Топамакс

General characteristics. Structure:

Active agent: топирамат 50 mg.

Excipients: sugar krupka [sucrose, starch syrup] of 150,00 mg, povidone of 34,733 mg, cellulose acetate of 18,076 mg. Structure of a solid gelatin capsule: gelatin of 80,6-83,5 mg, water of 12,5-15,4 mg, sorbitan laurate of 0,0397 mg, sodium lauryl sulfate of 0,0397 mg, titanium dioxide (E171) of 0,99 mg, Opacode Black S-1-17822/23 ink black (the structure blackened: shellac glaze solution in ethanol, ferrous oxide black, N - butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide) 5-10 mkg.

Pharmacological properties:

Pharmacodynamics.

Topiramat is the antiepileptic drug belonging to the class sulphamate - the replaced monosaccharides.

Topiramat blocks natrium channels and suppresses emergence of repeated action potentials against the background of long depolarization of a membrane of neuron. Topiramat increases activity of γ-aminobutyric acid of acid (GAMK) concerning the GAMK-some subtypes of receptors (including GAMKA-retseptorov), and also modulates activity of GAMKA-of receptors, interferes with activation kainaty sensitivity of a subtype kainat/AMPK (α-амино-3-гидрокси-5-метилизоксазол-4-пропионовая acid) - receptors to a glutamate, does not influence activity of N-methyl-D-aspartate (NMDA) concerning a subtype of NMDA receptors. These effects of a topiramat are dozozavisimy at concentration of drug in plasma from 1 µmol to 200 µmol, with the minimum activity ranging from 1 µmol to 10 µmol. Besides, топирамат activity of some isoenzymes of a karboangidraza oppresses. On expressiveness of this pharmacological effect топирамат considerably concedes to acetazoleamide – the known inhibitor of coal anhydrase therefore this activity of a topiramat is not considered the main component of its antiepileptic activity. 

Pharmacokinetics.

Topiramat is soaked up quickly and effectively. Its bioavailability makes 81%. Meal has no clinically significant effect on bioavailability of a topiramat. 13–17% of a topiramat contact proteins of plasma. After a single dose in a dose to 1200 mg the average volume of distribution makes 0,55–0,8 l/kg. The size of volume of distribution depends on a floor: at women it makes about 50% of the values observed at men that connect with higher content of fatty tissue in an organism of women.

After intake about 20% of the accepted dose are metabolized. However at the patients receiving the accompanying therapy by antiepileptic drugs which induce the enzymes which are responsible for metabolism of medicines metabolism of a topiramat about 50% increase. From plasma, urine and excrements of the person six almost inactive metabolites were allocated and identified. The main way of removal of not changed topiramat (70%) and its metabolites are kidneys. After peroral introduction the plasma clearance of a topiramat makes 20 – 30 ml/min. The pharmacokinetics of a topiramat has linear character, the plasma clearance remains to constants, and the area under a curve "concentration time" (AUC) increases in range of doses from 100 to 400 mg in proportion to a dose. At patients with normal function of kidneys from 4 to 8 days can be necessary for achievement of steady concentration in plasma. The size of the maximum concentration (Cmax) after multiple oral administration of 100 mg of drug twice a day on average made 6,76 mkg/ml. After multiple dose of doses on 50 and 100 mg twice a day the elimination half-life of a topiramat from plasma averaged 21 hour.

At patients with renal failures of average and heavy degree the plasma and renal clearance of a topiramat decreases (the clearance of creatinine (CC) ≤ 70 ml/min.), increase in equilibrium concentration of a topiramat in a blood plasma in comparison with the patients having normal function of kidneys is as a result possible. Besides, patients with renal failures, need more time for achievement of equilibrium concentration of a topiramat in blood. Use of a half of the recommended initial and maintenance dose is recommended to patients with an average or heavy renal failure.

Topiramat is effectively brought from plasma by a hemodialysis. The long hemodialysis can lead to decrease in concentration of a topiramat in blood below the quantity which is required for maintenance of anticonvulsant activity. In order to avoid bystry falling of concentration of a topiramat in plasma during a hemodialysis, purpose of an additional dose of the drug Topamaks® can be required. At dose adjustment it is necessary to take into account:

1) hemodialysis duration,

2) the size of clearance of the used system of a hemodialysis,

3) effective renal clearance of a topiramat at the patient who is on dialysis.

