Anticonvulsant drug

Active substance

Topiramate

Release form, composition and packaging

Excipients: microcrystalline cellulose - 31.4 mg, pregelatinized starch - 23.0 mg, colloidal silicon dioxide (aerosil) - 200 μg, magnesium stearate - 0.4 mg.

The composition of the film shell: opadry II 3.2 mg, including polyvinyl alcohol 1.28 mg, macrogol 0.65 mg, talc 0.47 mg, titanium dioxide 0.23 mg, quinoline yellow dye aluminum varnish 0.53 mg, sunset yellow dye aluminum varnish 0.04 mg.

Excipients: microcrystalline cellulose - 125.6 mg, pregelatinized starch - 92.0 mg, colloidal silicon dioxide (aerosil) - 800 μg, magnesium stearate - 1.6 mg.

The composition of the film shell: opadry II 12.8 mg, including polyvinyl alcohol 5.12 mg, macrogol 2.58 mg, talc 1.89 mg, titanium dioxide 0.93 mg, quinoline yellow dye aluminum varnish 2.10 mg, dye of sunset yellow aluminum varnish 0.16 mg.

10 pieces. - contour cell packaging (1) - cardboard packs.
10 pieces. - contour cell packaging (2) - cardboard packs.
10 pieces. - contour cell packaging (3) - cardboard packs.
10 pieces. - contour cell packaging (4) - cardboard packs.
10 pieces. - contour cell packaging (5) - cardboard packs.
100 pieces. - polymer cans (1) - cardboard packs.

pharmachologic effect

Topiramate is an antiepileptic agent, belongs to the class of sulfate-substituted monosaccharides. Blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Increases the activity of gamma-aminobutyric acid (GABA) in relation to some subtypes of GABA receptors (including GABA A receptors), and also modulates the activity of GABA A receptors themselves, prevents the activation of kainate / AMPA (a-amino-3- hydroxy-5-methylisoxazole-4-propionic acid) -receptors to glutamate, does not affect the activity of N-methyl-D-aspartate (NMDA) towards the NMDA receptor subtype. These effects of topiramate are dose-dependent at a topiramate concentration of 1 to 200 μmol / L, with a minimum activity ranging from 1 to 10 μmol / L.

In addition, topiramate inhibits the activity of some isoenzymes of carbonic anhydrase (II-IV). By the severity of this pharmacological effect topiramate is significantly inferior to the known inhibitor of carbonic anhydrase, therefore this action of topiramate is not the main component of its antiepileptic activity.

Pharmacokinetics

After oral administration, topiramate is rapidly and well absorbed from the gastrointestinal tract. Bioavailability is about 81%. After oral administration of 400 mg of topiramate, C max of 1.5 μg / ml is achieved within 2 hours. Food intake does not have a clinically significant effect on the bioavailability of topiramate. The value of C max after repeated oral administration of 100 mg of topiramate twice a day averaged 6.76 μg / ml.

Pharmacokinetics of topiramate is linear, plasma clearance remains constant, and the area under the concentration-time curve (AUC) in the dose range from 100 to 400 mg increases in proportion to the dose.

The connection with blood plasma proteins for topiramate is 13-17% in the range of plasma concentrations of 0.5-250.0 μg / ml. After a single dose of up to 1200 mg, the average Vd is 0.55–0.8 l / kg.

The V d value depends on gender: in women, it is approximately 50% of the values ​​observed in men, which is associated with a higher content of adipose tissue in the body of women.

C ss max when taking topiramate in patients with normal renal function is achieved after 4-8 days. Penetrates into breast milk and across the placental barrier.

After oral administration, about 20% of the dose taken is metabolized. Metabolized by hydroxylation, hydrolysis and glucuronidation. However, in patients receiving concomitant therapy (AEDs), which are inducers of microsomal enzymes, the metabolism of topiramate increased by up to 50%. Six practically inactive metabolites were isolated and identified from blood plasma, urine and feces. With the simultaneous administration of inducers of cytochrome P450 isoenzymes, the metabolic rate of topiramate is up to 50%.

The main route of elimination of unchanged topiramate (about 70%) and its metabolites is the kidneys. After oral administration, the plasma clearance of topiramate was 20-30 ml / min. After repeated oral administration of 50 and 100 mg twice a day, the half-life (T 1/2) of topiramate from blood plasma averages 21 hours. It is removed from plasma by hemodialysis.

Pharmacokinetics in special clinical situations. Renal and plasma clearance of topiramate with mild renal failure (creatinine clearance (CC) more than 70 ml / min) is not changed. At medium renal failure (CC 30-69 ml / min), renal and plasma clearance of topiramate is reduced by 42%, and in severe renal failure (CC less than 30 ml / min), renal and plasma clearance of topiramate is reduced by 54% or more.

In moderate and severe hepatic insufficiency, the plasma clearance of topiramate is reduced by 20-30%.

In elderly patients without renal and hepatic insufficiency, the clearance of topiramate is not changed.

The pharmacokinetics of topiramate in children, as in adults, is linear with a dose-independent clearance; the equilibrium concentration of topiramate in blood plasma increases in proportion to the dose increase. In children, the clearance of topiramate is increased, and T 1/2 is reduced, therefore, with the same dose per 1 kg of body weight, the concentration of topiramate in the blood plasma in children will be lower than in adults. In children, as in adults, antiepileptic drugs inducing microsomal liver enzymes cause a decrease in the concentration of topiramate in the blood plasma and increase the degree of its metabolism.

Indications

- in monotherapy in adults and children from 6 years of age with partial (with or without secondary generalization) or primary generalized tonic-clonic seizures;

- as part of complex therapy in adults and children over 3 years of age with partial secondary generalization or without or generalized tonic-clonic seizures, as well as for the treatment of seizures caused by Lennox-Gastaut syndrome;

- prevention of migraine attacks in adults after careful evaluation of all possible alternatives. Topiramate is not indicated for the treatment of acute migraine attacks.

Contraindications

- hypersensitivity to topiramate or any other component of the drug;

— childhood up to 6 years with monotherapy, up to 3 years as part of combination therapy for epilepsy;

- children under 18 years of age when used for the prevention of migraine;

- prevention of migraine in pregnant women or women of childbearing age who do not use effective contraception.

WITH caution: renal failure, liver failure, hypercalciuria, nephrourolithiasis (including history or family history).

Dosage

Inside, regardless of the meal. The tablets should not be divided.

For optimal seizure control, it is recommended to start treatment with low doses and then increase to the effective dose. When used as monotherapy, consideration should be given to the possible effect of discontinuation of concomitant antiepileptic drugs (AEDs) on seizure frequency. In cases where there is no need to abruptly cancel PEP, it is recommended to reduce their doses gradually, reducing the dose by 1/3 every 2 weeks. When canceling medicines, which are inducers of liver microsomal enzymes, the concentration of topiramate in the blood plasma will increase, which should be taken into account in the therapy.

Monotherapy

Adults at the beginning of monotherapy - 25 mg 1 time per day at night for 1 week. Then the dose is increased at intervals of 1-2 weeks by 25-50 mg / day (the daily dose is divided into 2 doses). In case of intolerance to such a therapy regimen, the dose is increased by a smaller amount or at large intervals. The dose is selected depending on the effectiveness and tolerability of the therapy. The recommended initial target dose is 100-200 mg / day, the maximum daily dose should not exceed 500 mg in monotherapy. Dosing recommendations apply to all adults, including elderly patients without renal disease.

Children over 6 years old with monotherapy in the first week of treatment - 0.5-1 mg / kg of body weight before bedtime. Then the dose is increased at intervals of 1-2 weeks by 0.5-1 mg / kg per day (the daily dose is divided into two doses). In case of intolerance to such a regimen of therapy, the dose is increased more smoothly or at large intervals between dose increases. The size of the dose and the rate of its increase are determined by the clinical efficacy and tolerability of therapy. The recommended dose range for monotherapy with topiramate in children is 100 mg / day and depends on the clinical efficacy (in children 6-16 years old, it is about 2 mg / kg / day).

As part of combination therapy

Adults

When prescribed as part of a combination therapy with other anticonvulsant drugs in adults, the initial dose is 25-50 mg 1 time per day at night for 1 week. Then the dose is increased by 25-50 mg every week until the effective dose is reached. The minimum effective dose is 200 mg / day, the average daily dose is 200-400 mg, the frequency of administration is 2 times a day. Doses over 1600 mg per day have not been studied. The criterion for dose selection is the clinical effect and tolerability, in some patients this effect can be achieved by taking the drug once a day.

Children

When prescribed as part of a combination anticonvulsant therapy in children over 3 years of age, the recommended total daily dose is 5-9 mg / kg for 2 doses. Dose selection begins with 25 mg / day (at the rate of 1-3 mg / kg / day) at night for 1 week. In the future, the dose can be increased by 1-3 mg / kg for 1-2 weeks and taken in 2 divided doses. The criterion for the correct selection of the dose is a stable clinical effect and good tolerance. Daily doses up to 30 mg / kg are generally well tolerated.

Prevention of migraine

The recommended total daily dose is 100 mg in 2 divided doses. Begin treatment with a dose of 25 mg or less at bedtime for 1 week. Then the dose is increased by 25 mg / day with an interval of 1 week. In case of intolerance to such a regimen, the dose is increased by a smaller amount or at long intervals. The dose is selected depending on the clinical effect. In some patients, a positive result is achieved with a daily dose of 50 mg / day. When using a daily dose of more than 100 mg / day, there is no additional effect as a prophylaxis for migraine.

Patients with renal failure. For patients with moderate (CC less than 70 ml / min) and severe (CC less than 30 ml / min) degree of renal failure, the recommended initial dose should be reduced by 2 times, and it should be increased by a smaller amount or at long intervals. The dose is selected depending on the clinical effect. It should be borne in mind that reaching an equilibrium concentration will take more time and will be from 10 to 15 days after each increase in the dose of Topiramate.

Patients requiring hemodialysis. Since topiramate can be removed by hemodialysis, on the days of its carrying out, the daily dose of the drug should be increased by 50%. The additional dose is divided into 2 parts and is administered before and after hemodialysis. The additional dose may differ depending on the characteristics of the dialysis and the equipment used. The dose is selected depending on the clinical effect.

In patients with hepatic impairment the drug Topiramate should be taken with caution under the supervision of a physician due to the reduced clearance of topiramate.

In elderly patients dose adjustment is not required.

Cancellation of the drug

Antiepileptic drugs, including topiramate, should be withdrawn gradually to minimize the possibility of an increase in the frequency of seizures, reducing the dose by 50-100 mg with an interval of 1 week for the treatment of epilepsy and 25-50 mg when using Topiramate for the prevention of migraine. In children, cancellation within 2-8 weeks. If, for medical reasons, the rapid cancellation of topiramate is necessary, then it is recommended to carry out appropriate monitoring of the patient's condition. The main route of elimination of topiramate and its metabolites unchanged is renal excretion. The rate of excretion by the kidneys depends on the function of the kidneys and does not depend on age. In patients with moderate to severe renal impairment, it may take 10-15 days to reach equilibrium plasma concentrations, compared with 4-8 days in patients with normal renal function.

As with the use of other AEDs, the dose selection scheme for Topiramate should be guided by therapeutic efficacy (that is, the degree of reduction in the frequency of seizures, the absence side effects) and should take into account the fact that in patients with impaired renal function, it may take a longer time to establish an equilibrium plasma concentration of topiramate for each dose.

