Coraxan® (Coraxan® )

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
Read on
Active substanceIwabradineIwabradine
Similar drugsTo uncover
  • Bravadin®
    pills inwards 
    KRKA-PHARMA, doo, Zagreb, Croatia     Croatia
  • Coraxan®
    pills inwards 
    Servier Laboratories     France
    • Dosage form: & nbspcoated tablets
    Composition:
    1 tablet of 5 mg contains the active substance ivabradine hydrochloride, 5.390 mg, which corresponds to 5 mg ivabradine in the form of a base.
    1 tablet of 7.5 mg contains the active substance ivabradine hydrochloride 8.085 mg, which corresponds to 7.5 mg ivabradine in the form of a base.
    Auxiliary substances: lactose monohydrate, magnesium stearate, corn starch, maltodextrin, silicon dioxide colloidal anhydrous, hypromellose, titanium dioxide (E171), macrogol 6000, glycerol, magnesium stearate, iron oxide yellow (E172), iron oxide red (E172).
    Description:
    Tablets 5 mg: oval, biconvex tablets, covered with a shell, orange-pink color with incisions from two lateral sides and engraving on two sides. On one side - in the form of a company logo, on the other - the figure 5.
    Tablets 7.5 mg: triangular tablets, covered with a shell, orange-pink color, with engraving on two sides. On one side - in the form of a company logo, on the other - the figure 7.5
    Pharmacotherapeutic group:Antianginal remedy
    ATX: & nbsp

