Procoralan - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Ivabradine

Procoralan 5 mg film-coated tablets
Procoralan 7.5 mg film-coated tablets

Why is Procoralan used? What is it for?

Procoralan (ivabradine) is a heart medicine used to treat:

  • of symptomatic stable angina pectoris (a disease causing chest pain) in adult patients whose heart rate is greater than or equal to 70 beats per minute. It is used in adult patients who cannot tolerate or cannot take heart medicines called beta - Blockers. It is also used in combination with beta-blockers in adult patients whose condition is not fully controlled with a beta-blocker
  • of chronic heart failure in adult patients whose heart rate is greater than or equal to 75 beats per minute. It is used in combination with conventional therapy, which includes treatment with a beta-blocker or when beta-blockers are contraindicated or not tolerated.

About "stable angina pectoris" (commonly called "angina"):

Stable angina is a heart disease that occurs when the heart does not get enough oxygen. It usually appears between the ages of 40 and 50. The most common symptom of angina is chest pain or discomfort. Angina is more likely to occur when the heart beats rapidly in situations such as "physical activity," emotion, exposure to cold or after eating. This increased heart rate can cause chest pain in people suffering from angina.

Information on chronic heart failure:

Chronic heart failure is a heart disease that occurs when the heart cannot pump enough blood to the rest of the body. The most common symptoms of heart failure are shortness of breath, fatigue, tiredness and swelling of the body. ankles.

How does Procoralan work?

Procoralan works primarily by reducing the heart rate by a few beats per minute. This reduces the heart's need for oxygen, particularly during those situations in which an angina attack is more likely. In this way Procoralan helps to control and decrease the number of angina attacks.

In addition, since an elevated heart rate adversely affects heart functioning and the life expectancy of patients with chronic heart failure, the specific heart rate lowering action of ivabradine helps improve heart functioning and life expectancy. in these patients.

Contraindications When Procoralan should not be used

Do not take Procoralan

  • if you are allergic to ivabradine or any of the other ingredients of this medicine
  • if your resting heart rate before treatment is too low (less than 70 beats per minute);
  • if you suffer from cardiogenic shock (a heart condition treated in hospital);
  • if you suffer from a heart rhythm disorder;
  • if you have a heart attack;
  • if you have very low blood pressure;
  • if you suffer from unstable angina (a severe form in which chest pain occurs very frequently and with or without effort);
  • if you have heart failure which has recently worsened;
  • if the heartbeat is imposed exclusively by the pacemaker;
  • if you have severe liver problems;
  • if you are already taking medicines to treat fungal infections (such as ketoconazole, itraconazole), macrolide antibiotics (such as iosamycin, clarithromycin, telithromycin or erythromycin given by mouth) or medicines to treat HIV infections (such as nelfinavir, ritonavir) or nefazodone (medicine to treat depression) or diltiazem, verapamil (used for high blood pressure or angina pectoris);
  • if you are a woman who is able to have children and does not use "appropriate contraception;"
  • if you are pregnant or trying to have a child;
  • if you are breastfeeding.

Precautions for use What you need to know before taking Procoralan

Talk to your doctor or pharmacist before taking Procoralan.

  • if you suffer from heart rhythm disturbances (such as irregular heartbeat, palpitations, increased chest pain) or severe atrial fibrillation (a form of arrhythmia that makes the heart beat irregular), or an abnormal "electrocardiogram (ECG) called" syndrome of the long QT ",
  • if you get tired easily, feel dizzy or short of breath (this could mean your heart is beating too slowly),
  • if you suffer from symptoms of atrial fibrillation (unusually high (over 110 beats per minute) or irregular heart rate at rest for no apparent reason making it difficult to measure),
  • if you have had a recent stroke (brain attack),
  • if you have mild to moderate low blood pressure,
  • if you suffer from uncontrolled blood pressure, particularly following a change in antihypertensive treatment,
  • if you have severe heart failure or heart failure with an abnormality in the electrocardiogram (ECG) called "bundle branch block",
  • if you suffer from chronic retinal disease,
  • if you have moderate liver problems, - if you have severe kidney problems.

If any of the above apply to you, talk to your doctor straight away before or while taking Procoralan.

Children

Procoralan should not be used in children and adolescents under the age of 18.

Interactions Which drugs or foods can modify the effect of Procoralan

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Be sure to tell your doctor if you are taking any of the following medicines, as your procoralan dose may need to be monitored or adjusted:

  • fluconazole (an antifungal medicine)
  • rifampicin (an antibiotic)
  • barbiturates (for insomnia or epilepsy)
  • phenytoin (for epilepsy)
  • Hypericum perforatum or St. John's wort (herbal product used for depression)
  • medicines that prolong the QT interval to treat rhythm disturbances or other conditions such as:
  • quinidine, disopyramide, ibutilide, sotalol, amiodarone (to treat heart rhythm disturbances)
  • bepridil (to treat angina pectoris)
  • certain types of medicines to treat anxiety, schizophrenia or other psychoses (such as pimozide, ziprasidone, sertindole)
  • medicines for malaria (such as mefloquine or halofantrine)
  • intravenous erythromycin (an antibiotic)
  • pentamidine (a pesticide)
  • cisapride (used for gastroesophageal reflux)
  • Some types of diuretics that can cause low blood potassium levels, such as furosemide, hydrochlorothiazide, indapamide (used to treat edema, for high blood pressure)

Procoralan with food and drink

Avoid grapefruit juice while taking Procoralan.

Warnings It is important to know that:

Pregnancy and breastfeeding

Do not take Procoralan if you are pregnant or planning to become pregnant (see "Do not take Procoralan"). If you are pregnant and have taken Procoralan, talk to your doctor.

Do not take Procoralan if you are able to have children, unless you are using appropriate contraceptive measures (see "Do not take Procoralan").

Do not take Procoralan if you are breastfeeding (see "Do not take Procoralan"). Talk to your doctor if you are breastfeeding or intend to breastfeed as breastfeeding should be discontinued if you take Procoralan.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

Procoralan can cause temporary luminous visual phenomena (a temporary brightness in the visual field, see "Possible side effects"). If this happens to you, be very careful when driving or operating machinery, particularly when there may be sudden changes in light intensity, especially when driving at night.

