Torepimat

General characteristics. Structure:

Active ingredient: 25 mg, 50 mg, 150 mg or 200 mg of a topiramat.

Pharmacological properties:

Pharmacodynamics. Topiramat is sulphamate - the replaced monosaccharide, is applied as antiepileptic means. The mechanism of action is connected, with decrease in epileptiform categories and action potentials due to blockade of potentsialzavisimy natrium channels; strengthening of activity of GAMK in the relations of GAMK-receptors; and also antagonism with glutamatergichesky receptors of a kainatny subtype. Drug does not influence activity To - methyl - In - aspartate (NMDA) concerning NMDA receptors. These effects of a topiramat are linearly dependent on concentration in plasma in the range of 1-200 µmol/l. Also топирамат ugayetat activity of some isoenzymes of a karboangidraza (II and IV), however this effect weaker, than at acetazoleamide, and is probably not the basic in anticonvulsant activity of drug.

Pharmacokinetics. Topiramat is quickly and fully soaked up from a GIT. Bioavailability - 80%. TCmax is 2 h after intake in a dose of 400 mg. Cmax after multiple dose in 100 mg 2 times a day - 6.76 mkg/ml.

Linkng with proteins of plasma makes 13-17%. After a single dose in a dose to 1200 mg the volume of distribution makes 0.55-0.8 l/kg and depends on a floor: at women it makes about 50% of the sizes observed at men. Equilibrium concentration at patients with normal functions of kidneys is reached approximately in 4-8 days, at a renal failure of-10-15 days. Gets into breast milk.

It is metabolized in a liver by a hydroxylation, hydrolysis and a glyukuronirovaniye with education 6 pharmacological of inactive metabolites. The pharmacokinetics after a single dose inside has linear character, the plasma clearance remains constant - 20-30 ml/min.; the area under a curve "concentration time" (AUC) increases in range of doses of 100-400 mg in proportion to a dose. T1/2 after multiple dose of 50 and 100 mg 2 times a day - 21 h.

At heavy hepatic and renal (KK less than 60 ml/min.) insufficiency plasma and renal clearance decrease. It is removed preferential by kidneys in not changed look (70%) and in the form of metabolites. Is removed from plasma by means of a hemodialysis.

It is necessary to consider that T1/2 of a topiramat at children is approximately twice shorter, than at adults. Respectively, at reception of the same dose of drug (in mg/kg) as at adults, at children concentration in plasma can be lower, than at adults. It should be noted, as at adults, and at children, simultaneous with topiramaty reception of the antiepileptic drugs inducing liver enzymes reduces equilibrium concentration of a topiramat in plasma.

Indications to use:

Epilepsy:

— as means of monotherapy: at adults and children is more senior than 3 years (including patients with for the first time the revealed epilepsy);

— as a part of complex therapy: at adults and children is more senior than 3 years at partial or generalized toniko-clonic attacks, and also attacks against the background of Lennox-Gasto's syndrome.

Migraine:

— prevention of attacks of migraine at adults (use of a topiramat for treatment of bad attacks of migraine is not studied).

Route of administration and doses:

Torepimat accept inside, irrespective of meal.

As monotherapy at adults, including elderly patients with normal function of kidneys, begin with low doses - 25-50 mg of 1 times a day for the night. In 1 week the daily dose is gradually increased by 25-50 mg. Further gradual building of a daily dose (on 25-50 mg) is carried out bucketed in 1-2 weeks, to an effective dose. In case of signs of intolerance of the offered titration mode, increase in a daily dose is carried out by smaller portions and/or through big intervals. The recommended daily dose makes 100 mg. The maximum daily dose - 500 mg. In cases of refractory epilepsy the daily dose can be increased to 1000 mg. Individual selection of a dose in the range specified here is carried out by the doctor on the basis of clinical effect. Mode of administration of drug: 2 times a day, in equal doses.

At drug use Torepimat as monotherapy, it is necessary to consider possible influence of cancellation of the accompanying anticonvulsant therapy (other antiepileptic drugs) on the frequency of attacks. In those. cases when it is undesirable to cancel sharply other antiepileptic drugs, their doses reduce gradually, reducing a daily dose for 1/3 each 2 weeks. At cancellation of the antiepileptic drugs which are inductors of microsomal enzymes of a liver, concentration of a topiramat will increase in plasma. In such situations, in the presence of clinical indications, the dose can be reduced.

