Топиромакс

General characteristics. Structure:

Active ingredient: topiramata of 25 mg or 100 mg;                                                                                                           
Excipients: cellulose microcrystallic, lactoses monohydrate, starch corn prezhelatinizirovanny, коповидон, sodium of starch glikolit, talc, silicon dioxide colloid anhydrous, magnesium stearate, a covering for drawing a cover of Opadry II White (Topiromaks 25) and Opadry II Yellow (Topiromaks 100).

Pharmacological properties:

Pharmacodynamics. Topiramat, being active ingredient of tablets of Topiromaks, - antiepileptic drug which belongs to a class of the sulphamatereplaced monosaccharides. Topiramat blocks natrium channels and emergence of repeated action potentials against the background of long depolarization of a membrane of neuron oppresses. Topiramat increases activity of γ-aminobutyric acid of acid (GAMK) of rather some subtypes of GAMK-receptors, and also modulates activity of GAMK-receptors, interferes with activation kainaty sensitivity of a subtype kainat/AMPK (-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 this pharmacological effect of a topiramat considerably concedes to acetazoleamide - the known inhibitor of coal anhydrase because of what this activity of a topiramat is not considered the main component of its antiepileptic activity.

Pharmacokinetics. Topiramat to be soaked up quickly and effectively. Bioavailability - 81%. Meal has no effect on bioavailability of a topiramat. 13 - 17% of a topiramat contact proteins of plasma. After one-time reception in a dose to 1 200 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 values which are observed at men that connect with higher content of fatty tissue in an organism of women.
After oral administration about 20% of the accepted dose are metabolized. But at patients who receive the accompanying therapy by the antiepileptic drugs inducing enzymes which are responsible for metabolism of medicines metabolism of a topiramat about 50% increased. From plasma, urine and excrements of the person 6 almost inactive metabolites are allocated and identified. The main way of removal of not changed topiramat (70%) and its metabolites are kidneys. After peroral introduction the plasmatic clearance of drug makes 20 - 30 ml/min. The pharmacokinetics of a topiramat has linear character, the plasmatic clearance remains to constants, and 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 constant concentration in plasma. The size Cmax after reusable oral administration of 100 mg of drug twice a day makes 6,76 mkg/ml. After reusable reception of doses on 50 and 100 mg twice a day the average elimination half-life of a topiramat from plasma is equal to about 21 hour.
At patients with renal failures the plasmatic and renal clearance of a topiramat decreases (CLCR) <= 60 ml/min.). At the people of advanced age who do not have diseases of kidneys, the plasmatic clearance of a topiramat does not change. Topiramat is effectively brought from plasma with use of a hemodialysis. At patients with an abnormal liver function from moderately expressed to heavy plasmatic clearance of a topiramat decreases.

Pharmacokinetics at children in a vozdasta up to 12 years.
Pharmacokinetic properties of a topiramat at children, as well as at adults, revealed when studying additional therapy, have linear character with dozonezavisimy clearance and stable levels of concentration in plasma which increase in proportion to a dose. However children have higher level of clearance and shorter elimination half-life. Therefore, levels of concentration of a topiramat in plasma for the same doses in milligrams on 1 kg of body weight can be lower for children in comparison with same at adults.

Indications to use:

- Epilepsy.
- As monotherapy for treatment of patients with for the first time the diagnosed epilepsy or for transition of patients with epilepsy to monotherapy.
- As additional therapy for treatment of adults and children is more senior than 3 years with partial or generalized toniko-clonic attacks.
- As additional therapy for treatment of adults and children at the attacks associated with Lennox-Gasto's syndrome.
- Migraine.
- For prevention of attacks of migraine at adults.

Route of administration and doses:

Epilepsy.
Monotherapy.
Adults. Selection of a dose it is necessary to begin with reception 25 mg of a topiramat for the night within a week. Further the dose can be increased by 25-50 mg within 1 or 2 weeks and to accept it in two steps. If the patient does not manage to adapt to increase in a dose, it is necessary to apply less considerable increases of a dose or to maintain more long intervals between increases. At selection of a dose are guided by a therapeutic effectiveness.