The plasma clearance of a topiramat decreases on average by 26% at patients with a liver failure of average or heavy degree. Therefore patients with a liver failure should apply топирамат with care.

At elderly patients without diseases of kidneys, the plasma clearance of a topiramat does not change.

Pharmacokinetics of a topiramat at children up to 12 years.

Pharmacokinetic parameters of a topiramat at children, the same as at the adults receiving this drug as auxiliary therapy have linear character, at the same time its clearance does not depend on a dose, and equilibrium concentration increase in plasma in proportion to increase in a dose. It is necessary to consider, however, the fact that at children the clearance of a topiramat is increased, and the period of its semi-removal shorter. Therefore, at the same dose, per 1 kg of body weight, concentration of a topiramat in plasma at children can be lower, than at adults. As well as at adults, the antiepileptic drugs inducing microsomal enzymes of a liver cause decrease in concentration of a topiramat in plasma in children.

Indications to use:

Epilepsy.

As means of monotherapy: at adults and children is more senior than 2 years with epilepsy (including at patients with for the first time the diagnosed epilepsy).

As a part of complex therapy: at adults and children is more senior than 2 years with partial or generalized toniko-clonic attacks, and also for treatment of attacks against the background of Lennox-Gasto's syndrome.

Migraine.

Prevention of attacks of migraine at adults. Topamaks's use for treatment of bad attacks of migraine is not studied.

Route of administration and doses:

Inside, regardless of meal. For achievement of optimum control of epileptic attacks at children and adult patients it is recommended to begin treatment with reception of low doses of drug with the subsequent gradual titration to an effective dose.

Capsules are intended for the patients experiencing difficulties with a proglatyvaniye of tablets (for example, children and elderly patients).

The Topamaks® capsules it is necessary to open, mix carefully contents of capsules with a small amount (about 1 teaspoon) of any soft food. This mix should be swallowed immediately, without chewing. It is not necessary to store the medicine mixed with food before the following reception.

The Topamaks® capsules can be swallowed entirely.

Partial or generalized toniko-clonic attacks, and also attacks against the background of Lennox-Gasto's syndrome.

Use in a combination with other anticonvulsant drugs at adult patients.

The minimal effective dose makes 200 mg a day. Usually total daily dose makes from 200 mg to 400 mg and is accepted in two steps. Increase in a daily dose to maximum – 1600 mg can be necessary for some patients. It is recommended to begin treatment with a low dose with the subsequent gradual selection of an effective dose. Selection of a dose is begun with 25 – 50 mg, accepting them for the night within 1 week. Further with week or two-week intervals the dose can be increased by 25–50 mg and to accept it in two steps. At selection of a dose it is necessary to be guided by clinical effect. At some patients the effect can be reached at administration of drug of 1 times a day. For achievement of optimum effect of treatment by the drug Topamaks® it is not obligatory to control its concentration in plasma.

These recommendations about a dose are applicable to all adult patients, including elderly people, in the absence of a disease of kidneys at them (see the section "Special Instructions").

The combined anticonvulsant therapy at children is more senior than 2 years.

The recommended total daily dose of the drug Topamaks® as means of additional therapy makes from 5 to 9 mg/kg and is accepted in two steps. It is necessary to begin selection of a dose with 25 mg (or less, based on an initial dose from 1 to 3 mg/kg a day), accepting them for the night within 1 week. Further with week or two-week intervals the dose can be increased by 1 – 3 mg/kg and to accept it in two steps. At selection of a dose it is necessary to be guided by clinical effect. Selection of a dose is begun with the capsule drug Topamaks® in a dosage of 15 mg or 25 mg. The daily dose to 30 mg/kg is usually well transferred.

Epilepsy (including for the first time diagnosed).

Monotherapy: general provisions.