    C.01.E.B.17   Iwabradine

    Pharmacodynamics:
    Ivabradine - a drug that slows the rhythm of the heart,the mechanism of which is the selective and specific suppression of If channels of the sinus node that control spontaneous diastolic depolarization in the sinus node and regulate the heart rate (HR).
    The effect on cardiac activity is specific for the sinus node, does not affect the timing of pulses at the intrapartum, atrial-ventricular and intraventricular conduction pathways, as well as the contractility of the myocardium. The processes of repolarization of the ventricles remain unchanged. Iwabradine can also interact with I and retinal canal channels, similar to If channels of the heart, involved in the onset of temporary changes in the visual perception system due to a change in the retina response to bright light stimuli. Under provocative circumstances (for example, rapid change of brightness) partial inhibition of the Ш channels by ivabradine causes the so-called phenomenon of change in light perception (photopsy). Photopsy is characterized by a transient change in brightness in a limited area of ​​the visual field.
    The main pharmacological feature of ivabradine is its ability to dose-dependent decrease in heart rate.Analysis of the dependence of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine up to 20 mg twice a day and revealed a tendency to achieve a plateau effect (no increase in the therapeutic effect), which reduces the risk of developing a severe, poorly tolerated bradycardia (heart rate less than 40 beats. / min.)
    When prescribing the drug at recommended doses, the decrease in heart rate is approximately 10 bpm. at rest and under physical exertion. As a result, the work of the heart decreases and myocardial oxygen demand decreases.
    Ivabradin does not affect intracardiac conduction, contractility (there is no negative inotropic effect) or processes of ventricular repolarization:
    - in clinical electrophysiological studies ivabradine had no effect on the timing of pulses from the atrioventricular or intraventricular conduction pathways, as well as to the corrected QT intervals.
    - In special studies involving more than 100 patients with left ventricular dysfunction (ejection fraction 30-45%), it was demonstrated that ivabradine does not affect the contractile function of the myocardium.
    Antianginal and antiischemic efficacy of ivabradine has been demonstrated in 4 double-blind, randomized trials (2 studies - placebo-controlled and 2 comparative studies with atenolol and amlodipine). In these studies, 3,222 patients with chronic stable angina participated, of which 2,188 received ivabradine.
    Determined that ivabradine in a dose of 5 mg 2 times a day had a favorable effect on all parameters of stress tests after 3-4 weeks of therapy. Efficiency was confirmed for a dose of 7.5 mg 2 times a day. In particular, the additional effect with increasing the dose from 5 to 7.5 mg twice a day was established in a comparative study with atenolol: the exercise time increased by approximately 1 minute after 1 month of ivabradine administration 5 mg 2 times a day, after that an additional 3-month dose of ivabradine 7.5 mg twice daily indicated a further increase in this indicator by 25 seconds. In this study, antianginal and antiischemic efficacy of ivabradine was also confirmed for patients aged 65 years and older.The efficacy of ivabradine in doses of 5 mg and 7.5 mg twice a day was noted in these studies for all parameters of stress tests (total duration of exercise, time to the limiting angina attack, time to onset of angina attack, and time to development of ST-segment depression by 1 mm below the isoline), and also was accompanied by a decrease in the incidence of angina attacks by about 70%. Dosage regimen with 2-fold application of ivabradine during the day allowed to provide equal efficiency for 24 hours.
    A randomized, placebo-controlled study of 725 patients did not show any additional efficacy of ivabradine when attached to the maximum dose of amlodipine at a drop in therapeutic activity (12 hours after ingestion), while at peak activity (3-4 hours after admission Inside) the additional efficacy of ivabradine has been proven. In studies of the clinical efficacy of the drug, the effects of ivabradine were completely preserved throughout
    3 and 4-month periods of treatment. During treatment, signs of pharmacological tolerance (decreased effectiveness) were absent, and after the cessation of treatment of the "withdrawal" syndrome was not noted.Antianginal and antiischemic effects of ivabradine were associated with a dose-related decrease in heart rate, as well as a significant reduction in the work product (heart rate x systolic blood pressure), both at rest and during physical exertion. The effect on the level of arterial pressure (BP) and the resistance of the peripheral vascular system was insignificant and clinically not pronounced.
    A sustained reduction in heart rate was demonstrated in patients taking ivabradine at least for 1 year (n = 713). No effect on the metabolism of glucose or lipids was observed.
    In patients with diabetes mellitus (n = 457) ivabradine demonstrates effectiveness and safety, as well as in other, comparable in size, groups of patients.
    Pharmacokinetics:
    Iwabradine is rapidly released from tablets and very readily soluble in water (> 10 mg / ml). The ivabradine molecule is an S-enantiomer, with no bioconversion according to the research data in vivo. It has been established that in man the main active metabolite of the drug is the N-desmethylated ivabradine derivative.
    Absorption and bioavailability
