Topiramat

General characteristics. Structure:

Active ingredient: 25 mg or 100 mg of a topiramat.

Excipients: cellulose microcrystallic, starch prezhelatinizirovanny, silicon dioxide colloid (aerosil), magnesium stearate, опадрай II (polyvinyl alcohol, macrogoal, talc, titanium dioxide, dye quinolinic yellow aluminum varnish and dye of a sunset yellow aluminum varnish).

The drug appointed by the specialist doctor (the neurologist, epileptology, the psychiatrist) at epilepsy, convulsive attacks or certain forms of attacks of migraine. Treatment is usually long, it can be carried out both as monotherapy, and in combination with other drugs.

Pharmacological properties:

Pharmacodynamics. Topiramat is antiepileptic means, sulfate - the replaced monosaccharides belongs to the class. Blocks natrium channels and suppresses emergence of repeated action potentials against the background of long depolarization of a membrane of neuron. Increases activity of piperidic acid (GAMK) concerning some subtypes of GAMK-receptors (including GAMKA-retseptorov), and also modulates activity GAMKA-retseptorov, interferes with activation kainat/AMPK (а-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 a topiramat in plasma 1 to 200 µmol/l, with the minimum activity ranging from 1 to 10 µmol/l.

Besides, топирамат activity of some isoenzymes of a karboangidraza (II-IV) oppresses. On expressiveness of this pharmacological effect топирамат considerably concedes to acetazoleamide - the known inhibitor of a karboangidraza therefore this action of a topiramat is not the main component of its antiepileptic activity.

Pharmacokinetics. After intake топирамат it is quickly and well soaked up from digestive tract. Bioavailability makes about 81%. After intake of 400 mg of a topiramat the maximum concentration in plasma (Cmax) of 1,5 mkg/ml is reached within 2 hours. Meal has no clinically significant effect on bioavailability of a topiramat. The size Cmax after multiple dose in 100 mg of a topiramat twice a day on average made 6,76 mkg/ml.

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.

Communication with proteins of a blood plasma for a topiramat makes 13-17% in the range of concentration in a blood plasma of 0,5-250,0 mkg/ml. 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: women have about 50% of the values observed at men that connect with higher content of fatty tissue in an organism of women. Equilibrium concentration at reception of a topiramat at patients with normal function of kidneys is reached in 4-8 days. Gets into breast milk and through a placental barrier.

After intake about 20% of the accepted dose are metabolized. It is metabolized by a hydroxylation, hydrolysis and a glyukuronirovaniye. However at the patients receiving the accompanying therapy by antiepileptic drugs (PEP) which are inductors of microsomal enzymes metabolism of a topiramat about 50% increased. From a blood plasma, urine and a calla six almost inactive metabolites were allocated and identified. At a concomitant use of inductors of isoenzymes of P450 cytochrome the metabolic rate of a topiramat makes up to 50%.

The main way of removal of not changed topiramat (about 70%) and its metabolites are kidneys. After intake the plasma clearance of a topiramat made 20–30 ml/min. After multiple dose inside twice a day the elimination half-life (T1/2) of a topiramat from a blood plasma averages 50 and 100 mg 21 hour. Is removed from plasma by means of a hemodialysis.

Pharmacokinetics in special clinical cases. The renal and plasma clearance of a topiramat at easy degree of a renal failure (the clearance of creatinine (CC) more than 70 ml/min.) is not changed. At average degree of a renal failure (KK of 30-69 ml/min.) the renal and plasma clearance of a topiramat is reduced by 42%, and at heavy degree of a renal failure (KK less than 30 ml/min.) the renal and plasma clearance of a topiramat is reduced by 54% and more.

At moderate and heavy degree of a liver failure the plasma clearance of a topiramat is reduced by 20-30%.

At elderly patients without renal and liver failure the clearance of a topiramat is not changed.

The pharmacokinetics of a topiramat at children, as well as at adults, has linear character with clearance, independent of a dose; equilibrium concentration of a topiramat increases in a blood plasma in proportion to increase in a dose. At children the clearance of a topiramat is increased, and T1/2 is reduced therefore at the same dose at the rate on 1 kg of body weight concentration of a topiramat in a blood plasma at children will 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 a blood plasma in children and increase extent of his metabolism.