Side effects

The frequency of side effects is classified in accordance with the recommendations of the World Health Organization: very often - at least 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0.1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - not less than 0.01%, including single messages.

The most common adverse reactions (with a frequency of ≥5% compared with placebo, reported in at least 1 double-blind controlled study): anorexia, decreased appetite, mental retardation, depression, slurred speech, insomnia, impaired coordination of movements, impaired attention, dizziness, dysarthria, impaired taste, hypesthesia, lethargy, memory loss, nystagmus, paresthesia, drowsiness, tremor, diplopia, visual impairment, diarrhea, nausea, increased fatigue, irritability, weight loss.

Children

Adverse reactions that, according to the results of double-blind clinical studies, were ≥2 times more common in children than in adults: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disturbances, aggression, apathy, sleep disturbance, suicidal thoughts, impaired attention, drowsiness, disturbed daily sleep rhythm, poor sleep quality, increased lacrimation, sinus bradycardia, general unsatisfactory condition, gait disturbance.

Adverse reactions that have arisen in clinical research exclusively in children: eosinophilia, psychomotor agitation, vertigo, vomiting, hyperthermia, fever, learning disabilities.

Table # 1. Adverse reactions of topiramate

* Revealed by the results of spontaneous messages in the post-registration period. Frequency calculated from clinical trials.

Overdose

Overdose signs and symptoms: convulsions, drowsiness, speech and vision disorders, diplopia, thinking disorders, coordination disorders, dizziness, lethargy, stupor, arterial hypotension, abdominal pain, dizziness, agitation and depression, metabolic acidosis... In most cases, the clinical consequences were not severe, but deaths have been observed after overdose with the use of a mixture of several drugs, including topiramate. There is a known case of an overdose of topiramate at a dose of up to 110 g, which led to a coma within 20-24 hours, and then after 3-4 days full recovery.

Treatment: there is no specific antidote, symptomatic therapy is carried out if necessary. It is necessary to immediately induce vomiting and gastric lavage, increase water intake. In in vitro studies, it has been shown to adsorb topiramate. Hemodialysis is the most effective method removing topiramate from the body. Patients are advised to adequately increase the volume of fluid intake.

Drug interactions

Effect of topiramate on the concentration of other antiepileptic drugs (PEP)

Simultaneous administration of topiramate with other AEDs (phenytoin, carbamazepine, phenobarbital, primidone) does not affect the values ​​of their stable plasma concentrations, with the exception of individual patients in whom the addition of topiramate to phenytoin may cause an increase in the plasma phenytoin concentration. This may be due to the inhibition of a specific polymorphic isoform of the enzyme of the cytochrome P450 system (CYP2Cmeph). Therefore, every patient who takes phenytoin and who develops Clinical signs or symptoms of toxicity, plasma phenytoin concentrations should be monitored.

In a study of pharmacokinetics in patients with epilepsy, the addition of topiramate to did not affect the equilibrium concentration of the latter at doses of 100-400 mg of topiramate per day. During treatment and after discontinuation of lamotrigine (average dose of topiramate 327 mg / day), the equilibrium concentration of topiramate did not change.

Valproic acid: the combined use of topiramate and valproic acid in patients who tolerate each drug well individually is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after one of the drugs is discontinued. This adverse event is not due to pharmacokinetic interactions. The relationship between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established. When topiramate and valproic acid are taken together, hypothermia (an unintentional decrease in body temperature below 35 ° C) may occur in combination with hyperammonemia or independently. This phenomenon can occur both after the start of joint administration of valproic acid and topiramate, and with an increase in the dose of topiramate.

The results of interaction with antiepileptic drugs are presented in table No. 2.

Table 2... Interaction of topiramate and other AEDs

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

Increased concentration in selected patients;

↓ - decrease in concentration in blood plasma;

NOR - not investigated.

Other drug interactions

Digoxin: in a study using a single dose of digoxin, the area under the concentration / time curve (AUC) of digoxin in plasma while taking topiramate decreased by 12%. The clinical relevance of this observation is unclear. When prescribing or discontinuing topiramate in patients taking digoxin, special attention should be paid to monitoring the serum digoxin concentration.

St. John's wort: when topiramate and St. John's wort preparations are taken together, the concentration of topiramate in the blood plasma may decrease, and, as a result, the effectiveness of the drug may also decrease. Clinical studies of the interaction of the drug Topiramate and drugs based on St. John's wort have not been conducted.

Oral contraceptives: in research drug interactions with oral contraceptives in which combination drug containing norethisterone (1 mg) and ethinylestradiol (35 μg), topiramate at doses of 50-800 mr per day did not have a significant line on the effectiveness of norethisterone and at doses of 50-200 mg per day on the effectiveness of ethinylestradiol. A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of topiramate 200-800 mg per day. The clinical significance of the described changes is not clear. The risk of reduced effectiveness of contraceptives and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with topiramate. Patients taking estrogen-containing contraceptives should inform their doctor about any changes in the timing and nature of menstruation. Contraceptive effectiveness can be reduced even in the absence of breakthrough bleeding.

Lithium: in healthy volunteers, a decrease in lithium AUC by 18% was observed while taking topiramate at a dose of 200 mg per day. In patients with manic-depressive psychosis, the use of topiramate at doses up to 200 mg per day did not affect the pharmacokinetics of lithium, however, at higher doses (up to 600 mg per day), the AUC of lithium was increased by 26%. With the simultaneous use of topiramate and lithium, the concentration of the latter in the blood plasma should be monitored.

Risperidone: drug interaction studies conducted with single and multiple administration of topiramate to healthy volunteers and patients with manic-depressive psychosis gave the same results. With the simultaneous use of topiratam in doses of 250 or 400 mg per day, the AUC of risperidone, taken at doses of 1-6 mg per day, decreases by 16% and 33%, respectively. At the same time, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of active substances (risperidone and 9-hydroxyrisperidone) did not change significantly. The change in the level of systemic exposure to risperidone / 9-hydroxyrisperidone and topiramate was not clinically significant, and this interaction is unlikely to have clinical significance.

Hydrochlorothiazide: drug interactions were evaluated in healthy volunteers with separate and joint administration of hydrochlorothiazide (25 mg) and topiramate (96 mg). The research results showed that with the simultaneous administration of topiramate and hydrochlorothiazide, there is an increase in the maximum concentration of topiramate by 27% and the area under the concentration curve of topiramate by 29%. The clinical significance of these studies has not been identified. Administration of hydrochlorothiazide to patients taking topiramate may require dose adjustment of topiramate. The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant therapy with topiramate.

With the simultaneous use of topiramate and metformin there was an increase in C max and AUC of metformin by 18 and 25%, respectively, while the clearance of metformin decreased by 20%. Topiramate did not affect the time to reach C max of metformin in blood plasma. The clearance of topiramate when used simultaneously with metformin decreased. The extent of the identified changes in clearance has not been studied. The clinical significance of the effects of metformin on the pharmacokinetics of topiramate is unclear. In the case of adding or canceling Topiramate in patients receiving metformin, the course of diabetes should be carefully monitored.

With simultaneous use pioglitazone and topiramate, a 15% decrease in the AUC of pioglitazone was detected, without a change in the C max of pioglitazone. These changes were not statistically significant. Also, for the active hydroxymetabolite pioglitazone, a decrease in C max and AUC by 13 and 16%, respectively, was detected, and for the active ketometabolite, a decrease in both C max and AUC by 60% was revealed. The clinical relevance of these data has not been clarified. In the case of the joint appointment of Topiramate and pioglitazone, the course of diabetes mellitus should be carefully monitored.

When applying glibenclamide(5 mg per day) alone or simultaneously with topiramate (150 mg per day) in patients with diabetes mellitus Type 2 AUC of glibenclamide decreased by 25%. The systemic exposure of 4-trans-hydroxyglibenclamide and 3-cis-hydroxyglibenclamide was also reduced by 13 and 15%, respectively. Glibenclamide did not affect the pharmacokinetics of topiramate at steady state. When prescribing glibenclamide and topiramate to patients simultaneously, it is necessary to take into account the possible pharmacokinetic interaction and carefully monitor the patient's condition to assess the course of diabetes mellitus.

Other drugs: concomitant use of topiramate with drugs that predispose to nephrolithiasis should be avoided due to the increased risk of kidney stones.

Additional drug interaction studies are presented in table 3.

Table No. 3. Results of additional studies of interactions between topiramate and various drugs(LP).

a - expressed in% of the values ​​of C max in blood plasma and AUC with monotherapy;

↔ - no changes in C max in blood plasma and AUC (up to 15% of the initial data);

b - with repeated ingestion of flunarizine, an increase in AUC was observed by 14%, which may be due to its accumulation in the process of reaching an equilibrium state;

NOR - not investigated.

special instructions

Antiepileptic drugs, including topiramate, should be withdrawn gradually to minimize the possibility of an increased seizure frequency. If, for medical reasons, a quick cancellation of topiramate is needed, then it is necessary to carry out appropriate monitoring of the patient's condition.

As with any disease, the dose selection scheme should be guided by the clinical effect and take into account the fact that in patients with impaired renal function, it may take a longer time for each dose to establish a stable concentration of topiramate in plasma for each dose (from 10 to 15 days, in contrast to 4-8 days in patients with normal renal function). The rate of excretion through the kidneys depends on the function of the kidneys and does not depend on age. During therapy with topiramate, it is very important to adequately increase the volume of fluid consumed, which can reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence physical activity or high temperatures.

Mood disorder / depression and suicide attempts.

When using the drug Topiramate, there is an increase in the incidence of mood disorders (including an increase in aggressiveness), psychotic reactions and depression.

During clinical studies, in patients with epilepsy, when using topiramate more often than in the placebo group, cases associated with an increase in suicidal activity (suicidal thoughts, suicidal attempts and completed suicide) were observed: the frequency was 0.5% in patients receiving topiramate (46 out of 8652 patients ) and 0.2% in patients receiving placebo. The mechanism behind this risk is unknown. When using topiramate, patients should be examined for suicidal thoughts and suicidal behavior. If suicidal activity is detected in patients, appropriate treatment should be considered. Patients, their relatives, and patient care personnel should be informed about the need to consult a doctor if signs of suicidal tendencies and suicidal behavior are detected.

Patients with any personality disorder need special monitoring, especially at the beginning of treatment with topiramate.

Nephrolithiasis

In patients with a predisposition to nephrolithiasis, the risk of kidney stones is increased, for the prevention of which an adequate increase in the volume of fluid intake is necessary. Risk factors for the development of nephrolithiasis are a history of nephrolithiasis (including in the family), hypercalciuria, concomitant therapy with drugs that contribute to the development of nephrolithiasis.

Impaired renal function

Caution should be exercised when prescribing Topiramate to patients with renal insufficiency (creatinine clearance<70 мл/мин). Это связано с тем, что у таких пациентов клиренс препарата понижен.

Liver dysfunction

In patients with impaired liver function, topiramate should be taken with caution because of the possible decrease in the clearance of this drug.

Myopia and secondary angle-closure glaucoma

When using topiramate, a syndrome has been described that includes acute myopia with concomitant secondary angle-closure glaucoma. Symptoms include an acute decrease in visual acuity and / or eye pain. Ophthalmological examination reveals myopia, flattening of the depth of the anterior chamber, hyperemia (redness of the eyes) and increased intraocular pressure, and there may also be mydriasis. The described syndrome may be associated with supraciliary effusion, which causes a shift in the lens and iris and the development of secondary angle-closure glaucoma. Typically, symptoms appear after a month of initial therapy. In contrast to primary open-angle glaucoma, which was rarely detected in patients under 40 years of age, secondary angle-closure glaucoma associated with the use of topiramate was observed in both children and adults. Treatment involves discontinuing Topiramate, if the doctor deems it appropriate, and taking appropriate measures to reduce intraocular pressure. Increased intraocular pressure in the absence of adequate treatment can lead to serious complications, including loss of vision.

