Topiramate - instructions for use, dose, side effects, contraindications

Excipients (for a dosage of 25.0 / 100.0 mg): lactose monohydrate - 32.8 / 131.2 mg, microcrystalline cellulose 9.0 / 36.0 mg, magnesium stearate, 0.7 mg / 2.8 mg , sodium carboxymethyl starch / (primogel) - 3.8 / 15.2 mg, pregelatinized starch - 3.7 / 14.8 mg;

shell: for the dosage of 25 mg (before the preparation of the tablet with a shell weighing 77.5 mg): titanium dioxide - 31.25%, hypromellose 3R - 29.875%, hypromellose 6cR - 29.875%, macrogol 8%, polysorbate 80 - 1%; for the dosage of 100 mg (to obtain a tablet with a shell with a mass of 307.5 mg): hypromellose 3cP - 31.9%, hypromellose 6cP - 31.9%, titanium dioxide 26.39%, macrogol 8%, polysorbate 80 - 1%, iron oxide dye yellow - 0,81%.

Description:Tablets coated with a film coat, white (for a dosage of 25 mg) or yellow with a brownish tinge (for a dosage of 100 mg) colors, round, biconcave. The core is broken in white or white with a grayish shade of color.

Pharmacotherapeutic group:Antiepileptic agent.

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.11 Topiramate

Pharmacodynamics:Antiepileptic drug belongs to the class of sulfamate-substituted monosaccharides. Topiramate reduces the frequency of occurrence of action potentials characteristic of a neuron in a state of persistent depolarization, which indicates the dependence of the blocking action of the drug on the sodium channels on the state of the neuron. Increases the activity of gamma-aminobutyric acid (GABA) against certain subtypes of GABA receptors (including GABA receptors), and also modulates the activity of the GABA receptors themselves; prevents the activation of kainate sensitivity of kainate / AMPK (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors to glutamate, does not affect the activity of N-methyl-O-aspartate (NMDA) against NMDA receptors. These effects are dose-dependent with a plasma topiramate concentration of 1-200 μmol / L, with a minimum activity of 1-10 μmol / l. Inhibits the activity of some isoenzymes of carbonic anhydrase (II-IV), but this effect is weaker than that of acetazolamide, and is probably not the main one in the anticonvulsant activity of topiramate.

Pharmacokinetics:

Suction

After oral administration topiramate quickly and largely absorbed from the gastrointestinal tract (GIT). Bioavailability - 80%. Eating does not have a clinically significant effect on the bioavailability of the drug. The maximum concentration in the blood plasma (C_m_Oh) after oral administration at a dose of 400 mg is achieved after 2 hours. After repeated oral administration at a dose of 100 mg twice a day, the average value of C_m_Oh was an average of 6.76 μg / ml. Pharmacokinetics after a single oral administration is linear, plasma clearance remains constant - 20-30 ml / min; area under the curve, "concentration / time" (AUC) in the dose range from 100 to 400 mg increases in proportion to the dose. The half-life (T_1/2) after repeated administration in doses of 50 and 100 mg twice a day is 21 hours.

Distribution

The connection with plasma proteins is 13-17%. Volume of distribution (Vd) after taking the drug at a dose of 1.2 g - 0.55-0.8 l / kg. Value Vd depends on the sex: in women it is 50% of the values observed in men. The equilibrium concentration (C_ss) when taking topiramate in patients with normal renal function is achieved after 4-8 days.

Metabolism

Metabolised in the liver by hydroxylation, hydrolysis and glucuronation with the formation of 6 pharmacologically inactive metabolites.Biotransformed about 20% of the dose. In patients receiving concomitant therapy with antiepileptic drugs that induce enzymes involved in the metabolism of drugs, the metabolism of topiramate was increased by 50%.

Excretion

It is excreted by the kidneys in unchanged form (70%) and in the form of metabolites. Penetrates into breast milk. It is removed from the plasma by hemodialysis.

Children under the age of 12 years pharmacokinetic parameters of topiramate are also linear in nature, and its clearance is independent of the dose, a C_ss in plasma increases in proportion to the increase in dose. In children, the clearance of topiramate is increased, and the half-life is shorter, therefore, at the same dose for 1 kg of body weight, the concentrations of topiramate in plasma in children may be lower than in adults.