Procoralan contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Procoralan: Posology

Always take this medicine exactly as your doctor or pharmacist has told you.

If in doubt, consult your doctor or pharmacist. Procoralan should be taken with meals.

If you are being treated for stable angina pectoris

The starting dose should not exceed one Procoralan 5 mg tablet twice a day. If you still have symptoms of angina and tolerate the daily dose of 5 mg twice a day well, the dose can be increased. The maintenance dose should not exceed 7.5 mg twice a day. Your doctor will prescribe the dose. The usual dose is one tablet in the morning and one tablet in the evening. In some cases (e.g. if you are elderly), your doctor may prescribe half the dose, e.g. half a 5 mg tablet of Procoralan 5 mg ( which corresponds to 2.5 mg ivabradine) in the morning and half a 5 mg tablet in the evening.

If you are being treated for chronic heart failure

The usual recommended starting dose is one Procoralan 5 mg tablet twice daily, to be increased if needed to one Procoralan 7.5 mg tablet twice daily. Your doctor will decide on the most suitable dose. 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 you to halve the dose, i.e. half a 5 mg tablet of Procoralan 5 mg (which corresponds to 2.5 mg ivabradine) in the morning and half a 5 mg tablet. the evening.

Overdose What to do if you have taken too much Procoralan

If you take more Procoralan than you should

A high dose of Procoralan could make you feel breathless or tired because your heart rate has been slowed down too much. If this happens, contact your doctor immediately.

If you forget to take Procoralan

If you forget to take a dose of Procoralan, take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose. The calendar printed on the blister containing the tablets will help you remember when you took your last tablet. by Procoralan.

If you stop taking Procoralan

Since the treatment of angina or chronic heart failure is usually for life, you should talk to your doctor before you stop taking this medicine. If you have the impression that the effect of Procoralan is too strong or too weak. , ask your doctor or pharmacist. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Procoralan

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The frequency of possible adverse reactions listed below is described using the following convention:

very common: may affect more than 1 in 10 patients

common: may affect up to 1 in 10 people

uncommon: may affect up to 1 in 100 patients

rare: may affect up to 1 in 1,000 patients

very rare: may affect up to 1 in 10,000 patients

not known: frequency cannot be estimated from the available data.

The most common adverse reactions occurring with this medicine are dose dependent and are related to its mechanism of action:

Very common:

Bright visual phenomena (brief moments of increased brightness, most often caused by sudden changes in light intensity). They can also be described as a halo, colored flashes, image breakdown or multiple images. These phenomena generally develop in the first two months of treatment after which they can occur repeatedly and resolve during or after treatment. Common: Change in heart function (symptoms are a slowing of heart rate). These phenomena occur particularly within the first 2-3 months from the start of treatment. Other side effects have also been reported:

Common:

Rapid and irregular contraction of the heart, abnormal perception of the heartbeat, uncontrolled blood pressure, headache, dizziness and blurred vision (blurred vision).

Uncommon:

Palpitations and irregular heartbeat, feeling sick (nausea), constipation, diarrhea, abdominal pain, dizziness (dizziness), difficulty breathing (dyspnoea), muscle cramps, changes in laboratory parameters: high blood levels of uric acid, excess eosinophils (a type of white blood cell) and elevated creatinine (breakdown product of muscle) in the blood, rash, angioedema (such as swelling of the face, tongue or throat, difficulty in breathing or swallowing), low blood pressure, fainting, feeling tired, feeling weak, abnormal heart trace on ECG, double vision, impaired vision.

Rare:

Hives, itching, redness of the skin, malaise.

Very rare:

Irregular heartbeat.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V *. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after "EXP". The expiry date refers to the last day of the month.

This medicine does not require any special storage conditions.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Procoralan contains

- The active substance is ivabradine (as hydrochloride). Procoralan 5 mg: One film-coated tablet contains 5 mg of ivabradine (equivalent to 5.390 mg of ivabradine hydrochloride). Procoralan 7.5 mg: One film-coated tablet contains 7.5 mg of ivabradine (equivalent to 8.085 mg of ivabradine hydrochloride).

- The other ingredients in the tablet core are: lactose monohydrate, magnesium stearate (E470B), maize starch, maltodextrin, colloidal anhydrous silica (E551), and in the tablet coating: hypromellose (E464), titanium dioxide (E171), macrogol 6000, glycerol (E422), magnesium stearate (E470B), yellow iron oxide (E172), red iron oxide (E172).

What Procoralan looks like and contents of the pack

Procoralan 5 mg tablets are salmon-colored, oblong, film-coated, scored on both sides, debossed with "5" on one side and on the other.

Procoralan 7.5 mg tablets are salmon-colored, triangular, film-coated tablets debossed with "7.5" on one side and the other.

The tablets are available in calendar packs (aluminum / PVC blisters) containing 14, 28, 56, 84, 98, 100 or 112 tablets. Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Procoralan can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

PROCORALAN 5 MG TABLETS COATED WITH FILM

▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information.Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

One film-coated tablet contains 5 mg of ivabradine (equivalent to 5.390 mg of ivabradine as hydrochloride).

Excipient with known effect: 63.91 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

Salmon-colored, oblong, film-coated tablet, scored on both sides, debossed with "5" on one side.

The tablet can be divided into equal halves.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Symptomatic treatment of chronic stable angina pectoris.

Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in adults with coronary artery disease and normal sinus rhythm and heart rate ≥ 70 bpm. Ivabradine is indicated:

- in adults who are unable to tolerate or who have a contraindication to the use of beta-blockers

- or in combination with beta-blockers in patients inadequately controlled with an optimal dose of beta-blocker

Treatment of chronic heart failure

Ivabradine is indicated in chronic heart failure NYHA class II to IV with systolic dysfunction, in patients with sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with conventional therapy including treatment with a beta-blocker or if therapy with a beta-blocker is contraindicated or not tolerated (see section 5.1).