    Quickly and almost completely absorbed in the gastrointestinal tract (GIT) after ingestion. The maximum concentration in the blood plasma is reached after 1.5 hours after ingestion on an empty stomach. Bioavailability is approximately 40%, which is due to the effect of "first passage" through the liver. The intake increases the absorption time by approximately 1 hour and increases the concentration in the blood plasma from 20% to 30%. To reduce interindividual variability, the drug should be taken with meals.
    Distribution
    Linkage to blood plasma proteins is approximately 70%. The volume of distribution is approximately 100 liters. The maximum concentration in blood plasma after long-term use at the recommended dose of 5 mg twice a day is approximately 22 ng / ml (CV = 29%). The average equilibrium concentration in the blood plasma is 10 ng / ml.
    Biotransformation
    Iwabradine is largely metabolized in the liver and intestines by oxidation in the presence of cytochrome P450 3A4 (CYP3A4). The main active metabolite is the N-desmethylated derivative (S 18982), part of it is a 40% dose of the parent compound and is characterized by similar pharmacokinetic and pharmacodynamic properties.Metabolism of the active metabolite of ivabradine also occurs in the presence of cytochrome CYP3 A4. Iwabradine has a low affinity for the enzyme CYP3A4, with no indication of induction or inhibition of the enzyme. In this regard, it is unlikely that ivabradine changes the metabolism or concentration of substrates of the enzyme CYP3A4 in blood plasma. On the other hand, the combined use of strong inhibitors or cytochrome P450 inducers can significantly affect ivabradine plasma concentrations (sections on "Interaction with other drugs" and "Special instructions").
    Excretion
    The half-life of ivabradine averages approximately 2 hours (70-75% of the area under the curve "plasma concentration / time" (AUC)) and the effective half-life is 11 hours. The total clearance is approximately 400 ml / min, and the renal clearance is approximately 70 ml / min. Excretion of metabolites and minor amounts of unchanged substance occurs at the same rate through the kidneys and gastrointestinal tract. About 4% of the ingested dose is excreted in the urine.
    Linearity and nonlinearity
    The pharmacokinetics of ivabradine are linear at doses of 0.5 to 24 mg.
    Special patient groups
    Elderly and old age
    Differences in such pharmacokinetic parameters as (A11C) and maximum plasma concentration (Cmax) between groups of patients older than 65 years, patients older than 75 years and the general population - were not observed
    Renal insufficiency
    The effect of renal failure (creatinine clearance from 15 to 60 ml / min) on the kinetics of ivabradine is minimal.
    Liver failure
    In patients with a mild degree of hepatic insufficiency (5-7 in the Child-Pugh classification), the AUC of ivabradine and its active metabolite is 20% greater than with normal liver function.
    The amount of data for patients with moderate (7 - 9 on the Child-Pugh classification) liver failure does not make it possible to conclude about the use of ivabradine in this group of patients. Clinical data on the use of ivabradin in patients with severe (more than 9 Child-Pugh classification) liver failure are currently not available.
    The relationship between pharmacokinetic and pharmacodynamic properties Analysis of the relationship between pharmacokinetic and pharmacodynamic properties allowed us to establish that the decrease in heart rate is directly proportional to the increase in plasma concentrations of ivabradine and active metabolite S 18982 at dosage levels up to 15-20 mg twice a day.At higher doses of the drug, the slowing of the heart rate does not have a proportional relationship with the concentrations of ivabradine in the blood plasma and is characterized by a tendency to achieve a plateau effect. The high level of ivabradine concentration that can be achieved with a combination of the drug with strong inhibitors of the CYP3 A4 enzyme can lead to a marked decrease in heart rate, but this risk is reduced when combined with moderate inhibitors of CYP3A4.
    Indications:Treatment of stable angina in patients with normal sinus rhythm with intolerance or contraindications to the use of beta-blockers.
    Contraindications:
    - Hypersensitivity to ivabradine or any of the excipients of the drug;
    - Bradycardia (heart rate at rest less than 60 bpm (before treatment));
    - Cardiogenic shock;
    - Acute myocardial infarction;
    - Severe arterial hypotension (systolic blood pressure less than 90 mm Hg and diastolic blood pressure less than 50 mm Hg);
    - Severe hepatic insufficiency (more than 9 on the Child-Pugh scale);
    - Syndrome of weakness of the sinus node;
    - Sinoatrial block;
    - Unstable or acute heart failure;
    - Presence of the artificial driver of a rhythm working in a mode of constant stimulation;
    - Unstable angina;
    - Atrioventricular (AV) blockade of the III degree;
    - Simultaneous use with strong inhibitors of cytochrome P450 ZA4 isoenzymes, such as antifungal agents of the azole group (ketoconazole, itraconazole), antibiotics of the macrolide group (clarithromycin, erythromycin for oral administration, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see the sections "Pharmacokinetics" and "Interaction with other drugs");
    - Pregnancy, the period of breastfeeding and the use in women of reproductive age that do not comply with reliable contraceptive measures (see section "Application during pregnancy and during breastfeeding");
    - Age to 18 years (efficacy and safety of the drug in this age group has not been studied);
    - Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