At cancellation of the accompanying anticonvulsant drugs for the purpose of monotherapy topiramaty it is necessary to consider possible influence of this step on the frequency of attacks. When there is no need to sharply cancel the accompanying anticonvulsant drugs for safety reasons, it is recommended to reduce their doses gradually, reducing a dose of the accompanying antiepileptic drugs by one third each 2 weeks. At cancellation of the drugs which are inductors of microsomal enzymes of a liver concentration of a topiramat will increase in blood. In such situations, in the presence of clinical indications the dose of the drug Topamaks® can be lowered.

Monotherapy: adults.

In an initiation of treatment the patient has to accept 25 mg of the drug Topamaks® before going to bed within 1 week. Then the dose is raised at an interval of 1 – 2 week on 25 or 50 mg (the daily dose is divided into two receptions). 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 more smoothly. At selection of a dose it is necessary to be guided by clinical effect. The initial dose at monotherapy topiramaty at adults makes 100 mg a day, and the maximum daily dose should not exceed 500 mg. Some patients with refractory forms of epilepsy transfer monotherapy topiramaty in doses to 1000 mg to days. These recommendations to a podozirovaniye concern to all adults, including elderly patients, without diseases of kidneys.

Monotherapy: children.

To children 2 years in the first week of treatment are aged more senior it is necessary to give топирамат in a dose of 0,5 - 1 mg/kg of body weight before going to bed. Then the dose is raised at an interval of 1 – 2 week on 0,5 – 1 mg/kg a day (the daily dose is divided into two receptions). If the child does not transfer such mode of increase in a dose, then it is possible to raise a dose more smoothly or to increase intervals between increases in a dose. The size of a dose and speed of its increase have to be defined by clinical result. The recommended range of doses at monotherapy topiramaty at children aged is more senior than 2 years makes 100 – 400 mg/days. Children with recently diagnosed partial attacks can appoint up to 500 mg a day.

Migraine.

The recommended general daily dose of a topiramat for prevention of attacks of migraine makes 100 mg, accepted in 2 receptions. In an initiation of treatment the patient has to accept 25 mg of the drug Topamaks® before going to bed within 1 week. Then the dose is increased at an interval of 1 week by 25 mg a day. 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 more smoothly. 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.

Special groups of patients.

1. The renal failure can be necessary for Patients with a moderate or heavy renal failure a dose decline. Use of a half of the recommended initial and maintenance dose is recommended.

2. The hemodialysis As топирамат is removed from plasma at a hemodialysis, in days of carrying out a hemodialysis it is necessary to enter the additional dose of the drug Topamaks® equal to about a half of a daily dose. The additional dose has to be divided into two doses accepted at the beginning and after completion of the procedure of a hemodialysis. The additional dose can vary depending on characteristics of the equipment used when carrying out a hemodialysis.

3. A liver failure Patients with a liver failure топирамат should apply with care.

Features of use:

Antiepileptic drugs, including also the drug Topamaks®, it is necessary to cancel gradually to minimize a possibility of increase in frequency of attacks. For reduction of a dose by 25-50 mg use the capsule drug Topamaks® in a dosage of 15 mg or 25 mg. In clinical trials of a dose reduced by 50–100 mg with week intervals for adults at therapy of epilepsy and by 25–50 mg at the adults receiving 100 mg of the drug Topamaks® a day for prevention of migraine. At children in clinical trials of Topamaks® gradually cancelled within 2–8 weeks. If on medical indications bystry drug withdrawal of Topamaks® is necessary, then it is recommended to exercise the corresponding control of a condition of the patient.

As well as in case of use of other antiepileptic drugs, at some patients accepting топирамат increase in frequency of attacks or new types of attacks is observed. This phenomenon can be an effect of overdose, decrease in concentration jointly of the used antiepileptic drugs, progressing of a disease or a paradoxical effect. Removal speed through kidneys depends on function of kidneys and does not depend on age. At patients with the moderated or expressed renal failure from 10 to 15 days, unlike 4–8 days at patients with normal function of kidneys can be necessary for achievement of steady concentration in plasma.

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 stable concentration in plasma for each dose.

At therapy topiramaty emergence of an oligogidroz (the reduced sweating) and an anhidrosis is possible. Reduction of sweating and a hyperthermia (fervescence) can arise at the children subject to influence of high temperature of the environment. In this regard at therapy topiramaty the adequate increase in volume of 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 is very important.