04.2 Posology and method of administration

Dosage

For the different strengths, film-coated tablets containing 5 mg and 7.5 mg of ivabradine are available.

Symptomatic treatment of chronic stable angina pectoris

It is recommended that the decision to initiate or titrate treatment is made after repeated heart rate measurements, an ECG or 24-hour ambulatory monitoring.

The starting dose of ivabradine should not exceed 5 mg twice daily in patients less than 75 years of age. After 3-4 weeks of treatment, if the patient is still symptomatic, if the starting dose is well tolerated and if the resting heart rate remains above 60 bpm, the dose can 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 a day.

If there is no improvement in angina symptoms within 3 months of starting therapy, ivabradine treatment should be discontinued.

In addition, if there is only a limited symptomatic response and when there is no clinically relevant reduction in resting heart rate within three months, treatment discontinuation should be considered.

If, during treatment, the resting heart rate decreases below 50 beats per minute (bpm) or if the patient reports symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dosage should be titrated, also considering the lowest dose of 2.5 mg twice a day (half a 5 mg tablet twice a day). After dose reduction, heart rate should be monitored (see section 4.4). Treatment should be discontinued if heart rate remains below 50 bpm or if symptoms of bradycardia persist despite dose reduction.

Treatment of chronic heart failure

Treatment should only be initiated in patients with stable heart failure. It is recommended that the treating physician has experience in the treatment of chronic heart failure.

The usual recommended starting dose of ivabradine is 5 mg twice daily. After two weeks of treatment, the dose can be increased to 7.5 mg twice daily if the resting heart rate is continuously above 60 bpm, or decreased to 2.5 mg twice daily (half a tablet). 5 mg twice daily) if the resting heart rate continuously remains below 50 bpm or if you have symptoms related to bradycardia such as dizziness, fatigue or hypotension. If the heart rate is between 50 and 60 bpm, the dose of 5 mg twice daily should be maintained.

If resting heart rate persistently decreases below 50 beats per minute (bpm) during treatment or if the patient reports symptoms related to bradycardia, the dosage should be reduced to the next lower dose in patients receiving 7 , 5 mg twice daily or 5 mg twice daily. If heart rate continuously increases above 60 beats per minute at rest, the dose may be titrated to the next higher dose in patients taking 2.5 mg twice daily or 5 mg twice daily.

Treatment should be discontinued if heart rate remains below 50 bpm or if symptoms of bradycardia persist (see section 4.4).

Special populations

Elderly patients

In patients 75 years of age or older, a lower starting dose (2.5 mg twice daily, i.e. half a 5 mg tablet twice daily) should be considered before a dose increase if necessary.

Patients with renal insufficiency

No dose adjustment is required in patients with renal insufficiency and creatinine clearance greater than 15 ml / min (see section 5.2).

No data are available in patients with creatinine clearance below 15 ml / min. Ivabradine should therefore be used with caution in this patient group.

Patients with hepatic insufficiency

No dose adjustment is necessary in patients with mild hepatic impairment. Caution should be exercised when prescribing ivabradine to patients with moderate hepatic impairment. Ivabradine is contraindicated in patients with severe hepatic impairment as it has not been studied in this patient group and a large increase in systemic concentration is expected (see sections 4.3 and 4.5).

Pediatric population

The safety and efficacy of ivabradine in the treatment of chronic heart failure in children below 18 years of age have not been established.

Available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

The tablets should be taken orally twice a day, i.e. once in the morning and once in the evening, during meals (see section 5.2).

04.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Resting heart rate below 70 beats per minute, before treatment

- Cardiogenic shock

- Acute myocardial infarction

- Severe hypotension (

- Severe hepatic insufficiency

- Sinus node syndrome

- Sino-atrial block

- Acute or unstable heart failure

- People with pacemakers (heart rate set exclusively by the pacemaker)

- Unstable angina

- Third degree AV block

- In combination with potent cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, iosamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see sections 4.5 and 5.2)

- In combination with verapamil or diltiazem which are moderate inhibitors of CYP3A4 with heart rate reducing properties (see section 4.5)

- Pregnancy, lactation and women of childbearing potential not using appropriate contraceptive measures (see section 4.6)

04.4 Special warnings and appropriate precautions for use

Special warnings

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

Ivabradine is indicated only for the symptomatic treatment of chronic stable angina pectoris as ivabradine has shown no benefit on cardiovascular outcomes (eg myocardial infarction or cardiovascular death) (see section 5.1).

Heart rate measurement

Since heart rate may fluctuate considerably over time, when determining heart rate prior to initiating ivabradine treatment and when considering dose titration in patients receiving ivabradine, repeated heart rate measurements should be considered. an ECG or 24-hour outpatient monitoring. The above also applies to patients with a low heart rate, particularly when the heart rate decreases below 50 bpm, or after a dose reduction (see section 4.2).

Cardiac arrhythmias

Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and is likely to lose its effectiveness when a tachyarrhythmia (i.e. ventricular or supraventricular tachycardia) occurs. Ivabradine is therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere with the function of the sinoatrial node.

In patients treated with ivabradine, the risk of developing atrial fibrillation is increased (see section 4.8). Atrial fibrillation has been reported most commonly in patients taking concomitant amiodarone or potent class I antiarrhythmics. It is recommended that patients treated with ivabradine be checked regularly for atrial fibrillation (prolonged or paroxysmal). they should also include ECG monitoring, if clinically indicated (eg in the case of aggravated angina, palpitations, irregular pulse).

Patients should be informed of the signs and symptoms of atrial fibrillation and should be advised to contact their physician should these signs and symptoms occur.

If atrial fibrillation develops during treatment, the balance of benefits and risks of continuing ivabradine treatment should be carefully reconsidered.

Chronic heart failure patients with intraventricular conduction defects (left bundle bundle block, right bundle bundle block) and ventricular dyssynchrony should be monitored closely.

Use in patients with second degree AV block

Ivabradine is not recommended in patients with second degree AV block.