As a part of a combination therapy (with other anticonvulsant drugs) at adults, including elderly patients with normal function of kidneys, begin with low doses - 25-50 mg of 1 times a day for the night. In 1 week the daily dose is gradually increased by 25-50 mg. Further gradual building of a daily dosage (on 25-50 mg) is carried out bucketed in 1-2 weeks, to an effective dose. The average effective daily dose makes 200-400 mg. If necessary the daily dose is increased further, but, without exceeding the maximum daily dose in 1600 mg. Selection of an individual effective dose in the range of 200-1600 mg is carried out on the basis of clinical effect. Mode of administration of drug: 2 times a day, in equal dosages. In some cases the required clinical effect is reached at reception of 1 times a day.

At monotherapy at children 3 years with body weight less than 25 kg are more senior, in the first week of treatment Torepimat appoint in a dose 0.5-1 mg/kg of body weight before going to bed. Then the dose is raised at an interval of 1-2 weeks on 0.5-1 mg/kg a day, the daily dose is divided into 2 receptions. At intolerance of such mode the dose can be raised at a smaller size and/or with big intervals. The size of a dose and speed of its increase are defined by clinical performance of therapy. The recommended range of doses at monotherapy topiramaty at children is more senior than 3 years makes 3-6 mg/kg a day. At recently diagnosed partial attacks the dose can be brought to 500 mg a day.

As a part of a combination therapy with other anticonvulsant drugs at children 3 years with body weight less than 25 kg the recommended total daily dose are more senior makes from 5 to 9 mg/kg. Is accepted in 2 receptions, equal shares. Selection of a dose is begun with 25 mg a day (or less, at the rate of 1-3 mg on 1 kg of body weight of the child a day), at the same time drug is accepted once for the night within 1 week. Further, with week or two-week intervals the daily dose can be increased by 1-3 mg/kg, to accept drug in 2 receptions. At selection of a dose it is necessary to be guided by clinical effect. The daily dose to 30 mg/kg of body weight, as a rule, is well transferred.

In days of carrying out a hemodialysis Torepimat it is necessary to appoint in addition in a dose, equal 1/2 daily doses, in 2 receptions (before and after the procedure).

It is necessary to cancel drug gradually to minimize, a possibility of increase in frequency of attacks (on 100 mg/week).

Prevention of attacks of migraine. The recommended general daily dose of a topiramat for prevention of attacks of migraine makes 100 mg and is accepted in 2 receptions. In an initiation of treatment appoint 25 mg before going to bed within 1 week. Then the dose is increased by 25 mg/days at an interval of 1 week. If the patient does not transfer such mode of increase in a dose, then it is possible to increase intervals between increases in a dose, or to raise a dose at a smaller size. At selection of a dose it is necessary to be guided by clinical effect. At some patients the positive take is achieved at a daily dose of a topiramat of 50 mg. In clinical trials patients received various daily doses of a topiramat, but no more than 200 mg a day.

Features of use:

Use at pregnancy and feeding by a breast. Special researches in which топирамат it would be applied to treatment of pregnant women were not conducted. Nevertheless, it is impossible to exclude possible communication between use of a topiramat during pregnancy and inborn malformations (for example, craniofacial defects, a hypospadias and anomalies of various systems of an organism). The specified malformations were recorded both at monotherapy topiramaty, and at its use within complex therapy. Besides, results of researches with data of the accounting of pregnancies demonstrate that the risk of development of teratogenic effects at the combined treatment by antiepileptic drugs can be higher, than at monotherapy. Torepimat it is not necessary to apply during pregnancy, except emergency cases if the potential advantage for mother justifies risk for a fruit. The limited number of observations allows to assume that it топирамат is allocated with breast milk. In need of drug use Torepimat in the period of a lactation it is necessary to stop breastfeeding or to cancel drug.

Use at abnormal liver functions. With care at a liver failure.

Use at renal failures. With care at a renal failure.

Use for children. It is contraindicated to children up to 3 years.

Special instructions. Antiepileptic drugs, including топирамат, it is necessary to cancel gradually to minimize a possibility of increase in frequency of attacks. In clinical trials of a dose reduced by 50-100 mg with week intervals: for adults at therapy of epilepsy and on 25-50 mg at the adults receiving 100 mg of a topiramat a day for prevention of migraine. At children in clinical trials топирамат gradually cancelled within 2-8 weeks. If on medical indications bystry cancellation of a topiramat is necessary, then it is recommended to exercise the corresponding control of a condition of the patient.

