Ranex® (Ranexa®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceRanolazineRanolazine
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  • Ranex®
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    BERLIN-PHARMA, CJSC     Russia
    • Dosage form: & nbspExtended-release tablets coated with a film sheath
    Composition:

    Tablets 500 mg Core:

    Active substance: ranolazine - 500.0 mg.

    Excipients: cellulose microcrystalline - 70.67 mg, copolymer of methacrylic acid and ethyl acrylate (1: 1) - 66.67 mg, hypromellose - 13.33 mg, magnesium stearate-13.33 mg, sodium hydroxide - 2.667 mg; x

    Shell: Fallen II orange 85F93265 [macrogol 3350 - .4.04 mg, polyvinyl alcohol partially hydrolysed - 8.00 mg, talc - 2.96 mg, titanium dioxide - 4.86 mg, iron dye oxide yellow, (E 172) - 0.118 mg, dye iron oxide red, (E 172) - 0.022 mg, carnauba wax (trace amounts)].

    Tablets 1000 mg Core:

    Active substance: ranolazine - 1000.0 mg.

    Excipients: cellulose microcrystalline - 141.34 mg, copolymer of methacrylic acid and ethyl acrylate (1: 1) - 133.34 mg, hypromellose - 26.66 mg, magnesium stearate-26.66 mg, sodium hydroxide - 5.334 mg;

    Sheath: Fallen II yellow 33G92144 [triacetin - 2.40 mg, hypromellose 6cP - 16.00 mg, lactose monohydrate 8.40 mg, macrogol 3350 3.20 mg, titanium dioxide 9.19 mg, iron oxide yellow oxide, E 172 0.81 mg, carnauba wax (trace amounts) ].


    Description:

    Description Tablets 500 mg

    The tablets are covered with a film membrane, biconvex, oval, light orange color with an embossed "500" or "GSI500 "on one side.

    Tablets 1000 mg

    The tablets are covered with a film membrane, biconvex, oval, pale yellow with an embossed "1000" or "GSI1000 "on one side.

    Pharmacotherapeutic group:antianginal
    ATX: & nbsp

    C.01.E.B   Other drugs for the treatment of heart disease

    C.01.E.B.18   Ranolazine

    Pharmacodynamics:

    Ranolasin, an active ingredient in Raneks®, is an inhibitor of late sodium ion current in myocardial cells. Decreased intracellular accumulation of sodium leads to a decrease in the excess of intracellular calcium ions. This reduces intracellular ion imbalance in ischemia. Reducing the excess of intracellular calcium promotes relaxation of the myocardium and, thus, reduces the diastolic stress of the ventricular wall. Clinical evidence of inhibition of late sodium current under the action of ranolazine is a significant shortening of the interval QTc (QTc - corrected value QT taking into account the frequency of the cores(HR)) and a positive effect on diastolic relaxation, revealed in an open study involving patients with the syndrome of an elongated interval QT (patients with the syndrome LQT-3, having gene mutations SCN5A AKPQ). These effects of the drug do not depend on changes in heart rate, blood pressure (BP) or the degree of vasodilation.

    When ranolazine is used, the incidence of angina attacks decreases weekly and nitroglycerin is consumed for sublingual use compared with placebo, regardless of the sex of the patients.

    During the treatment, the development of tolerance to ranolazine does not occur. After a sharp discontinuation of the drug, the incidence of angina attacks does not increase. Ranolazine has a significant advantage compared with placebo in increasing the time to the onset of an angina attack and before the onset of a segment depression ST on 1 mm at reception 500 - 1000 mg 2 times a day. The drug significantly improves the tolerance of exercise. For ranalazine, a dose-response relationship is fixed: when taking a higher dose, the antianginal effect was higher than with a lower dose.

    When adding ranolazine (1500 mg or 2000 mg per day, divided into 2 doses, compared with placebo for 12 notdel) to treatment with atenolol 50 mg / day, or amlodipine 5 mg / day, or diltiazem 180 mg / day, proved the effectiveness of the drug Raneksa, superior to placebo in the off-bearing the duration of exercise for both study doses of the drug (24 seconds more compared with placebo). However, there was no difference in the duration of the exercise burden between the two doses of Raneks®.