Use in patients with reduced heart rate

Ivabradine should not be administered to patients with a pre-treatment resting heart rate below 70 beats per minute (see section 4.3).

If, during treatment, the resting heart rate persistently decreases below 50 bpm or if the patient reports symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose should be reduced, or the treatment should be stopped. if the heart rate remains below 50 bpm or if symptoms due to bradycardia persist (see section 4.2).

Combination with calcium channel blockers

The combined use of ivabradine with calcium channel blockers that reduce heart rate such as verapamil or diltiazem is contraindicated (see sections 4.3 and 4.5). There was no safety concern from the combination of ivabradine with nitrates and dihydropyridine-type calcium channel blockers such as amlodipine. "Additional efficacy" of ivabradine in combination with calcium channel blockers of the dihydropyridine type has not been demonstrated (see section 5.1).

Chronic heart failure

Heart failure must be stable before considering ivabradine treatment. Ivabradine should be used with caution in patients with NYHA functional class IV heart failure, as limited data are available in this population.

Stroke

The use of ivabradine is not recommended immediately following a stroke as no data is available.

Visual function

Ivabradine affects retinal function (see section 5.1). To date, there is no evidence of a toxic effect of ivabradine on the retina, however the effects on retinal function of longer term treatment are currently unknown. to one year. Discontinuation of treatment should be considered in the event of unexpected worsening of visual function. Caution should be exercised in patients with retinitis pigmentosa.

Precautions for use

Patients with hypotension

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

Atrial fibrillation - Cardiac arrhythmias

There is no evidence of a risk of (excessive) bradycardia upon return to sinus rhythm when pharmacological cardioversion is undertaken in patients receiving ivabradine. However, in the absence of comprehensive data, non-urgent electrical cardioversion (DC) should be considered 24 hours after the last ivabradine intake.

Use in patients with congenital long QT syndrome or treated with QT prolonging medicinal products

The use of ivabradine in patients with congenital long QT syndrome or treated with QT prolonging medicinal products should be avoided (see section 4.5). If the combination proves necessary, careful cardiac monitoring should be undertaken.

Reduced heart rate, such as that caused by ivabradine, can exacerbate QT interval prolongation, which can result in severe arrhythmias, and in particular Twists toe.

Hypertensive patients requiring changes in antihypertensive treatment

In the SHIFT study, more patients reported episodes of increased blood pressure while on ivabradine (7.1%) than patients on placebo (6.1%). These episodes occurred more frequently shortly after the antihypertensive treatment was changed, were transient, and did not affect the effect of ivabradine treatment.

When treatment modifications are made in chronic heart failure patients receiving ivabradine, blood pressure should be monitored after an appropriate time interval (see section 4.8).

Excipients

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

04.5 Interactions with other medicinal products and other forms of interaction

Pharmacodynamic interactions

Combinations not recommended

Medicines that prolong QT

- Cardiovascular drugs that prolong QT (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone)

- Non-cardiovascular drugs that prolong QT (e.g., pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin)

Concomitant use of cardiovascular and non-cardiovascular QT-prolonging medicinal products with ivabradine should be avoided as QT-interval prolongation may be exacerbated by reduced heart rate. If the combination proves necessary, careful attention should be given. cardiac monitoring (see section 4.4).

Concomitant use with precautions

Diuretics that cause potassium loss (thiazide diuretics and loop diuretics): Hypokalaemia may increase the risk of arrhythmias. Since ivabradine can cause bradycardia, the result of the combination of hypokalaemia and bradycardia is a predisposing factor for serious arrhythmias, especially in patients with both congenital and drug-induced long QT syndrome.

Pharmacokinetic interactions

Cytochrome P450 3A4 (CYP3A4)

Ivabradine is metabolised only by CYP3A4 and is a very weak inhibitor of this cytochrome. Ivabradine has been shown not to affect the metabolism and plasma concentrations of other CYP3A4 substrates (weak, moderate and potent inhibitors). CYP3A4 inhibitors and inducers may interact with ivabradine and affect its metabolism and pharmacokinetics to a clinically significant level. Drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while drug inducers decrease. An increase in the plasma concentration of ivabradine may be associated with a risk of excessive bradycardia (see section 4.4).

Contraindications to use in combination

The concomitant use of potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, iosamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated (see section 4.3). The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and iosamycin (1 g once daily) increase the mean plasma ivabradine concentration by 7-8 fold.

Moderate CYP3A4 inhibitors: Specific interaction studies in healthy volunteers and patients have shown that the combination of ivabradine with heart rate lowering medicinal products such as diltiazem or verapamil leads to an increase in ivabradine concentration (increase in area under the curve). (AUC) of 2-3 times) and an additional decrease in heart rate of 5 bpm. The concomitant use of ivabradine with these medicinal products is contraindicated (see section 4.3).

Combination use not recommended

Grapefruit juice: ivabradine concentration is doubled following co-administration with grapefruit juice. Therefore the intake of grapefruit juice should be avoided.

Precaution for use in combination

- Moderate CYP3A4 inhibitors: The use of ivabradine in combination with other moderate CYP3A4 inhibitors (eg fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if the resting heart rate is higher at 70 bpm, checking the heart rate.

- CYP3A4 inducers: CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum perforatum [St. John's wort]) may decrease ivabradine concentration and activity. Concomitant use of CYP3A4 inducer medicinal products may require dose adjustment of ivabradine. Combined use of ivabradine 10 mg twice daily with St. John's wort has been shown to result in a 50% reduction in ivabradine AUC. Intake of St. John's wort should be limited during treatment. with ivabradine.

Other uses in association

Specific drug interaction studies have shown no clinically significant effects on the pharmacokinetics and pharmacodynamics of ivabradine for the following medicinal products: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlopidine , lacipidine), digoxin and warfarin Furthermore, there were no clinically significant effects of ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of aspirin.

During clinical trials pivotal Phase III the following medicinal products have been routinely combined with ivabradine without any evidence of safety: angiotensin converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, anti-aldosterone agents, nitrates short- and long-lasting, HMG CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetic agents, aspirin and other antiplatelet drugs.