Patients with impaired renal function (creatinine clearance <60 ml / min) renal and plasma clearance of topiramate are reduced. The time to reach the equilibrium concentration in patients with moderate or severe renal dysfunction is 10 to 15 days.

In patients with moderately and strongly pronounced impaired hepatic function the plasma clearance is reduced.

In the elderly the plasma clearance does not change.

Indications:

- Monotherapy for epilepsy (including the first diagnosed) in adults and children older than 6 years.

- As part of complex therapy: partial or generalized tonic-clonic seizures in adults and children older than 3 years; seizures associated with Lennox-Gastaut syndrome, in adults and children older than 3 years.

- Preventing migraine attacks in adults (use of the drug topiramate for the treatment of acute migraine attacks has not been studied).

Contraindications:Hypersensitivity to topiramate and other components of the drug, the period of breastfeeding, children's age (up to 3 years - for use in complex therapy, up to 6 years - for epilepsy monotherapy, up to 18 years - for the prevention of migraine attacks), lactose intolerance , lactase deficiency, or glucose-galactose malabsorption.

Carefully:Renal / hepatic insufficiency, nephrourolythiasis (including in the anamnesis, including family history), hypercalciuria, pregnancy.

Pregnancy and lactation:

In studies on animals, the teratogenic effect of the drug has been reported.Special controlled studies in which topiramate would not have been used to treat pregnant women. Pregnancy registration data indicate an increased risk of developing congenital malformations in newborns whose mothers received topiramate monotherapy during the first trimester of pregnancy. The frequency of congenital malformations in newborns whose mothers received during pregnancy topiramate, was increased three-fold, compared with newborns whose mothers did not take antiepileptic drugs, in addition, they often met reduced body weight (less than 2500 g).

Pregnancy registration data and other studies indicate that the risk of congenital malformations in combination treatment antiepileptic drugs may be higher than with monotherapy.

The use of topiramate in pregnancy is possible only in cases where the intended use for the mother exceeds the potential risk to the fetus. Women of childbearing age with the treatment of topiramate should use reliable methods of contraception.

There is evidence that topiramate excreted in breast milk.If you need to use the drug during lactation, you should decide whether to stop breastfeeding.

Dosing and Administration:

Inside, regardless of food intake. Tablets should not be divided.

Epilepsy

It is recommended to begin treatment with taking the drug in low doses, followed by titration to an effective dose. With the withdrawal of concomitant anticonvulsant drugs for the purpose of monotherapy with topiramate, it is necessary to take into account the possible effect of withdrawal of previous therapy on the frequency of seizures. In cases where there is no need to abruptly cancel the concomitant anticonvulsant for safety reasons, it is recommended that the dose be reduced gradually, reducing the dose of the concomitant antiepileptic drug by one-third every 2 weeks. With the withdrawal of drugs that are inducers of microsomal "hepatic" enzymes, the concentrations of topiramate in the blood will increase. In such situations, in the presence of clinical indications, the dose of topiramate can be reduced.

To achieve the optimal effect of treatment with the drug, it is not necessary to monitor its concentration in the plasma.

Adults with monotherapy epilepsy (including elderly patients with normal renal function) at the beginning of treatment - 25 mg once a 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 two doses. If the treatment regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose is selected depending on the effect. The recommended initial dose is 100-200 mg / day, the maximum daily dose is 500 mg; The daily dose is divided into two doses. In some cases with monotherapy of refractory to the treatment of epilepsy, the dose of topiramate is 1 g / day.

Children older than 6 years with monotherapy epilepsy in the first week of treatment topiramate prescribe a dose of 0.5-1 mg / kg body weight once a day before bedtime. Then the dose is increased at intervals of 1-2 weeks by 0.5-1 mg / kg / day, the daily dose divided into two doses. If this mode is intolerant, the dose can be increased by a smaller amount or at longer intervals. The magnitude of the dose and the rate of its increase are determined by the clinical efficacy and tolerability of therapy. The recommended initial dose for monotherapy with topiramate in children over 6 years is 100 mg / day and depends on the clinical efficacy (in children 6-16 years of age it is about 2 mg / kg / day).