Removal speed through kidneys depends on functions of kidneys and does not depend on age. At patients with the moderated or expressed renal failure in plasma from 10 to 15 days, unlike 4-8 can be necessary for achievement of steady concentration: days at patients with normal function of kidneys.

As well as at any disease, the scheme of selection of a dose has to be guided by clinical effect (i.e. extent of monitoring attacks, lack of side effects) and to consider that at patients with a renal failure more long time can be necessary for establishment of equilibrium concentration in plasma for each dose.

At therapy topiramaty adequate increase in volume is very important. the consumed liquid, capable to reduce risk of development of a nephrolithiasis, and also side effects which can arise under the influence of exercise stresses or the increased temperatures.

Frustration mood/depression. At treatment topiramaty the increased frequency of emergence of frustration of mood and a depression is observed.

Suicide attempts. At use antiepileptic the drugs including containing топирамат the risk of emergence суицидальньгх thoughts and suicide - behavior at the patients receiving these drugs on any of indications increases. The mechanism of increase in this risk is unknown. In this regard it is necessary to kotrolirovat a condition of patients for the purpose of identification of signs of suicide thoughts and to appoint the corresponding treatment. It is necessary to recommend to patients (and if necessary to the persons who are looking after them) immediately to ask for medical care in case of signs of suicide thoughts and suicide behavior.

Nephrolithiasis. At some patients, in particular with predisposition to a nephrolithiasis, the risk of formation of concrements in kidneys and emergence of the related symptoms, such as renal colic can increase. To reduce this risk, adequate increase in volume of the consumed liquid is necessary. Risk factors of development of a nephrolithiasis are a nephrolithiasis in the anamnesis (including in family), the hypercalcuria, the accompanying therapy by drugs which promote development of a nephrolithiasis.

Abnormal liver function. At patients with abnormal liver functions топирамат it is necessary to apply with care because of possible decrease in clearance of a topiramat.

Myopia and secondary closed-angle glaucoma. At use of a topiramat the syndrome including an ostruyumiopiya with the accompanying secondary closed-angle glaucoma is described. Symptoms include acute decrease in visual acuity and/or eye pain. At ophthalmologic inspection the myopia, flattening - an anterior chamber of an eye, a hyperemia (reddening) of an eyeglobe, increase in intraocular pressure can be found. The mydriasis can be observed. This syndrome can be followed by secretion of the liquid leading to an ectopia lentis and an iris of the eye forward with development of secondary closed-angle glaucoma. Symptoms usually appear in 1 month after the beginning of use of a topiramat. Unlike primary open angle glaucoma which is seldom observed at patients up to 40 years secondary closed-angle glaucoma is observed at use of a topiramat both for adults, and for children. At emergence of the syndrome including the myopia connected with closed-angle glaucoma treatment includes the termination of reception of a topiramat as soon as the attending physician finds possible it, and the appropriate measures directed to decrease in intraocular pressure. Usually these measures lead to normalization of intraocular pressure. The increased intraocular pressure of any etiology in the absence of adequate treatment can lead to serious complications, up to sight loss.

Metabolic acidosis. At use of a topiramat there can be giperkhloremicheskiya, not connected with deficit of anions, metabolic acidosis (for example, decrease in concentration of bicarbonates in plasma below normal value in the absence of a respiratory alkalosis). Similar decrease in concentration of bicarbonates of blood serum is a consequence of the inhibiting effect of a topiramat on a renal karboangidraza. In most cases, decrease in concentration of bicarbonates happens at the beginning of administration of drug though this effect can be shown in any period of treatment topiramaty. Extent of decrease in concentration usually weak or moderate (average value makes 4 mmol/l at use at. it is higher than 100 mg of adult patients in a dose in day and about 6 mg a day on body weight kg at use for children). In rare instances at patients lower than 10 mmol/l were noted decrease in concentration of bicarbonates. Some diseases or ways of treatment contributing to development of acidosis (for example, diseases of kidneys, a serious respiratory illness, the epileptic status, diarrhea, surgical interventions, a ketogenic diet, reception of some medicines) can be the accessory factors strengthening bicarbonate - the reducing effect of a topiramat.

At children the chronic metabolic acidosis can, lead to growth delay. Effect of a topiramat on growth and possible complications connected with bone system at children and at adults were not studied systematically.