Pediatric population

Interaction studies have only been performed in adults.

04.6 Pregnancy and lactation

Women of childbearing age

Women of childbearing potential must use appropriate contraceptive measures during treatment (see section 4.3).

Pregnancy

Data on the use of ivabradine in pregnant women do not exist or are limited in number. Animal studies have shown reproductive toxicity. These studies have shown embryotoxic and teratogenic effects (see section 5.3). The potential risk to humans. humans is unknown, therefore ivabradine is contraindicated during pregnancy (see section 4.3).

Feeding time

Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated during lactation (see section 4.3).

Women requiring ivabradine treatment should stop breastfeeding and choose an alternative method of feeding for the baby.

Fertility

Studies in rats showed no effect on male and female fertility (see section 5.3).

04.7 Effects on ability to drive and use machines

A specific study was conducted on healthy volunteers to evaluate the possible influence of ivabradine on driving performance and no change in driving performance was found. However, in post-marketing experience, cases of impaired driving ability have been reported. due to visual symptoms. Ivabradine can cause transient light phenomena consisting mainly of phosphenes (see section 4.8). The possible occurrence of these light phenomena must be taken into consideration when driving or operating machinery in situations where sudden changes in light intensity may occur, especially when driving at night.

Ivabradine does not affect the ability to use machines.

04.8 Undesirable effects

Summary of the safety profile

Ivabradine has been studied in clinical trials involving nearly 45,000 patients. The most common adverse reactions observed with ivabradine, luminous phenomena (phosphenes) and bradycardia, are dose-dependent and are correlated with the pharmacological effect of the medicinal product.

Table of adverse reactions

The following adverse reactions were observed during clinical studies and are listed using the following frequency: very common (≥1 / 10); common (≥1 / 100,

Organic system classification Frequency Term of reference Disorders of the blood and lymphatic system Uncommon Eosinophilia Metabolism and nutrition disorders Uncommon Hyperuricemia Nervous system disorders common Headache, usually during the first month of treatment Dizziness, possibly related to bradycardia Uncommon* Syncope, possibly related to bradycardia Eye disorders Very common Luminous phenomena (phosphenes) common Blurred vision Uncommon* Diplopia Weakening of visual function Ear and labyrinth disorders Uncommon Dizziness Cardiac pathologies common Bradycardia 1st degree AV block (prolongation of PQ interval to ECG) Ventricular extrasystoles Atrial fibrillation Uncommon Palpitations, supraventricular extrasystoles Very rare 2nd degree AV block, 3rd degree AV block Sinus node syndrome Vascular pathologies common Uncontrolled blood pressure Uncommon* Hypotension, possibly related to bradycardia Respiratory, thoracic and mediastinal disorders Uncommon Dyspnea Gastrointestinal disorders Uncommon Nausea Constipation Diarrhea Abdominal pain* Skin and subcutaneous tissue disorders Uncommon* Angioedema Rash Rare* Erythema Itching Urticaria Musculoskeletal and connective tissue disorders Uncommon Muscle cramps General disorders and administration site conditions Uncommon* Asthenia, possibly related to bradycardia Fatigue, possibly related to bradycardia Rare* Malaise, possibly related to bradycardia Diagnostic tests Uncommon Elevated creatinine. Prolongation of the QT interval on the ECG

* Frequency calculated from clinical trials for adverse events reported from spontaneous reports

Description of selected adverse reactions

Light phenomena (phosphenes) were reported by 14.5% of patients, described as a "transient increased brightness in a" limited area of ​​the visual field. They are usually triggered by sudden changes in light intensity. Phosphenes can also be described as a halo, image decomposition (stroboscopic or kaleidoscopic effects), intense colored lights or multiple images (retinal persistence). The appearance of phosphenes usually occurs within the first two months of therapy, after which they can occur repeatedly.

Phosphenes are generally reported as being of mild or moderate intensity. All phosphenes resolved during or after treatment and the majority (77.5%) resolved during treatment. Less than 1% of patients changed their daily habits or had to stop treatment due to phosphenes.

Bradycardia was reported by 3.3% of patients, mostly during the first 2-3 months after initiation of treatment. 0.5% of patients had severe bradycardia with heart rate less than or equal to 40 bpm.

In the SIGNIFY study, atrial fibrillation was observed in 5.3% of patients taking ivabradine compared to 3.8% of patients in the placebo group. In a pooled analysis of all double-blind controlled Phase II / III clinical trials of at least three months duration, which included more than 40,000 patients, the incidence of atrial fibrillation was 4.86% in ivabradine-treated patients, compared to 4.08% of the control group, which corresponds to a hazard ratio of 1.26, 95% CI [1.15 - 1.39].

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the website: www.agenziafarmaco .gov.it / it / managers of the Italian Medicines Agency.

04.9 Overdose

Symptoms

Overdose can lead to severe and prolonged bradycardia (see section 4.8).

Management

Severe bradycardia should be treated symptomatically in a specialist setting. In the case of bradycardia with poor haemodynamic tolerance, symptomatic treatment including intravenous use of beta-agonist drugs such as isoprenaline may be considered. If necessary, temporary cardiac electro-stimulation can be instituted.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: cardiac therapy.

ATC code: C01EB17.

Mechanism of action

Ivabradine is a drug that selectively reduces heart rate by acting through selective and specific inhibition of the cardiac pacemaker current THE f, which controls spontaneous diastolic depolarization in the sinus node and regulates heart rate. Cardiac effects are specific for the sinus node with no effect on intra-atrial, atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular repolarization.

Ivabradine can also interact with current THE h present in the retina and which has characteristics very close to that of the cardiac current THE f. This current intervenes in the temporal resolution process of the visual system, reducing the retinal response to intense light stimuli. In some triggering circumstances (e.g. rapid changes in brightness), a partial inhibition of THE h on the part of ivabradine underlies the light phenomena that may occasionally be reported by patients. Light phenomena (phosphenes) are described as a "transient increased brightness in a" limited area of ​​the visual field (see section 4.8).