In adults in combination therapy with other anticonvulsants (including elderly patients with normal renal function) in the first week of treatment topiramate appoint a dose of 25-50 mg once a day at night. Then increase the dose by 25-50 mg at intervals of 1-2 weeks and take a daily dose in two divided doses. The minimum effective dose is 200 mg, the average daily dose is 200-400 mg, the frequency of administration is two times a day. If necessary, an increase in the daily dose to a maximum of 1600 mg is possible. The criterion for choosing the dose is the clinical effect, which in some patients can be achieved with the drug once a day;

In children older than 3 years in combination therapy with other anticonvulsant drugs, the dose is started with 25 mg (or less, 1-3 mg / kg / day) once a day at night for 1 week. In the future, at intervals of 1-2 weeks the dose can be increased by 1-3 mg / kg and take the drug in two divided doses. When choosing a dose should be guided by the clinical effect. The recommended total daily dose is 5-9 mg / kg, the frequency of administration is two times a day.

The daily dose to 30 mg / kg of body weight, as a rule, is well tolerated.

Migraine (adult patients)

For prevention of migraine attacks at the beginning of treatment topiramate appoint 25 mg once a day before bedtime for 1 week. Then the dose is increased by 25 mg / day at intervals of 1 week. If the treatment regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose is selected depending on the clinical effect and tolerability. In some cases, a positive result is achieved with a daily dose of topiramate 50 mg. The recommended total daily dose is 100 mg and is taken in two doses, the maximum daily dose is 200 mg.

Dosing regimen in special clinical cases

Patients with renal insufficiency

In patients with impaired renal function (creatinine clearance < 60 ml / min) renal and plasma clearance of topiramate are reduced. In patients with renal insufficiency, a longer time (10-15 days) may be required for each dose in order to establish an equilibrium plasma topiramate concentration than in patients with normal renal function. Because the topiramate it is removed from the plasma during hemodialysis; on its days, an additional dose of a drug equal to half the daily dose should be given in two divided doses (before and after the procedure).

Patients with hepatic insufficiency

Patients with mild to severe liver function impairment topiramate should be administered with caution, since plasma clearance in these patients is reduced.

Elderly patients

In elderly patients with normal renal function, dose adjustment is not required.

Side effects:

Frequency distribution of side effects is made in accordance with the following gradation: Often (>10%), often (>1% and <10%), infrequently (>0.1% and <1%), rarely (>0.01% and <0.1%), rarely (<0,01%).

Disturbances from the nervous system: Often - drowsiness, dizziness, paresthesia, in children - apathy, violation of attention; often - impaired coordination of movements, nystagmus, lethargy, memory impairment, violation of concentration of attention, tremor, amnesia, abnormal gait, hypesthesia, perversion of taste sensations, impaired thinking, speech disorders, dysarthria, cognitive disorders, apathy, mental impairment, psychomotor disorders, sedation ; infrequently - loss of taste sensitivity, akinesia, loss of smell, aphasia, burning sensation (mainly on face and limbs), cerebellar syndrome, disturbed circadian rhythm of sleep, clumsiness, postural dizziness, increased salivation, sensitivity disorder, dysgraphia, dyskinesia, dysphasia, "over the body, hyperesthesia, hypogeousia, hypokinesia, hyposmia, peripheral neuropathy, parosmia, pre-stupor states, repetitive speech, impaired sense of touch, stupor, fainting, no reaction to irritate whether, apraxia, aura, complex partial seizures, convulsions, dystonia, tonic-clonic seizures by type "grand mal", in children - psychomotor hyperactivity.

Disorders of the psyche: hasto - delayed thinking, pronounced speech disorders, confusion, depression, insomnia, aggressive reactions, agitation, irritability, disorientation, emotional lability, in children - behavior change, learning disability; infrequently - apathy, cries, impaired sexual arousal, dyspharmia, increased distraction, early waking up in the morning, upbeat and euphoric mood,auditory and visual hallucinations, hypomanic states, decreased libido, mania, panic state, paranoid states, perseveration of thinking, violation of reading skills, restlessness, sleep disorders, suicidal ideation or attempts, tearfulness; rarely a feeling of despair or despair.