Frustration mood / depression.

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

Suicide attempts.

At use of antiepileptic drugs, including the drug Topamaks®, the risk of emergence of suicide thoughts and suicide behavior at the patients accepting these drugs on any of indications increases.

In double blind clinical trials, the frequency of development of the phenomena connected with a suicide (suicide thoughts, attempts of a suicide, a suicide) made 0,5% at the patients receiving топирамат (at 46 people from 8652) that is about 3 times higher in comparison by the patients receiving placebo (0,2%; at 8 people from 4045). One case of a suicide was recorded in a double blind research of bipolar disorder at the patient receiving топирамат.

Thus, it is necessary to control 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 patients) at once to ask for medical care in case of signs of suicide thoughts or suicide behavior.

Nephrolithiasis.

At some patients, in particular, with predisposition to a nephrolithiasis, the risk of formation of stones in kidneys and emergence of the related symptoms, such as renal colic, kidney pain, a stitch 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.

Renal failure.

It is necessary to be careful at purpose of the drug Topamaks® to patients with a renal failure (clearance of creatinine <70 ml/min.). It is connected with the fact that at such patients the clearance of drug is lowered.

Abnormal liver function.

At patients with abnormal liver functions топирамат it is necessary to apply with care because of possible decrease in clearance of this drug.

Myopia and secondary closed-angle glaucoma.

At use of the drug Topamaks® the syndrome including an acute myopia 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 of 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 the drug Topamaks®. 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 administration of drug of Topamaks® 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. At purpose of a topiramat patients with diseases of eyes in the anamnesis need to estimate the attitude of the expected advantage towards possible risk of use.

Defects of a field of vision.

Defects of a field of vision were observed at the patients accepting топирамат irrespective of existence at them the increased intraocular pressure. During clinical trials the majority of such cases had reversible character, and defects of a field of vision disappeared after therapy cancellation topiramaty. At emergence of problems with sight during reception of a topiramat, it is necessary to consider the possibility of the termination of therapy.

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 hydrocarbonates in plasma below normal level in the absence of a respiratory alkalosis). Similar decrease in concentration of hydrocarbonates of blood serum is a consequence of the inhibiting effect of a topiramat on a renal karboangidraza. In most cases, decrease in concentration of hydrocarbonates 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 when using at adult patients in a dose higher than 100 mg a day and about 6 mg a day on body weight kg when using in pediatric practice). In rare instances at patients decrease in concentration of hydrocarbonates lower than the level of 10 mmol/l was noted. 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 a hydrocarbonate - 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 were not studied systematically at children and at adults.

Due to the above, at treatment topiramaty it is recommended to conduct necessary researches, including definition of concentration of hydrocarbonates in serum. In case of symptoms of a metabolic acidosis (for example, deep kussmaulevsky breath, диспноэ, anorexia, nausea, vomiting, increased fatigue, tachycardia or arrhythmia) carrying out definition of concentration of hydrocarbonates in serum is recommended. At emergence of a metabolic acidosis and its persistirovaniya, it is recommended to lower a dose or to stop reception of a topiramat.

Disturbance of cognitive functions.

Disturbance of cognitive functions at epilepsy has the multifactorial nature, and can be caused by the disease prime cause, directly epilepsy or antiepileptic therapy. At the adult patients accepting топирамат the cases of disturbance of cognitive functions demanding a dose decline or the termination of therapy were noted. Data on influence of a topiramat on cognitive functions at children are insufficient, and its effects demand further studying.

Suralimentation.

If the patient loses body weight at treatment by the drug Topamaks®, then it is necessary to consider a question of expediency of suralimentation.

Influence on ability to manage vehicles and mechanisms.

Топамакс® affects the central nervous system and can cause drowsiness, dizziness and other symptoms. It can also cause a vision disorder. These adverse phenomena can constitute danger to the patients driving the car and moving mechanisms, especially during the period, reaction of the patient to drug will not be established yet.

Side effects:

Undesirable reactions are given with distribution on frequencies and systems of bodies. Frequency of undesirable reactions was classified as follows: very often (≥1/10), it is frequent (≥1/100, <1/10), infrequently (≥1/1000 and <1/100), is rare (≥1/10000 and <1/1000) and frequency is unknown (frequency cannot be estimated according to the available data).