Pharmacodynamic effects

The main pharmacodynamic property of ivabradine in humans is a specific dose-dependent reduction in heart rate. Analysis of reduced heart rate with doses up to 20 mg twice daily indicates that there is a tendency to reach a plateau, which is consistent with the reduced risk of having severe bradycardias with a rate below 40 bpm (see section 4.8).

At normally recommended doses, the reduction in heart rate is approximately 10 bpm at rest and during exercise. This leads to a reduction in cardiac workload and oxygen consumption by the myocardium. Ivabradine does not affect intracardiac conduction, contractility (absence of negative inotropic effect) or ventricular repolarization:

- in electrophysiological clinical studies, ivabradine had no effect on atrioventricular or intraventricular conduction times or corrected QT interval;

- in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) between 30 and 45%), ivabradine had no adverse effect on the ejection fraction.

Clinical efficacy and safety

The antianginal and anti-ischemic efficacy of ivabradine was evaluated in five randomized, double-blind clinical trials (three versus placebo, and the others versus atenolol and amlodipine, respectively). These studies included a total of 4,111 patients with angina pectoris. chronic stable, of which 2,617 treated with ivabradine.

Ivabradine 5 mg twice daily was found to be effective on exercise test parameters within 3-4 weeks of treatment. Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over the dose of 5 mg twice daily was established in a controlled study comparing to atenolol: the total duration of exercise assessed at the minimum efficacy value was increased by approximately 1 minute after one month of treatment with 5 mg twice daily and further improved by nearly 25 seconds after a subsequent 3 month period of forced titration to 7.5 mg twice daily. In this study, the antianginal and anti-ischemic benefits of ivabradine are have been confirmed in patients ≥ 65 years of age. The efficacy of 5 and 7.5 mg twice daily on the ergometric test parameters was found to be consistent in all studies (total duration of exercise, time to discontinuation of anginal pain stress test, time to onset of anginal pain and time to onset of the 1 mm ST-segment displacement) and was associated with an approximately 70% decrease in the frequency of anginal attacks. The twice daily regimen gave "uniform efficacy in" span of 24 hours.

In a randomized placebo-controlled study in 889 patients, ivabradine given on top of atenolol 50 mg once daily demonstrated additive efficacy on all exercise test parameters (ETT) at the trough of drug activity ( 12 hours after oral intake).

In a randomized placebo-controlled study in 725 patients, ivabradine did not show additive efficacy in addition to amlodipine 10 mg once daily at the trough of drug activity (12 hours after oral intake). while an additive efficacy was demonstrated at peak (3-4 hours after oral intake).

In a randomized, placebo-controlled study in 1,277 patients, ivabradine demonstrated statistically significant additive efficacy on treatment response (defined as reduction of at least 3 angina attacks per week and / or lengthening of at least 60 seconds in time to subslevel). of 1 mm of the ST segment during the stress test al treadmill) in addition to amlodipine 5 mg once daily or nifedipine GITS 30 mg once daily, at the minimum of drug activity (12 hours after oral ivabradine intake) for a treatment period of 6 weeks (OR = 1, 3, 95% CI [1.0-1.7]; p = 0.012). Ivabradine did not show additive efficacy on other exercise test parameters (secondary endpoints) at drug minimum activity, while it was shown additive efficacy at peak activity (3-4 hours after oral ivabradine intake).

The efficacy of ivabradine was fully maintained during the treatment periods of 3 or 4 months in the clinical efficacy studies. There was no evidence of drug tolerance development (loss of efficacy) during treatment, nor of any phenomena rebound after abrupt discontinuation of treatment. The antianginal and anti-ischemic effects of ivabradine were associated with dose-dependent reduction in heart rate and with a significant reduction in the rate-pressure product (heart rate x systolic blood pressure) at rest and during exercise. Effects on blood pressure and peripheral vascular resistance were minor and clinically insignificant.

A sustained reduction in heart rate was demonstrated in patients treated with ivabradine for at least one year (n = 713). No influence on lipid or carbohydrate metabolism was observed.

The antianginal and anti-ischemic efficacy of ivabradine is also maintained in diabetic patients (n = 457) with a safety profile similar to that observed in the general population.

A large outcome study, BEAUTIFUL, was conducted in 10,917 patients with coronary artery disease and left ventricular dysfunction (LVEF acute myocardial infarction or hospitalization for new onset or worsening heart failure. The study showed no difference in the composite primary outcome rate. in the ivabradine group versus the placebo group (ivabradine relative risk: placebo 1.00, p = 0.945).

In the post-hoc analysis of a subgroup of patients with symptomatic angina at randomization (n = 1507), there were no safety reports of cardiovascular death, hospitalization for acute myocardial infarction or heart failure (ivabradine 12, 0% versus placebo 15.5%, p = 0.05).

A large clinical outcome study, SIGNIFY, was conducted in 19,102 patients with coronary artery disease and without clinically evident heart failure (LVEF> 40%), in addition to optimal background therapy. A higher regimen than the approved posology was used (starting dose 7.5 mg twice daily (5 mg twice daily, if age ≥ 75 years) and titrated up to 10 mg twice daily. ). The main efficacy criterion was the composite of cardiovascular death or non-fatal myocardial infarction. The study showed no difference in the frequency of the composite primary endpoint (PCE) in the ivabradine group versus the placebo group (relative risk ivabradine / placebo 1.08, p = 0.197). Bradycardia was reported in 17.9% of patients in the ivabradine group (2.1% in the placebo group). 7.1% of patients received verapamil, diltiazem or potent CYP3A4 inhibitors during the study.

A statistically significant small increase in PCE was observed in a prespecified subgroup of patients with angina at baseline, CCS class II or higher (n = 12,049) (annual rates 3.4% vs 2.9%, relative risk ivabradine / placebo 1.18, p = 0.018), but not in the subgroup of the total anginal patient population in CCS ≥ I class (n = 14,286) (relative risk ivabradine / placebo 1.11, p = 0.110).