Metabolic acidosis

When using topiramate, hyperchloremic, not associated with anion deficiency, metabolic acidosis may occur. Such a decrease in the concentration of blood serum bicarbonates is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, a decrease in the concentration of hydrocarbonates in the blood plasma occurs at the beginning of taking topiramate, although this effect can manifest itself at any period of treatment with Topiramate. The decrease in the concentration of hydrocarbonates in the blood plasma is usually weak or moderate (the average concentration in the blood plasma is 4 mmol / l when used in adult patients at a dose of more than 100 mg / day and in children at a dose of about 6 mg / kg / day). A decrease in the concentration of bicarbonates in blood plasma less than 10 mmol / l was noted in rare cases. Certain diseases or treatments that predispose to the development of acidosis (for example, kidney disease, severe respiratory illness, status epilepticus, diarrhea, surgery, increased production of ketone bodies in the body, certain medications) may be additional factors that increase bicarbonate-lowering topiramate effect. Chronic metabolic acidosis increases the risk of developing nephrolithiasis. In children, chronic metabolic acidosis can cause osteomalacia and slow growth. The effect of topiramate on growth and possible complications of the skeletal system in children has not been systematically studied in children and adults.

When treating with topiramate, the necessary studies should be carried out, including the determination of the concentration of hydrocarbons in the blood serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or stop taking the drug.

Enhanced nutrition

If the patient loses weight while taking topiramate, then it is necessary to consider the feasibility of enhanced nutrition.

With topiramate therapy, oligohydrosis or anhidrosis may occur. Decreased sweating and hyperthermia can occur in children exposed to high ambient temperatures. In this connection, adequate fluid intake is very important to reduce the risk of side effects, including nephrolithiasis.

Laboratory indicators

In 0.4% of patients taking topiramate, hypokalemia was observed, defined as a decrease in serum potassium concentration below 3.5 mmol / L.

Influence on the ability to drive vehicles and use mechanisms

Topiramate has a weak or moderate effect on the ability to drive and operate machinery. Topiramate acts on the central nervous system and can cause drowsiness, dizziness, and other symptoms. It can also cause visual impairment. These adverse reactions can pose a potential threat to patients when driving vehicles and working with mechanisms, especially during the period of establishing individual sensitivity to the drug. During the period of treatment, care must be taken when driving vehicles and working with mechanisms.

Pregnancy and lactation

There are no specific controlled studies in which topiramate has been used to treat pregnant women. There is evidence of a possible link between the use of topiramate during pregnancy and congenital malformations (eg, craniofacial defects (cleft lip / cleft palate), hypospadias, fetal and newborn weight deficiency). These malformations were recorded both with topiramate monotherapy and with its simultaneous use with other antiepileptic drugs (AEDs). . Pregnancy registration data and the results of studies of monotherapy with topiramate indicate an increase in the likelihood of having children with a deficiency in body weight (less than 2500 g). The connection of these cases with the reception of topiramate has not been established. Data from other studies indicate that the risk of teratogenic effects in combination treatment with other antiepileptic drugs may be higher than with monotherapy.

The use of topiramate during pregnancy is contraindicated. During treatment with the drug, it is necessary to use effective methods of contraception.

The limited number of patient observations suggests that topiramate is excreted in breast milk, so breastfeeding should be discontinued while using the drug.

Women of fertile potential are encouraged to use effective contraception and consider alternative treatments. If topiramate is used during pregnancy, or if the patient becomes pregnant while taking this drug, the doctor should warn her of the potential risk to the fetus.

No dose adjustment is required in elderly patients.

Conditions of dispensing from pharmacies

The drug is dispensed by prescription.

Storage conditions and periods

Store in a dark place at a temperature not exceeding 25 ° C. Keep out of the reach of children. Shelf life is 2 years. Do not use after the expiration date printed on the package.

Film-coated tablets - 1 tab .:

• Active ingredients: topiramate - 100 mg;
• Excipients: microcrystalline cellulose - 125.6 mg, pregelatinized starch - 92.0 mg, colloidal silicon dioxide (aerosil) - 800 μg, magnesium stearate - 1.6 mg;
• film shell: opadry II 12.8 mg, including polyvinyl alcohol 5.12 mg, macrogol 2.58 mg, talc 1.89 mg, titanium dioxide 0.93 mg, quinoline yellow dye aluminum varnish 2.10 mg, dye of sunset yellow aluminum varnish 0.16 mg.

30 tablets per pack.

Description of the dosage form

Tablets are yellowish-beige, round, biconvex; at the break of white or almost white.

pharmachologic effect

Antiepileptic drug, belongs to the class of sulfate-substituted monosaccharides.

Topiramate reduces the frequency of action potentials characteristic of a neuron in a state of persistent depolarization, which indicates the dependence of the blocking effect of the drug on sodium channels on the state of the neuron. Topiramate potentiates the activity of GABA in relation to some subtypes of GABA receptors (including GABAA receptors), and also modulates the activity of the GABAA receptors themselves, prevents kainate from activating the sensitivity of kainate / AMPK receptors to glutamate, does not affect the activity of N-methyl Β-D-aspartate in relation to NMDA receptors. These effects of topiramate are dose-dependent at plasma topiramate concentrations ranging from 1 μM to 200 μM, with a minimum activity ranging from 1 μM to 10 μM.

In addition, topiramate inhibits the activity of some isoenzymes of carbonic anhydrase, but this effect is weaker in topiramate than in acetazolamide and, apparently, is not the main one in the antiepileptic activity of topiramate.

Pharmacokinetics

Compared with other anticonvulsants, topiramate has a long half-life, linear kinetics, predominant renal clearance, low plasma protein binding, and the absence of clinically significant metabolites.

Topiramate is not characterized by a powerful inducing effect on liver microsomal enzymes. Topiramate is allowed to be taken regardless of food intake. Monitoring the concentration of topiramate is not required. According to the results of clinical studies, the relationship between the plasma concentration of topiramate and its effectiveness and adverse reactions has not been established.

Suction.

Topiramate is absorbed quickly and efficiently. After oral administration of 100 mg of topiramate, the average maximum plasma concentration (Cmax) in healthy volunteers is 1.5 mg / ml and is achieved within 2-3 hours (tmax). After taking 100 mg of 14C-mech topiramate, 81% of the radioactivity is found in the urine. Food intake does not have a clinically significant effect on the bioavailability of topiramate.

Distribution.

Plasma proteins bind 13-17% of topiramate. The binding sites of topiramate on erythrocytes are saturated when its plasma concentration is more than 4 mg / ml. The volume of distribution is inversely proportional to the dose. The volume of distribution (after a single oral administration of 100-1200 mg) is 0.55 - 0.8 l / kg, depending on gender: in women it is approximately 50% of the values ​​observed in men, which is associated with a higher content of adipose tissue in the body women; this circumstance has no clinical significance.

Metabolism.

After oral administration in healthy volunteers, about 20% of the dose taken is metabolized. However, in patients taking concomitant therapy with anticonvulsants - inducers of liver microsomal enzymes, the metabolism of topiramate increases up to 50%. Six metabolites formed by hydroxylation, hydrolysis and glucuronidation were isolated and identified from human plasma, urine and feces. The amount of each metabolite does not exceed 3% of the total radioactivity detected after administration of 14C-topiramate. The two metabolites with the greatest structural similarity to topiramate have practically no anticonvulsant activity.

Excretion.

Unchanged topiramate and its metabolites are excreted by the kidneys (at least 81% of the dose taken). Within 4 days, about 66% of unchanged 14C-topiramate is excreted in the urine. After taking 50 and 100 mg of topiramate twice a day, the average renal clearance is 18 and 17 ml / min, respectively. Topiramate undergoes tubular reabsorption, which is confirmed by the results of a study in rats with the simultaneous administration of probenecid: there was a significant increase in renal clearance of topiramate. After oral administration, the plasma clearance of topiramate is approximately 20-30 ml / min.

Topiramate has a low interindividual variation in plasma concentrations, i.e. has predictable pharmacokinetics. With a single dose of 100-400 mg to healthy volunteers, the pharmacokinetics of topiramate is linear, plasma clearance remains constant, and the area under the concentration-time curve (AUC) increases in proportion to the dose. The time to reach equilibrium concentration in patients with normal renal function is 4-8 days. The average Cmax after repeated oral administration of 100 mg in healthy volunteers is 6.76 μg / ml. The average plasma elimination half-life after repeated administration of 50 and 100 mg of topiramate twice a day is 21 hours.

With the simultaneous use of topiramate in doses of 100-400 mg twice a day with phenytoin or carbamazepine, the concentration of the former in plasma increased in proportion to the dose.

In patients with moderate to severe renal impairment (creatinia clearance (CC))<70 мл/мин) плазменный и почечный клиренс топирамата снижается. В связи с этим у таких пациентов возможно повышение равновесной концентрации топирамата в плазме крови по сравнению с пациентами с нормальной функцией почек. Кроме того, пациентам с нарушениями функции почек для достижения равновесной концентрации топирамата в плазме требуется больше времени. Пациентам с нарушениями функции почек средней и тяжелой степени рекомендуется принимать половину рекомендованной начальной и поддерживающей дозы. Топирамат хорошо выводится из плазмы с помощью гемодиализа. Длительный гемодиализ может привести к снижению концентрации топирамата в крови ниже необходимого для поддержания противосудорожной активности. Во избежание быстрого снижения концентрации топирамата в плазме во время гемодиализа, может потребоваться прием дополнительной дозы препарата топирамата. При коррекции дозы следует принимать во внимание: продолжительность гемодиализа, клиренс используемой системы гемодиализа, эффективный почечный клиренс топирамата у пациента, находящегося на диализе.

In patients with moderate to severe hepatic insufficiency, the plasma clearance of topiramate is reduced by an average of 26%. Therefore, patients with hepatic impairment should use topiramate with caution.

In elderly patients without renal disease, the plasma clearance of topiramate does not change.

Pharmacokinetics of topiramate in children under 12 years of age.

The pharmacokinetics of topiramate in children, as well as in adults taking it as part of a combination therapy, is linear, while the clearance of topiramate does not depend on the dose, and the equilibrium plasma concentrations increase in proportion to the dose. However, in children, the clearance of topiramate is increased and the half-life is shorter. In this regard, at the same dose, per 1 kg of body weight, plasma concentrations of topiramate in children may be lower than in adults. In children, as in adults, anticonvulsants that induce liver microsomal enzymes cause a decrease in plasma topiramate concentrations.

Indications for use of Topiramate

Partial or generalized tonic-clonic seizures as monotherapy and in combination with other anticonvulsants; adjunctive therapy in the treatment of seizures associated with Lennox-Gastaut syndrome (in adults and children); newly diagnosed epilepsy (in adults and children over 2 years old).

Contraindications to the use of Topiramate

Hypersensitivity to topiramate.

It should be used with caution in renal and hepatic failure, nephrourolithiasis (including personal and family history), hypercalciuria.

Topiramate Use during pregnancy and children

Adequate and strictly controlled clinical studies of the safety of the use of topiramate during pregnancy have not been conducted.