The most frequent undesirable reactions (which frequency was more than 5% and exceeded that in group of placebo at least for one of indications during controlled clinical trials of a topiramat) are: anorexia, a loss of appetite, the slowed-down thinking, a depression, disturbances of the free speech, sleeplessness, lacks of coordination of movements, disturbance of concentration of attention, dizziness, a dysarthtia, a dysgeusia, a hypesthesia, block, memory disturbances, a nystagmus, paresthesia, drowsiness, a tremor, a diplopia, a sight illegibility, diarrhea, nausea, fatigue, irritability and decrease in body weight.

Infections and invasions: very often: назофарингит*.

Disturbances from blood and lymphatic system:

- often: anemia;

- infrequently: leukopenia, lymphadenopathy, thrombocytopenia, eosinophilia;

- seldom: нейтропения*.

Disturbances from immune system:

- often: hypersensitivity;

- frequency is unknown: allergic hypostasis *, swelled конъюнктивы*.

Disturbances from metabolism and food:

- often: anorexia, loss of appetite;

- infrequently: metabolic acidosis, hypopotassemia, increase in appetite, polydipsia;

- seldom: giperkhloremichesky acidosis.

Mental disturbances:

- very often: depression;

- often: the slowed-down thinking, sleeplessness, disturbances of the free speech, alarm, confusion of consciousness, a disorientation, aggressive reactions, disturbances of mood, excitement, emotional lability, depressive mood, anger, a behavior disorder;

- infrequently: suicide thoughts, attempts of a suicide, a hallucination, psychotic frustration, auditory hallucinations, visual hallucinations, apathy, the complicated speech, sleep disorders, affective lability, decrease in a libido, the excited state, crying, a disfemiya, euphoric mood, paranoia, thinking perseveration, the panic attacks, tearfulness, disturbance of skills of reading, backfilling disturbance, flattening of emotions, pathological thinking, loss a libido, slackness, intrasomnichesky frustration, absent-mindedness, early awakenings in the mornings, panic reactions, high spirits;

- seldom: mania, panic frustration, feeling of a hopelessness *, hypomania.

Disturbances from the central nervous system:

- very often: paresthesias, drowsiness, dizziness;

- often: disturbance of concentration of attention, memory disturbance, amnesia, cognitive frustration, disturbance of thinking, psychomotor disturbances, spasms, incoordination of movements, tremor, block, hypesthesia, nystagmus, dysgeusia, disturbance of feeling of balance, dysarthtia, intentsionny tremor, sedation;

- infrequently: oppressed consciousness, toniko-clonic attacks as "grand mal", disturbance of a field of vision, difficult partial attacks, disturbance of the speech, a psychomotor hyperactivity, a syncope, touch disturbances, hypersalivation, a hypersomnia, aphasia, the repeating speech, a hypokinesia, dyskinesia, postural dizziness, poor quality of a dream, a burning sensation, an anesthesia, a parosmiya, a cerebral syndrome, a dizesteziya, a hypogeusia, a stupor, awkwardness, aura, an ageusia, a dysgraphia, a dysphasia, peripheral neuropathy, a preunconscious state, dystonia, feeling of "goosebumps" on a body;

- seldom: apraxia, disturbance of a circadian rhythm of a dream, hyperesthesia, hyposmia, anosmia, essential tremor, akineziya, lack of reactions to irritants.

Disturbances from an organ of sight:

- often: sight illegibility, diplopia, vision disorder;

- infrequently: visual acuity reduction, scotoma, a myopia *, strange feelings in eyes *, a xerophthalmus, a photophobia, a nictitating spasm, the raised dacryagogue, a photopsia, a mydriasis, a presbyopy;

- seldom: a unilateral blindness, a passing blindness, glaucoma, accommodation disturbance, disturbance of visual space perception, an ophthalmic migraine, the century *, a night blindness, an amblyopia swelled;

- frequency is unknown: closed-angle glaucoma *, maculopathia *, mobility disturbances глаза*.