    Pregnancy and lactation:
    The drug Coraxan® is contraindicated for use in pregnancy.At the moment, there is insufficient data on the use of the drug during pregnancy.
    Pre-clinical studies of ivabradine revealed embryotoxic and teratogenic effects.
    Breastfeeding period
    The use of Koraxan ® during breastfeeding is contraindicated. In animal studies, it has been shown that ivabradine is excreted in breast milk.
    Women who need treatment with drugs containing ivabradine, should stop breastfeeding.
    Women of reproductive age
    Women of reproductive age must follow reliable contraceptive measures during the treatment with Koraxan (see "Contraindications").

    Dosing and Administration:
    Therapy with Coraxan is recommended as an alternative for the symptomatic treatment of stable angina in patients with normal sinus rhythm with intolerance or contraindications to the use of beta-blockers.
    Coraxan tablets are intended for oral administration, with a 2-fold dosing regimen during the day, i.e. morning and evening with meals.The usual recommended initial dose of Coraxan is 5 mg per day. Depending on the therapeutic effect, after 3-4 weeks of administration, the dose of the drug can be increased to 7.5 mg twice a day. If the background of therapy, the heart rate decreases to less than 50 bpm. or the patient has symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), it is necessary to choose a lower dose of the drug. If the amount of heart rate is not normalized when the Coraxan dose is lowered and remains at a level less than 50 bpm, then the drug should be withdrawn.
    Application in the elderly
    The use of Coraxan in patients 75 years of age and older has been studied in a limited number of patients, so for this age group it is recommended to start treatment with an initial dose of 2.5 mg (1/2 tablets 5 mg) 2 times a day, an increase in the daily dose depending on the patient's condition .
    Renal insufficiency
    When creatinine clearance is above 15 ml / min, the usual dosing regimen is recommended. Because of the lack of clinical data on the use of Coraxan in creatinine clearance below 15 ml / min, the drug should be taken with caution.
    Liver failure
    There is no need for any change in the dosage regimen of the drug with mild hepatic insufficiency. Care should be taken with a moderate degree of hepatic insufficiency. With severe hepatic insufficiency, taking the drug is contraindicated, since this group of patients did not carry out studies.
    Side effects:
    The drug was used in studies involving almost 14,000 patients. The most frequent side effects of ivabradine were dose-dependent and were associated with the mechanism of action of the drug.
    The list of undesirable reactions
    The incidence of adverse reactions that have been noted in clinical studies is given in the following gradation: very often (> 1/10); often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); rarely (> 1/10000, <1/1000); very rarely (<1/10000); frequency (frequency can not be calculated from available data).

    From the sense organs
    Very often: changes in light perception (photopsy): noted in 14.5% of patients and described as a transient change in brightness in a limited area of ​​the visual field. As a rule, similar phenomena were provoked by a sharp change in the intensity of illumination in the zone of the visual field.Basically, a photopsy occurred in the first two months of treatment followed by a repetition. The severity of the photopsy, as a rule, was mild or moderate. The appearance of a photopsy stopped on the background of continuation of therapy (in 77.5% of cases) or after its completion. In less than 1% of patients, the onset of photopsy was the reason for refusing treatment. Often: blurred vision. Infrequently: vertigo
    Unspecified frequency: diplopia, impaired vision.
    From the side of the cardiovascular system
    Often: bradycardia: 3.3% of patients, especially in the first 2-3 months of therapy, in 0.5% of patients developed a pronounced bradycardia with a heart rate of not more than 40 beats per minute; AY blockade of the 1st degree; ventricular extrasystole, a short-term increase in blood pressure.
    Infrequent: palpitations, supraventricular extrasystole. Very rarely: atrial fibrillation, AV blockade of II and III degree, weakness syndrome of the sinus node.
    From the digestive system
    Infrequently: nausea, constipation, diarrhea.
    From the central nervous system
    Often: headache, especially in the first month of therapy; dizziness, possibly associated with bradycardia.
    Unspecified frequency: syncope, possibly associated with bradycardia.
    From the respiratory system
    Infrequent: shortness of breath.
    From the side of the musculoskeletal system
    Infrequent: muscle spasms.
    Laboratory and instrumental indicators
    Infrequent: hyperuricemia, eosinophilia, increased creatinine concentration in the blood plasma, prolongation of the QT interval on the ECG.
    From the skin and subcutaneous fat
    Unspecified frequency: skin rash, itching, erythema, angioedema, hives.
    General disorders and symptoms
    Unspecified frequency: asthenia, increased fatigue, malaise, possibly associated with bradycardia.
    Overdose:
    Overdosing with the drug can lead to severe prolonged bradycardia, poorly tolerated by patients.
    Treatment of severe bradycardia should be symptomatic and conducted in specialized departments. In the case of bradycardia in combination with adverse changes in hemodynamic parameters, symptomatic treatment with intravenous administration of beta-adrenomimetics, such as isoprenaline, is indicated. If necessary, consider the possibility of temporarily installing an artificial pacemaker.

    Interaction:

    Pharmacodynamic interaction

    Not recommended combinations

    Drugs that extend the QT interval

    - drugs that extend the QT interval (for example, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone)

    - drugs that extend the QT interval, not related to cardiovascular agents (eg, pimazide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin in / in).

