a mean heart rate reduction of 15 bpm. A heart rate reduction versus placebo was maintained throughout the study.
The primary endpoint was a composite of cardiovascular mortality and hospitalisation for worsening heart failure.
The superiority of ivabradine as compared to placebo was tested on the time to first occurrence of the primary composite endpoint. A Cox proportional hazards model adjusted on beta-blocker intake at randomisation was used to estimate the treatment effect, 95% confidence interval (CI) and associated p-value.
In the randomised set (RS), the study demonstrated a statistically significant relative risk reduction of 18% p < 0.0001 in the rate of the primary composite endpoint for which the study was powered. The absolute risk reduction was 4.2% (see Table 5). The results on the primary endpoint were mainly driven by the heart failure endpoints, hospitalisation for worsening heart failure (absolute risk reduced by 4.7%) and deaths from heart failure (absolute risk reduced by 1.1%). The Kaplan-Meier curves of the time to first event of the primary composite endpoint are presented in Figure 1. The curves can be seen to diverge at 3 months from treatment initiation indicating an early treatment effect in favour of ivabradine (lower curve). Treatment with ivabradine for one year would prevent one cardiovascular death or hospital admission for worsening heart failure for every 26 patients treated.
There was a significant improvement in NYHA class at last recorded value, 887 (28%) of patients on ivabradine improved versus 776 (24%) of patients on placebo (p = 0.001).
Sub-group analysis of the primary composite endpoint in the RS population showed an effect in favour of ivabradine in all pre-specified sub-groups: age, gender, beta-blocker treatment or not, ischaemic or non-ischaemic heart failure aetiology, NYHA class, and background history of diabetes or hypertension, and baseline heart rate (see Figure 2).
Efficacy results in the sub-group of patients aged ≥ 65 years were consistent with those in the overall population, although the benefits tended to be less marked compared with patients aged < 65 years (see Figure 2). The relative risk reduction of the primary composite endpoint was 24% in those aged < 65 years compared to 11% in those aged ≥ 65 years. Interaction tests showed that the differences were not statistically significant, and there was no heterogeneity between these groups. Furthermore, the benefits in patients aged ≥ 75 years old were similar to those of the overall population.
The study demonstrated an effect in the primary composite endpoint in favour of ivabradine in both sub-groups of patients according to baseline heart rate < 77 bpm and ≥ 77 bpm. This effect was statistically significantly greater in patients with baseline heart rate ≥ 77 bpm (n = 3357, hazard ratio = 0.75, 95% CI [0.67, 0.85]) compared to those with baseline heart rate < 77 bpm (n = 3144, hazard ratio = 0.93, 95% CI [0.80, 1.08]) (see Figure 2).
This finding was not unexpected from the known pharmacology of ivabradine and particularly given that the effect of the drug in blocking sinoatrial node If channels is greatest when these channels are most likely to be open, i.e. when heart rate is highest. The SHIFT trial results demonstrate that baseline heart rate is a treatment effect modifier.

Treatment effect in patients with baseline heart rate ≥ 77 bpm.

The median baseline heart rate was a pre-specified sub-group analysis (77 bpm). The baseline characteristics in this patient population did not differ substantially from the randomised set (RS), nor were there any relevant differences between the treatment groups.
Approximately 13.5% of patients were not able to take beta-blockers due to contraindications. Of those able to tolerate beta-blockers, 54% were able to be administered at least half the target daily dose at randomisation, and 25% of patients on beta-blockers were at target doses at randomisation.
In ivabradine treated patients with a baseline heart rate ≥ 77 bpm, the primary composite endpoint was reduced by 25% (p < 0.0001); cardiovascular death by 19% (p = 0.0137) (absolute risk reduced by 3.0%); and hospitalisation for worsening heart failure by 31% (p < 0.0001) (absolute risk reduced by 6.6%) (see Table 6), compared to patients on placebo. In those patients, treatment with ivabradine led to a significant improvement of all outcomes, including CV and all cause mortality.
The Kaplan-Meier curves of the time to first event of the primary composite endpoint are presented in Figure 3. The curves can be seen to diverge as early as 1 month from treatment initiation. This early treatment effect in favour of ivabradine (lower curve) is consistent with the effect seen in the RS (see Figure 1).
In ivabradine treated patients with a baseline heart rate < 77 bpm, the primary composite endpoint was reduced by 7% [hazard ratio = 0.93, 95% CI [0.80; 1.08]] and did not reach statistical significance compared to patients on placebo. The components of the primary composite endpoint; cardiovascular death [hazard ratio = 1.07, 95% CI [0.87; 1.31]] and hospitalisation for worsening heart failure [hazard ratio = 0.83, 95% CI [0.69; 1.00]] did not differ statistically from placebo.

Systolic heart failure in Australian clinical practice.