    Effects revealed in electrocardiography: In patients treated with Ranex ®, there was a dose-dependent and concentration of ranolazine in the blood plasma, lengthening the interval QTc (about 6 ms with 1000 mg bid 2 times a day), a decrease in the amplitude of the T wave and, in some cases, a double-humped T wave. The electrocardiogram parameters in patients taking ranolazine are the result of both drug inhibition of the fast potassium rectifying current rate that lengthens the ventricular action potential, and inhibition of late sodium current, which shortens the ventricular potential of the action. Population analysis showed that the use of ranolazine both in patients with stable angina and in healthy volunteers leads to lengthening QTc relative to the baseline level by an average of 2.4 ms with ranolazine concentration in the plasma of 1000 ng / ml.If patients have clinically significant hepatic impairment, the rate of lengthening QTc was higher. In patients who received ranolazine, a significantly lower incidence of arrhythmias compared with placebo, including ventricular tachycardia type "pirouette" > 8 abbreviations for 1 episode.

    Effects on hemodynamics: Patients treated with ranolazine in monotherapy or in combination with other anti-anginal agents showed a slight decrease in heart rate (<2 bpm) and a decrease in systolic blood pressure (<3 mm Hg)

    Pharmacokinetics:

    Suction: After taking ranolazine inside the maximum concentration of ranolazine in the blood plasma (Cmax), as a rule, is achieved in 2-6 hours. When taking ranolazine 2 times a day, the equilibrium concentration is usually achieved within 3 days. The average absolute bioavailability of ranolazine after oral administration is 35-50%, with a high degree of individual variability. When the dose is raised from 500 to 1000 mg twice daily, a 2.5-3 fold increase is observed AUC (area under the concentration-time curve) in the equilibrium state.

    In healthy volunteers, Cmax in the equilibrium state is approximately 1770 ng / ml, in the equilibrium state AUC0-12 on average, 13,700 ng h / ml after taking the drug at 500 mg 2 times a day. Eating food does not affect the speed and completeness of absorption of ranolazine.

    Distribution: Approximately 62% of ranolazine binds to blood plasma proteins, mainly with alpha-1 acidic glycoproteins and slightly with albumin. The average volume of distribution in the equilibrium statethe (Vss) is about 180 liters.

    Metabolism: Ranolazine is subject to rapid and almost complete metabolism, mainly in the liver. The most important ways of metabolizing ranolazine are O-demethylation and N-dealkylation. Ranolazine is metabolized mainly by isoenzyme CYP3A4, as well as isoenzyme CYP2D6. When taking 500 mg twice a day in people with insufficient isoenzyme activity CYP2D6, index AUC exceeds the same value for people with a normal metabolic rate of 62%. A similar difference for a dose of 1000 mg twice a day was 25%.

    Allocation: In unchanged form, less than 5% of the dose of ranolazine is secreted by the kidneys and through the intestine.The clearance of ranolazine depends on the dose, decreasing when it rises. The half-life of ranolazine in the equilibrium state after oral administration is about 7 hours.

    Special patient groups Chronic heart failure (III - IV functional classes by classification NYHA)

    In chronic heart failure (CHF), an increase in the concentration of ranolazine in the blood plasma is approximately 1.3 times.

    Renal insufficiency In patients with mild, moderate and severe renal failure, compared to healthy volunteers, the indicator AUC ranolazine was an average of 1.7-2 times inyshe.

    A significant individual variable variability AUC in volunteers with kidney failure. AUC pharmacologically active metabolites was increased 5-fold in patients with severe renal insufficiency.

    The duration of ranolazine in the blood plasma increases by 1.2 times in patients with moderate renal insufficiency (creatinine clearance 30-60 ml / min). In patients with severe renal insufficiency (creatinine clearance <30 ml / min), an increase in the duration of ranolazine in blood plasma was found to be 1.3-1.8 times.

    The effect of dialysis on the pharmacokinetics of ranolazine has not been studied.

    Liver failure Index AUC ranolazine does not change in patients with mild liver failure, but increases 1.8-fold in the case of moderate-level liver failure (7-9 on the Child-Pugh scale); in such patients, the interval elongation was more pronounced QTc. The experience with ranolazine in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale) is absent.

    Elderly age

    Clinically significant changes in pharmacokinetic parameters of ranolazine were not observed depending on age.