Due to the above at treatment topiramaty it is recommended to conduct necessary researches, including definition of concentration of bicarbonates in serum. At emergence of a metabolic acidosis and its persistirovaniya, it is recommended to lower a dose or to stop reception of a topiramat.

Laboratory indicators. The hypopotassemia defined as decrease in potassium concentration in blood serum is lower than 3,5 mmol/l, was observed at 0,4% of the patients receiving топирамат.

Suralimentation. If at the patient body weight at treatment decreases topiramaty, then it is necessary to consider a question of expediency of suralimentation.

Influence on ability to driving of motor transport and to control of mechanisms. During treatment it is necessary to be careful at control of vehicles and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Frequency of development of the side effects developing at use of a topiramat is classified according to WHO recommendations: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0.1%, but less than 1%; seldom - not less than 0.01%, but less than 0.1%; very seldom - less than 0.01%, including separate messages.

Infections: very seldom - a nasopharyngitis.

Disturbances from blood and lymphatic system: often - anemia; infrequently - the leukopenia, a lymphadenopathy, thrombocytopenia, at children is an eosinophilia; very seldom - a neutropenia.

Disturbances from TsNS: very often - drowsiness, dizziness, paresthesias, at children is apathy, disturbance of attention; often - a lack of coordination of movements, a nystagmus, slackness, memory disturbance (including anemia), disturbance of concentration of attention, a tremor, amnesia, gait disturbance, a hypesthesia, a perversion of flavoring feelings, disturbance of thinking, decrease in cerebration, psychomotor disturbances, sedative action, disturbance of the speech, a dysarthtia, cognitive frustration, apathy, mental lameness; infrequently - loss of flavoring sensitivity, a hypokinesia, an akineziya, decrease in sense of smell, aphasia, apraxia, emergence of epileptic aura, a burning sensation in extremities or on a face, a cerebellar syndrome, disturbance of a circadian rhythm of a dream, difficult partial attacks, spasms, postural dizziness, a dizesteziya, the strengthened salivation, a dysgraphia, dyskinesia, a dysphasia, an allotopia, feeling of "goosebumps" on a body, toniko-clonic attacks as "grand mal", the hyperesthesia, a hypogeusia, a hypokinesia, a hyposmia, a peripheral neyropaniya, a parosmiya, preunconscious states, the repeating speech, touch disturbance, a stupor, a syncope, lack of reactions to incentives, at children is a psychomotor hyperactivity.

Mental disturbances: often - the slowed-down thinking, the expressed disturbances of the speech, confusion of consciousness, a depression, sleeplessness, aggressive reactions, excitement, irritability, a disorientation, emotional lability, erectile dysfunction, at children is change of behavior, not learnability (difficulty with reading, the letter, the account); infrequently - an anorgazmiya, sexual dysfunction, tearfulness, early awakenings on ugra, euphoric mood, apathy, auditory and visual hallucinations, hypomaniacal states, reduction of a libido, a mania, panic state, paranoid states, thinking perseveration, disturbance of skills of reading, a disfemiya, the raised otvlekayemost, sleep disorders, the suicide ideas or attempts, tearfulness; very seldom - feeling of despair.

Disturbances from digestive tract and gepatobiliarny system: very often - appetite reduction, anorexia; often - nausea, diarrhea; infrequently - an abdominal pain, a lock, discomfort in a stomach, the dispepsichesky phenomena, dryness in a mouth, gastritis, a gastroesophageal reflux, bleeding of gums, weight in a stomach, at children is vomiting, an unpleasant smell from a mouth, a meteorism, a glossodynia, mouth pain, disturbance of sensitivity in an oral cavity; infrequently - discomfort in epigastric area, hypersecretion of sialadens, thirst.

Disturbances from skeletal and muscular system and connecting fabric: often - a mialgiya, including in a thorax, muscular spasms, muscular spasms, an arthralgia; infrequently - stitches, muscular exhaustion, muscular weakness, constraint of muscles; very seldom - a swelling of joints, discomfort in extremities.

Disturbances from cardiovascular system: infrequently - bradycardia, a heart consciousness, blood "inflows", orthostatic hypotension, Reynaud's syndrome.

General disturbances: very often - fatigue, irritability, a body degrowth; often - an adynamy, concern; children have an increased temperature; infrequently face edema, allergic reactions, giperkhloremichesky acidosis, hypopotassemia, increase in appetite, metabolic acidosis, polydipsia, cold snap of extremities; very much - it is rare - generalized hypostasis, a grippopodobny syndrome, allergic hypostasis, conjunctival hypostasis, increase in body weight.

