Topiramat

General characteristics. Structure:

Active agent: топирамат 25 mg and 100 mg;

excipients: hydrophosphate calcium dihydrate (65 mg, 120 mg), starch prezhelatinizirovanny (C*Pharm starch.) (70,5 mg, 111 mg), magnesium hydroxycarbonate heavy (magnesium carbonate heavy) (30 mg, 50 mg), magnesium stearate (1,5 mg, 3 mg), povidone (8 mg, 16 mg); structure of a film cover - Selekoat AQ–02140 (6 mg, 12 mg) [a gipromelloz (gidroksipropilmetiltsellyuloz), a macrogoal (polyethyleneglycol 400), a macrogoal (polyethyleneglycol 6000), titanium dioxide, dye a sunset yellow].

Description
Tablets, film coated orange color, round, biconvex. On cross section of white or almost white color.

Pharmacological properties:

Pharmacodynamics. Antiepileptic drug.
Reduces the frequency of emergence of the repeated action potentials characteristic of neuron is able permanent depolarization, blocking natrium channels. Increases activity of γ-aminobutyric acid of acid (GAMK) concerning some subtypes of GAMK-receptors (including GAMK[A] - receptors), and also modulates activity of receptors; interferes with activation kainaty sensitivity of a subtype kainat/AMPK (-аминî–3-гидроксè–5-метилизоксазоë–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 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.

Activity of some isoenzymes of a karboangidraza oppresses, however this effect is not the basic in antiepileptic activity of a topiramat.

Pharmacokinetics. Absorption: Topiramat is soaked up quickly and effectively. Bioavailability — 80%. Meal has no clinically significant effect on bioavailability. The maximum concentration in a blood plasma is reached in 2 hours.

Distribution: 13–17% of a topiramat contact proteins of plasma. Distribution volume (after single oral administration of 1,2 g) makes 0,55 — 0,8 l/kg, depends on a floor: at women it makes about 50% of the values observed at men. Gets into breast milk.

Metabolism: It is metabolized in a liver by a hydroxylation, hydrolysis, a glyukuronirovaniye with formation of six pharmacological inactive metabolites.

After peroral introduction the plasma clearance of drug 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 equilibrium concentration in plasma.

Removal: After multiple dose of doses on 50 and 100 mg 2 times a day the elimination half-life of a topiramat from plasma averaged 21 hour.

The main way of removal of not changed topiramat (70%) and its metabolites are kidneys. At a renal failure (clearance of creatinine less than 60 ml/min.) and a heavy liver failure plasma and renal clearance decrease.

Topiramat effectively leaves from plasma by a hemodialysis.

Indications to use:

Epilepsy.
As means of monotherapy:
Topiramat is applied at adults and children is more senior than 3 years with epilepsy (including at patients with for the first time the diagnosed epilepsy).

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

Route of administration and doses:

Inside, regardless of meal.

Monotherapy

At use as monotherapy it is necessary to consider possible influence of cancellation of the accompanying anticonvulsant therapy on the frequency of attacks. When there is no need to sharply cancel the accompanying anticonvulsant therapy for safety reasons, it is recommended to reduce a dose of the accompanying medicine on one third each 2 weeks. At cancellation of the medicines which are inductors of "hepatic" enzymes, concentration of a topiramat will increase in blood. In such situations in the presence of clinical indications the dose of a topiramat can be lowered.

Adult patients at the beginning of performing monotherapy have to accept 25 mg of a topiramat of 1 times a day before going to bed within 1 week. Then the dose is raised at an interval of 1–2 weeks on 25 or 50 mg (the daily dose is divided into two receptions). At intolerance the patient of such mode of increase in a dose 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 recommended dose at monotherapy topiramaty at adults makes 100 mg a day, and the maximum daily dose — 500 mg. Some patients with refractory forms of epilepsy transfer monotherapy topiramaty in doses to 1 g/days.

To children is more senior than 3 years at monotherapy in the first week of treatment — 0,5–1 mg/kg of body weight a day, 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). 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. At selection of a dose and speed of its increase it is necessary to be guided by clinical performance.

The recommended range of doses at monotherapy topiramaty at children aged is more senior than 3 years makes 3–6 mg/kg a day. The maximum daily dose for children with recently diagnosed partial attacks does not exceed 500 mg a day.

 

Use in a combination with other anticonvulsant drugs
Adults have an initial dose — 50 mg of 1 times a day for the night within 1 week. Further the dose can be increased by 25–50 mg in 1–2 weeks before achievement of an effective dose. Usually average 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. At some patients the effect can be reached at administration of drug of 1 times a day.

The combined anticonvulsant therapy at children is more senior than 3 years. The recommended total day dose of a topiramat 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), for the night, within 1 week. Further the dose can be increased by 1 — 3 mg/kg in 1–2 weeks and to accept it in two steps. The day dose to 30 mg/kg is usually well transferred.