Indications to use:

In monotherapy at adults and children since 6 years with partial (with secondary generalization or without) or initially generalized toniko-clonic spasms.

As a part of complex therapy at adults and children is more senior than 3 years with partial with secondary generalization or without or generalized toniko-clonic spasms, and also for treatment of the spasms caused by Lennox-Gasto's syndrome.

Prevention of attacks of migraine at adults after careful assessment of all possible alternatives. Topiramat is not intended for treatment of bad attacks of migraine.

Route of administration and doses:

Inside, irrespective of meal. Tablets should not be divided.

For optimum control of attacks it is recommended to begin treatment with low doses with the subsequent increase up to an effective dose. At use as monotherapy it is necessary to consider possible influence of cancellation of the accompanying antiepileptic drugs (PEP) on the frequency of attacks. When there is no need to sharply cancel PEP, their doses are recommended to be reduced gradually, reducing doses by 1/3 each 2 weeks. At cancellation of the medicines which are inductors of microsomal enzymes of a liver, concentration of a topiramat will increase in a blood plasma that should be considered in the carried-out therapy.

Monotherapy. Adults. The adult at the beginning of performing monotherapy - on 25 mg of 1 times a day for the night within 1 week. Then the dose is raised at an interval of 1-2 weeks on 25-50 mg/days (the daily dose is divided into 2 receptions). At intolerance of such mode of therapy the dose is raised at a smaller size or through big intervals. The dose is selected depending on efficiency and portability of the carried-out therapy. The recommended initial target dose – 100-200 mg/days, the maximum daily dose should not exceed 500 mg at monotherapy. Recommendations about dosing concern to all adults, including the elderly patients who do not have diseases of kidneys.

To children 6 years at monotherapy in the first week of treatment are more senior - on 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 two receptions). At intolerance of such mode of therapy the dose is raised more smoothly or through big intervals between increases in a dose. The size of a dose and speed of its increase are defined by clinical performance and portability of therapy. The recommended range of doses at monotherapy topiramaty at children of 100 mg/days also depends on clinical performance (at children of 6-16 years it makes about 2 mg/kg/days).

As a part of a combination therapy. Adults. At appointment as a part of a combination therapy with other anticonvulsant medicines at adults an initial dose – 25-50 mg of 1 times a day for the night during 1 week. Further the dose is increased by 25-50 mg every week before achievement of an effective dose. The minimal effective dose makes 200 mg/days, an average daily dose - 200-400 mg, frequency rate of reception - 2 times a day. Doses more than 1600 mg a day are not studied. As criterion of selection of a dose serves the clinical effect and portability, at some patients this effect can be reached at administration of drug of 1 times a day. Recommendations about dosing concern to all adults, including the elderly patients who do not have diseases of kidneys.

Children. At appointment as a part of the combined anticonvulsant therapy at children 3 years the recommended total daily dose - 5-9 mg/kg for 2 receptions are more senior. Selection of a dose is begun with 25 mg/days (at the rate of 1-3 mg/kg/days) for the night within 1 week. Further the dose can be increased by 1-3 mg/kg within 1-2 weeks and to accept in 2 receptions. As criterion of the correct selection of a dose serves the stable clinical effect and good tolerance. The day dose to 30 mg/kg is usually well transferred.

Prevention of migraine. The recommended general daily dose of 100 mg in 2 receptions. Begin treatment with a dose on 25 mg or less before going to bed within 1 week. Then the dose is increased by 25 mg / by cут at an interval of 1 week. At intolerance of such mode the dose is raised at a smaller size or through big intervals of time. The dose is selected depending on clinical effect. At some patients the positive take is achieved at a daily dose of 50 mg/days. At use of a daily dose more than 100 mg/days of additional effect as prevention of migraine are not observed.

Patients with a renal failure. For patients moderated (less than 70 ml/min.) and heavy (KK less than 30 ml/min.) degree of a renal failure the recommended initial dose has to be reduced by KK twice, and it is necessary increase it by smaller size or through big intervals of time. The dose is selected depending on clinical effect. It must be kept in mind that achievement of equilibrium concentration will demand a bigger amount of time and will make from 10 to 15 days after each increase in a dose of drug Topiramat.