    Co-administration with QT-prolonging drugs may increase heart rate reduction, so careful cardioversion should be performed if necessary for co-administration.


    Pharmacokinetic interaction

    Cytochrome P 450 ZA4 (CYP3A4)

    Iwabradine is metabolized in the liver by the enzymes of the cytochrome P450 system (CYP3A4) and is a very weak inhibitor of this cytochrome. Iwabradine does not have a significant effect on the metabolism and concentration in the blood plasma of other substrates of cytochrome CYP3A4. At the same time, inhibitors and inducers of CYP3A4 interact with ivabradine and affect its metabolism and pharmacokinetic properties. It was found that inhibitors of cytochrome CYP3A4 increase, and cytochrome CYP3A4 inducers reduce plasma concentrations of ivabradine.Increased concentration of ivabradine in blood plasma increases the risk of developing severe bradycardia.

    Contraindicated combinations

    Simultaneous application with strong inhibitors of cytochrome P 450, such as antifungal agents of the azole group (ketoconazole, intraconazole), antibiotics from the macrolide group (clarithromycin, erythromycin oral, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone, ketoconazole (200 mg once a day) or josamycin (1 g 2 times a day) increase the average concentration of ivabradine in blood plasma by 7-8 times.

    Not recommended combinations

    CYP3A4 inhibitors of moderate action. The combined use of ivabradine and augmenting heart rate, diltiazem or verapamil was well tolerated by patients and was accompanied by an increase in the concentration of ivabradine 2-3 times, with an additional decrease in heart rate of about 5 bpm. This combination is not recommended.

    Combinations that require caution when applying

    CYP3A4 inhibitors of moderate action: simultaneous application of ivabradine with other inhibitors of CYP3A4 (for example, fluconazole) should begin with an initial dose of 2.5 mg 2 times a day. At a heart rate less often 60 bpm. careful control of heart rate is necessary.

    Grapefruit juice. Against the background of taking grapefruit juice there was an increase in the concentration of ivabradine in the blood 2 times. During the treatment with ivabradine, the intake of grapefruit juice and St. John's wort is to be minimized. Inductors CYP3 A4, such as rifampicin, barbiturates, phenytoin and herbal preparations containing Hypericum perforatum (Hypericum perforatum), when combined, can lead to a decrease in blood concentrations and activity of ivabradine and require the selection of a higher dose of ivabradine. During the treatment with ivabradine, the use of drugs and products containing St. John's Wort is to be minimized. Combined use with other drugs The absence of a clinically pronounced effect on the pharmacodynamics and pharmacokinetics of ivabradine following drugs has been demonstrated: proton pump inhibitors (omeprazole, lansoprazole ), inhibitors of phosphodiesterase-5 (sildenafil), inhibitors of HMG-CoA reductase (simvastatin), blockers of "slow" calcium channels derivatives of dihydropyridine series (amlodipine, lacidipine), digoxin and warfavin. Shown, that ivabradine has no clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, pharmacokinetics and pharmacokinetic dynamics of digoxin, warfavin, and the pharmacodynamics of acetylsalicylic acid.

    In a pilot Phase III trial, the use of the following drugs has been specifically restricted, and therefore they can be administered in combination with ivabradine without special precautions: angiotensin converting enzyme (ACE) inhibitors, AT II receptor antagonists, diuretics, nitrates of short and prolonged actions, inhibitors of HMG-CoA reductase, fibrates, proton pump inhibitors, oral hypoglycemic agents, acetylsalicylic acid and other antithrombotic agents.