The use of topiramate during pregnancy can damage the fetus. Pregnancy register data show that fetal exposure to topiramate increases the risk of congenital malformations (eg, craniofacial defects such as cleft lip / cleft palate, hypospadias and developmental abnormalities of various body systems). These malformations were recorded both with topiramate monotherapy and with its use in combination therapy. Compared with the group of patients not taking antiepileptic drugs, data from the register of pregnant women with topiramate monotherapy indicate an increase in the frequency of births of children with low body weight (less than 2500 g). A causal relationship has not been established.

When treating women of childbearing age, the expected benefits of therapy for the mother and the potential risk to the fetus should be weighed and alternative treatment options should be considered. If topiramate is used during pregnancy or if pregnancy occurs during the treatment period, the patient should be warned of the potential risk to the fetus.

The limited number of observations suggests that topiramate is excreted in breast milk. If necessary, use during lactation should decide on the termination of breastfeeding.

Do not use in children under 2 years of age.

Topiramate Side effects

The most common adverse reactions (with a frequency> 5% compared with placebo, reported in at least 1 double-blind controlled study): anorexia, decreased appetite, mental retardation, depression, slurred speech, insomnia, impaired coordination of movements, impaired attention, dizziness, dysarthria, impaired taste, hypesthesia, lethargy, memory loss, nystagmus, paresthesia, drowsiness, tremor, diplopia, visual impairment, diarrhea, nausea, increased fatigue, irritability, weight loss.

Adverse reactions that, according to the results of double-blind clinical studies, were> 2 times more common in children than in adults: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disturbances, aggression, apathy, sleep disturbances, suicidal thoughts, impaired attention, drowsiness, disturbed daily sleep rhythm, poor sleep quality, increased lacrimation, sinus bradycardia, general unsatisfactory condition, gait disturbance.

Adverse reactions that have arisen in clinical trials exclusively in children: eosinophilia, psychomotor agitation, vertigo, vomiting, hyperthermia, fever, learning disabilities.

Adverse reactions are given by frequency and organ systems. The frequency of adverse reactions was classified as follows: very frequent (> 1/10), frequent (> 1/100.<1/10), нечастые (>1/1000 and<1/100), редкие (>1/10000 and<1/1000) и очень редкие (<1/10000), частота неизвестна - по имеющимся данным частоту оценить невозможно.

Infections: very common - nasopharyngitis.

On the part of the blood and lymphatic system:

• Often - anemia;
• infrequently - leukopenia, thrombocytopenia, lymphadenopathies, eosinophilia; rarely - neutropenia.

From the immune system:

• Often - hypersensitivity;
• frequency unknown - angioedema, conjunctival edema.

From the nervous system:

• Very often - drowsiness, dizziness, paresthesia;
• often - impaired coordination, nystagmus, lethargy, memory impairment, impaired concentration, tremor, amnesia, hypshesia, perversion of taste sensations, loss of taste sensitivity, impaired thinking, impaired speech, cognitive impairment, mental impairment, psychomotor impairments, convulsions, intense tremor, sedative effect;
• infrequently - aphasia, tonic-clonic seizures of the "grand mal" type, complex partial seizures, burning sensation (mainly on the face and in the extremities), cerebellar syndrome, clumsiness, postural dizziness, increased salivation, dysesthesia, dysgraphia, dyskinesia, dysphasia, " goose bumps, hypogeusia, hypokinesia, peripheral neuropathy, parosmia, light-headedness, repetitive speech, loss of sensitivity, aura, dystonia, stupor, fainting, in children - psychomotor hyperactivity;
• rarely - apraxia, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of reaction to stimuli, in children - disturbance of the circadian rhythm of sleep.

Mental disorders:

• Very often - depression;
• often - slow thinking, confusion, insomnia, agitation, anxiety, irritability, disorientation, mood disturbances, emotional lability, anger;
• infrequently - apathy, erectile dysfunction, sexual dysfunction, sexual arousal disorder, dysfemia, early awakening in the morning, euphoria, auditory and visual hallucinations, hypomanic states, decreased libido, panic attacks, paranoia, perseveration of thinking, impaired reading skills, sleep disturbances, suicidal thoughts, suicidal attempts, tearfulness;
• rarely - mania, anorgasmia, a sense of despair, decreased sensations during orgasm, in children - apathy, crying.

On the part of the organ of vision:

• Often - blurred vision, diplopia, visual impairment; infrequently - blepharospasm, myopia, photopsia, presbyopia, scotoma, decreased visual acuity, increased lacrimation, mydriasis, photophobia, sensation of a foreign body in the eye, dry eyes; rarely - violation of accommodation, glaucoma, amblyopia, edema of the eyelids, ciliated scotoma, visual agnosia, one-sided blindness, transient blindness, night blindness;
• frequency unknown - angle-closure glaucoma, eye mobility disorders, maculopathy.

On the part of the organ of hearing and balance: often - vertigo, ear pain, ringing in the ears.

• Uncommon - deafness, incl. neurosensory and unilateral, discomfort in the ears, hearing impairment.

On the part of the cardiovascular system:

• Infrequently - bradycardia, incl. sinus, palpitations, "hot flashes" of blood, hypotension, incl. orthostatic; rarely, Raynaud's phenomenon.

From the respiratory system:

• Often - shortness of breath, nasal congestion, epistaxis, cough, in children -
• rhinorrhea;
• infrequently - dysphonia. shortness of breath on exertion, hypersecretion in the paranasal sinuses.

From the gastrointestinal tract and hepatobiliary system:

• Very often - nausea, diarrhea;
• often - decreased appetite, anorexia, constipation, epigastric pain, dryness of the oral mucosa, dyspepsia, stomach discomfort, paresthesia in the oral cavity, gastritis, vomiting, abdominal pain;
• infrequently - pancreatitis, flatulence, gastroesophageal reflux, pain in the lower abdomen, hypesthesia in the oral cavity, bleeding gums, bad breath, glossodynia, pain in the oral cavity, polydipsia, increased appetite, hypersecretion of salivary glands, epigastric discomfort in the abdomen, thirst, increased activity of liver enzymes;
• rarely - hepatitis, liver failure.

From the musculoskeletal system and connective tissue:

• Often, myalgia, muscle cramps, muscle cramps, muscle weakness;
• arthralgia, musculoskeletal pain in the chest area;
• infrequently - muscle stiffness, joint swelling, flank pain, muscle
• fatigue;
• rarely - discomfort in the limbs.

From the side of the night and urine of the excretory system:

• Often - nephrolithiasis, dysuria, pollakiuria;
• infrequently - calculi in the urine, hematuria, urinary incontinence, frequent urge to
• urination, renal colic, pain in the kidney area;
• rarely - ureteral calculi, renal tubular acidosis.

On the part of the skin and subcutaneous tissues:

• Often - skin rash, alopecia, itching;
• infrequently - anhidrosis, facial skin hypesthesia, localized urticaria, erythema, generalized itching, macular rash, skin pigmentation disorders, rashes, facial edema;
• infrequently - erythema multiforme, periorbital edema, unpleasant skin odor, Steven-Johnson syndrome;
• very rarely - generalized edema; frequency unknown - toxic epidermal necrolysis.

Laboratory indicators:

• Uncommon - crystalluria, hypokalemia;
• rarely - a decrease in the content of hydrocarbons in the blood;
• hyperchloremic acidosis.

• Very often - fatigue, weight loss;
• often - asthenia, weight gain, increased body temperature;
• infrequently - metabolic acidosis, cold extremities, flu-like diseases;
• rarely - facial edema, calcification.

Identified by the results of spontaneous messages in the post-registration period.

Frequency calculated from clinical trials.

Drug interactions

When used simultaneously with topiramate, phenytoin and carbamazepine reduce its concentration in blood plasma. This is due to the induction of enzymes under the influence of phenytoin and carbamazepine, with the participation of which the metabolism of topiramate is carried out. In some cases, with the use of topiramate, an increase in the concentration of phenytoin in the blood plasma was observed.

With the simultaneous use of a single dose of topiramate and digoxin, a decrease in the AUC of digoxin is possible.

With the simultaneous use of an oral contraceptive containing norethindrone and ethinyl estradiol, topiramate did not significantly affect the clearance of norethindrone, but the plasma clearance of ethinyl estradiol increased significantly. Thus, while taking topiramate with oral contraceptives, their effectiveness may be reduced.

In patients taking metformin, pioglitazone, glibenclamide with the simultaneous use or withdrawal of topiramate, fluctuations in plasma glucose levels are possible. With these combinations, plasma glucose should be monitored.

With the simultaneous use of topiramate with drugs that predispose to the development of nephrolithiasis, the risk of kidney stones may increase.

Dosage Topiramate

Individual, depending on the indications, the patient's age, renal function and the effectiveness of the therapy.

Overdose

Symptoms: increased side effects.

Treatment: gastric lavage or induction of vomiting, supportive therapy. In severe cases, hemodialysis is possible.

Precautionary measures

The use of topiramate for the treatment of acute migraine attacks has not been studied.

Patients with impaired renal function and patients on hemodialysis require correction of the dosage regimen of topiramate.

Topiramate should be discontinued gradually in order to minimize the possibility of an increase in the frequency of seizures. In clinical studies in adults for the treatment of epilepsy, the dose was reduced by 50-100 mg with an interval of 1 week. and 25-50 mg in adults receiving topiramate at a dose of 100 mg / day for the prevention of migraine. In children in clinical trials, topiramate was gradually withdrawn over 2-8 weeks. If, for medical reasons, rapid cancellation of topiramate is required, it is recommended to monitor the patient's condition.

To reduce the risk of developing nephrolithiasis during treatment, the amount of fluid consumed should be increased.

Against the background of the use of topiramate, a decrease in sweating and hyperthermia is possible, especially in young children, in conditions of an increased ambient temperature. Replenishing fluid loss before and during activities such as exercise or high temperatures can reduce the risk of complications from overheating.

During the period of treatment, it is necessary to monitor the condition of patients in order to identify signs of suicidal idealization and prescribe appropriate treatment. Patients (and, if necessary, caregivers) should be advised to seek immediate medical attention if signs of suicidal idealization or suicidal behavior appear.

In the event of violations by the organ of vision, incl. syndrome, including myopia associated with angle-closure glaucoma, topiramate should be discontinued as soon as the attending physician deems it possible. If necessary, measures should be taken to lower the intraocular pressure.

In order to avoid the occurrence of metabolic acidosis, during the period of treatment with topiramate, it is recommended to carry out the necessary studies, including the determination of the concentration of bicarbonates in the serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or stop taking topiramate. In children, chronic metabolic acidosis can lead to stunted growth. The effect of topiramate on growth and possible complications associated with the skeletal system have not been systematically studied in children and adults.

If body weight decreases during treatment, the diet should be adjusted.

During the period of treatment, the patient should avoid drinking alcohol.

Influence on the ability to drive vehicles and control mechanisms.

It should be used with caution in patients engaged in potentially hazardous activities that require increased attention and speed of psychomotor reactions, because topiramate may cause drowsiness, dizziness, or visual disturbances.

Formula: C12H21NO8S, chemical name: 2,3: 4,5-di-O-isopropylidene-beta-D-fructopyranose sulfamate.
Pharmacological group: neurotropic / antiepileptic drugs.
Pharmachologic effect: antiepileptic.

