Toreal

General characteristics. Structure:

Active ingredient: each tablet contains 25 mg or 100 mg of a topiramat.

Excipients: lactose (sugar milk), starch corn prezhelatinizirovanny, cellulose microcrystallic, carboxymethylstarch of sodium, gipromelloz (gidroksipropilmetiltsellyuloz), magnesium stearate;

Cover excipients: powder of Opadray of the II yellow color [polyvinyl alcohol; polyethyleneglycol 4000 (macrogoal); talc; titanium dioxide; ferrous oxide yellow].

Description: tablets, coated yellow color, round, biconvex.

Pharmacological properties:

Pharmacodynamics. Topiramat belongs to sulfate - to the replaced monosaccharides. Blocks natrium channels and suppresses emergence of repeated action potentials against the background of long depolarization of a membrane of neuron. Increases activity of γ-aminobutyric acid (GAMK) concerning some subtypes of GABA-receptors. Interferes with activation kainaty sensitivity of a subtype kainat/AMPK (альфа-амино-3-гидрокси-5-метилизоксазол-4-пропионовая acid) – receptors to a glutamate, without influencing activity of N-methyl-D-aspartate (NMDA) concerning NMDA receptors. The specified effects of a dozozavisima. Besides, топирамат inhibits activity of some isoenzymes of a karboangidraza. This effect is much weaker, than at acetazoleamide karboangidraza inhibitor, and is not the main component of antiepileptic activity of a topiramat. Presumably gets into breast milk.

Pharmacokinetics. Topiramat is quickly and well soaked up. Meal does not render clinically significant effect on its bioavailability which makes about 80%. Communication with proteins of plasma of 13-17%. The average volume of distribution is 0,55-0,8 l/kg for a single dose to 1200 mg. This indicator depends on a floor: at women these values make 50% of the sizes observed at men that connect with higher content of fatty tissue at women. About 20% of a topiramat are metabolized. To 50% of a topiramat it is metabolized at the patients who are at the same time accepting other antiepileptic drugs (PEP) inducing metabolizing enzymes. From plasma, urine and a calla of the person six almost inactive metabolites of a topiramat are allocated. Not changed топирамат and its metabolites, are generally removed through kidneys. The plasma clearance makes about 20-30 ml/min.

After a single dose, the pharmacokinetics has linear character, the plasma clearance is constant, and the area under a curve "concentration/time" increases in range of doses from 100 to 400 mg in proportion to a dose. At normal function of kidneys 4-8 days for achievement of equilibrium plasma concentration can be required by patients. Average value of the maximum concentration after multiple dose in 100 mg of a topiramat twice a day makes 6,76 mkg/ml. The elimination half-life after multiple dose of 50 and 100 mg twice a day makes 21 hour.

At patients with renal failures (the clearance of creatinine <60 ml/min.) decreases plasma and renal clearance of a topiramat; at patients with a final stage of a renal failure the plasma clearance of a topiramat decreases. The plasma clearance of a topiramat does not change at patients of advanced age in the absence of disturbances of a funtion of kidneys. The plasma clearance of a topiramat decreases at patients with moderately and heavy abnormal liver functions.

The pharmacokinetics of a topiramat at children, also as at adults, has linear character. The clearance of drug does not depend on a dose, equilibrium concentration increases in a blood plasma in proportion to a dose. However, higher values of clearance and shorter elimination half-life are characteristic of children. Therefore, concentration of a topiramat in a blood plasma at reception of identical doses per kg of body weight can be lower at children in comparison with adults. As well as at adults, at reception of other PEP inducing liver enzymes equilibrium concentration of a topiramat in a blood plasma decreases.

Topiramat is effectively brought from a blood plasma at a hemodialysis.

Indications to use:

Monotherapy of epilepsy at children since 3 years and adults (including at patients with for the first time the established epilepsy);
auxiliary therapy at children since 3 years and adults at insufficient efficiency of PEP of the first choice at partial or generalized toniko-clonic attacks, and also at attacks against the background of Lennox-Gasto's syndrome.

Route of administration and doses:

The general.
Inside, swallowing a tablet entirely, not chewing, irrespective of meal. For optimum control of attacks it is recommended to begin treatment with low doses with the subsequent increase up to an effective dose.