Ophthalmologic disturbances: often - a diplopia, a vision disorder, a xerophthalmus; infrequently - accommodation disturbance, an amblyopia, a nictitating spasm, a passing blindness, a unilateral blindness, the raised dacryagogue, a mydriasis, night, a blindness, a photopsia, a presbyopy, scotoma, including ciliary, visual acuity reduction; very seldom - unpleasant feelings in eyes, it is closed coal glaucoma, the involuntary movements of eyeglobes, the century, a myopia, a maculopathia, konjyuktivalny hypostasis swelled.

Disturbances from body of an ear: often - ear pains, a ring in ears, at children - вертиго; infrequently - deafness, including neurosensory and unilateral, discomfort in ears, a hearing disorder.

Disturbances from respiratory system: often - the complicated breath, nasal bleeding; infrequently - a hoarseness, a hoarseness, an asthma at an exercise stress; in okolonosovy bosoms, children have a nose congestion, hypersecretion a rhinorrhea.

Disturbances from skin and hypodermic fabrics: often - rash, an alopecia, an itch, reduction of sensitivity of the person; infrequently - lack of sweating, allergic dermatitis, erubescence, disturbance of a xanthopathy, makulezny rash, a face edema, an unpleasant smell of skin, a small tortoiseshell; very seldom - a polymorphic erythema, paraorbital hypostasis, Stephens-Johnson's syndrome, a toxic epidermal necrolysis.

Disturbances from kidneys and urinary tract: often - a nephrolithiasis, a dysuria, a pollakiuria; infrequently - an urolithiasis, a hamaturia, an urine incontience, frequent desires to an urination, renal colic, kidney pains; very seldom -
pochechnokanaltsevy acidosis.

Change of laboratory indicators: infrequently - reduction of maintenance of hydrocarbonates in blood, a crystalluria, a leukopenia, a hypopotassemia (decrease in potassium concentration in serum is lower than 3.5 mmol/l).

Interaction with other medicines:

Influence of a topiramat on concentration of other antiepileptic drugs (PEP). The concomitant use of a topiramat with other PEP (Phenytoinum, carbamazepine, valproic acid, phenobarbital, Primidonum) does not exert impact on values of their equilibrium concentration in plasma, except for certain patients, at which addition of a topiramat to Phenytoinum can cause increase in concentration of Phenytoinum in plasma. It can be connected - with oppression of a specific polymorphic isoform of enzyme of system of P450 cytochrome (CYP2Cmeph) - Therefore at each patient who accepts Phenytoinum and at whom clinical signs or symptoms of toxicity develop it is necessary to watch concentration of Phenytoinum in plasma. In a pharmacokinetics research at patients with epilepsy addition of a topiramat to a lamotridzhin did not influence equilibrium concentration of the last at doses of a topiramat of 100-400 mg a day. In process and after cancellation of a lamotridzhin (an average dose 327. mg, in days) equilibrium concentration of a topiramat did not change.

Impact of other PEP on concentration of a topiramat. Phenytoinum and carbamazepine reduce concentration of a topiramat in plasma. Addition or cancellation of Phenytoinum or carbamazepine against the background of treatment topiramaty can demand change of a dose of the last. The dose should be selected, being guided by achievement of necessary clinical effect. Addition or cancellation of valproic acid does not cause clinically significant changes of concentration of a topiramat in plasma and, therefore, does not demand change of a dose. Results of these interactions are summed up in the following table:

The added PEP	Concentration of PEP	Concentration of a topiramat
Phenytoinum	NC or increase 25%*	Decrease in 48%
Carbamazepine	NC	Decrease in 40%
Valproic acid	Decrease in 11%	Decrease in 14%
Phenobarbital	NC
Primidonum	NC

* = increase in concentration in plasma for 25% at the certain patients who are usually accepting Phenytoinum 2 times a day

NC = change of concentration in plasma less than for 10%

= it is not investigated

Other medicinal interactions. Digoxin: in a research using a single dose of digoxin the area under a curve "concentration time" (AUC) of digoxin at a concomitant use of a topiramat decreases by 12%. The clinical importance of this observation is not clear. At appointment or cancellation of a topiramat by the patient accepting digoxin, special attention needs to be paid to monitoring of concentration of digoxin in serum.