Pharmacological properties

Topiramate is an antiepileptic drug that belongs to the class of sulfate-substituted monosaccharides. Topiramate blocks sodium channels and suppresses the appearance of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Topiramate increases the frequency of activation of GABAA receptors by gamma-aminobutyric acid. Topiramate increases the flux of chlorine ions induced by gamma-aminobutyric acid into the neuron, enhances inhibitory GABAergic transmission. Topiramate blocks the activation of glutamate receptors by kainate (a subtype of kainate / alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and inhibits excitatory glutamatergic neurotransmission. Topiramate does not affect the NMDA receptor activity of N-methyl-D-aspartate. Topiramate reduces the activity of some isoenzymes of carbonic anhydrase, but this effect is weaker than that of acetazolamide and, probably, is not the main one in antiepileptic activity.
Topiramate did not show mutagenic and genotoxic effects in in vitro and in vivo tests.
There are no data on the possible carcinogenicity of topiramate in humans. A study of carcinogenicity when administered to mice with 20, 75 and 300 mg / kg for 21 months showed that when a dose of 300 mg / kg was administered, the incidence of bladder tumors (mainly smooth muscle tumors that are histomorphologically unique for mice) significantly increased in individuals of both sexes. ... The concentration of topiramate in the blood serum of mice that received 300 mg / kg was approximately 50-100% of the equilibrium concentration, which was observed in patients with monotherapy with topiramate at the recommended dose of 400 mg and 150-200% of the equilibrium concentration in patients who received 400 mg of topiramate together with phenytoin. In rats that received doses of up to 120 mg / kg for 2 years (approximately 3 times higher than the maximum recommended dose for humans in terms of mg / m 2), no carcinogenic effect of topiramate was detected.
When conducting studies on animals (rats, mice, rabbits), the teratogenic effect of topiramate has been registered. In rabbits that received the drug in doses of 35 mg / kg or more, embryonic and fetal mortality increased; teratogenic effect (mainly vertebral and costal changes) was expressed at doses of 120 mg / kg. At doses of 35 mg / kg and above, signs of maternal toxicity were observed (clinical signs, decreased weight gain, mortality). With the introduction of 20, 100 and 500 mg / kg of the drug to pregnant mice during the period of organogenesis, the incidence of fetal deformities (mainly craniofascial defects) increased. When a dose of 500 mg / kg was used, a decrease in the ossification of the skeleton and body weight in the embryo was observed, as well as the increase in the body weight of pregnant females. When the drug was administered in doses of 400 mg / kg or more to pregnant rats during the period of organogenesis, the frequency of appearance of limb deformities (micromelia, ectrodactyly, amelia) in offspring increased. At doses of 100 mg / kg or more, a decrease in body weight gain was observed in females; at doses of 400 mg / kg or more, clinical signs of maternal toxicity were manifested. At low doses (20 mg / kg), embryotoxicity was manifested (an increase in the frequency of structural abnormalities, a decrease in the body weight of the embryo). In the offspring of rats who received the drug at doses of 200 mg / kg during the last period of pregnancy and breastfeeding, a slowdown in physical development and a decrease in viability was shown; at doses of 2 mg / kg and more, a decrease in body weight was revealed in the period before and / or after cessation of breastfeeding. A study of the embryonic and fetal development and postnatal period of the offspring of rats who received the drug showed a continuing (persistent) decrease in body weight at doses of 30 mg / kg or more and a slowdown in physical development at doses of 400 mg / kg. Topiramate in rats crosses the placental barrier and into breast milk.
Topiramate is rapidly absorbed in the gastrointestinal tract, bioavailability does not depend on food intake and is 81%. Topiramate binds to plasma proteins by 13 - 17%. The average volume of distribution depends on the sex of patients (in women it is 2 times less than in men, which is associated with a higher content of adipose tissue in the body of women) and is 0.55 - 0.8 l / kg for single doses up to 1200 mg. The maximum concentration is 6.76 μg / ml (with repeated oral administration 2 times a day, 100 mg). The maximum concentration is reached after 2 hours when taking the drug at a dose of 400 mg. The equilibrium concentration of topiramate in the blood serum is reached within 4 to 8 days in patients with normal functional state of the kidneys. The equilibrium concentration of topiramate in the blood serum is achieved within 10-15 days in patients with severe impairment of the functional state of the kidneys. In the range of doses of 200 - 800 mg per day, the concentration of topiramate in the blood serum is proportional to the dose taken, that is, in the range of doses of 200 - 800 mg per day, the pharmacokinetics of topiramate is linear. Topiramate is metabolized by about 20% to form 6 inactive metabolites. But in patients who receive concomitant treatment with other antiepileptic drugs that induce enzymes that are responsible for the metabolism of drugs, the metabolism of topiramate increases by up to 50%. Topiramate is mainly excreted by the kidneys (unchanged 70%). The half-life is 21 hours. Plasma clearance of topiramate is 20-30 ml / min. In children, the clearance of topiramate is increased, and its half-life is shorter. In patients with impaired renal function (with creatinine clearance less than 60 ml / min), renal and plasma clearance decrease. Patients with moderate to severe renal impairment are advised to use half the recommended starting and maintenance dose. In case of violation of the functional state of the liver, the plasma clearance of topiramate decreases.

Indications

Generalized or partial tonic-clonic seizures as monotherapy and together with other anticonvulsant drugs; newly diagnosed epilepsy; adjunctive treatment for seizures associated with Lennox-Gastaut syndrome; prevention of migraine attacks in adults.

Dosing and administration of topiramate

Topiramate is taken orally, regardless of food intake. Doses and regimen of topiramate use are set by the doctor individually, depending on the indications, the patient's age, drug tolerance, concomitant treatment and other factors.

Adults with monotherapy: the initial dose is 25 mg once a day (at night) for 7 days, then the dose is increased by 25-50 mg per day (divided into two doses) with an interval of 7-14 days until a clinical effect is achieved; the recommended dose is 100 mg per day, the maximum daily dose is 500 mg (for some patients with refractory forms of epilepsy, it is possible up to 1000 mg per day). Children over 2 years old: in the first 7 days of therapy - 0.5-1 mg / kg at night, then the dose is increased by 0.5-1 mg / kg per day (divided into 2 doses) with an interval of 7-14 days; the recommended doses are 3 - 6 mg / kg per day (for children with recently diagnosed partial seizures - up to 500 mg per day).

In combination with other anticonvulsant drugs: adults - 25-50 mg at night for 7 days, then the dose is increased by 25-50 mg with an interval of 7-14 days and taken in 2 divided doses; the minimum effective dose is 200 mg per day, the average daily dose is 200-400 mg, the maximum is 1600 mg. Children over 2 years old: - 1 - 3 mg / kg per day at night for 7 days, then the dose is increased by 1 - 3 mg / kg with an interval of 7 - 14 days and taken in 2 doses; the recommended daily dose is 5-9 mg / kg.

Treatment begins with 25 mg of the drug once a day before bedtime for 7 days, then the dose is increased with an interval of 7 days by 25 mg per day, if the patient does not tolerate such a dose increase regimen, then the dose can be increased more smoothly or the intervals between dose increases; the recommended total daily dose of topiramate is 100 mg, in some patients a positive result is achieved with a daily dose of 50 mg topiramate; in clinical studies for the prevention of migraine attacks, patients received various daily doses of the drug, but not more than 200 mg per day.
When discontinuing concomitant anticonvulsants for topiramate monotherapy, consideration should be given to the possible effect of this step on seizure frequency. When there is no need to abruptly discontinue concomitant anticonvulsants for safety reasons, their doses should be reduced gradually (by one third every 14 days). With the withdrawal of drugs that are inducers of microsomal hepatic enzymes, plasma levels of topiramate will increase. In this case, in the presence of clinical indications, the dose of topiramate can be reduced.
The dose selection scheme for topiramate should be guided by the clinical effect (absence of adverse reactions, the degree of seizure control) and take into account the fact that in patients with impaired renal function, a longer period of time may be needed to establish a stable plasma concentration for each dose.
Topiramate is effectively eliminated from plasma by hemodialysis. Patients on hemodialysis may require an additional dose of the drug. When adjusting the dose, one should take into account: the duration of hemodialysis, the amount of clearance of the used hemodialysis system, the effective renal clearance of topiramate in a patient undergoing hemodialysis.
Topiramate should be withdrawn gradually to minimize the possibility of increased seizure frequency. In clinical trials, doses have been reduced by 50-100 mg at weekly intervals for adults in the treatment of epilepsy and by 25-50 mg in adults for the prevention of migraine. In children in clinical trials, the drug was discontinued gradually over 2 to 8 weeks. If necessary, for medical reasons, the rapid cancellation of topiramate is recommended appropriate monitoring of the patient's condition.
Some people using topiramate may experience new types of seizures or an increase in seizure frequency. This phenomenon may be a consequence of a decrease in the level of jointly used antiepileptic drugs, an overdose, a paradoxical effect, or the progression of the disease.
With topiramate therapy, the incidence of mood disorders and depression increases, and the risk of suicidal thoughts and suicidal behavior also increases. It is necessary to monitor the condition of patients to identify signs of suicidal thoughts and prescribe appropriate therapy. Patients (and their caregivers) should be advised to seek immediate medical attention if signs of suicidal thoughts or suicidal behavior appear.
When treating with topiramate, it is possible to reduce sweating (oligohidrosis) and develop anhidrosis. Decreased sweating and increased body temperature (hyperthermia) can occur in children who are exposed to high ambient temperatures. Therefore, when treating with topiramate, it is very important to adequately increase the volume of fluid consumed, which can reduce the risk of developing nephrolithiasis and adverse reactions that may occur under the influence of elevated temperatures or physical exertion.
Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of kidney stones and associated symptoms (kidney pain, renal colic, flank pain). To reduce this risk, an adequate increase in fluid intake is recommended. Risk factors for the development of nephrolithiasis are hypercalciuria, a history of nephrolithiasis (including family history), concomitant treatment with drugs that promote the development of nephrolithiasis.
Topiramate is used with caution in patients with impaired liver function due to a possible decrease in drug clearance.
Topiramate is used with caution in patients with impaired renal function, since in such patients the clearance of the drug is reduced.
During treatment, a syndrome may develop, which includes acute myopia and secondary angle-closure glaucoma. Symptoms include eye pain and / or an acute decrease in visual acuity. An ophthalmological examination can reveal a flattening of the anterior chamber of the eye, myopia, increased intraocular pressure, redness of the eyeball. Possible mydriasis. This syndrome can be accompanied by the release of fluid, which leads to the displacement of the iris and lens forward with the development of secondary angle-closure glaucoma. Symptoms usually appear 1 month after starting treatment. Secondary angle-closure glaucoma is observed with the use of topiramate in adults and children, in contrast to primary open-angle glaucoma, which is rarely observed in patients under 40 years of age. With the development of this syndrome, it is necessary to carry out appropriate measures aimed at lowering intraocular pressure, and to stop taking topiramate as soon as the attending physician considers it possible. As a rule, these measures lead to the normalization of intraocular pressure. Increased intraocular pressure of any origin in the absence of adequate therapy can lead to serious complications, including loss of vision. When prescribing topiramate to patients who have a history of eye disease, the ratio of the intended benefit to the possible risk of using the drug should be assessed.
In patients taking topiramate, visual field defects were observed, regardless of whether they had increased intraocular pressure. In most cases, such cases were reversible, and after discontinuation of topiramate therapy, visual field defects disappeared. If you experience problems with vision while using topiramate, you should consider discontinuing treatment.
In patients taking topiramate, there have been cases of impairment of cognitive functions, which required a dose reduction or discontinuation of treatment. Cognitive impairment in epilepsy has a multifactorial nature and can be caused by the cause of the disease, epilepsy itself, or antiepileptic treatment.
When using topiramate, hyperchloremic metabolic acidosis (for example, a decrease in serum bicarbonate levels below normal levels in the absence of respiratory alkalosis) may develop, which is not associated with anionic deficiency. Such a decrease in the level of blood plasma bicarbonates is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In many cases, a decrease in the content of hydrocarbons occurs at the beginning of treatment, but this effect can develop at any period of therapy with topiramate. The decrease in concentration is usually mild to moderate. In rare cases, patients have had a severe decrease in the concentration of hydrocarbons. Certain therapies or diseases that predispose to the development of acidosis (for example, severe respiratory illness, ketogenic diet, kidney disease, diarrhea, status epilepticus, surgery, certain medications) may be additional factors that enhance the bicarbonate-reducing effect of topiramate. Chronic metabolic acidosis in children can lead to stunted growth. During therapy with topiramate, the necessary studies should be carried out, which include the determination of the plasma level of hydrocarbons. When symptoms of metabolic acidosis appear (for example, dyspnoea, deep Kussmaul breathing, anorexia, nausea, fatigue, vomiting, arrhythmia, tachycardia), it is recommended to determine the plasma level of hydrocarbons. With the development of metabolic acidosis and its persistence, the dose should be reduced or the administration of topiramate should be discontinued.
With a significant loss of body weight during therapy with topiramate, the use of nutritional supplements or increased nutrition is necessary.
The use of topiramate for the treatment of acute migraine attacks has not been studied.
It is not recommended to take topiramate together with drugs that depress the central nervous system (including alcohol).
During treatment with topiramate, it is necessary to refuse to engage in potentially hazardous activities that require increased attention and speed of psychomotor reactions (including driving and other mechanisms).