The dose used in the study, higher than the approved one, did not fully explain the results obtained.

The SHIFT study is a large, multicenter, international, randomized, controlled, double-blind placebo outcome study in 6,505 adult patients with chronic heart failure (from 4 weeks), NYHA class II to IV, with a reduced left ventricular ejection fraction (LVEF 35%) and a resting heart rate ≥ 70 bpm.

Patients received conventional therapy that included beta-blockers (89%), ACE inhibitors and / or angiotensin II antagonists (91%), diuretics (83%) and anti-aldosterone agents (60%). In the group treated with ivabradine, 67% of patients were treated with 7.5 mg twice daily. Median follow-up was 22.9 months. Treatment with ivabradine was associated with a mean reduction in heart rate of 15 bpm compared with at baseline of 80 bpm The difference in heart rate between the ivabradine arm and placebo was 10.8 bpm at 28 days, 9.1 bpm at 12 months and 8.3 bpm at 24 months.

The study demonstrated a clinically and statistically significant 18% relative risk reduction in the frequency of the primary composite endpoint of cardiovascular mortality and hospitalization for worsening heart failure (hazard ratio: 0.82, 95% CI [0.75; 0.90] - p

Effect of treatment on the primary composite endpoint, its components and secondary endpoints


Ivabradine (N = 3241) n (%) Placebo (N = 3264) n (%) Hazard ratio [95% CI] p-value Primary composite endpoint 793 937 0,82 [0,75; 0,90] Composite components: - cardiovascular mortality 449 491 0,91 [0,80; 1,03] 0,128 - hospitalization for worsening heart failure 514 672 0,74 [0,66; 0,83] Other secondary endpoints: - all causes of mortality 503 552 0,90 [0,80; 1,02] 0,092 - mortality from heart failure 113 151 0,74 [0,58;0,94] 0,014 - hospitalization for all causes 1231 1356 0,89 [0,82;0,96] 0,003 - hospitalization for cardiovascular causes 977 1122 0,85 [0,78; 0,92] 0,0002

The observed reduction in the primary endpoint was maintained regardless of gender, NYHA classification, ischemic or non-ischemic aetiology of heart failure, and previous history of diabetes or hypertension.

In the subgroup of patients with CF 75 bpm (n = 4,150), a greater reduction in the primary composite endpoint of 24% was observed (hazard ratio: 0.76, 95% CI [0.68, 0.85] -p

In this subgroup of patients, the safety profile of ivabradine is consistent with that of the total population.

A significant effect on the primary composite endpoint was observed in the total group of patients receiving beta-blocker therapy (hazard ratio: 0.85, 95% CI [0.76; 0.94]).

In the subgroup of patients with CF 75 bpm and at the optimal recommended dose of beta-blocker, no statistically significant benefit was observed on the primary composite endpoint (hazard ratio: 0.97, 95% CI [0.74; 1.28]) and other endpoints secondary, including hospitalization for worsening heart failure (hazard ratio: 0.79, 95% CI [0.56; 1.10]) or death from heart failure (hazard ratio: 0.69, 95% Cl [0.31; 1.53]).

A significant improvement in the NYHA class was reported at the latest survey: it improved in 887 patients (28%) treated with ivabradine compared with 776 patients (24%) treated with placebo (p = 0.001).

Pediatric population

A randomized, double-blind, placebo-controlled study was performed in 116 pediatric patients (17 aged 6 to 12 months, 36 aged 1 to 3 years, and 63 aged 3 to 18 years) with chronic heart failure and dilated cardiomyopathy (DCM) in addition to the optimal basic treatment. 74 patients received ivabradine (with a 2: 1 ratio). The starting dose was 0.02 mg / kg twice daily in the 6 to 12 month age group, 0.05 mg / kg twice daily in the 1 to 3 year age group and in the 1 to 3 year age group. 3 and 18 years with body weight body weight ≥ 40 kg. The dose was adjusted based on the therapeutic response with a maximum dose of 0.2 mg / kg twice daily, 0.3 mg / kg twice daily and 15 mg / kg twice daily, respectively. In this study, ivabradine was administered as an oral liquid formulation or as a twice daily tablet. The absence of pharmacokinetic differences between the 2 formulations was demonstrated in an open-label, randomized, two-period cross-over study conducted in 24 healthy adult volunteers.

A 20% reduction in heart rate, without bradycardia, was achieved in 69.9% of patients in the ivabradine group versus 12.2% in the placebo group during the 2 to 8-week titration period (odds ratio: E = 17.24, 95% CI [5.91; 50.30]).

The mean ivabradine dose that resulted in a 20% reduction in heart rate was 0.13 ± 0.04 mg / kg twice daily, 0.10 ± 0.04 mg / kg twice daily, respectively. day and 4.1 ± 2.2 mg twice daily in age subgroups 1 to 3 years, 3 to 18 years and body weight

After 12 months of treatment, the mean left ventricular ejection fraction increased from 31.8% to 45.3% in the ivabradine group compared with an increase from 35.4% to 42.3% in the placebo group. C "was an improvement in NYHA class in 37.7% of patients treated with ivabradine compared with 25.0% of patients in the placebo group. These improvements were not statistically significant.

The safety profile over one year was similar to that described in adult patients with chronic heart failure.

The long-term effects of ivabradine on growth, puberty and general development as well as the long-term efficacy of ivabradine therapy in childhood to reduce cardiovascular disease / mortality have not been studied.

The European Medicines Agency has waived the obligation to submit the results of studies with Procoralan in all subsets of the pediatric population for the treatment of angina pectoris.

The European Medicines Agency has waived the obligation to submit the results of studies with Procoralan in children under 6 months of age in the treatment of chronic heart failure.

05.2 Pharmacokinetic properties

Under physiological conditions, ivabradine is rapidly released from tablets and is highly soluble in water (> 10 mg / ml). Ivabradine is the S-enantiomer and no bioconversion has been demonstrated in vivo. The N-demethylated derivative of ivabradine has been identified as the major active metabolite in humans.