    In elderly patients, due to age-related decline in kidney function,action of ranolazine.

    Body mass

    In patients with a body weight of 40 kg, it was noted that the action of ranolazine was 1.4 times greater than that of patients with a body weight of 70 kg.

    Indications:stable angina
    Contraindications:

    - Hypersensitivity to actionor any of themogative substances (see section Composition)',

    - lactase deficiency, hereditary lactose intolerance, glucose-galactose malabsorption syndrome (only for a dosage of 1000 mg);

    - severe renal failure (creatinine clitoris <30 ml / min); hepatic impairment of an average (7-9 on the Child-Pugh scale) or severe (more than 9 on the Child-Pugh scale) severity;

    - simultaneous application with strong inhibitors of isoenzyme CYP3A4 (itraConazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone);

    - simultaneous use with antiarrhythmicsclass facilities IA (eg, quinidine) or class III (eg, dofetilide), other than amiodarone; with sotalol.

    - children under 18 years of age (efficiency and safetyhave not been established);

    • pregnancy;

    • the period of breastfeeding.

    Carefully:

    - Hepatic insufficiency of mild severity (5-6 points according to the Child-Pugh classification);

    • renal failure of mild or moderate severity (creatinine clearance 30-80 ml / min);

    • age over 75 years;

    • body weight less than 60 kg;

    • chronic heart failure (III-IV functional classes by classification NYHA);

    • congenital elongated interval syndrome QT in the anamnesis, in the family anamnesis; The acquired interval elongation QT;

    • isoenzyme deficiency CYP2D6;

    • simultaneous application with inhibitors of isoenzyme CYP3A4 average strength of action (diltiazem, fluconazole, erythromycin);

    • simultaneous application with inductors of isoenzyme activity CYP3A4 (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort (Hypericum perforatum));

    • concomitant use with inhibitors P-gp (P-glycoprotein) (verapamil, ciclosporin).

    Pregnancy and lactation:

    There are no data on the use of ranolazine in pregnant women.

    The penetration of ranolazine into breast milk has not been investigated.

    Due to the lack of data, the use of Ranex ® during pregnancy and during breastfeeding is contraindicated.

    Dosing and Administration:

    The recommended initial dose of Ranex ® for adults is 500 mg 2 times a day. After 2-4 weeks, the dose can be increased to 1000 mg twice a day if necessary. The maximum daily dose is 2000 mg.

    If side effects caused by taking Raneks® (eg, dizziness, nausea, or vomiting) occur, it is necessary to reduce the single dose to 500 mg. If after this the symptoms do not disappear, the drug should be discontinued.Tablets should be swallowed whole, squeezed with enough liquid, without crushing, breaking or chewing.

    Eating does not affect the bioavailability of the drug, so it can be taken regardless of meals.

    For patients with CHF (III-IV functional classes by classification NYHA), with renal insufficiency of mild and moderate severity (creatinine clearance 30-80 ml / min), mild liver failure (5-6 points according to the Child-Pugh classification), as well as for patients with body weight less than 60 kg and patients older than 75 years, titration of the dose is recommended.

    Side effects:

    The side effects observed in patients taking Raneks® are generally mild to moderate in severity and usually develop during the first 2 weeks of use.

    The side effects listed below are those for which a possible association with the use of Raneks® has been recognized.

    The incidence of side effects was determined as: very often (> 1/10), often (> 1/100; <1/10), infrequently (> 1/1000; <1/100), rarely (> 1/10 000; <1/1000) and very rarely (<1/10 000).

    From the side of metabolism and nutrition:

    Infrequently: decreased appetite, anorexia, dehydration.

    From the side of the psyche:

    Infrequently: anxiety, insomnia, confusion, hallucinations.

    Rarely: disorientation.

    From the nervous system:

    Often: dizziness, headache. Infrequently: inhibition, fainting, hyperoscension, drowsiness, tremor, postural dizziness, paresthesia.

    Rarely: amnesia, confusion, loss of consciousness, movement coordination disorders, gait disturbances, parosmia.

    From the side of the organ of vision:

    Infrequently: blurred visionconstruction, diplopia.

    On the part of the hearing organs and labyrinthine disorders:

    Infrequently: vertigo, noise in the ears.

    Rarely: hearing loss.