Means, the oppressing TsNS: combined use of a topiramat with the medicines exerting the oppressing impact on TsNS and also with alcohol is not recommended.

Oral contraceptives: in a research of medicinal interaction with oral contraceptives in which the combined drug containing Norethisteronum (1 mg) and ethinylestradiol (35 mkg) топирамат in doses of 50-800 mg a day was used had no significant effect on efficiency of Norethisteronum and in doses of 50-200 mg a day - on efficiency of ethinylestradiol. Essential dozozavisimy decrease in efficiency of ethinylestradiol was observed at doses of a topiramat of 200-800 mg a day. The clinical importance of the described changes is not clear. The risk of decrease in efficiency of contraceptives and strengthening of breakthrough bleedings has to be considered at the patients accepting oral contraceptives in combination with topiramaty. The patients accepting estrogensoderzhashchy contraceptives need to report about any changes in terms and character of periods. Efficiency of contraceptives can be reduced even in the absence of "breakthrough" bleedings.

Lithium: at healthy volunteers decrease in AUC of lithium by 18% at a concomitant use of a topiramat in a dose of 200 mg a day was observed. At patients with bipolar disorder use of a topiramat in doses to 200 mg a day did not influence lithium pharmacokinetics, however at higher doses of 0do 600 mg a day) AUC of lithium was raised for 26%. At simultaneous use of a topiramat and lithium it is necessary to control concentration of the last in a blood plasma.

Hydrochlorothiazide: purpose of a gidrokhlorota of azide to the patients accepting топирамат can demand dose adjustment of a topiramat.

Metforminum, пиоглитазон, Glibenclamidum: at joint appointment with topiramaty it is necessary to control carefully a condition of the patient for assessment of a current of a diabetes mellitus.

Other drugs. Simultaneous use of a topiramat with the drugs contributing to a nephrolithiasis can increase risk of formation of concrements in kidneys. During treatment topiramaty it is necessary to avoid use of the drugs contributing to a nephrolithiasis as they can cause the changes promoting a nephrolithiasis.

Valproic acid. The combined use of a topiramat and valproic acid for the patients who are well transferring each drug separately is followed by a giperammoniyemiya with encephalopathy or without it. In most cases symptoms and signs disappear after cancellation of one of drugs. This adverse phenomenon is not caused by pharmacokinetic interaction. Communication between a giperammoniyemiya and use of a topiramat separately or in a combination with other drugs is not established.

Contraindications:

— children's age up to 3 years;

— deficit of lactase;

— lactose intolerance;

— glyukozo-galaktozny malabsorption;

— hypersensitivity to a topiramat or other components of drug.

With care: a liver or renal failure, a nephrolithiasis in the anamnesis (including family), a hypercalcuria.

Overdose:

Symptoms: spasms, drowsiness, disturbances of the speech and sight, diplopia, disturbances of thinking, lack of coordination of movements, lethargy, stupor, lowering of arterial pressure, abdominal pain, dizziness, excitement and depression. In most cases the known clinical effects were not heavy, however fatal cases after overdose using a combination of several medicines, including топирамат are known. The overdose topiramaty can cause a heavy metabolic acidosis (see the section "Special Instructions").

Treatment: at acute overdose it is necessary to wash out at once a stomach or to cause vomiting. Use of absorbent carbon is inefficient since in experiments in the researches in vitro it was shown that absorbent carbon adsorbs топирамат. If necessary it is necessary to carry out symptomatic therapy. Efficiently removal of a topiramat from an organism the hemodialysis is. Adequate increase in volume of the consumed liquid is recommended to patients.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

7 pieces - blisters (1) - packs cardboard.
7 pieces - blisters (2) - packs cardboard.
7 pieces - blisters (3) - packs cardboard.
7 pieces - blisters (4) - packs cardboard.
7 pieces - blisters (6) - packs cardboard.
7 pieces - blisters (8) - packs cardboard.
7 pieces - blisters (9) - packs cardboard.
7 pieces - blisters (10) - packs cardboard.
10 pieces - blisters (1) - packs cardboard.
10 pieces - blisters (2) - packs cardboard.
10 pieces - blisters (4) - packs cardboard.
10 pieces - blisters (3) - packs cardboard.
10 pieces - blisters (6) - packs cardboard.
10 pieces - blisters (8) - packs cardboard.
10 pieces - blisters (9) - packs cardboard.
10 pieces - blisters (10) - packs cardboard.