In days of carrying out a hemodialysis топирамат it is necessary to apply in addition in a dose, equal ½ daily doses, in 2 receptions (before and after the procedure).

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

Features of use:

Topiramat it is necessary to cancel gradually to minimize a possibility of increase in frequency of attacks. In clinical tests of a dose reduced by 50–100 mg with week intervals for adults at therapy of epilepsy. At children in clinical trials Topiramat gradually cancelled within 2–8 weeks. If on medical indications bystry cancellation of Topiramat is necessary, then it is recommended to exercise the corresponding control of a condition of the patient.

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.

Nephrolithiasis.

At some patients, in particular, with predisposition to a nephrolithiasis, the risk of formation of stones in nights and emergence of the related symptoms, such as renal colic can increase. To reduce this risk, adequate increase in volume of the consumed liquid is necessary.

Risk factors of development of a nephrolithiasis are a nephrolithiasis in the anamnesis (including in family), the hypercalcuria, the accompanying therapy by drugs which promote development of a nephrolithiasis.

Abnormal liver function.

At patients with abnormal liver functions топирамат it is necessary to apply with care because of possible decrease in clearance of 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 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. Symptoms usually appear in 1 month after the beginning of use of a topiramat. Unlike primary open angle glaucoma which is seldom observed at patients up to 40 years secondary closed-angle glaucoma is observed at use of a topiramat both for adults, and for children. Treatment includes the termination of reception of a topiramat and the appropriate 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). Similar decrease in concentration of hydrocarbonates of blood serum is a consequence of the inhibiting effect of a topiramat on a renal karboangidraza. Decrease in concentration usually weak or moderate (average value makes 4 mmol/l at use for 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. At children the chronic metabolic acidosis can lead to growth delay. Due to the above, at treatment topiramaty it is recommended to conduct necessary researches, including definition of concentration of hydrocarbonates in serum. At emergence of a metabolic acidosis and its persistirovaniya, it is recommended to lower a dose or to stop reception of a topiramat.

Suralimentation.

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

 

Topiramat affects the central nervous system and can cause drowsiness, dizziness, a vision disorder and other symptoms.

Therefore during treatment it is necessary to be careful at control of vehicles and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Medicinal incompatibility: examples are not known.

Side effects:

Side effects are given with distribution on frequencies and systems of bodies.

Frequency of side effects was classified as follows: very frequent (> 1/10), frequent (> 1/100, <1/10), infrequent (> 1/1000 and <1/100), rare (> 1/10000 and <1/1000) and very rare (<1/10000).

General disturbances:

very often: increased fatigue, irritability, decrease in body weight;
often: an adynamy, concern, children have an increased body temperature;
infrequently: face edema, metabolic acidosis, polydipsia, cold snap of extremities;
very seldom: generalized hypostasis, grippopodobny syndrome.

From the central nervous system:

very often: an ataxy (a lack of coordination of movements), decline in the ability to concentration of attention, dizziness, paresthesias;
often: drowsiness, disturbance of thinking;
seldom — a nystagmus, emotional lability, a tremor, amnesia, a perversion of flavoring feelings, disturbance of the speech (aphasia, a dysarthtia).

From the alimentary system:

very often: loss of appetite;
often: nausea, diarrhea, a lock, dyspepsia, dryness in a mouth, gastritis, a gastroesophageal reflux;
infrequently: a meteorism, an unpleasant smell from a mouth, the increased salivation, thirst.

From a musculoskeletal system:

often: arthralgia, muscular spasms, muscular spasms, mialgiya, including thorax;
infrequently: constraint of muscles; very seldom: a swelling of joints, discomfort in extremities.

Disturbances from cardiovascular system:

infrequently: bradycardia, tachycardia, orthostatic hypotension;

From sense bodys:

From an organ of sight, it is frequent: a vision disorder, (diplopia), the raised dacryagogue, a mydriasis, a night blindness, decrease in visual acuity; very seldom: conjunctival hypostasis, in 1 month from the beginning of therapy development of intraocular hypertensia, as a result — a myopia, closed-angle glaucoma is possible.

From an acoustic organ: often: ear pains, a ring in ears, at children вертиго;

infrequently: discomfort in ears, a hearing disorder, deafness, including, neurosensory deafness and unilateral deafness.

From respiratory system:

often: the complicated breath, nasal bleeding;

infrequently: in okolonosovy bosoms, children have a nose congestion, hypersecretion a rhinorrhea.

From integuments: often: alopecia, itch.

Allergic reactions: infrequently: allergic dermatitis, small tortoiseshell.

Disturbances from an urinary system: seldom: a lithogenesis in kidneys (nephrolithiasis), disturbances of an urination.

Laboratory indicators:

infrequently: in blood — increase in quantity of leukocytes, thrombocytes (a leukopenia, thrombocytopenia), at children in blood is increase in quantity of eosinophils (eosinophilia), decrease in concentration of a hydrocarbonate, potassium concentration in blood, detection of crystals in urine (crystalluria); very seldom: reduction of quantity of neutrophils (neutropenia).