Contraindications for use

Hypersensitivity, age up to 2 years (safety and efficacy of use have not been established), breastfeeding.

Restrictions on use

Renal and / or hepatic failure, hypercalciuria, nephrourolithiasis (including past and family history), pregnancy.

Application during pregnancy and lactation

There have been no adequate and well-controlled studies on the use of topiramate during pregnancy. When used in pregnant women, topiramate may harm the fetus. Pregnancy records indicate that infants who have been exposed to topiramate in utero are at increased risk of congenital malformations (eg, craniofacial defects such as cleft palate or lip, hypospadias, and malformations of various body systems). These malformations were recorded during monotherapy with topiramate, and when used in conjunction with other drugs. Also, the data of registration of pregnancies with monotherapy with topiramate indicate an increase in the likelihood of having children with low body weight (less than 2500 g). With combined treatment with antiepileptic drugs, the risk of teratogenic effects is higher than with topiramate monotherapy. The use of topiramate during pregnancy is possible if the expected effect of treatment for the mother is higher than the possible risk for the fetus. When treating women who are able to become pregnant, the treating physician should weigh the benefits / risks of therapy and consider alternative treatment options. If topiramate is used during pregnancy, or if the patient becomes pregnant while taking this drug, she must be warned of the possible risk to the fetus. During lactation, it is necessary to stop breastfeeding during therapy with topiramate or stop taking the drug during breastfeeding.

Side effects of topiramate

Circulatory system, blood (hemostasis, hematopoiesis) and lymphatic system: bradycardia, palpitations, sinus bradycardia, hypotension, hot flashes, orthostatic hypotension, hot flushes, Raynaud's phenomenon, anemia, leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia, neutropenia.
The immune system: hypersensitivity, allergic edema, conjunctival edema.
Metabolism and nutrition: decreased appetite, anorexia, increased appetite, hypokalemia, metabolic acidosis, polydipsia, hyperchloremic acidosis.
Nervous system, psyche and sensory organs: paresthesia, depression, slow thinking, dizziness, insomnia, memory impairment, drowsiness, impaired free speech, confusion, anxiety, disorientation, mood disorders, aggressive reactions, agitation, depressed mood, emotional lability, anger, impaired concentration, cognitive disorders, amnesia, impaired thinking, seizures, psychomotor disorders, tremors, impaired coordination of movements, lethargy, suicidal thoughts, behavioral disturbances, attempts at suicide, psychotic disorders, hallucinations, auditory hallucinations, apathy, visual hallucinations, sleep disturbances, difficulty speaking, affective lability, , dysgeusia, nystagmus, imbalance, intentional tremor, dysarthria, sedation, tonic-clonic grand mal seizures, depressed consciousness, visual field impairment, speech impairment, fainting, complex partial seizures, psychomotor hyperactivity, sensory impairments, hypersomnia , saliva bleeding, aphasia, decreased libido, agitation, dysfemia, crying, euphoric mood, perseveration of thinking, paranoia, panic attacks, impaired reading skills, tearfulness, sleep disturbance, pathological thinking, flattening of emotions, repetitive speech, dyskinesia, hypokinesia, postural dizziness burning sensation, psychomotor hyperactivity, vertigo, poor sleep quality, loss of sensitivity, cerebral syndrome, parosmia, dysesthesia, stupor, hypogeusia, loss of libido, intrasomnic disorder, lethargy, absent-mindedness, panic reactions, early awakening in the morning, clumsiness, ageusia, aheusia dysgraphia, peripheral neuropathy, dysphasia, light-headedness, feeling of "goose bumps" dystonia, over the body, disturbance of the circadian rhythm of sleep, apraxia, hyperesthesia, high spirits, panic disorder, mania, a sense of hopelessness, hyposmia, hypomania, anosmia, akinesia, essremia lack of reactions to stimuli, impaired fitness learning disabilities, blurred vision, visual impairment, diplopia, decreased visual acuity, myopia, scotoma, strange sensations in the eyes, photophobia, dry eyes, blepharospasm, photopsia, increased lacrimation, mydriasis, one-sided blindness, presbyopia, transient blindness, impaired accommodation, glaucoma, impaired visual spatial perception, eyelid edema, atrial fibrillation, night blindness, angle-closure glaucoma, amblyopia, eye mobility disorders, maculopathy, vertigo, ear discomfort, ear pain, ringing in the ears, deafness, sensorineural deafness, one-sided deafness, impairment hearing.
Respiratory system: nasopharyngitis, epistaxis, shortness of breath, nasal congestion, cough, rhinorrhea, hypersecretion in the paranasal sinuses, shortness of breath on exertion, dysphonia.
Digestive system: nausea, vomiting, diarrhea, constipation, dyspepsia, epigastric pain, abdominal pain, stomach discomfort, dry mouth, impaired sensitivity in the oral cavity, abdominal discomfort, gastritis, pancreatitis, gastroesophageal reflux, flatulence, lower pain abdomen, bleeding gums, decreased sensitivity in the oral cavity, bloating, tenderness in the abdomen, epigastric discomfort, hypersalivation, bad breath, pain in the oral cavity, glossodynia, hepatitis, liver failure.
Skin and subcutaneous tissue: alopecia, pruritus, rash, anhidrosis, urticaria, sensitivity disorder in the face, erythema, macular rash, generalized pruritus, skin pigmentation disorder, facial swelling, allergic dermatitis, Stevens-Johnson syndrome, skin odor change, erythema polymorphism, localized urticaria, paraorbital edema, toxic epidermal necrolysis.
Musculoskeletal system and connective tissue: arthralgia, myalgia, muscle spasms, muscle cramps, musculoskeletal chest pain, muscle weakness, joint swelling, side pain, muscle stiffness, muscle fatigue, limb discomfort.
Genitourinary system: nephrolithiasis, dysuria, pollakiuria, exacerbation of urolithiasis, stress urinary incontinence, kidney stones, hematuria, frequent urge to urinate, urinary incontinence, pain in the kidney area, renal colic, exacerbation of urolithiasis, renal tubular acidosis, erectile dysfunction , sexual dysfunction.
General disorders: fatigue, asthenia, fever, irritability, poor health, gait disturbances, anxiety, hyperthermia, flu-like syndrome, thirst, slowness, drunkenness, cold extremities, anxiety, pyrexia, facial edema, calcification.
Laboratory indicators: weight loss, weight gain, crystalluria, leukopenia, eosinophilia, abnormal tandem gait test result, increased activity of liver enzymes in the blood serum, decrease in the content of hydrocarbons in the blood.

Interaction of topiramate with other substances

Carbamazepine (40%) and phenytoin (50%) reduce serum topiramate concentration.
Topiramate reduces the area under the concentration-time curve of digoxin by 12%.
Topiramate reduces the serum phenytoin concentration.
Concurrent use of topiramate with drugs that predispose to nephrolithiasis may increase the risk of kidney stones.
Haloperidol, lowering the seizure threshold, weakened the effect of topiramate; dose adjustment is necessary.
Hydrochlorothiazide increases the maximum concentration and area under the concentration-time curve of topiramate by more than 30%.
With the combined use of topiramate and diazepam with epilepsy, an increase in the frequency of grand mal seizures is possible; may require an increase in the dose of topiramate.
Caution is necessary when using zonisamide topiramate together, since there are no data that exclude the possibility of pharmacodynamic interaction.
When topiramate and levetiracetam are used together, the risk of developing anorexia increases.
When topiramate and metformin are used together, the plasma clearance of drugs is mutually reduced; topiramate increases the mean values ​​of the maximum concentration and the area under the concentration-time curve of metformin.
Topiramate enhances the effect of propofol.
Perampanel insignificantly affects the clearance of topiramate.
Topiramate, inhibiting the cytochrome P450 isoenzyme - CYP2Cmeph, can increase the concentration of phenytoin in the blood serum, resulting in phenytoin toxicity; caution is needed.
Topiramate, inducing hepatic enzymes, increases the clearance of sex hormones, resulting in breakthrough bleeding and / or a decrease in the contraceptive efficacy of jointly used oral contraceptives (desogestrel, linestrenol, dienogest, ethinylestradiol, combinations of gestodene + ethinylestradiol + , drospirenone + ethinylestradiol + [calcium levomefolinate], levonorgestrel + ethinylestradiol, norgestrel + estradiol, norelgestromin + ethinylestradiol, chlormadinone + ethinylestradiol, cyproterone + estradiol, cyproterone + ethinylestradiol.
Concomitant use of topiramate and alprazolam, buprenorphine, buspirone, haloperidol, hydroxyzine, diazepam, droperidol, zolpidem, isoflurane, quetiapine, ketamine, clozapine, clonazepam, codeine, lorazepam, methohexital, morfinazapine, rehexital, perfidazolene, rezapanil risperidone, temazepam, thioridazine, trifluoperazine, fentanyl, flurazepam, fluphenazine, chlordiazepoxide, chlorpromazine, chlorprothixene, enflurane, estazolam mutually enhances the depression of the central nervous system.
The combined use of topiramate and acetazolamide, dorzolamide increases the risk of kidney stones; sharing is not recommended.
When topiramate and valproic acid are used together, the concentration of both drugs in the blood is mutually reduced.
When topiramate and eslicarbazepine acetate are used together, the effect of topiramate may decrease, most likely due to a decrease in its bioavailability.
With the combined use of topiramate and lithium preparations, the concentration of the latter in the blood plasma should be monitored.
With the combined use of topiramate and metformin, there is an increase in the area under the concentration-time curve and the maximum concentration of metformin by 25% and 18%, respectively, a decrease in the clearance of metformin by 20%, a decrease in the clearance of topiramate; monitoring of the condition of patients is necessary to assess the course of diabetes mellitus.
When topiramate and pioglitazone are used together, the area under the concentration-time curve decreases by 15% of pioglitazone, as well as its metabolites; monitoring of the condition of patients is necessary to assess the course of diabetes mellitus.
With the combined use of topiramate and glibenclamide, there is a decrease in the area under the concentration-time curve by 25% glibenclamide; monitoring of the condition of patients is necessary to assess the course of diabetes mellitus.
The combined use of topiramate and valproic acid in patients who tolerate each drug well individually is accompanied by hyperammonemia with or without encephalopathy. After discontinuation of one of the drugs, symptoms and signs disappear in most cases. This phenomenon is not caused by pharmacokinetic interactions. Also, when topiramate and valproic acid are used together, hypothermia can occur with or without hyperammonemia. This phenomenon can occur after the start of the combined use of valproic acid and topiramate and with an increase in the daily dose of topiramate.
With the combined use of topiramate and drugs based on St. John's wort, the concentration of topiramate in serum may decrease, as a result of which the effectiveness of the drug may also decrease.
With the combined use of topiramate and amitriptyline, an increase in the maximum concentration and the area under the concentration-time curve of nortriptyline (amitriptyline metabolite) occurs.
With the combined use of topiramate and propranolol, there is an increase in the maximum concentration of 4-OH propranolol, topiramate, the area under the concentration-time curve of topiramate.
With the combined use of topiramate and diltiazem, there is a decrease in the area under the concentration-time curve of diltiazem and an increase in the area under the concentration-time curve of topiramate.
When topiramate and flunarizine are used together, there is an increase in the area under the concentration-time curve of flunarizine.