The patients needing a hemodialysis. As топирамат it can be removed by means of a hemodialysis, in days of its carrying out the daily dose of drug has to be increased by 50%. The additional dose is divided into 2 parts and is entered before a hemodialysis and after its termination. The additional dose can differ depending on characteristics of dialysis and the used equipment. The dose is selected depending on clinical effect.

At patients with a liver failure drug Topiramat should be taken with caution under control of the doctor because of reduced clearance of a topiramat.

Dose adjustment is not required from elderly patients.

Drug withdrawal. Antiepileptic drugs, including топирамат, should be cancelled gradually to minimize a possibility of increase in frequency of attacks, lowering a dose by 50-100 mg at an interval of 1 week at treatment of epilepsy and on 25-50 at Topiramat's use for prevention of migraine. Children have a cancellation 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. The main way of removal of a topiramat and its metabolites in not changed look is excretion kidneys. Removal speed kidneys depends on function of kidneys and does not depend on age. At patients with moderately or strongly expressed renal failures 10-15 days in comparison with 4-8 days at patients with normal function of kidneys can be necessary for achievement of equilibrium concentration in a blood plasma.

As well as at use of other PEP, the scheme of selection of a dose of drug Topiramat has to be guided by a therapeutic effectiveness (that is extent of decrease in frequency of attacks, lack of side effects) and has to consider that at patients with renal failures more long time can be necessary for establishment of equilibrium concentration of a topiramat in a blood plasma for each dose.

Features of use:

Special controlled researches in which топирамат it was applied to treatment of pregnant women were not conducted. Are available this, testimonial of possible communication between use of a topiramat during pregnancy and inborn malformations (for example, craniofacial defects ("labium leporium" / "a wolf mouth"), a hypospadias, deficit of body weight of a fruit and the newborn). The specified malformations were recorded both at monotherapy topiramaty, and at its simultaneous use with other antiepileptic drugs (PEP). Given the accounting of pregnancies and results of researches of monotherapy topiramaty demonstrate increase in probability of the birth of children with deficit of body weight (less than 2500). Connection of these cases with reception of a topiramat is not established. Data of other researches demonstrate that the risk of development of teratogenic effects at the combined treatment with other antiepileptic drugs can be higher, than at monotherapy.

Use of a topiramat at pregnancy is contraindicated. For the period of treatment by drug use of effective methods of contraception is necessary.

The limited number of observations of patients allows to assume that it топирамат is allocated with breast milk therefore during drug use breastfeeding should be stopped.

The women having genital potential are recommended to use effective methods of contraception and to consider alternative types of treatment. If топирамат it is applied during pregnancy or if the patient became pregnant during reception of this drug, the doctor should warn her about potential risk for a fruit.

Antiepileptic drugs, including топирамат, should be cancelled gradually to minimize a possibility of increase in frequency of attacks. If on medical indications bystry cancellation of a topiramat is necessary, then it is necessary to exercise the corresponding control of a condition of the patient.

As well as at any disease, the scheme of selection of a dose has to be guided by clinical effect and consider that at patients with a renal failure more long time can be necessary for establishment of stable concentration of a topiramat in plasma for each dose (from 10 to 15 days, unlike 4-8 days at patients with normal function of kidneys). Removal speed through kidneys depends on function of kidneys and does not depend on age. 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 and suicide attempts.

At drug use Topiramat is observed increase in frequency of emergence of frustration of mood (including increase in aggression), psychotic reactions and a depression.

During clinical trials at patients with epilepsy at use of a topiramat more often than in group of placebo, the cases connected with increase in suicide activity (suicide thoughts, suicide attempts and a complete suicide) were observed: frequency made 0,5% at the patients receiving топирамат (46 of 8652 patients) and patients of the receiving placebos have 0,2%. The origins of this risk are unknown. At use of a topiramat it is necessary to conduct examination of patients on existence of suicide thoughts and suicide behavior. At detection of suicide activity at patients it is necessary to consider the possibility of performing the corresponding treatment. Patients, their relatives, personnel on care of the patient should be informed on need to see a doctor at identification of signs of a suicide orientation and suicide behavior.

Patients with any personal frustration need special control, especially an initiation of treatment topiramaty.