    From the cardiovascular system: Infrequently: "tides" of blood to the face, marked decrease in blood pressure.

    Rarely: cold extremities, orthostatic hypotension.

    From the respiratory system, chest and mediastinum:

    Infrequently: shortness of breath, cough, nosebleeds.

    Rarely: sensation of compression in the throat.

    From the digestive tract:

    Often: constipation, nausea, vomiting.

    Infrequently: pain in the abdomen, dryness of the oral mucosa, dyspepsia, flatulence, discomfort in the stomach.

    Rarely: pancreatitis, erosive duodenitis, oral cavity hyperesthesia.

    From the skin and subcutaneous tissues:

    Infrequently: itching, hyperhidrosis.

    Rarely: allergic dermatitis, urticaria, cold sweat, skin rash, angioedema.

    From the musculoskeletal system:

    Infrequently: pain in the extremities, muscle spasms, swelling of the joints.

    Rarely: muscle weakness.

    From the side of the kidneys and urinary tract: Infrequently: dysuria, hematuria, chromaturia. Rarely: acute renal failure, forthe hold of urine.

    From the genitourinary system:

    Rarely: erectile disfunction.

    General disorders:

    Often: asthenia.

    Infrequently: increased fatigue, peripheraledema.

    Other violations:

    Infrequently: increase of creatine concentrationnin in blood plasma, increased urea concentration in blood plasma, lengthening of the coriuminterval QTc, thrombocytosis and leukocytosis, weight loss.

    Rarely . increased activity of "hepatic" enzymes.

    Overdose:

    Symptoms: dizziness, nausea and moaningta. With intravenous administration of ranolazine, the following symptoms were additionally noted: diplopia, inhibition, fainting. The severity of symptoms may increase with increasing doses.

    Treatment: symptomatic under careful supervision of a doctor.

    Within 30 minutes after taking the drug it is possible to take measures to prevent its absorption from the gastrointestinal tract (gastric lavage, reception of activated charcoal).

    Hemodialysis is ineffective.

    Interaction:

    Ranolasin is a substrate of cytochrome CYP3A4. Simultaneous application of ranolinzine with inhibitors of isoenzyme CYP3A4

    Inductors of isoenzyme CYP3A4 Do not start taking ranolazine in patients receiving isoenzyme inducers CYP3A4 (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort (Hypericum perforatum)). Since, for example, rifampicin (600 mg once daily) reduces the equilibrium concentration of ranolazine in the blood plasma by approximately 95%. Inhibitor inhibitors CYP2D6

    Ranolasin is partially metabolized by isoenzyme CYP2D6. The simultaneous use of ranolazine with isozyme inhibitors CYP2D6 can lead to an increase in the concentration of ranolazine in the blood plasma. The simultaneous use of ranolazine 1000 mg 2 times a day with a strong inhibitor of isoenzyme CYP2D6 paroxetine 20 mg once a day increases the average concentration of ranolazine in the blood plasma in the equilibrium state by approximately 1.2 times. Correction of the dose is not required.The simultaneous use of ranolazine 500 mg 2 times a day and a strong inhibitor of isoenzyme CYP2D6 may lead to an increase AUC ranolazine by approximately 62%.

    Inhibitors / Substrates P-sp (P-glycoprotein)

    Ranolazin is a substrate P-gp. Inhibitors P-gp (eg, ciclosporin, verapamil) increase the concentration in the blood plasma. Verapamil (120 mg three times a day) raises the equilibrium concentration of ranolazine by 2.2 times. For patients, sextreatment with inhibitors P-gp, titration of the dose of ranolazine is recommended. You may need to reduce the dose of ranolazine.

    On the other hand, ranolazine is a mild inhibitor P-gp and can increase the concentration of substrates P-gp in the blood plasma. Tissue distribution of drugs that are transported by P-gp, can be increased. Substrates of the isoenzyme CYP2D6 There is evidence that ranolazine is a weak isoenzyme inhibitor CYP2D6. Receiving ranolazine 750 mg twice a day increases the concentration of metoprolol in blood plasma by 1.8 times. Therefore, with simultaneous application with ranolazine, the effect of metoprolol or other isozyme substrates may be enhanced CYP2D6 (eg, propafenone and flecainide, to a lesser extent, tricyclic antidepressants and antipsychotics), which may require a reduction in the dose of these drugs. Substrates of the isoenzyme CYP2B6 Potential for inhibition of isoenzyme CYP2B6 not installed. During the assignment together with the isoenzyme substrates CYP2B6 (eg, bupropion, efavirenz, cyclophosphamide) it is recommended to be careful.