Disturbances from an acoustic organ and balance:

- often: вертиго, a ring in ears, ear pain;

- infrequently: deafness, unilateral deafness, neurosensory deafness, discomfort in an ear, a hearing disorder.

Disturbances from cardiovascular system:

- infrequently: bradycardia, sinus bradycardia, heart consciousness.

Disturbances from vascular system:

- infrequently: hypotension, orthostatic hypotension, inflows, hot inflows;

- seldom: Reynaud's phenomenon.

Disturbances from respiratory system, bodies of a thorax and a mediastinum:

- often: short wind, nasal bleeding, nose congestion, rhinorrhea, cough *;

- infrequently: an asthma at an exercise stress, hypersecretion in paranasal sinuses, a dysphonia.

Disturbances from digestive tract:

- very often: nausea, diarrhea;

- often: vomiting, a lock, pain in epigastric area, dyspepsia, an abdominal pain, dryness in a mouth, discomfort in a stomach, disturbance of sensitivity in an oral cavity, gastritis, discomfort in a stomach;

- infrequently: pancreatitis, a meteorism, a gastroesophageal reflux, pain in the lower part of a stomach, decrease in sensitivity in an oral cavity, bleeding of gums, abdominal distention, discomfort in epigastric area, sensitivity in a stomach, hypersalivation, pain in an oral cavity, an unpleasant smell from a mouth, a glossodynia.

Disturbances from gepatobiliarny system:

- seldom: hepatitis, liver failure.

Disturbances from skin and hypodermic fabrics:

- often: alopecia, rash, itch;

- infrequently: an anhidrosis, disturbance of sensitivity in a face, a small tortoiseshell, an erythema, a generalized itch, macular rash, disturbance of a xanthopathy, allergic dermatitis, a swelling of the person;

- infrequently: Stephens-Johnson's syndrome *, a polymorphic erythema *, change of a smell of skin, paraorbital hypostasis *, the localized urticaria;

- frequency is unknown: toxic epidermal некролиз*.

Disturbances from skeletal and muscular system and connecting fabric:

- often: arthralgia, muscular spasms, mialgiya, muscular spasms, muscular weakness, skeletal muscular thorax pain;

- infrequently: a swelling of joints *, constraint of muscles, stitches, fatigue in muscles;

- seldom: discomfort in конечностях*.

Disturbances from kidneys and urinary tract:

- often: nephrolithiasis, pollakiuria, dysuria;

- infrequently: an urolithiasis aggravation (stones in kidneys), an urine incontience at a tension, a hamaturia, an urine incontience, frequent desires to an urination, renal colic, pains in kidneys;

- seldom: an urolithiasis aggravation (stones in an urethra) pochechnokanaltsevy ацидоз*.

Disturbances from generative organs and a mammary gland:

- infrequently: erectile dysfunction, sexual dysfunction.

The general frustration and disturbances caused by a route of administration:

- very often: fatigue;

- often: the increased body temperature, an adynamy, irritability, gait disturbances, feeling sick, concern;

- infrequently: hyperthermia, thirst, grippopodobny syndrome *, sluggishness, cold snap of extremities, feeling of intoxication, feeling of concern;

- seldom: face edema, calcification.

Change of laboratory indicators:

- very often: decrease in body weight;

- often: increase in body weight *;

- infrequently: a crystalluria, abnormal test result "tandem gait", a leukopenia, increase in activity of liver enzymes in blood serum, it is rare: reduction of maintenance of hydrocarbonates in blood.

Disturbances of social functioning: infrequently: disturbance of ability to training.

* – undesirable reaction is registered in the post-registration period from spontaneous messages. Frequency is calculated on the basis of these clinical trials.

Special groups:

Children:

The list of undesirable reactions which during controlled clinical trials were registered at children in 2 and more times more often than at adults is included below: a loss of appetite, increase in appetite, giperkhloremichesky acidosis, a hypopotassemia, behavior disorders, aggressive reactions, apathy, backfilling disturbance, suicide thoughts, disturbance of concentration of attention, block, disturbance of a circadian rhythm of a dream, poor quality of a dream, the raised dacryagogue, sinus bradycardia, feeling sick, gait disturbances.