The recommended level of an initial target dose of Topiromaks at monotherapy at adults - 100 mg a day, and the maximum recommended dose makes 500 mg a day. Some patients with refractory forms of epilepsy well transfer monotherapy by Topiromaks in a dose of 1000 mg to days. The specified recommendations concerning dosing can be applicable for all adult patients, including patients of advanced age in the absence of diseases of kidneys at them.

Children in a vozdasta of 3 years.
Treatment of children for 3 years it is necessary to begin with reception 0,5 - 1 mg/kg of a topiramat for the night within the first week. Further the dose can be increased by 0,5 - 1 mg/kg a day with an interval of 1 or 2 weeks; the daily dose can be divided into two receptions. If the child cannot adapt to the recommended mode of selection of a dose, it is possible to use less considerable increases of a dose or more long intervals of time between increase. At selection of a dose it is necessary to be guided by a therapeutic effectiveness.

The recommended level of an initial target dose of Topiromaks at monotherapy at children in a vozdasta of 3 years makes 3 - 6 mg/kg of body weight a day. In case the diagnosis "partial epileptic seizures" is recently made, children can receive a dose of 500 mg a day.
In case of need reception of smaller doses it is necessary to use other drugs of a topiramat with a possibility of such dosing.

Additional therapy.

Adults. Treatment is begun with selection of a dose, accepting 25 - 50 mg of drug for the night within a week. Further with a week or two-week interval the dose can be increased by 25 - 50 mg and to divide it into 2 receptions. At selection of a dose it is necessary to be guided by therapeutic effect. At some patients the effect can be reached at administration of drug of 1 times a day.

Minimal effective dose - 200 mg. The maintenance dose makes from 200 to 400 mg a day and is accepted to two receptions. Some patients well transfer the dose exceeding 1 600 mg a day.

The provided recommendations concerning dosing can be applicable for all adult patients, including patients of advanced age, in the absence of diseases of kidneys at them.

Children aged from 3 years.
The recommended daily dose of Topiromaks for additional therapy averages 5 - 9 mg/kg of body weight, divided into 2 receptions. Treatment is begun with selection of a dose, accepting 25 mg (or less, having taken as a basis a dosage of 1 - 3 mg/kg of body weight a day) for the night within a week. Further with an interval of 1 or 2 weeks the dose can be increased by 1 - 3 mg/kg of body weight a day and to take it for two receptions before achievement of therapeutic effect. At selection of a dose it is necessary to be guided by therapeutic effect.

Migraine.
For prevention of attacks of migraine the recommended daily dose of a topiramat makes 100 mg divided into 2 receptions. It is necessary to begin administration of drug with reception of 25 mg in the evening within a week. Further the dose is increased by 25 mg a day at an interval of a week after each increase in a dose. It is possible to use less considerable increment of a dose or more long intervals between increments if the patient badly transfers the specified mode of the choice of a dose.

At some patients the positive take is achieved at a daily dose of a topiramat of 50 mg. In clinical trials patients received daily doses of a topiramat to 200 mg. At selection of a dose it is necessary to be guided by a therapeutic effectiveness.

Features of use:

Use during pregnancy or feeding by a breast.
During pregnancy of Topiromaks it is not recommended to apply.
Topiramat gets into breast milk therefore it is necessary to resolve an issue of expediency of the termination of breastfeeding or the termination of administration of drug, considering degree of its importance for mother.

Children.
Топиромакс it is applied to treatment of epilepsy at children of 3 years as monotherapy or additional therapy.

Топиромакс, as well as other antiepileptic drugs, it is necessary to cancel gradually to minimize a possibility of increase in frequency of attacks, reducing a dose by 100 mg at an interval of 1 week. At some patients drug withdrawal was accelerated and took place without complications.

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   from 10 to 15 days, in comparison with 4 - 8 days at patients with normal function of kidneys can be necessary for achievement of stable concentration in plasma.

As well as at any disease, the scheme of selection of a dose has to oriyenirovatsya on a therapeutic effectiveness (i.e. extent of decrease in frequency of attacks, lack of side effects) and to consider that at patients with renal failures more long time can be necessary for establishment of stabler concentration of a topiramat in plasma for each dose.