    Special instructions:
    Cardiac arrhythmia
    Coraxan is not effective for the treatment or prevention of cardiac arrhythmias. Its effectiveness falls against the background of the development of tachyarrhythmias (for example, ventricular or supraventricular tachycardia).Also, Coraxan is not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function. In therapy with Coraxan, regular monitoring is recommended for the development of atrial fibrillation (paroxysmal or persistent). In the clinical indications (eg, with complicated angina, severe heartbeat, irregular heart rhythm), an electrocardiogram (ECG) should be included in the current control. II degree Coraxan is not recommended for treatment with AV blockade II degree.
    Use in patients with a reduced heart rate
    Coraxan is not recommended in patients who have a heart rate less than 60 beats per min prior to administration of the medication.
    If the background of therapy, the heart rate decreases to less than 50 bpm. or the patient has symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), it is necessary to choose a lower dose of the drug. If the amount of heart rate is not normalized when the Coraxan dose is lowered and remains at a level less than 50 bpm, then the drug should be withdrawn.
    Combined use as part of antianginal therapy
    The use of Coraxan in conjunction with blockers of "slow" calcium channels slowing heart rate, such as verapamil or diltiazem, is not recommended.
    With the combined use of Coraxan with nitrates, blockers of "slow" calcium channels of dihydropyridine derivatives, such as amlodipine, no impact on safety and efficacy was identified.
    Chronic heart failure
    Before the appointment of Coraxan, the patient should be examined for chronic heart failure. In the presence of chronic cardiac insufficiency of functional class III-IV (according to the NYHA classification), Coroxan is contraindicated due to the lack of sufficient data on the efficacy and safety of the drug. Due to the insufficient number of patients examined, the drug should be administered with caution in asymptomatic left ventricular dysfunction and in chronic heart failure class II (according to the NYHA classification).
    Stroke
    It is not recommended to prescribe the drug in the acute period of a stroke,there is no data on its use in this period.
    Functions of visual perception (Visualfunction)
    Coraxan acts on the function of the retina. At present, there is no evidence of toxic action of ivabradine on the retina of the eye. The consequences of Coraxan's action on the retina with long-term use to date are not known. If there are violations of visual functions not described in the instruction, it is necessary to consider the issue of stopping Koraxan. The drug should be taken with caution to patients with retinitis pigmentosa (retinitis pigmentosa). Excipients
    The composition of excipients of the drug includes lactose, therefore, patients with galactose intolerance, deficiency of Lapp lactase or glucogalactosal absorption of Koraxan is not recommended.
    Arterial hypotension
    Due to the lack of clinical data, Coraxan should be administered with caution to patients with mild to moderate arterial hypotension.
    Coraxan is contraindicated in severe arterial hypotension (systolic blood pressure below 90 mmHg and diastolic blood pressure below 50 mmHg);
    Atrial fibrillation (atrial fibrillation) - cardiac arrhythmias
    There is no evidence of a risk of developing a bradycardia with the use of Coraxan in restoring sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if possible, to postpone DC-card dioversion, reception of Coraxan should be stopped 24 hours before it is carried out. Use in patients with congenital syndrome of an extended QT interval or patients taking drugs that extend the QT interval
    Coraxan should not be prescribed in the congenital syndrome of the extended QT-interval, as well as in combination with drugs that slow the QT interval. If it is not possible to avoid therapy with Coraxan, careful cardiac monitoring is necessary. Moderate hepatic impairment
    With moderate hepatic insufficiency, therapy with Coraxan should be done with caution.
    Severe renal insufficiency
    In severe renal failure (creatinine clearance less than 15 ml / min,), therapy with Coraxan should be carried out with caution.
    Effect on the ability to drive transp. cf. and fur:It has been shown that basically Coraxan's application does not affect the ability to drive, but due to the possibility of a photopsy, caution should be exercised when driving vehicles and / or performing work requiring high speed of psychomotor reactions.
    Form release / dosage:Pills.
    Packaging:For 14 tablets per blister (PVC / Al). For 1, 2 and 4 blisters with instructions for medical use in a pack of cardboard. When packaging (packaging) / production at a Russian company LLC "Serdiks" For 14 tablets in a blister (PVC / Al). For 1, 2 and 4 blisters with instructions for medical use in a pack of cardboard.
    Storage conditions:In places inaccessible to children. Special storage conditions are not required.
    Shelf life:
    3 years.
    DO NOT USE AFTER THE TERM OF THE YEAR ENDED PACKAGING.

    Terms of leave from pharmacies:On prescription
    Registration number:LS-000885
    Date of registration:18.08.2010
    The owner of the registration certificate:Servier LaboratoriesServier Laboratories France
    Manufacturer: & nbsp
    Representation: & nbspServier Laboratories Servier Laboratories France
    Information update date: & nbsp18.03.2014
    Illustrated instructions
      Instructions
      Up