The population in Australian clinical practice that is most relevant to the SHIFT study population comprises patients with unpreserved systolic function, with elevated heart rate in sinus rhythm.
The National Benchmarking and Evidence Based National Clinical Guidelines for Heart Failure Management Programs (BENCH) study was an Australian multi-centre prospective cohort study of systolic heart failure designed to examine the characteristics and components of heart failure management programs and their effect on patient outcomes. The baseline characteristics of the usual care arm of this study is compared to overall SHIFT population in Table 7. Both studies recruited patients with systolic heart failure with at least one prior hospitalisation for worsening heart failure. Table 7 shows that overall the two populations are similar therefore the SHIFT study is applicable to Australian patients with systolic heart failure.
Ophthalmic safety. A 97-patient randomised placebo-controlled study collected data documenting the function of the cone and rod systems and the ascending visual pathway (i.e. electroretinogram (ERG), static and kinetic visual fields, colour vision, visual acuity). Fifty patients were treated with ivabradine for chronic stable angina pectoris over three years. Although patients did not show any permanent retinal toxicity there were three patients who had bilateral relevant ERG abnormalities affecting the cone system. The changes in ERG were reversible in two patients after cessation of ivabradine therapy. The third patient did not attend the final assessment.

5.2 Pharmacokinetic Properties

Under physiological conditions, ivabradine is rapidly released from tablets and is highly soluble (> 10 mg/mL, pH 2-7.5). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo. The N-desmethylated derivative of ivabradine has been identified as the main active metabolite in humans.

Absorption.

Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in approximately 1 hour under fasting condition. The absolute bioavailability of ivabradine tablets is around 40%, due to a first-pass effect in the gut and liver. Food delayed absorption by approximately 1 hour and increased plasma exposure by 20 to 30%. To minimise intra-individual variability in exposure, ivabradine should be taken during meals (see Section 4.2 Dose and Method of Administration).

Distribution.

Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady state is close to 100 L in patients. The maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is about 20 nanogram/mL. The average plasma concentration is 10 nanogram/mL at steady state.

Metabolism.

Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P4503A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative, and its exposure (measured by AUC) is about 40% of that of the parent compound with similar pharmacokinetic and pharmacodynamic properties. The metabolism of this active metabolite also involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4 induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma concentrations. Conversely, potent inhibitors and inducers may substantially affect ivabradine plasma concentrations (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Excretion.

The main elimination half-life of ivabradine is 2 hours (70 to 75% of the AUC) in plasma, and an effective half-life is 11 hours. The total clearance is about 400 mL/min and the renal clearance is about 70 mL/min. Metabolites are equally excreted in the faeces and urine. About 4% of an oral dose is excreted unchanged in urine. The kinetics of ivabradine are linear over an oral dose range of 0.5 to 24 mg.

Special populations.

The impact of renal impairment (creatinine clearance from 15 to 60 mL/min) on ivabradine pharmacokinetics is minimal, in relation with the low contribution of renal clearance (about 20%) to total elimination for both ivabradine and its main active metabolite S18982 (see Section 4.4 Special Warnings and Precautions for Use).
In patients with mild hepatic impairment (Child-Pugh score up to 7) AUC of unbound ivabradine and the main active metabolite were about 20% higher than in subjects with normal hepatic function. Data are limited in patients with moderate hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use). No data are available in patients with severe hepatic impairment (see Section 4.3 Contraindications).
PK/PD relationship analysis has shown that heart rate decreases almost linearly with increasing ivabradine and the N-desmethylated derivative plasma concentrations for doses of up to 15 to 20 mg twice daily. At higher doses, the decrease in heart rate is no longer proportional to ivabradine plasma concentrations and tends to reach a plateau. High exposures to ivabradine that may occur when ivabradine is given in combination with potent CYP3A4 inhibitors may result in an excessive decrease in heart rate although this risk is reduced with moderate CYP3A4 inhibitors (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

5.3 Preclinical Safety Data

Genotoxicity.

The weight of evidence from a battery of in vivo and in vitro studies supports a conclusion that ivabradine is unlikely to pose a genotoxic risk in patients.
Ivabradine did not induce gene mutation in bacteria (Ames test), chromosome aberration in mice or rats in vivo, or DNA damage in rat hepatocytes in vivo.
Weakly positive or equivocal results were observed at high concentrations (of more than 10,000 times the maximum observed concentrations seen in patients at therapeutic doses) in several in vitro tests, which examined the potential for gene mutation in mouse lymphoma cells, chromosome aberration in human lymphocytes and DNA damage in rat hepatocytes.

Carcinogenicity.

Long term studies in mice at oral doses up to 450 mg/kg/day (reduced to 180 mg/kg/day after 80 weeks of treatment) and in rats at 120 mg/kg/day (reduced to 60 mg/kg/day after one year of treatment) showed no increase in tumour incidences. These doses resulted in ivabradine exposures 10 to 100 times human exposure at 7.5 mg twice daily based on AUC.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Lactose, magnesium stearate, starch maize, maltodextrin, colloidal anhydrous silica.

Film coating.

Hypromellose, titanium dioxide (E171), macrogol 6000, glycerol, magnesium stearate, yellow iron oxide (E172), red iron oxide (E172).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store in a dry place below 30°C.

6.5 Nature and Contents of Container

Supplied calendar packs of aluminium/PVC blister strips packed in cardboard boxes containing 14 or 56 film-coated tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

155974-00-8 (base).

7 Medicine Schedule (Poisons Standard)

S4: Prescription-only Medicine.

Summary Table of Changes