Nephrolithiasis. At patients with predisposition to a nefrorolitiaz the risk of formation of stones in kidneys which prevention requires adequate increase in volume of the consumed liquid increases. 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 drug Topiramat 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 the broken function of a liver топирамат it is necessary to accept carefully because of possible decrease in clearance of this drug.

Myopia and secondary closed-angle glaucoma. At use of a topiramat 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 an ophthalmologic research reveal a myopia, flattening of depth of an anterior chamber, a hyperemia (reddening of eyes) and the increased intraocular pressure, and also there can be a mydriasis. The described syndrome can be connected with a supratsiliarny exudate which causes shift of a crystalline lens and iris of the eye and development of secondary closed-angle glaucoma. As a rule, symptoms arise after a month of primary therapy. Unlike primary open angle glaucoma which was seldom revealed at patients up to 40 years the secondary closed-angle glaucoma connected using a topiramat was observed both at children, and at adults. Treatment Topiramat provides drug withdrawal if the doctor counts it reasonable, and acceptance of the appropriate measures for decrease in intraocular pressure. The increased intraocular pressure 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. 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 in a blood plasma happens at the beginning of reception of a topiramat though this effect can be shown in any period of treatment by drug Topiramat. Decrease in concentration of hydrocarbonates in a blood plasma usually weak or moderate (average concentration in a blood plasma of 4 mmol/l at use for adult patients in a dose more than 100 mg/days and children in a dose have about 6 mg/kg/days). Decrease in concentration of hydrocarbonates in a blood plasma less than 10 mmol/l was noted in rare instances. 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, the increased formation of ketonic bodies in an organism, reception of some medicines), can be the accessory factors strengthening bicarbonate - the reducing effect of a topiramat. The chronic metabolic acidosis increases risk of development of a nephrolithiasis. At children the chronic metabolic acidosis can become the reason of osteomalacy and lead to growth rate delay. Effect of a topiramat on growth and possible complications of bone system at children systematically were not studied at children and adults.

At treatment topiramaty it is necessary to conduct necessary researches, including definition of concentration of hydrocarbonates in blood serum. At emergence of a metabolic acidosis and its persistirovaniya, it is recommended to lower a dose or to stop administration of drug.

Suralimentation. If the patient loses weight at reception of a topiramat, then it is necessary to consider a question of expediency of suralimentation.

At therapy topiramaty emergence of an oligogidroz or anhidrosis is possible. Reduction of sweating and a hyperthermia can arise at the children subject to influence of high temperature of the environment. In this connection, the adequate consumption of liquid capable to reduce risk of side effects, including a nephrolithiasis is very important.

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

Data on possible influence of drug on ability to manage vehicles and mechanisms. Topiramat exerts weak or moderate impact on ability to manage vehicles and to work with mechanisms. Topiramat affects the central nervous system and can cause drowsiness, dizziness and other symptoms. It can also cause vision disorders. The specified undesirable reactions can pose a potential threat to patients at management of vehicles of them and work with mechanisms, especially during establishment of individual sensitivity to drug. During treatment it is necessary to be careful at control of vehicles and works with mechanisms.

Side effects:

Frequency of side effects is classified according to recommendations of World Health Organization: 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 - not less than 0, 01%, including single messages.

The most widespread undesirable reactions (with a frequency of ³5% in comparison with group of placebo, noted, at least, in 1 double blind controlled research): anorexia, loss of appetite, cerebration delay, depression, muffled speech, sleeplessness, lack of coordination of movements, disturbance of attention, dizziness, dysarthtia, disturbance of flavoring feelings, hypesthesia, slackness, decrease in memory, nystagmus, paresthesias, drowsiness, tremor, diplopia, vision disorder, diarrhea, nausea, increased fatigue, irritability, decrease in body weight.

Children. Undesirable reactions which by results of double blind clinical trials by ³2 times met at children more often, than at adults: a loss of appetite, increase in appetite, giperkhloremichesky acidosis, a hypopotassemia, a behavior disorder, aggression, apathy, backfilling disturbance, suicide thoughts, disturbance of attention, drowsiness, disturbance of a day-night rhythm of a dream, poor quality of a dream, the raised dacryagogue, a sinus bradycardia, the general unsatisfactory state, gait disturbance.