Overdose

In case of an overdose of topiramate, convulsions, speech and visual impairments, drowsiness, diplopia, impaired coordination, impaired thinking, stupor, lethargy, dizziness, agitation, depression, abdominal pain, arterial hypotension, severe metabolic acidosis develop. In most cases, the clinical consequences were not severe, but deaths after overdose were noted. There is a known case of overdose when the patient took a dose of topiramate from 96 to 110 g, which resulted in a coma, which lasted 20 to 24 hours; overdose symptoms resolved after 3 to 4 days.
Treatment: induction of vomiting or gastric lavage, intake of activated charcoal, supportive and symptomatic treatment; adequate increase in the volume of fluid consumed; it is possible to carry out hemodialysis.

Antiepileptic agent of the group of sulfate-substituted monosaccharides. Topiramate reduces the frequency of action potentials characteristic of a neuron in a state of persistent depolarization, which indicates the dependence of the blocking effect of topiramate on sodium channels on the state of the neuron. Topiramate potentiates the activity of GABA in relation to some subtypes of GABA receptors (including GABA receptors), and also modulates the activity of GABA A receptors themselves, prevents kainate from activating the sensitivity of kainate / AMPK receptors to glutamate, and does not affect the activity of N-methyl-D -aspartate in relation to NMDA receptors.
After taking the drug inside, topiramate is quickly and effectively absorbed in the gastrointestinal tract. Bioavailability after taking a dose of 100 mg is about 81%. Food intake does not have a clinically significant effect on the bioavailability of topiramate. In healthy volunteers, the average value of the maximum concentration after repeated oral administration of 100 mg 2 times a day is 6.76 μg / ml. Plasma protein binding is 13-17%. After a single oral administration in a dose of up to 1200 mg, the volume of distribution is 0.55-0.8 l / kg; its value depends on gender. In women, the values ​​are approximately 50% of the values ​​observed in men, which is associated with a higher content of adipose tissue in the body of women. After a single oral administration, the pharmacokinetics of topiramate is linear, plasma clearance remains constant at 20-30 ml / min, and AUC in the dose range from 100 to 400 mg increases in proportion to the dose. In patients with normal renal function, it may take 4 to 8 days to reach equilibrium.
About 20% of topiramate is biotransformed with the formation of 6 metabolites, 2 of which generally retain the structure of topiramate and either do not have anticonvulsant activity, or exhibit it to a minimum extent. Topiramate and its metabolites are excreted mainly in the urine. After repeated administration of the drug, 50 and 100 mg 2 times a day, the elimination half-life averages 21 hours. In patients with impaired renal function (creatinine clearance less than 60 ml / min), renal and plasma clearance of topiramate decreases. The time to reach equilibrium in patients with moderate or severe renal impairment is 10 to 15 days. In patients with moderate to severely impaired liver function, plasma clearance decreases. In the elderly, the plasma clearance of topiramate does not change.

Indications for the use of the drug Topiramate

Partial or generalized tonic-clonic seizures in adults and children (as monotherapy or in combination with other anticonvulsants); seizures associated with Lennox-Gastaut syndrome in adults and children (as a means of additional therapy).

Application of the drug Topiramate

When using topiramate as part of a combination therapy with other anticonvulsants in adult patients, the minimum effective dose is 200 mg / day. The average daily dose is 200-400 mg, the frequency of administration is 2 times a day. It is recommended to start treatment with a dose of 25-50 mg once a day at night for 1 week. Further, the dose should be increased by 25-50 mg at intervals of 1-2 weeks until the effective dose is selected. Frequency rate of admission - 2 times a day. If necessary, it is possible to increase the daily dose to a maximum of 1600 mg. The criterion for dose selection is the clinical effect. In some patients, the effect is achieved when taking topiramate 1 time per day. When using topiramate as part of combination therapy with other anticonvulsants in children over 2 years of age, the recommended total daily dose is 5 to 9 mg / kg and is taken in 2 divided doses. Dose selection begins with 25 mg / day (or less, at the rate of 1-3 mg / kg of body weight per day), at night for 1 week. In the future, at weekly or two-week intervals, the dose can be increased by 1-3 mg / kg, taking the drug in 2 doses. When choosing a dose, one should be guided by the clinical effect. A daily dose of up to 30 mg / kg body weight is usually well tolerated. Topiramate can be taken with or without food.
When using topiramate as monotherapy, the possible effect of discontinuation of concomitant anticonvulsant therapy on the frequency of seizures should be considered. In cases where it is undesirable to abruptly cancel concomitant therapy, the dose of drugs is reduced gradually, reducing the dose by 1/3 every 2 weeks. With the abolition of drugs that are inducers of microsomal hepatic enzymes, the concentration of topiramate in the blood plasma will increase. In such situations, in the presence of clinical indications, the dose of topiramate can be reduced. For adults, at the beginning of monotherapy, topiramate should be taken 25 mg 1 time per day before bedtime for 1 week. Then the dose is increased at intervals of 1-2 weeks by 25-50 mg / day (the daily dose is divided into 2 doses). In case of intolerance to such a therapy regimen, the dose is increased by a smaller amount or at longer intervals. The dose is selected depending on the clinical effect. The recommended dose is 100 mg per day, the maximum daily dose is 500 mg. In some cases, with monotherapy refractory to treatment of epilepsy, the dose of topiramate may be 1000 mg / day. For children over 2 years of age, with monotherapy in the first week of treatment, topiramate is prescribed at a dose of 0.5-1 mg / kg of body weight per day (the daily dose is divided into 2 doses). The size of the dose and the rate of its increase are determined by the clinical efficacy and tolerability of therapy. On average, the dose is increased with an interval of 1-2 weeks by 0.5-1 mg / kg / day. The dose range for monotherapy with topiramate in children over 2 years of age is 3-6 mg / kg / day. With recently diagnosed partial seizures, the dose can be up to 500 mg / day. The drug is taken 2 times a day. When prescribing the drug to patients with moderate or severe impairment of renal function, it should be borne in mind that it may take 10-15 days to reach an equilibrium state in this category of patients, as opposed to 4-8 days in patients with normal function. kidneys. Since topiramate is removed from the blood during hemodialysis, on the days of it, an additional dose of the drug should be prescribed equal to half the daily dose in 2 doses (before and after the procedure). Topiramate should be withdrawn gradually to minimize the possibility of increased seizure frequency. It is recommended to reduce the dose by 100 mg every week.

Contraindications to the use of the drug Topiramate

Hypersensitivity to topiramate.

Side effects of the drug Topiramate

Often (especially during the dose selection period) - ataxia, impaired concentration, confusion, dizziness, fatigue, paresthesia, drowsiness, impaired thinking, rarely - agitation, amnesia, anorexia, aphasia, depression, emotional lability, speech disorders, diplopia, nystagmus, visual impairment, taste perversion; in some cases - an increase in functional liver function tests, hepatitis, liver failure (with simultaneous use with other drugs), rarely - nausea, nephrolithiasis, weight loss.

Special instructions for the use of the drug Topiramate

Adequate and strictly controlled clinical studies of the safety of topiramate during pregnancy have not been conducted, therefore, its appointment is possible only if the intended benefit to the mother outweighs the potential risk to the fetus. The excretion of topiramate in breast milk has not been studied in controlled studies. The limited number of observations suggests that topiramate is excreted in breast milk. If it is necessary to use topiramate, the issue of stopping breastfeeding should be resolved.
Topiramate should be withdrawn gradually to minimize the possibility of increased seizure frequency. When using topiramate, the risk of kidney stones may increase, especially in patients with a predisposition to nephrolithiasis, as well as against the background of the use of other drugs that contribute to the development of nephrolithiasis. To reduce the risk of developing nephrolithiasis, you should increase the amount of fluid consumed. If, while taking topiramate, the patient's body weight decreases, the diet should be adjusted. In patients with impaired liver function, topiramate should be used with caution due to a possible decrease in the clearance of this drug. Patients taking topiramate should refrain from drinking alcohol. Topiramate should not be prescribed to children under the age of 2 years. With caution, topiramate should be prescribed to patients engaged in potentially hazardous activities that require increased attention and speed of psychomotor reactions, since drowsiness and dizziness are possible during its use.

Drug interactions Topiramate

When used simultaneously with carbamazepine, valproic acid, phenobarbital, primidone, topiramate does not affect the value of their equilibrium concentrations in blood plasma. The simultaneous use of topiramate in some cases led to an increase in the concentration of phenytoin. Phenytoin and carbamazepine, with simultaneous use, reduce the concentration of topiramate in the blood plasma. With the simultaneous use of valproic acid does not affect the concentration of topiramate in the blood plasma. With the simultaneous use of a single dose of topiramate, the AUC of digoxin decreased by 12%. With the simultaneous use of oral contraceptives containing norethindrone and ethinyl estradiol with topiramate, topiramate did not significantly affect the clearance of norethindrone, however, the plasma clearance of the estrogenic component increased significantly. Thus, with the simultaneous administration of topiramate with oral contraceptives, their effectiveness may be reduced. With the simultaneous administration of metformin and topiramate, the average values ​​of the maximum concentration and AUC of metformin increase by 18 and 25%, respectively, while the average value of clearance decreases by 20%, while the plasma the clearance of topiramate is reduced. The clinical significance of this interaction has not been established. With the simultaneous use of topiramate with drugs that predispose to nephrolithiasis, the risk of kidney stones may increase.

Overdose of the drug Topiramate, symptoms and treatment

An increase in the manifestations of the described side effects is possible.
Treatment: gastric lavage; if necessary, symptomatic therapy is carried out. The use of activated carbon is not shown, since it has been experimentally established that activated carbon does not adsorb topiramate. An effective way to remove topiramate from the body is hemodialysis.