As a part of complex therapy.
Adults: minimal effective dose of 200 mg/days. A usual daily dose of 200-400 mg (for 2 receptions). Maximum daily dose of 1600 mg. Treatment is begun with 25-50 mg daily for the night within 1 week. Then the dose is raised on 25-50 mg a day within 1-2 weeks, with frequency rate of reception by 2 times a day. At intolerance of such mode of dosing, the dose is raised at a smaller size or through big intervals. The dose and frequency rate of reception are selected depending on clinical effect.

Children are more senior than 3 years: the recommended daily dose makes 5-9 mg/kg of body weight, divided into 2 receptions. Treatment begin with a dose 25 mg for the night within 1 week. Then the dose is raised on 1-3 mg/kg/day within 1-2 weeks, with frequency rate of reception by 2 times a day, to achievement of optimum clinical effect.

Monotherapy.
Adults: treatment is begun with 25 mg for the night within 1 week. Then the dose is raised on 25-50 mg a day within 1-2 weeks, with frequency rate of reception by 2 times a day. At intolerance of such mode of dosing, the dose is raised at a smaller size or through big intervals. The dose and frequency rate of reception are selected depending on clinical effect. The recommended initial dose of a topiramat for monotherapy at adults with for the first time the established epilepsy makes 100 mg/day, most recommended dose - 500 mg/day. These doses are recommended for all adults, including elderly with normal function of kidneys.

Children of 3 years: treatment begin with a dose 0,5-1 mg/kg of body weight for the night for 1 week. Then the dose is raised on 0,5-1 mg/kg/day for 1-2 weeks, frequency rate of reception - 2 times a day. At intolerance of such mode of dosing, the dose is raised at a smaller size or through big intervals. The dose and frequency rate of reception are selected depending on clinical effect. The recommended range of doses – 3-6 mg/kg of body weight. Children with recently established partial attacks can appoint up to 500 mg a day.

Features of use:

At administration of drug women are recommended to use adequate contraception. Topiramat, as well as other PEP, is recommended to cancel, gradually reducing a dose, for reduction of potential risk of increase in frequency of attacks.

Renal failure: with moderately and strongly expressed renal failures 10-15 days can be necessary for patients for achievement of an equilibrium condition of concentration in plasma unlike 4-8 days for patients with normal function of kidneys. As well as at all patients, gradual increase in a dose has to be carried out according to clinical results (such as control of attacks, the frequency of side effects), considering that more time for achievement of a stable state after each dose can be required by patients with a moderate or heavy renal failure.

Nephrolithiasis: at some patients who are especially predisposed to a nephrolithiasis the risk of formation of nephroliths which is followed by such symptoms as renal colic, a stitch and in a kidney can increase. It is recommended to carry out adequate hydration for decrease in risk of formation of nephroliths.

Liver failure: at patients with abnormal liver functions the clearance of a topiramat decreases.

Myopia and secondary closed-angle glaucoma: at development of a myopia, it is recommended to cancel топирамат as quickly as clinically perhaps and to take the measures directed to decrease in intraocular pressure.


Metabolic acidosis.

At use of a topiramat there can be giperkhloremicheskiya, not connected with deficit of anions, metabolic acidosis (for example, decrease in concentration of bicarbonates in plasma below normal level in the absence of a respiratory alkalosis). This decrease in concentration of bicarbonates of blood serum is a consequence of the inhibiting effect of a topiramat on a renal karboangidraza. In this regard, at treatment topiramaty it is recommended to define periodically concentration of bicarbonates in blood serum.

Diet.

At decrease in body weight during therapy topiramaty it is reasonable to consider the possibility of purpose of additional food.

During treatment it is recommended to abstain from driving and works of demanding increased concentration of attention and speed of psychomotor reactions.

Side effects:

Neurologic and mental disorders: hyperexcitability, dizziness, headache, disturbances of the speech and sight, psychomotor block, ataxy, fatigue, difficulties of concentration of attention, confusion of consciousness, paresthesia, drowsiness, disturbances of thinking, diplopia, anorexia, nystagmus, depression, perversion of flavoring feelings, excitement, cognitive frustration, emotional lability, ataxy, apathy, psychotic symptoms, agressive behavior, suicide ideas or attempts; in addition children have frustration of the personality, the strengthened salivation, a hyperkinesia, hallucinations.