Also noted were nervousness, headache, psychomotor retardation, ataxia; additionally in children - - personality disorders, hyperkinesia; rarely - psychotic symptoms, hallucinations.

Disorders from the gastrointestinal tract: oChen often - decreased or increased appetite, anorexia; often - nausea, diarrhea; infrequently - abdominal pain, constipation, stomach discomfort, dyspepsia, dry mouth, impaired sensation in the oral cavity, gastritis, gastroesophageal reflux, gingival hemorrhage, heaviness in the stomach; infrequently - bad breath, discomfort in the epigastric region, flatulence, glossodynia, pain in the mouth, hypersecretion of the salivary glands, pancreatitis, thirst, in children - vomiting.

Disturbances from the liver and bile ducts: rarely - Increased activity of "liver" transaminases, hepatitis, liver failure.

Co the side of the musculoskeletal and connective tissue: hasto - myalgia, muscle spasms, muscle cramps, muscular pains in the thorax, arthralgia; infrequently - pain in the side, fatigue, weakness, stiffness of the muscles; rarely - swelling of the joints, discomfort in the extremities.

Disorders from the cardiovascular system: infrequently - bradycardia, palpitations, "hot flashes" of blood, orthostatic hypotension, Raynaud phenomenon.

Disorders from the side of the organ of vision: hasto - diplopia, visual impairment, dry eyes; infrequently - discomfort, amblyopia, blepharospasm, transient blindness, unilateral blindness, increased lacrimation, mydriasis, night blindness, photopsy, presbyopia, scintillation scotoma, scotoma, visual acuity reduction; rarely - unpleasant sensations in the eyes, zakratougolnaya glaucoma, violation of eye movements, eyelid edema, myopia, conjunctival edema, maculopathy.

Hearing disorders and labyrinthine disturbances: hasto - pain in the ears, ringing in the ears, in children - dizziness; infrequently - deafness, sensorineural deafness, one-sided deafness, discomfort in the ears, hearing loss.

Disturbances from the respiratory system, chest and mediastinal organs: often - shortness of breath, nosebleeds; infrequently - hoarseness, dyspnea with exercise, nasal congestion, hypersecretion in the paranasal sinuses, in children - rhinorrhea; rarely - Nasopharyngitis.

Disturbances from the skin and subcutaneous tissues: often - rash, alopecia, itching, decreased sensitivity on the face; infrequently - Absence of sweating, allergic dermatitis, redness of the skin, skin pigmentation disorder, facial edema, unpleasant skin odor, urticaria; rarely - decreased sweating (mainly in children); rarely - erythema multiforme, pemphigus, paraorbital edema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Disorders from the kidneys and urinary tract: often - nephrolithiasis, dysuria, pollakiuria ;, infrequently - urolithiasis, hematuria, urinary incontinence, frequent urge to urinate, renal colic, kidney pain; rarely - renal tubular acidosis. Violations of the genitals and breast: often - erectile disfunction, infrequently anorgasmia, sexual dysfunction.

Violations of the blood and lymphatic system: often - Anemia; infrequently - leukopenia, lymphadenopathy, thrombocytopenia, in children - eosinophilia; rarely - neutropenia.

Disorders from the metabolism and nutrition: Often - weight reduction body; rarely - increase in body weight.

General disorders: Often - fatigue, irritability; often - asthenia, anxiety in children, elevated temperature; infrequently - edema of the face, allergic reactions, cold extremities, polydipsia, calcification; rarely generalized edema, flu-like syndrome, allergic edema.

Laboratory indicators: infrequently - decrease in the content of hydrocarbonates in the blood (on average by 4 mmol / l), crystalluria, leukopenia, hypokalemia (decrease in serum potassium levels below 3.5 mmol / l), metabolic acidosis, hyperchloremic acidosis.

Overdose:

Symptoms: cramps, drowsiness, speech and vision impairment, diplopia, thinking disorders, coordination disorders, lethargy, stupor, lowering of blood pressure, abdominal pain, dizziness, agitation and depression.In most cases, the clinical consequences were not severe, but there were deaths after an overdose using a mixture of several medicines, including topiramate. Possible development of severe metabolic acidosis.