The undesirable reactions arising in clinical trials only at children: eosinophilia, psychomotor excitement, вертиго, vomiting, hyperthermia, fever, training disturbance.

Table No. 1. Undesirable reactions of a topiramat.

System and organ class	Very often	Often	Infrequently	Seldom	Frequency is unknown
Infections and invasions	Nasopharyngitis *
From hemopoietic and lymphatic system		Anemia	Leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia	Neutropenia *
From immune system		Hypersensitivity			Quincke's disease *, chemosis *
From metabolism and food		Anorexia, loss of appetite	Metabolic acidosis, hypopotassemia, increase in appetite, polydipsia	Giperkhloremi-chesky acidosis
From mentality	Depression	Cerebration delay, sleeplessness, muffled speech, concern, confusion of consciousness, disorientation, aggression, changes of mood, agitation, differences of mood, depressive mood, anger, behavior disorder	Suicide thoughts, suicide attempts, hallucinations (including acoustical and visual), psychotic frustration, apathy, lack of the spontaneous speech, sleep disorder, emotional lability, decrease libido, nervousness, crying, disfemiya, euphoria, paranoia, perseverations, panic attacks, tearfulness, reading disturbance, backfilling disturbance, emotional coldness, disturbance of thinking, lack of a libido, apathy, sleeplessness, otvlekayemost, early morning awakening, panic reaction, high spirits	Mania, panic frustration, feeling of despair *, hypomania
From a nervous system	Paresthesias, drowsiness, вертиго	Disturbance of attention, memory disturbance, amnesia, disturbance of cognitive functions, disturbance of intellectual functions, disturbance of psychomotor skills, spasms, incoordination of movements, tremor, lethargy, hypesthesia, nystagmus, dysgeusia, balance disturbance, dysarthtia, intentsionny tremor, sedation	Consciousness oppression, big convulsive attacks, narrowing of fields of vision, difficult partial attacks, disturbance of the speech, psychomotor initiation, syncope, sensitivity disturbance, hypersalivation, hypersomnia, aphasia, repetition of words, hypokinesia, dyskinesia, postural dizziness, poor quality of a dream, feeling burning, anesthesia, parosmiya, cerebellar syndrome, dizesteziya, hypogeusia, stupor, awkwardness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, pricking	Apraxia, disturbance of a circadian rhythm of a dream, hyperesthesia, hyposmia, anosmia, loss of sense of smell, akineziya, lack of reaction to irritants
From an organ of sight		Vision disorder, diplopia, illegibility of visual perception	Decrease in visual acuity, scotoma, myopia *, pathological feelings in an eye *, a xerophthalmus, a photophobia, a nictitating spasm, dacryagogue, a photopsia, a mydriasis, a presbyopy	Unilateral blindness, passing blindness, glaucoma, accommodation disturbance, disturbance of solid vision, ophthalmic migraine, the century *, a night blindness, an amblyopia swelled	Closed-angle glaucoma *, maculopathia *, disturbance of the movement of eyes *
From hearing and a labyrinth		Vertigo, sonitus, ear pain	Deafness, unilateral hearing loss, neurosensory relative deafness, discomfort in an ear, decrease in hearing
From heart			Bradycardia (including sinus), heart consciousness
From vessels			Orthostatic hypotension, lowering of arterial pressure, "inflows", vasculomotor disturbances	Reynaud's syndrome
From respiratory system, bodies of a thorax and a mediastinum		Short wind, nasal bleeding, nose congestion, rhinorrhea	Asthma at loading, hypersecretion of okolonosovy bosoms, a dysphonia
From digestive tract	Nausea, diarrhea	Vomiting, lock, pain in epigastriums, dyspepsia, an abdominal pain, dryness in a mouth, discomfort in a stomach, paresthesia of a mucous membrane of an oral cavity, gastritis, discomfort in a stomach	Pancreatitis, meteorism, gastroesophageal reflux, pain in the bottom of a stomach, a hypesthesia of a mucous membrane of an oral cavity, an odontorrhagia, abdominal distention, discomfort in epigastriums, irritation of a peritoneum, hypersalivation, cheek pain, an unpleasant smell from a mouth, a glossodynia
From a liver and biliary tract				Hepatitis, hepatic insufficiency
From skin and hypodermic fabrics		Alopecia, rash, itch	Anhidrosis, hypesthesia of the person, small tortoiseshell, erythema, generalized itch, makulezny rash, skin discoloration, allergic dermatitis, face edema	Stephens-Johnson's syndrome *, mnogoformny erythema *, unpleasant smell of skin, periorbital hypostasis *, focal small tortoiseshell	Toxic epidermal necrolysis *
From musculoskeletal system		Arthralgia, muscular spasm, mialgiya, muscle contracture, muscular weakness, breast muscle pain	Hypostasis of joints *, constraint, musculoskeletal stitches, muscular exhaustion	Discomfort in extremities *
From kidneys and urinary tract		Nephrolithiasis, pollakiuria, dysuria	Uric concrement, urine incontience, hamaturia, imperative desires to an urination, renal colic, kidney pain	Concrement in an urethra, renal kanaltsiyevy acidosis
From generative organs and a mammary gland			Disturbance of an erection, disturbance of sexual function
The general disturbances and disturbances in an injection site	Fatigue	Fever, adynamy, irritability, balance disturbance, unpleasant feelings, indisposition	Hyperthermia, thirst, grippopodobny syndrome, adynamy, cold snap of extremities, feeling of intoxication, feeling of nervousness	Face edema, calcification
From a laboratory instrumental-nykh of indicators	Decrease in body weight	Increase in body weight *	Crystalluria, pathological leukopenia, increase in activity of microsomal enzymes of a liver	Decrease in content of bicarbonates in serum
Social circumstances			Training disturbance