Absorption and bioavailability

Ivabradine is rapidly and almost completely absorbed following oral administration with a plasma peak reached in approximately one hour under fasted conditions. The absolute bioavailability of the film-coated tablets is approximately 40%, due to the first pass effect in the intestine and liver.

Food delays absorption by about one hour and increases its presence in the plasma by 20 to 30%. It is recommended that the tablet be taken with meals to decrease intra-individual variability in concentration (see section 4.2).

Distribution

Ivabradine is approximately 70% bound to plasma proteins and, in patients, the volume of distribution at steady state is close to 100 L. Maximum plasma concentration following chronic administration at the recommended dose of 5 mg twice daily is 22 ng / mL (CV = 29%). Mean steady-state plasma concentration is 10 ng / mL (CV = 38%).

Biotransformation

Ivabradine is extensively metabolised by the liver and intestine by oxidations catalysed only by cytochrome P450 3A4 (CYP3A4). The main active metabolite is the N-desmethyl derivative (S18982), with a concentration of approximately 40% of that of the parent molecule. The metabolism of this active metabolite also involves CYP3A4. Ivabradine has a low affinity for CYP3A4, shows no clinically relevant induction or inhibition of CYP3A4 and is therefore unlikely to alter the metabolism or plasma concentrations of CYP3A4 substrates. In contrast, potent inhibitors and inducers may substantially alter plasma concentrations. ivabradine (see section 4.5).

Elimination

Ivabradine is eliminated with a principal half-life of 2 hours (70-75% of the AUC) in plasma and an effective half-life of 11 hours. Total clearance is approximately 400 mL / min and renal clearance is approximately 70 mL / min. Excretion of metabolites occurs in equal parts with faeces and urine. Approximately 4% of an oral dose is excreted unchanged in the urine.

Linearity / Non Linearity

The kinetics of ivabradine are linear over the oral dose range of 0.5-24 mg.

Special populations

- Elderly: No pharmacokinetic differences (AUC and Cmax) were observed between elderly (≥ 65 years) or very elderly (≥ 75 years) patients and the general population (see section 4.2).

- Renal insufficiency: the impact of renal impairment (creatinine clearance 15 to 60 ml / min) on ivabradine pharmacokinetics is minimal, in accordance with the modest contribution of renal clearance (approximately 20%) to total excretion. ivabradine and its major metabolite S18982 (see section 4.2).

- Hepatic impairment: In patients with mild hepatic impairment (Child Pugh score up to 7), the AUC of free ivabradine and its major active metabolite is approximately 20% higher than in subjects with normal hepatic function. Data are insufficient to draw conclusions in patients with moderate hepatic insufficiency. There are no data available in patients with severe hepatic impairment (see sections 4.2 and 4.3).

- Pediatric population: The pharmacokinetic profile of ivabradine in pediatric chronic heart failure patients aged 6 months to 18 years is similar to the pharmacokinetic profile described in adults when applying an age- and weight-based titration scheme.

Pharmacokinetic / pharmacodynamic relationship (PK / PD)

Analysis of the PK / PD relationship showed that heart rate decreases practically linearly with increasing plasma concentrations of ivabradine and S18982 for doses up to 15-20 mg twice daily. At higher doses, the decrease in heart rate is no longer proportional to the plasma concentrations of ivabradine and tends to achieve a plateau. High concentrations of ivabradine, which may occur when ivabradine is co-administered with potent CYP3A4 inhibitors, may result in an excessive decrease in heart rate although this risk is reduced with moderate CYP3A4 inhibitors (see sections 4.3, 4.4 and 4.5). . The PK / PD relationship of ivabradine in pediatric chronic heart failure patients aged 6 months to 18 years is similar to that described in adults.

05.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproductive toxicity studies have shown that ivabradine has no effect on the fertility of male and female rats. When pregnant animals were treated during organogenesis with dosages close to therapeutic ones, a higher incidence of fetuses with defects was observed. in rats and a small number of fetuses with ectrodactyly in rabbits.

In dogs treated with ivabradine (doses of 2, 7 or 24 mg / kg / day) for one year, reversible changes in retinal function were observed but were not found to be associated with damage to ocular structures. These data are consistent with the pharmacological effects of ivabradine and are attributable to its interaction with the current THE h activated in hyperpolarization, present in the retina, and which shares a wide homology with the cardiac pacemaker current THE f.

Other long-term repeated dose studies and carcinogenicity studies did not reveal any changes of clinical relevance.

Environmental Risk Assessment (Environmental Risk Assessment, WAS)

The environmental risk assessment of ivabradine was conducted in accordance with the European guidelines of ERA.

The results of these evaluations support the absence of an environmental risk of ivabradine and ivabradine does not pose an environmental hazard.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Nucleus

Lactose monohydrate

Magnesium stearate (E470B)

Cornstarch

Maltodextrin

Colloidal anhydrous silica (E551)

Coating film

Hypromellose (E464)

Titanium dioxide (E171)

Macrogol 6000

Glycerol (E422)

Magnesium stearate (E470B)

Yellow iron oxide (E172)

Red iron oxide (E172)

06.2 Incompatibility

Not relevant.

06.3 Period of validity

3 years.

06.4 Special precautions for storage

This medicine does not require any special storage conditions.

06.5 Nature of the immediate packaging and contents of the package

Aluminum / PVC blister contained in cardboard boxes.

Packs

Calendar packs containing 14, 28, 56, 84, 98, 100 or 112 film-coated tablets.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

Les Laboratoires Servier

50, rue Carnot

92284 Suresnes cedex

France

08.0 MARKETING AUTHORIZATION NUMBER

EU / 1/05/316/001 - 007

037061013

037061025

037061049

037061052

037061064

037061076

A.I.C. No. 037061037 / E: Procoralan 5 mg film-coated tablets - pack of 56 tablets

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

Date of first authorization: 25/10/2005

Date of most recent renewal: 25/10/2010

10.0 DATE OF REVISION OF THE TEXT

03/2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

none:  training-physiology prostate-health pioglitazone