During therapy topiramaty adequate increase in volume of the used liquid is very important that can reduce risk of development of a nephrolithiasis, and also the side effects connected with influence of exercise stresses and the increased temperatures.

 Topiromaks's use for treatment of bad attacks of migraine is not studied.
During treatment topiramaty the increased frequency of emergence of frustration of mood and a depression is observed.
At patients, especially at having tendency to a nephrolithiasis, the risk of formation of stones in kidneys and emergence of the related symptoms, such as renal colic can increase. To umenshit this risk, the corresponding increase in volume of the liquid consumed by the patient is necessary. Risk factors of development of a nephrolithiasis is tendency to formation of stones in kidneys in the past, a nephrolithiasis in the family anamnesis, a hypercalcuria. Any of these risk factors cannot predetermine sufficiently emergence of stones during reception of a topiramat. Besides, the risk can be increased at the patients accepting the accompanying drugs causing development of a nephrolithiasis.

Patients with disturbances of functions of a liver of Topiromaks need to appoint with care as the clearance of a topiramat can decrease.
When using a topiramat manifestation of the syndrome representing the acute myopia associated with secondary zakrytouglovy glaucoma was registered. The syndrome included a bad attack of decrease in visual acuity and/or eye pain. Ophthalmologic manifestations can include a myopia, reduction of depth of an anterior chamber, a hyperemia (reddening of eyes) and the increased intraocular pressure. Also the mydriasis can be observed. The described syndrome can be connected with a supratsiliarny exudate that causes shift of a crystalline lens and iris of the eye and development of secondary zakrytouglovy glaucoma. As a rule, symptoms arose after a month of primary therapy topiramaty. Unlike primary otkrytouglovy glaucoma which is seldom observed at patients up to 40 years the secondary zakrytouglovy glaucoma connected using a topiramat was observed both at children, and at adults. Treatment provides drug withdrawal if the doctor counts it reasonable, and acceptance of the appropriate measures for decrease in intraocular pressure.
The increased intraocular pressure of any etiology in the absence of adequate treatment can lead to serious complications or even to sight loss.

Metabolic acidosis.
At treatment topiramaty there can be giperkholesterinemicheskiya, not connected with deficit of anions, metabolic acidosis (for example, decrease in concentration of bicarbonates in plasma below normal level in the absence of a respiratory alkalosis). Decrease in concentration of bicarbonates of blood serum is a consequence of inhibition topiramaty a hepatic karboangidraza. In most cases decrease in concentration of bicarbonates happens administration of drug in the beginning though this effect can be shown in any of the treatment periods topiramaty. Level of decrease in concentration, as a rule, small or moderate (average value makes 4 mmol/l when using by adult patients in a dose of 100 mg a day and about 6 mg a day on body weight kg when using in pediatric practice). In certain cases at patients decrease in concentration lower than the level of 10 mmol/l was noted. 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 bikarbonatponizhayushchy effect of a topiramat.

The chronic metabolic acidosis can cause growth delay in children.
Therefore at treatment topiramaty it is recommended to conduct necessary researches, including definition of concentration of bicarbonates in blood serum. At emergence of a metabolic acidosis and its persistirovaniya it is recommended to lower a dose or to stop reception of a topiramat.
If at the patient during reception Topiromaks body weight decreases, the supporting diet or suralimentation can be recommended.

Drug contains lactose therefore it is not recommended to patients with insufficiency of lactase, a galactosemia or a syndrome of disturbance of absorption of glucose or a galactose.

Ability to influence speed of response at control of motor transport or work with other mechanisms.
Топиромакс affects the central nervous system and can cause drowsiness emergence, dizziness and other similar symptoms. The specified side effects very poorly or are moderately expressed, but can be potentially dangerous to the patients managing motor transport or for those, хто works with the equipment, especially in that case when the patient has no individual experience of use of drug yet.

Side effects:

As most often Topiromaks apply together with other antiepileptic drugs, it is impossible to define what of drugs caused development of side effect.