* Are revealed by results of spontaneous messages in the post-registration period. Frequency is calculated according to clinical trials.

Interaction with other medicines:

Influence of a topiramat on concentration of other nrotivoepilenticheskikh nrenaratov (PEP). The concomitant use of a topiramat with other PEP (Phenytoinum, carbamazepine, valproic acid, phenobarbital, Primidonum) does not exert impact on values of their steady concentration in plasma, except for certain patients in whom 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 the course of treatment and after cancellation of a lamotridzhin (an average dose of a topiramat of 327 mg/days) equilibrium concentration of a topiramat did not change.

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 dose of a topiramat.

Results of interaction with antiepileptic drugs are presented in the table No. 2.

Table No. 2. Interaction of a topiramat and other PEP.

PEP	Concentration of PEP in a blood plasma	Concentration of a topiramat in a blood plasma
Phenytoinum	↔ / (increase in concentration in isolated cases)	↓ (48%)
Carbamazepine	↔	↓ (40%)
Valproic acid	↔	↔
Phenobarbital	↔
Primidonum	↔
Lamotridzhin	↔ (at a dose of a topiramat to 400 mg/days)	↓ (13%)

↔ - change of concentration in a blood plasma less than 10%;

↑ - increase in concentration at certain patients;

↓ - decrease in concentration in a blood plasma;

- it was not investigated.

Other medicinal interactions.

Digoxin: in a research with use of a single dose of digoxin the area under a curve concentration/time (AUC) of digoxin in plasma at a concomitant use of a topiramat decreased 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 oppressing the TsNS functions and also with alcohol is not recommended.

The St. John's Wort which is made a hole: at joint reception of a topiramat and drugs of a St. John's Wort of the topiramat which is made a hole concentration in a blood plasma can decrease, and, as a result, efficiency of drug can also decrease. Clinical trials of interaction of drug Topiramat and drugs on the basis of the St. John's Wort which is made a hole were 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) топирамат in doses 50-800 mr in day was used did not render essential the line 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 have to report to the attending physician 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 maniac-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 repeated introduction of a topiramat to healthy volunteers and sick maniac-depressive psychosis yielded identical results. At simultaneous use of a topiratam 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 a 9-gidroksirisperidon) changed slightly. Change of level 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 joint purpose 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 a curve of concentration 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 correction of a dose of a topiramat. Pharmacokinetic parameters of a hydrochlorothiazide were not exposed to significant change at the accompanying therapy topiramaty.

At simultaneous use of a topiramat and Metforminum increase in Cmax and AUC metformin by 18 and 25% respectively whereas the clearance of Metforminum decreased by 20% was noted. Topiramat did not influence time of achievement of Cmax of Metforminum in a blood plasma. The clearance of a topiramat at simultaneous use with Metforminum decreased. 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 Topiramat's cancellation at the patients receiving Metforminum it is necessary to monitorirovat a current of a diabetes mellitus carefully.