    Digoxin

    There is evidence of an increase in the concentration of digoxin in the blood plasma by an average of 1.5 times with the simultaneous use of digoxin and ranolazin. Therefore, control concentration of digoxin at the beginning and after the end of therapy with ranolazine.

    Substrates of the isoenzyme CYP3A4 Ranolasin is a weak inhibitor of the isoenzyme CYP3A4, which can lead to an increase in the concentration of isoenzyme substrates CYP3A4 in blood plasma and require correction of the dose of sensitive isoenzyme substrates CYP3A4 (e.g., simvastatin, lovastatin) and isoenzyme substrates CYP3A4 with a narrow therapeutic range (for example, ciclosporin, tacrolimus, sirolimus, everolimus).

    Simvastatin

    Metabolism and clearance of simvastatin are highly dependent on isoenzyme CYP3A4. Receiving ranolazine 1000 mg twice a day increases the concentration of lactone simvastatin and simvastatin acid in the blood plasma approximately 2 times. The use of simvastatin in high doses is associated with the development of rhabdomyolysis, and cases of rhabdomyolysis with simultaneous application of ranolazine and simvastatin have also been described. The maximum dose of simvastatin for patients concomitantly taking ranolazine, should not exceed 20 mg / day. Atorvastatin

    The simultaneous use of ranolazine 1000 mg twice a day and atorvastatin 80 mg once a day increases Stach and AUC Atorvastatin 1.4 and 1.3 times, respectively, Stach and AUC metabolites of atorvastatin change by no more than 35%. With the simultaneous use of ranolazine and atorvastmay require a reduction in the dose of atorvastatin and proper clinical control.

    For other statins metabolized with participation of isoenzyme CYP3A4 (lovastatin), a dose adjustment may be required.

    Tacrolimus, ciclosporin, sirolimus, everolimus

    Increased plasma concentrations of tacrolimus, substrate isoenzyme CYP3A4, was observed in patients on the background of ranolazine. With the simultaneous use of tacrolimus and ranolazine, it is recommended that the concentration of tacrolimus in the blood plasma be monitored and, if necessary, dose adjustment should be performed. This approach is also recommended for other isoenzyme substrates CYP3A4 with a narrow therapeutic range (for example, ciclosporin, sirolimus, everolimus).

    Substrates of the conveyor of organic cations 2 (OCT2)

    With the simultaneous use of ranolazine 500 mg and 1000 mg twice a day and metformin 1000 mg twice a day, the concentration of metformin in the blood plasma in patients with type 2 diabetes is 1.4 and 1.8 times higher, respectively. It is possible to increase the concentration in the blood plasma of other substrates of OST2, including pindolol and varenicline, with simultaneous application with rananolin. Drugs that extend the OTC interval There is a theoretical likelihood that with the simultaneous use of ranolazine and other drugs, the lengtheninginterval QTc, pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase.These drugs include certain antihistamines (for example, terfenadine, astemizole, misolastine), certain antiarrhythmics (for example, quinidine, disopyramide, procainamide), and erythromycin and tricyclic antidepressants (eg, imipramine, doxepin, amitriptyline),

    Special instructions:

    The drug Raneksa is used for a long time.

    Renal insufficiency

    For patients with renal insufficiency light or moderate severity (clearance creatinine 30-80 ml / min) is recommended titradiation dose. Ranex® counter preparationzane patients with renal insufficiency of severe severity (creatinine clearance <30 ml / min).

    Given the possibility of reducing the function kidneys with age, in elderly patients and senile age is needed regularly monitor the status assessment kidney function with prolonged use of Ranex ®.

    Liver failure

    For patients with hepatic failuremild degree of severity (5-6 points for scale Child-Pugh) is recommended titration dose. The drug Raneksa is contraindicatedto patients with hepatic insufficiency average (7-9 on the Child-Pugh scale) or severe (more than 9 on the Child-I drink) of a degree of gravity.