From   the central nervous system: nervousness, dizziness, headache, disturbances of the speech and sight, psychomotor block, ataxy, fatigue, disturbances of concentration of attention, difficulty with storing, confusion of consciousness, drowsiness, disturbances of thinking, anorexia, nystagmus, diplopia, paresthesia, depression; in addition children have frustration of the personality, hypersalivation, a hyperkinesia; much more rare - disturbance of flavoring feelings, excitement, cognitive frustration, emotional lability (a problem with mood), lacks of coordination of movements and gait, apathy, psikhozo-psychotic symptoms, aggressive reactions; very seldom - suicide thoughts and attempts, at children in addition are hallucinations.

From a digestive tract: the dispeptic phenomena, nausea, an abdominal pain, diarrhea, dryness of lips, it is rare - increase in hepatic transaminases, hepatitis, a liver failure.

Others: a body degrowth, an adynamy, a nephrolithiasis, олигогидроз (generally at children), a metabolic acidosis, fever, and also reactions from skin and mucous (a multiformny erythema, a pempigus, Stephens-Johnson's syndrome, a toxic epidermal necrolysis) at patients who received Topiromaks along with other drugs causing reactions from skin and mucous; seldom - a leukopenia; very seldom - a neutropenia. The thromboembolism phenomena were in some cases noted though the interrelation of the reason with reception of medicine was not proved. Emergence of a syndrome (as a rule, in a month from the beginning of therapy) is possible which is characterized by a myopia against the background of the increased intraocular pressure.

Interaction with other medicines:

Topiromaks's influence on other antiepileptic drugs.
The concomitant use of Topiromaks and other antiepileptic drugs (Phenytoinum, carbamazepine, valproic acid, phenobarbital, Primidonum) does not influence value of their stable concentration in plasma, except for certain patients who have a concomitant use of Topiromaks and Phenytoinum can cause increase in concentration of Phenytoinum in plasma. It can be connected with oppression of a specific polymorphic isoform of enzyme (CYP2Cmeph). At each patient accepting Phenytoinum and at which clinical signs or symptoms of intoxication develop it is necessary to control Phenytoinum level in plasma.

Influence of other antiepileptic drugs on Topiromaks.
Phenytoinum and carbamazepine reduce concentration of a topiramat in plasma. Addition (or cancellation) Phenytoinum or carbamazepine to treatment by Topiromaks can demand change of doses of the last. The dose should be selected, being guided by obtaining necessary therapeutic effect.

Addition (or cancellation) valproic acid does not cause therapeutic significant changes of concentration of a topiromat in plasma and, respectively, does not demand change of doses of Topiromaks.

Interaction with phenobarbital and Primidonum was not investigated.
Other medicinal interactions.
Digoxin. At appointment (or cancellation) Topiromaks to patients who accept digoxin needs to pay special attention to routine monitoring of concentration of digoxin in serum.

Means, the oppressing functions of the central nervous system (CNS). Effects of combined use of a topiramat with the alcohol or other substances oppressing the TsNS functions were not studied. It is recommended not to accept Topiromaks along with the alcohol intake or drugs causing TsNS function oppression.

Oral contraceptives. At use of the oral contraceptives containing norethindrone (1 mg) and ethinylestradiol (35 mg) топирамат in doses of 50 - 800 mg a day did not influence efficiency of norethindrone and in doses of 50 - 200 mg a day - efficiency of ethinylestradiol. Essential dozozavisimy decrease in efficiency of ethinylestradiol was observed when dosing a topiromat of 200 - 800 mg a day. The clinical importance of the given changes is unknown. The risk of decrease in efficiency of contraceptives and strengthening of breakthrough bleedings has to be considered at the patients accepting oral contraceptives together with Topiromaks. The patients accepting oral contraceptives it is necessary to ask to report about any changes in a menstrual cycle.

Lithium drugs. It is recommended to carry out monitoring of level of lithium at simultaneous use with topiramaty.

Risperidon. At simultaneous use with topiramaty in the increasing doses from 100, 250 and 400 mg a day decrease in the area under a curve "concentration time" (AUC) of the risperidon appointed in doses of 1 - 6 mg a day to 16% and 33% for dosing of 250 and  400 mg of a topiramat a day respectively was observed.