At simultaneous use of a pioglitazon and topiramat reduction of AUC of a pioglitazon by 15%, without change of Cmax of a pioglitazon was revealed. These changes were not statistically significant. Also for an active hydroxymetabolite of a pioglitazon decrease in Cmax and AUC by 13 and 16% respectively was revealed, and for an active ketometabolite decrease and Cmax and AUC by 60% was revealed. The clinical importance of these data is not found out. In case of joint appointment of Topiramat and a pioglitazon it is necessary to control a current of a diabetes mellitus carefully.

At Glibenclamidum use (5 mg a day) separately or along with topiramaty (150 mg a day) at patients with a diabetes mellitus 2 AUC types of Glibenclamidum decreased by 25%. Also system exposure - 4 and and 3 - cis-hydroxyglibenclamidum was reduced by 13 and 15% respectively. Glibenclamidum did not influence pharmacokinetics of a topiramat in an equilibrium state. At appointment patients at the same time of Glibenclamidum and a topiramat need to take possible pharmacokinetic interaction into account and to carefully control a condition of patients for assessment of a current of a diabetes mellitus.

Other drugs: it is necessary to avoid simultaneous use of a topiramat with the drugs contributing to a nephrolithiasis because of increase in risk of formation of stones in kidneys.

Additional researches of medicinal interaction are presented in the table No. 3.

Table No. 3. Results of additional researches of interaction between topiramaty and various medicines (M).

Medicine (M)	Concentration of LP in plasma of a krovi	Concentration of a topiramat in plasma of a krovi
Amitriptyline	increase in Cmax and AUC of a metabolite of a nortriptilin by 20%
Digidroergotamin (inside and hypodermic introduction (п / to))	↔	↔
Haloperidol	increase in AUC metabolite for 31%
Propranolol	increase in Cmax for 4-OH propranolol for 17% (топирамат 50 mg)	increase in Cmax by 9%, increase in AUC by 16% ( mg propranolol 40 and 80 each 12 hours)
Sumatriptan (inside and п / to)	↔
Pizotifen	↔	↔
Diltiazem	reduction of AUC diltiazem by 25% and a dezatsetildiltiazem for 18%, and ↔ for N-demetildiltiazema	increase in AUC by 20%
Venlafaksin	↔	↔
Flunarizin	increase in AUC by 16% (50 mg each 12 h) b	↔

^and. - it is expressed in % of _{Cmax values} in a blood plasma and AUC at monotherapy;

↔ - lack of changes _{of Cmax} in a blood plasma and AUC (to 15% of basic data);

^{b -} at multiple dose in a flunarizin increase in AUC by 14% was observed that can be connected with its accumulation in process of achievement of an equilibrium state;

- it was not investigated.

Contraindications:

Hypersensitivity to a topiramat or any other component of drug; children's age up to 6 years at monotherapy, up to 3 years as a part of a combination therapy of epilepsy;

Children's age up to 18 years at use for prevention of migraine.

Prevention of migraine at pregnant women or women of childbearing age not using effective contraception.

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

Overdose:

Signs and symptoms of overdose: spasms, drowsiness, disturbances of the speech and sight, diplopia, disturbances of thinking, lack of coordination, dizziness, lethargy, stupor, arterial hypotension, abdominal pain, dizziness, excitement and depression, metabolic acidosis. 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 case at overdose is known topiramaty in a dose to 110 g that led to a coma within 20-24 hours, and further in 3-4 days a complete recovery.

Treatment: there is no specific antidote, if necessary symptomatic therapy is carried out. It is necessary to cause at once vomiting and to wash out a stomach, to increase water consumption. In the researches in vitro it was shown that absorbent carbon adsorbs топирамат.

Hemodialysis – the most effective way of removal of a topiramat from an organism. Adequate increase in volume of the consumed liquid is recommended to patients.

Storage conditions:

To store in the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 2 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets film coated 25 mg and 100 mg.

On 10 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished or on 100 tablets in bank polymeric.

On 1, 2, 3, 4, 5 blister strip packagings or to one bank together with the application instruction place in a pack from a cardboard.