    Elderly age (over 65 years)

    In elderly patients, there may be an increase in the action of the Ranex® drug due to the age-related decline in kidney function. There is an increased incidence of side effects.

    Body weight (less than 60 kg)

    Dose selection for patients with a body weight of less than 60 kg should be done with caution, since cases of side effects in these patients were observed more often.

    Chronic heart failure Dose selection for patients with moderate or severe heart failure (III-IV functional classes by classification NYHA) should be conducted with care. It is necessary to carry out regular monitoring of the development of side effects, if necessary, the dose of the drug should be reduced or treatment should be canceled.

    Interval lengthening QT A population analysis of pooled data from a study of patients and healthy volunteers showed that the dependence of the duration of the interval QTc of the concentration in the blood plasma can be estimated as 2.4 ms per 1000 ng / ml,which is approximately equal to an increase from 2 to 7 ms for a range of plasma concentrations corresponding to a dose of 500 to 1000 mg of ranolazine taken 2 times per day. Therefore, care must be taken when treating patients with congenital lengthening interval QT in the anamnesis, the presence of lengthening QT in the family history, patients with known acquired lengthening interval QT, as well as patients receiving treatment with drugs that affect the interval QTc.

    Insufficient isoenzyme activity CYP2D6:

    The risk of an increase in the incidence of side effects in these groups is increased in patients with insufficient isoenzyme activity CYP2D6 (patients with a "slow" metabolism) compared with patients with a normal ability to metabolize the isoenzyme CYP2D6 (patients with "fast" metabolism). Precautions are developed taking into account the risk for patients with a "slow" isoenzyme metabolism CYP2D6 and are necessary in the event that the status of isoenzyme metabolism CYP2D6 is unknown. For patients with "fast" isoenzyme metabolism CYP2D6 there is no need for such precautions.In patients who have been identified (for example, by genotyping) or a previously known intensive status of isoenzyme metabolism CYP2D6, Raneksa® drug should be used with caution if the patient has a combination of several of the above risk factors.

    Effect on the ability to drive transp. cf. and fur:

    Studies on the influence of Ranex ® on the ability to drive transport means and management mechanisms have not been conducted. Given the possibility of side effects such as dizziness, blurred vision, double vision, confusion, impaired coordination of movements and hallucinations, caution should be exercised in the management of vehicles and mechanisms, as well as classes of potentially hazardous activities that require high concentration and speed of psychomotor reactions .

    Form release / dosage:

    Tablets of prolonged action oncovered with a film coating, 500 mg.

    For 10, 15 or 20 tablets in a contour cell packaging (blister) made of PVC / PVDC / aluminum foil.

    For 3, 6, 10 blisters for 10 tablets or 2 blisters for 15 tablets or 3, 5 blisters for 20 tablets with instructions for use in a cardboard pack.

    Tablets of prolonged action covered with a film membrane, 1000 mg.

    For 10 or 15 tablets in a contour cell packaging (blister) made of PVC / PVDC / aluminum foil.

    For 3, 6, 10 blisters for 10 tablets or 2, 4 blisters for 15 tablets with instructions for use in a cardboard bundle.

    Packaging:

    Tablets of prolonged action oncovered with a film coating, 500 mg.

    For 10, 15 or 20 tablets in a contour cell packaging (blister) made of PVC / PVDC / aluminum foil.

    For 3, 6, 10 blisters for 10 tablets or 2 blisters for 15 tablets or 3, 5 blisters for 20 tablets with instructions for use in a cardboard pack.

    Tablets of prolonged action covered with a film membrane, 1000 mg.

    For 10 or 15 tablets in a contour cell packaging (blister) made of PVC / PVDC / aluminum foil.

    For 3, 6, 10 blisters for 10 tablets or 2, 4 blisters for 15 tablets with instructions for use in a cardboard bundle.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C. '

    Keep the medicine out of the reach of children!

    Shelf life:

    4 years.

    Do not use after the expiration date stated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001978
    Date of registration:23.01.2013
    The owner of the registration certificate:BERLIN-PHARMA, CJSC BERLIN-PHARMA, CJSC Russia
    Manufacturer: & nbsp
    Representation: & nbspBERLIN-CHEMI / MENARINI PHARMA GmbH BERLIN-CHEMI / MENARINI PHARMA GmbH Germany
    Information update date: & nbsp29.05.2014
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