The list of undesirable reactions which during controlled clinical trials were registered only at children is included below: eosinophilia, psychomotor hyperactivity, вертиго, vomiting, hyperthermia, pyrexia, disturbance of ability to training.

Interaction with other medicines:

Influence of drug of Topamaks on concentration of other antiepileptic drugs (PEP).

The concomitant use of drug of Topamaks 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 in whom addition of drug of Topamaks 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 (CYP2C19 isoenzyme). 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 the course of therapy and after cancellation of a lamotridzhin (an average dose of 327 mg a day) equilibrium concentration of a topiramat did not change.

Impact of other antiepileptic drugs on concentration of drug of Topamaks.

Phenytoinum and carbamazepine reduce concentration of drug of Topamaks in plasma. Addition or cancellation of Phenytoinum or carbamazepine against the background of treatment by drug of Topamaks 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 drug of Topamaks in plasma and, therefore, does not demand change of a dose of drug of Topamaks.

Results of these interactions are summed up in the following table:

Concentration of PEP:

Phenytoinum: ↔ **;

Carbamazepine: ↔;

Valproic acid: ↔;

Phenobarbital: ↔;

Primidonum: ↔.

Kontsentrats ия drug of Topamaks:

Phenytoinum: ↓ (48%);

Carbamazepine: ↓ (40%);

Valproic acid: ↔; 

Phenobarbital:;

Primidonum:.

↔ = Lack of effect

** = Increase in concentration at single patients

↓ = Decrease in concentration in plasma

= it was not investigated

PEP = antiepileptic drug

Other medicinal interactions.

Digoxin: in a research with use of a single dose the area under curve AUC ("concentration time") of digoxin in plasma at a concomitant use of the drug Topamaks® decreased by 12%. The clinical importance of this observation is not clear. At appointment or drug withdrawal of Topamaks® by the patient accepting digoxin, special attention needs to be paid to monitoring of concentration of digoxin in serum.

Means, the oppressing TsNS: within clinical trials of an effect of a concomitant use of drug of Topamaks with the alcohol or other substances oppressing the TsNS functions were not studied. It is recommended not to accept Topamaks together with the alcohol or other drugs causing TsNS function oppression.

The St. John's Wort which is made a hole. At joint reception of Topamaks and drugs on the basis of a St. John's Wort of made a hole (Hypericum perforatum) concentration of a topiramat in plasma can decrease and, as a result, efficiency of drug can also go down. Clinical trials of interaction of the drug Topamaks® and drugs on the basis of the St. John's Wort which is made a hole it was not carried out.

Oral contraceptives: in a research of medicinal interaction with oral contraceptives in which the combined drug containing Norethisteronum (1 mg) and ethinylestradiol (35 mkg) was used Topamaks in doses of 50-800 mg a day 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 the drug Топамакс® 200-800 of 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 the drug Topamaks®. 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 maniacal depressive psychosis use of a topiramat in doses to 200 mg a day did not influence lithium pharmacokinetics, however at higher doses (to 600 mg a day) the lity was raised by AUC for 26%. At simultaneous use of a topiramat and lithium it is necessary to control concentration of the last in a blood plasma.

Risperidon: the researches of medicinal interaction conducted with single and multiple dose of a topiramat by healthy volunteers and patients with bipolar disorder yielded identical results. At a concomitant use of a topiramat in doses of 250 or 400 mg in days of AUC of the risperidon accepted in doses of 1-6 mg a day decreases respectively by 16% and 33%. At the same time the pharmacokinetics of a 9-gidroksirisperidon did not change, and the total pharmacokinetics of active agents (a risperidon and 9 gidroksirisperidon) changed slightly. Change of system influence of a risperidona/9-gidroksirisperidon and topiramat was not clinically significant, and this interaction can hardly have clinical value.

Hydrochlorothiazide: medicinal interaction was estimated on healthy volunteers at separate and combined use of a hydrochlorothiazide (25 mg) and a topiramata (96 mg). Results of researches showed that at a concomitant use of a topiramat and a hydrochlorothiazide there is an increase in the maximum concentration of a topiramat by 27% and the squares under curve AUC of a topiramat for 29%. The clinical importance of these researches is not revealed. Purpose of a hydrochlorothiazide to the patients accepting топирамат can demand dose adjustment of a topiramat. Pharmacokinetic parameters of a hydrochlorothiazide were not exposed to significant change at the accompanying therapy topiramaty.