List of pharmacies where you can buy Topiramate:

• Saint Petersburg

film-coated tablets

Owner / Registrar

VALENTA PHARMACEUTICS, PJSC

International Classification of Diseases (ICD-10)

Pharmacological group

Anticonvulsant drug

pharmachologic effect

Antiepileptic drug, belongs to the class of sulfate-substituted monosaccharides.

Topiramate reduces the frequency of action potentials characteristic of a neuron in a state of persistent depolarization, which indicates the dependence of the blocking effect of the drug on sodium channels on the state of the neuron. Topiramate potentiates the activity of GABA in relation to some subtypes of GABA receptors (including GABA A receptors), and also modulates the activity of GABA A receptors themselves, prevents the activation of the sensitivity of kainate / AMPK receptors to glutamate by kainate, does not affect the activity of N α-methyl-D-aspartate in relation to NMDA receptors. These effects of topiramate are dose-dependent at plasma topiramate concentrations ranging from 1 μM to 200 μM, with a minimum activity ranging from 1 μM to 10 μM.

In addition, topiramate inhibits the activity of some isoenzymes of carbonic anhydrase, but this effect is weaker in topiramate than in acetazolamide and, apparently, is not the main one in the antiepileptic activity of topiramate.

Pharmacokinetics

After oral administration, topiramate is absorbed quickly and efficiently. Bioavailability - 81%. Food intake does not have a clinically significant effect on the bioavailability of topiramate. Plasma protein binding is 13-17%. After a single dose in doses up to 1.2 g, the average Vd is 0.55-0.8 l / kg. The V d value depends on gender: in women it is approximately 50% of the values ​​observed in men, which is associated with a higher content of adipose tissue in the body of women. Pharmacokinetics of topiramate is linear. Plasma clearance remains constant, while the AUC in the dose range from 100 to 400 mg increases in proportion to the dose. C ss in plasma is reached after 4-8 days. After repeated oral administration at a dose of 100 mg 2 times / day, C max averages 6.76 μg / ml. After oral administration, about 20% of the dose taken is metabolized. In human plasma, urine and feces, 6 practically inactive metabolites have been identified. It is excreted mainly by the kidneys unchanged (70%) and in the form of metabolites. Plasma clearance is 20-30 ml / min. After repeated administration in doses of 50 mg and 100 mg 2 times / day, T 1/2 of topiramate from plasma averages 21 hours.

Epilepsy: as a monotherapy for initial treatment in patients over 2 years of age - partial or primary generalized tonic-clonic seizures; as part of complex therapy in patients over 2 years old - partial or generalized tonic-clonic seizures, as well as seizures against the background of Lennox-Gastaut syndrome.

Migraine: prevention of migraine attacks in adults.

Hypersensitivity to topiramate.

From the nervous system: paresthesia, drowsiness, dizziness, impaired attention, memory impairment, amnesia, psychomotor disorders, convulsions, improper coordination, tremor, lethargy, hypesthesia, nystagmus, dysgeusia, imbalance, articulation disorder, intentional tremor (dynamic), sedation, depression of consciousness, seizures of the type of large seizures, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, fainting, sensory disturbances, salivation, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness, poor sleep quality, burning sensation, loss of sensitivity, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, pre-syncope, dystonia, apraxia, disturbance of the circadian rhythm of sleep, hyperesthesia, hyposremia, anosmia, essential thymus incentives, learning disabilities.

Mental disorders: depression, slow thinking, cognitive disorders, insomnia, severe speech disorders, anxiety, confusion, disorientation, aggression, mood lability, anxious agitation, emotional lability, depressed mood, anger, inappropriate behavior, suicidal ideas or attempts, auditory and visual hallucinations, psychotic disorder, apathy, lack of spontaneous speech, sleep disturbances, affective lability, decreased libido, anxiety, tearfulness, dysfemia, euphoria, paranoid states, perseveration of thinking, panic attack, tearfulness, impaired reading skills, flattening of emotions, falling asleep disorder, pathological thinking, loss of libido, lethargy, intrasomnic disorder, pathologically increased distractibility, early awakening in the morning, panic reaction, mania, panic disorder, feelings of despair, hypomania.

On the part of the organ of vision: blurred vision, diplopia, visual impairment, decreased visual acuity, scotoma, myopia, pathological sensations in the eyes, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia, one-sided blindness, transient blindness, glaucoma, impaired accommodation, visual impairment depth perception, atrial fibrillation, eyelid edema, night blindness, amblyopia, angle-closure glaucoma, maculopathy, oculomotor disorders.

From the hematopoietic system: anemia, leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia, neutropenia.

From the immune system: hypersensitivity, allergic edema, conjunctival edema.

From the side of metabolism: anorexia, decreased appetite, metabolic acidosis, hypokalemia, increased appetite, polydipsia, hyperchloremic acidosis.

On the part of the organ of hearing and balance: vertigo, ringing in the ears, ear pain, deafness, one-sided deafness, sensorineural deafness, discomfort in the ears, hearing impairment.

On the part of the cardiovascular system: bradycardia, sinus bradycardia, heart palpitations, orthostatic hypotension, flushing, hyperemia, Raynaud's phenomenon.

From the respiratory system: nasopharyngitis, dyspnea, epistaxis, nasal congestion, rhinorrhea, cough, shortness of breath on exertion, hypersecretion in the paranasal sinuses, dysphonia.

From the digestive system: nausea, diarrhea, vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, stomach discomfort, oral paresthesia, gastritis, abdominal discomfort, pancreatitis, flatulence, gastroesophageal reflux disease, lower pain abdomen, oral hypoesthesia, bleeding gums, bloating, epigastric discomfort, soreness throughout the abdomen, hypersecretion of the salivary glands, oral pain, bad breath, glossodynia, hepatitis, liver failure.

On the part of the skin and subcutaneous tissues: alopecia, pruritus, rash, anhidrosis, facial hypoesthesia, urticaria, erythema, generalized pruritus, macular rash, skin discoloration, allergic dermatitis, facial edema, Stevens-Johnson syndrome, erythema multiforme, unpleasant skin odor, periorbital edema, localized urticaria, toxic epidermal necrolysis.

From the musculoskeletal system: arthralgia, muscle cramps, myalgia, muscle cramps, muscle weakness, muscle chest pain, joint swelling, muscle stiffness, side pain, muscle fatigue, limb discomfort.

From the urinary system: nephrolithiasis, pollakiuria, dysuria, urinary calculi, stress urinary incontinence, hematuria, urgent painful urge to urinate, renal colic, pain in the kidney area, ureteral calculi, renal tubular acidosis.

On the part of the reproductive system: erectile dysfunction, sexual dysfunction.

General reactions: fatigue, pyrexia, asthenia, irritability, gait disturbance, unusual sensations, malaise, hyperthermia, thirst, flu-like state, inertia, cold extremities, drunkenness, anxiety, facial edema, calcification.

From the side laboratory indicators: decrease in body weight, increase in body weight, crystalluria, abnormal tandem gait test, leukopenia, increased activity of liver enzymes, hypokalemia, decrease in the content of hydrocarbons in the blood.

special instructions

The use of topiramate for the treatment of acute migraine attacks has not been studied.

It should be used with caution in renal and hepatic failure, nephrourolithiasis (including personal and family history), hypercalciuria.

Patients with impaired renal function and patients on hemodialysis require correction of the dosage regimen of topiramate.

Topiramate should be discontinued gradually in order to minimize the possibility of an increase in the frequency of seizures. In clinical studies in adults for the treatment of epilepsy, the dose was reduced by 50-100 mg with an interval of 1 week. and 25-50 mg in adults receiving topiramate at a dose of 100 mg / day for the prevention of migraine. In children in clinical trials, topiramate was gradually withdrawn over 2-8 weeks. If, for medical reasons, rapid cancellation of topiramate is required, it is recommended to monitor the patient's condition.

To reduce the risk of developing nephrolithiasis during treatment, the amount of fluid consumed should be increased.

Against the background of the use of topiramate, a decrease in sweating and hyperthermia is possible, especially in young children, in conditions of an increased ambient temperature. Replenishing fluid loss before and during activities such as exercise or high temperatures can reduce the risk of complications from overheating.

During the period of treatment, it is necessary to monitor the condition of patients in order to identify signs of suicidal idealization and prescribe appropriate treatment. Patients (and, if necessary, caregivers) should be advised to seek immediate medical attention if signs of suicidal idealization or suicidal behavior appear.

In the event of violations by the organ of vision, incl. syndrome, including myopia associated with angle-closure glaucoma, topiramate should be discontinued as soon as the attending physician deems it possible. If necessary, measures should be taken to lower the intraocular pressure.

In order to avoid the occurrence of metabolic acidosis, during the period of treatment with topiramate, it is recommended to carry out the necessary studies, including the determination of the concentration of bicarbonates in the serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or stop taking topiramate. In children, chronic metabolic acidosis can lead to stunted growth. The effect of topiramate on growth and possible complications associated with the skeletal system have not been systematically studied in children and adults.

If body weight decreases during treatment, the diet should be adjusted.

During the period of treatment, the patient should avoid drinking alcohol.

Influence on the ability to drive vehicles and use mechanisms

It should be used with caution in patients engaged in potentially hazardous activities that require increased attention and speed of psychomotor reactions, because topiramate may cause drowsiness, dizziness, or visual disturbances.

In case of liver dysfunction

Use with caution in patients with impaired liver function due to a possible decrease in the clearance of topiramate.

Application during pregnancy and lactation

Adequate and strictly controlled clinical studies of the safety of the use of topiramate during pregnancy have not been conducted.

The use of topiramate during pregnancy can damage the fetus. Pregnancy register data show that fetal exposure to topiramate increases the risk of congenital malformations (eg, craniofacial defects such as cleft lip / cleft palate, hypospadias and developmental abnormalities of various body systems). These malformations were recorded both with topiramate monotherapy and with its use in combination therapy. Compared with the group of patients not taking antiepileptic drugs, data from the register of pregnant women with topiramate monotherapy indicate an increase in the frequency of births of children with low body weight (less than 2500 g). A causal relationship has not been established.

When treating women of childbearing age, the expected benefits of therapy for the mother and the potential risk to the fetus should be weighed and alternative treatment options should be considered. If topiramate is used during pregnancy or if pregnancy occurs during the treatment period, the patient should be warned of the potential risk to the fetus.

The limited number of observations suggests that topiramate is excreted in breast milk. If necessary, use during lactation should decide on the termination of breastfeeding.

Drug interactions

When used simultaneously with topiramate, phenytoin and carbamazepine reduce its concentration in blood plasma. This is due to the induction of enzymes under the influence of phenytoin and carbamazepine, with the participation of which the metabolism of topiramate is carried out. In some cases, with the use of topiramate, an increase in the concentration of phenytoin in the blood plasma was observed.

With the simultaneous use of a single dose of topiramate and digoxin, a decrease in the AUC of digoxin is possible.

With the simultaneous use of an oral contraceptive containing norethindrone and ethinyl estradiol, topiramate did not significantly affect the clearance of norethindrone, but the plasma clearance of ethinyl estradiol increased significantly. Thus, while taking topiramate with oral contraceptives, their effectiveness may be reduced.

In patients taking metformin, pioglitazone, glibenclamide with the simultaneous use or withdrawal of topiramate, fluctuations in plasma glucose levels are possible. With these combinations, plasma glucose should be monitored.

With the simultaneous use of topiramate with drugs that predispose to the development of nephrolithiasis, the risk of kidney stones may increase.

Individual, depending on the indications, the patient's age, renal function and the effectiveness of the therapy.