The minimum changes in pharmacokinetics of active metabolites were observed (рисперидон + 9-gidroksirisperidon) and no changes were observed concerning a 9-gidroksirisperidon. Also clinically znachimy changes in pharmacokinetics of active metabolites of both a risperidon, and a topiramat were not observed.

Hydrochlorothiazide. At a concomitant use of a topiramat and a hydrochlorothiazide there is an increase in the maximum concentration (Cmax) in a topiramat by 27% and the squares under a curve of concentration (AUC) of a topiramat for 29%. 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 considerable changes at the accompanying therapy topiramaty. Researches showed decrease in level of potassium in blood serum at use of a topiramat or hydrochlorothiazide which was more essential at use of a topiramat and hydrochlorothiazide in a combination.

At co-administration to Topiromaks's patients and such drugs as Metforminum, пиоглитазон, Glyburidum it is necessary to pay special attention to a careful research of the diabetic status of these patients.

Other drugs. Simultaneous use of Topiromaks and other drugs causing emergence of a nephrolithiasis can increase risk of formation of concrements in kidneys. During treatment by Topiromaks it is necessary to avoid use of such drugs as they can cause the physiological changes leading to emergence of a nephrolithiasis.

 Valproic acid. Simultaneous use of a topiramat with valproic acid caused a giperammoniyemiya with or without encephalopathy in patients who well transferred therapy by the specified drugs separately. In most cases symptoms disappeared after the termination of reception of one of drugs. The specified side effect is not connected with pharmacokinetic interaction. Communication of development of a giperammoniyemiya with  monotherapy topiramaty or with simultaneous use of other antiepileptic drugs is not established.

At amitriptyline co-administration its concentration does not change, however Cmax and AUC for a metabolite of a nortriptalin increases by 20%. Concentration of a topiramat at the same time was not investigated.

Concentration of dihydroergotamine at peroral and hypodermic appointment along with topiramaty was not investigated.

At use of a haloperidol of Cmax and AUC did not change, at the same time AUC for a metabolite increased by 31% and concentration of a topiramat was not investigated.

At purpose of a topiramat in a dose of 50 mg and propranolol of 80 mg Cmax that AUC propranolol did not change; Cmax  for 4-IT-propranolol increased by 17%; Cmax increased by 16% and for 17% AUC of a topiramat increased. 

Sumatriptan (orally and subcutaneously). There are no changes of Cmax and AUC of a sumatriptan, concentration of a topiramat at the same time was not investigated.

Pizotifen. There are no changes of Cmax and AUC of a pizotifen and a topiramat.
At purpose of diltiazem - AUC for diltiazem decreased by 20% and for 18% concentration of a dezatsetiltiazem umenshatsya. There are no changes of Cmax that AUC N-dimetildiltiazema; at the same time AUC of a topiramat increases by 20%.

Use of a venlafaksin - there are no changes of Cmax that AUC of a venlafaksin and topiramat.

Contraindications:

Hypersensitivity to any component of drug. Period of pregnancy and feeding by a breast.

Overdose:

Symptoms: spasms, drowsiness, disturbances of the speech and sight, diplopia, disturbances of thinking, lack of coordination, lethargy, stupor, arterial hypotension, abdominal pain, dizzinesses, excitement or depression. In most cases clinical manifestations were not heavy.

The overdose of a topiramat can cause a heavy metabolic acidosis, (see. "Features of use").

Treatment. At acute overdose it is necessary to wash out a stomach at once, to accept absorbent carbon. If necessary carry out symptomatic therapy. The hemodialysis is effective for removal of a topiramat from an organism. Adequate increase in volume of the used liquid is recommended to patients.

Storage conditions:

To store in original packaging at a temperature not over 25 ˚С.
To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Топиромакс 25: on 10 tablets in the blister; on 1 or 3 blisters in a pack cardboard.
Топиромакс 100: on 10 tablets in the blister; on 1 or 3 blisters in a pack cardboard.