Metforminum: medicinal interaction was estimated on the healthy volunteers receiving Metforminum or a combination of Metforminum and a topiramat. Results of researches showed that at a concomitant use of a topiramat and Metforminum there is an increase in the maximum concentration and the square under an AUC metformin curve for 18% and for 25% respectively whereas the clearance of Metforminum at simultaneous use with topiramaty decreased by 20%. Topiramat did not influence time of achievement of the maximum concentration of Metforminum in a blood plasma in any way. The clearance of a topiramat at simultaneous use with Metforminum decreases. Extent of the revealed changes of clearance is not studied. The clinical importance of impact of Metforminum on pharmacokinetics of a topiramat is not clear. In case of addition or drug withdrawal of Topamaks at the patients receiving Metforminum it is necessary to control carefully a condition of the patient for assessment of a current of a diabetes mellitus.

Pioglitazon: medicinal interaction was estimated on healthy volunteers at separate and simultaneous use of a pioglitazon and topiramat. Reduction of the square under curve AUC of a pioglitazon for 15%, without change of the maximum concentration of drug was revealed. These changes were not statistically significant. For an active hydroxymetabolite of a pioglitazon decrease in the maximum concentration and the square under curve AUC for 13% and for 16% respectively was also revealed, and for an active ketometabolite decrease and the maximum concentration and the square under curve AUC for 60% was revealed. The clinical importance of these data is not found out. At simultaneous use by patients of drug of Topamaks and pioglitazon, it is necessary to control carefully a condition of the patient for assessment of a current of a diabetes mellitus.

Glibenclamidum: the research of medicinal interaction for studying of pharmacokinetics of Glibenclamidum (5 mg a day) in an equilibrium state applied separately or along with topiramaty (150 mg a day) at patients with a diabetes mellitus 2 types was conducted. At use of a topiramat of AUC glibenclamide decreased by 25%. Also system exposure – 4 and and 3-tsis-gidroksi-Glibenclamidum was reduced (respectively by 13% and 15%). Glibenclamidum did not influence pharmacokinetics of a topiramat in an equilibrium state. Statistically doubtful decrease in AUC of a pioglitazon by 15% in the absence of change of Cmax is revealed. At purpose of a topiramat the patient receiving Glibenclamidum (or purpose of Glibenclamidum the patient receiving топирамат), 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 drug of Topamaks with the drugs contributing to a nephrolithiasis can increase risk of formation of stones in kidneys. During treatment by drug of Topamaks it is necessary to avoid use of the drugs contributing to a nephrolithiasis as they can cause the physiological 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. At joint reception of a topiramat and valproic acid there can be a hypothermia (inadvertent decrease in body temperature below 35 °C) in combination with a giperammoniyemiya or is independent. This phenomenon can arise as after the beginning of joint reception of valproic acid and a topiramat, and at increase in a day dose of a topiramat.

Contraindications:

Hypersensitivity to any of components of this drug, children's age up to 2 years.

Overdose:

Signs and symptoms of overdose of the drug Topamaks®: spasms, drowsiness, disturbances of the speech and sight, diplopia, disturbances of thinking, lack of coordination of movements, lethargy, stupor, arterial hypotension, abdominal pain, dizziness, excitement and depression. In most cases clinical effects were not heavy, but fatal cases after overdose with use of mix of several medicines, including топирамат were celebrated. The overdose of a topiramat can cause a heavy metabolic acidosis (see the section "Special Instructions"). The overdose case when the patient accepted a dose of a topiramat from 96 to 110 g that caused the coma proceeding 20-24 hours is known. 3-4 days later the condition of the patient returned to norm.

Treatment. At acute overdose of the drug Topamaks® if shortly before it the patient ate food, it is necessary to wash out at once a stomach or to cause vomiting. 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 in the dry place at a temperature not above 25 °C. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Capsules of 50 mg. On 28 or 60 capsules in a bottle from polyethylene of high density. The bottle together with the instruction on a medical use is placed in a cardboard pack.