Interaction with other medicines:

Influence of a topiramat on concentration of other antiepileptic drugs (PEP)

The concomitant use of a topiramat with other PEP (Phenytoinum, carbamazepine, valproic acid, phenobarbital, Primidonum) does not exert impact on values of their equilibrium concentration in plasma, except for certain patients in whom addition of a topiramat to Phenytoinum can cause increase in concentration of Phenytoinum in plasma. 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 a topiramat

Phenytoinum and carbamazepine reduce concentration of a topiramat in plasma. Addition or cancellation of Phenytoinum or carbamazepine against the background of treatment topiramaty can demand change of a dose of the last. The dose should be selected, being guided by achievement of necessary clinical effect. Addition or cancellation of valproic acid does not cause clinically significant changes of concentration of Topiramat in plasma and, therefore, does not demand change of a dose of Topiramat.

Other medicinal interactions

Digoxin: in a research at a concomitant use of Topiramat with use of a single dose of AUC digoxin of digoxin in plasma decreased by 12%. At use or Topiramat's cancellation by the patient accepting digoxin, special attention needs to be paid to routine monitoring of concentration of digoxin in serum.

Topiramat together with the alcohol or other drugs causing TsNS function oppression is not recommended to accept.

Oral contraceptives: Essential dozozavisimy decrease in efficiency of ethinylestradiol was observed at Topiramat's doses of 200-800 mg a day. 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 Topiramat. The patients accepting estrogensoderzhashchy contraceptives need to report about any changes in terms and character of periods. Efficiency of contraceptives can be reduced further in the absence of breakthrough bleedings.

Lithium drugs: At simultaneous use of a topiramat and drugs of lithium it is necessary to control concentration of lithium in a blood plasma.

Risperidon: At simultaneous 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%. The total pharmacokinetics of active agents (a risperidon and a 9-gidroksirisperidon) changed slightly.

Hydrochlorothiazide: At a concomitant use of a topiramat and a hydrochlorothiazide there is an increase in the maximum concentration of a topiramat by 27% and AUC of a topiramat by 29%. Use of a hydrochlorothiazide for 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: At a concomitant use of a topiramat and Metforminum there is an increase in the maximum concentration and AUC metformin by 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 combined 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 Topiramat's cancellation at the patients receiving Metforminum it is necessary to pay special attention to a careful research of a condition of the patients sick with a diabetes mellitus.

Pioglitazon: In clinical tests reduction of AUC of a pioglitazon by 15%, without change of the maximum concentration of drug is revealed. These changes were not statistically significant. At combined use by Topiramat's patients and a pioglitazona, it is necessary to pay special attention to a careful research of a condition of the patients sick with 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 of Glibenclamidum decreased by 25%. Also the level of system influence of active metabolites was reduced. Glibenclamidum did not influence pharmacokinetics of a topiramat in an equilibrium state. At use of a topiramat for the patients receiving Glibenclamidum (or use of Glibenclamidum for the patients 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 Topiramat with the drugs contributing to a nephrolithiasis can increase risk of formation of stones in kidneys.

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.

Additional researches of medicinal interaction showed:

Amitriptyline: at simultaneous use of amitriptyline with topiramaty there is an increase in the maximum concentration and AUC of a metabolite of a nortriptilin by 20%;

Haloperidol: at simultaneous use of a haloperidol with topiramaty there is an increase in AUC of a haloperidol by 31%;

Diltiazem: at simultaneous use of diltiazem with topiramaty there is a reduction of AUC of diltiazem by 25%, increase in AUC of a topiramat by 20%.

Contraindications:

Hypersensitivity, pregnancy, lactation period.
Topiramat in this dosage form (tablet), because of difficulties at a proglatyvaniye is not recommended for use for children up to 3 years.

With care
At a renal and liver failure, a nefrourolitiaza (including in the past and in the family anamnesis), hypercalcurias.

Use at pregnancy and a lactation
Due to the lack of clinical data, it is not applied to treatment of pregnant women.
Topiramat is excreted with breast milk at women. Administration of drug is contraindicated to women during feeding by a breast. If administration of drug in the period of a lactation is necessary, breastfeeding should be stopped.

Overdose:

Overdose symptoms: strengthening of dozozavisimy side effects.

Treatment: At acute overdose it is necessary to wash out a stomach at once. If necessary it is necessary to carry out symptomatic therapy. Efficiently removal of a topiramat from an organism the hemodialysis is.

Storage conditions:

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

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 25 mg and 100 mg
On 7, 10, 15 or 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 1, 2, 4, 8 blister strip packagings on 7 tablets or on 1, 3, 6 blister strip packagings on 10 tablets or on 2, 4 blister strip packagings on 15 tablets, or on 1, 2 blister strip packagings on 30 tablets together with the application instruction place in a pack from a cardboard.