Treatment: gastric lavage, if necessary - symptomatic therapy. Patients are advised to adequately increase the amount of fluid consumed. In studies in vitro it was shown that Activated carbon adsorbs topiramate. An effective way to remove topiramate from the body is hemodialysis.

Interaction:

The effect of topiramate on the concentration of other antiepileptic drugs (PEP)

Simultaneous reception of topiramate with other PEP (phenytoin, carbamazepine, valproic acid, phenobarbital primidon) does not affect the equilibrium concentration in the plasma. The simultaneous application of topiramate led in some cases to an increase in the concentration of phenytoin, which is apparently due to the inhibition of the isoenzyme of the cytochrome P450 system (CYP2C19). Therefore, with the development of symptoms of toxicity in patients receiving phenytoin, it is necessary to control the concentration of phenytoin in the blood plasma.

Addition of topiramate to lamotrigine did not affect the equilibrium concentration of the latter at doses of topiramate 100-400 mg / day. During and after lamotrigine withdrawal (average dose 327 mg / day) the equilibrium concentration of topiramate did not change.

The effect of other PEP on the concentration of topiramate in blood plasma

Phenytoin and carbamazepine with simultaneous application with topiramate reduce

concentration of topiramate in plasma. Adding 'or canceling phenytoin or

carbamazepine against a background of treatment with topiramate may require a dose change

the latter. The dose is selected depending on the development of the necessary clinical

effect.

The addition or elimination of valproic acid does not cause clinically significant changes in the concentration of topiramate in the blood plasma and does not require a change in the dose of topiramate.

The effect of phenobarbital and primidone on the concentration of topiramate has not been studied. Interaction with other medicinal products

With simultaneous application of a single dose of topiramate, the value AUC digoxin decreased by 12%. The clinical significance of this effect has not been established.When prescribing or reversing topiramate in patients receiving digoxin, it is necessary to monitor the concentration of digoxin in the serum.

It is not recommended simultaneous reception with topiramate ethanol or others drugs, depressing the central nervous system.

When used simultaneously with topiramate oral contraceptive, containing norethisterone (1 mg) and ethinyl estradiol (35 μg), topiramate in doses of 50-800 mg / day, did not have a significant effect on the effectiveness of norethisterone and in doses of 50-200 mg / day - on the effectiveness of ethinyl estradiol. The clinical significance of the described changes is unclear. A significant dose-dependent decrease in the efficacy of ethinylestradiol was observed with doses of topiramate 200-800 mg / day. The risk of reducing the effectiveness of contraceptives and strengthening breakthrough bleeding should be considered in patients taking oral contraceptives in combination with topiramate. Patients taking estrogen-containing contraceptives should inform the doctor about any changes in the timing and nature of menstruation. The effectiveness of contraceptives can be reduced even in the absence of breakthrough bleeding.

With the simultaneous administration of topiramate with drugs lithium, it is recommended to monitor the level of lithium in the blood of patients. In healthy volunteers, there was a decrease AUC lithium by 18% with the simultaneous administration of topiramate at a dose of 200 mg / day. In patients with bipolar disorder, the use of topiramate at doses up to 200 mg / day did not affect the pharmacokinetics of lithium, but at higher doses (up to 600 mg / day) the value AUC lithium was increased by 26%.

With simultaneous application of topiramate in daily doses of 250 mg or 400 mg AUC risperidone, taken in doses of 1-6 mg / day, is reduced, respectively, by 16% and 33%. In this case, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed insignificantly. The change in the systemic level of risperidone / 9-hydroxysperidone and topiramate was not clinically significant, and this interaction is unlikely to be of clinical significance.

With the simultaneous administration of topiramate and hydrochlorothiazide there was an increase in Cmof topiramate by 27% and its AUC on 29%. The clinical significance of these studies has not been revealed.When administering hydrochlorothiazide to patients receiving topiramate, it may be necessary to correct the dose of topiramate. There were no significant changes in the pharmacokinetic parameters of hydrochlorothiazide with concomitant therapy with topiramate.