Gastrointestinal frustration: dispepsichesky phenomena, nausea, abdominal pains, diarrhea, dryness of lips, increase in activity of hepatic transaminases, hepatitis, liver failure.

From eyes: emergence of a syndrome of a myopia against the background of increase in intraocular pressure with acute decrease in visual acuity and pain in an eye is possible. Myopia, reduction of depth of an anterior chamber of an eye, hyperemia of a mucous membrane of an eye and increase in intraocular pressure, mydriasis. The possible mechanism of these disturbances is increase in a supratsiliarny exudate that leads to anteposition of a crystalline lens and an iris of the eye and, as a result, – to development of secondary closed-angle glaucoma.

From skin and mucous membranes: mnogoformny erythema, pempigus, Stephen-Johnson's syndrome and toxic epidermal necrolysis.

Others: decrease in body weight, a leukopenia, a nephrolithiasis, олигогидроз (generally at children), a metabolic acidosis.

Interaction with other medicines:

Influence of a topiramat on other PEP.
Does not influence concentration of carbamazepine, phenobarbital, Primidonum. At simultaneous use with AUC valproic acid of valproic acid the topiramata – for 14% decreases by 11%. In some cases, at use with Phenytoinum, increase in concentration of Phenytoinum in plasma is possible.

Influence of other PEP on топирамат.
At combined use of a topiramat with Phenytoinum and carbamazepine reduction of concentration of a topiramat in plasma is possible, thus at addition or cancellation of Phenytoinum or carbamazepine dose adjustment of a topiramat is recommended.

Digoxin: the area under a pharmacokinetic curve of digoxin decreases by 12%. Oral contraceptives: топирамат in a dose of 50-800 mg/day had no significant effect on efficiency of norethindrone and in a dose of 50-200 mg/day – on efficiency of ethinylestradiol. Essential dozozavisimy decrease in efficiency of ethinylestradiol was observed at reception of a topiramat in a dose of 200-800 mg/day. The patients accepting oral contraceptives have to report to the doctor about any changes of nature of bleeding.

Metforminum: At simultaneous use with topiramaty average values of the maximum concentration and the area under a curve of concentration of Metforminum increase by 18% and 25% respectively whereas average value of the general clearance decreases by 20%. Topiramat did not make impact on time of achievement of Cmax of Metforminum. The plasma clearance of a topiramat under the influence of Metforminum decreases. Clinical value of impact of Metforminum on pharmacokinetics of a topiramat is not clear. At appointment or cancellation of a topiramat against the background of therapy as Metforminum it is necessary to control a condition of carbohydrate metabolism.

Hydrochlorthiazidum: at a concomitant use 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 means oppressing the central nervous system (CNS): the concomitant use with topiramaty ethanol and other means, the oppressing TsNS is not recommended.

Pioglitazon: reduction of the square under a curve of concentration of a pioglitazon for 15%, without change of the maximum concentration of drug is revealed. For an active hydroxymetabolite of a pioglitazon decrease in the maximum concentration and the square under a concentration curve for 13% and for 16% respectively is revealed, and for an active ketometabolite decrease and the maximum concentration and the square under a concentration curve for 60% is revealed. The clinical importance of these data is unknown.

Other means: топирамат, when sharing with other drugs contributing to a nephrolithiasis in particular with inhibitors of a karboangidraza (acetazoleamide) can increase risk of a nephrolithiasis. In usage time of a topiramat patients have to avoid reception of such drugs as they can create the physiological conditions increasing risk of formation of nephroliths.

Contraindications:

Hypersensitivity to any of drug components;
children's age up to 3 years;
pregnancy and period of a lactation.

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

Overdose:

Symptoms: spasms, disturbance of consciousness up to a coma, a lowering of arterial pressure, a heavy metabolic acidosis, strengthening of expressiveness of side effects.

Treatment: gastric lavage, symptomatic therapy. An effective way of removal of a topiramat from an organism - a hemodialysis.

Storage conditions:

List B. In the dry, protected from light place at a temperature not over 25 ˚С. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated, 25 mg or 100 mg. On 14 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. On 28 tablets in banks polymeric with opening control.

2 blister strip packagings or one bank polymeric together with the application instruction in a pack from a cardboard.