With the simultaneous administration of topiramate and metformin there is an increase FROMmOh and AUC metformin by 18% and 25%, respectively, whereas the clearance of metformin with simultaneous administration with topiramate was reduced by 20%. Topiramate did not affect the time to reach the maximum concentration of metformin in the blood plasma. The clearance of topiramate when combined with metformin is reduced. The degree of revealed changes in clearance is not studied. The clinical significance of the effects of metformin on the pharmacokinetics of topiramate is not clear. In the case of the addition or withdrawal of topiramate in patients receiving metformin, special attention should be given to a careful study of the diabetic status of these patients.

For separate and joint purposes pioglitazone and topiramate was found to decrease AUC pioglitazone by 15%, without change in Cmah of the drug. These changes were not statistically significant.For the active hydroxy metabolite of pioglitazone, a decrease in Cmah and AUC by 13% and 16%, respectively, and for active ketometabolite, a decrease in Cmah and AUC by 60%. The clinical significance of these data is not clear. When co-prescribing patients topiramate and pioglitazone, special attention should be given to careful research - the diabetic status of these patients.

When used simultaneously with topiramate, the value AUC glibenclamide: decreased by 25%. The level of systemic action of active metabolites, 4-trans-hydroxyglybeneclamide and 3-cis-hydroxyglybene clamid, was also reduced (by 13% and 15%, respectively). Glibenclamide did not affect the pharmacokinetics of topiramate in the equilibrium state. When prescribing topiramate to patients receiving glibenclamide (or

administration of glibenclamide to patients receiving topiramate), you should carefully monitor the patient's condition for assessing the course of diabetes.

With simultaneous application of topiramate with other drugs predisposing to the development of nephrolithiasis, may increase the risk of kidney stones.During the treatment with topiramate, the use of such drugs should be avoided, as they can cause physiological changes that promote nephrolithiasis.

Combined application of topiramate and valproic acid in patients who tolerate each drug well, it is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and symptoms disappear after the withdrawal of one of the drugs. This adverse event is not caused by pharmacokinetic interaction. The relationship between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established.

With simultaneous reception of topiramate with amitriptyline meanings C_max and AUC nortriptyline (metabolite amitriptyline) increased by 20%. With the simultaneous reception with the topiramate of the value C_max and AUC dihydroergotamine, sumatriptan, pisotifen, venlafaxine did not change (< 15% of the initial data).

With the simultaneous administration of topiramate with haloperidol value AUC metabolite haloperidol increased by 31%.

With the simultaneous administration of topiramate (50 mg) with propranolol (80 mg) there was an increase in C_max 4-OH propranolol by 17% and an increase in C_max and AUC of topiramate, respectively by 9% and 16%.

With simultaneous reception of topiramate with diltiazem there was a decrease AUC diltiazem by 25% and deacetylldithiasem by 18%, the values of C_max and AUC N- demethylidylthiazema did not change; there was an increase AUC of topiramate by 20%. With simultaneous reception of topiramate with flunarisin (50 mg every 12 hours) there was an increase AUC flunarizine by 16%. With repeated administration of flunarizine (monotherapy), there was an increase AUC by 14%, which may be due to the accumulation of the drug in the process of achieving equilibrium concentration.

Special instructions:

The dose of topiramate and the rate of its increase are determined individually in accordance with clinical efficacy (the degree of control of seizures, the frequency of migraine attacks) and the tolerability of therapy.

With the withdrawal of topiramate to reduce the risk of increased seizure frequency, the doseshould be reduced gradually: in adults with epilepsy therapy, 50-100 mg once a day a week; in adults receiving topiramate in a dose of 100 mg / day for the prevention of migraine attacks by 25-50 mg per week. Children are recommended to carry out a gradual withdrawal of the drug within 2-8 weeks.If the medical indications require a rapid discontinuation of the drug, it is recommended that appropriate monitoring of the patient's condition be performed.

In patients with renal dysfunction to establish an equilibrium concentration of topiramate in plasma for each dose may need a longer time (10-15 days) than in patients with normal renal function (4-8 days). Against the background of taking topiramate, the risk of kidney stones and related symptoms, such as renal colic, may increase, especially in patients with a predisposition to nephrolithiasis. The risk factors for developing nephrolithiasis are nephrolithiasis in history (including family history), hypercalciuria, concomitant therapy with other drugs that promote the development of nephrolithiasis.

To reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical exertion or high temperatures, an adequate increase in the amount of fluid consumed is necessary.

When treating topiramate, there is an increased incidence of mood disorders and depression.

When using antiepileptic drugs, including topiramate, increased risk of suicidal thoughts and suicidal behavior in patients taking these drugs for any of the indications. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs showed an increased risk of suicidal ideation and suicidal behavior (0.43% with antiepileptic drugs versus 0.24% with placebo). The mechanism of this risk is unknown. The incidence of suicidal-related events (suicidal ideation, suicide attempts, suicide) was 0.5% in patients who received topiramate (in 46 of 8652 patients) compared with 0.2% in patients receiving placebo (8 patients from 4045). Therefore, it is necessary to monitor the status of patients in order to identify signs of suicidal tendencies and prescribe appropriate treatment. It is necessary to recommend patients (and if necessary, carers of patients) immediately seek medical help in case of signs of suicidal tendencies or suicidal behavior.

With the use of topiramate, the development of a syndrome involving acute myopia

with concomitant, secondary, closed-angle glaucoma. Symptoms include acute reduction sharpnesses vision and / or pain in the eye. Ophthalmic examination may reveal myopia; flattening of the anterior chamber of the eye, hyperemia (redness) of the eyeball, increased intraocular pressure. There may be mydriasis. This syndrome can be accompanied by the secretion of fluid, leading to a shift in the lens and iris forward with the development of secondary closed-angle glaucoma. Symptoms usually appear 1 month after starting the drug. Unlike primary open angle glaucoma, which is rarely seen in patients under 40 years of age, secondary occlusive glaucoma is observed with topiramate in both adults and children. In the event of a syndrome involving myopia associated with occlusive glaucoma, treatment includes stopping the use of topiramate as soon as the attending physician deems it possible and appropriate measures aimed at lowering the intraocular pressure.Usually these measures lead to normalization of intraocular pressure. Increased intraocular pressure of any etiology in the absence of adequate treatment can lead to serious complications, including loss of vision. With the use of topiramate, hyperchloremic, metabolic acidosis unrelated to an anion deficiency (for example, a decrease in the concentration of hydrogencarbonates in the plasma below the normal level in the absence of respiratory alkalosis) may occur. Such a decrease in serum bicarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carboanhydrase. In most cases, the decrease in the concentration of hydrocarbonates occurs at the beginning of the drug, although this effect may occur in any period of treatment with topiramate. The degree of concentration reduction is usually weak or moderate (mean value is 4 mmol / L when administered at a dose of more than 100 mg / day in adult patients and about 6 mg / kg / day when applied in pediatric practice). In rare cases, the concentration of hydrocarbonates decreased below 10 mmol / l. Some diseases or methods of treatment,predisposing to the development of acidosis (eg, kidney disease, severe respiratory diseases, status epilepticus, diarrhea, surgical interventions, ketogenic diet, intake of certain medications) may be additional factors that enhance bicarbonate-reducing effect of topiramate.

In children, chronic metabolic acidosis can lead to slower growth. The effect of topiramate on growth and possible complications associated with the bone system has not been systematically studied in children and adults.

In connection with the above, in the treatment with topiramate it is recommended to carry out the necessary studies, including, determination of the concentration of hydrocarbonates atserum. When there is metabolic acidosis and its persistence, it is recommended to reduce the dose or stop taking topiramate.

If the weight of the body decreases with the use of topiramate, then the question of the advisability of enhanced nutrition should be considered.

In patients with impaired hepatic function topiramate It should be used with caution because of the possible reduction in the clearance of topiramate.

Effect on the ability to drive transp. cf. and fur:

On the background of taking topiramate, there may be drowsiness, dizziness, visual impairment and other adverse effects that may be dangerous for patients who drive and move vehicles. During the period of drug treatment, care should be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:Film coated tablets, 25 mg and 100 mg.

Packaging:

10 tablets in a contoured cell packaging made of polyvinylchloride / polyvinylidene chloride film and aluminum foil printed or lacquered aluminum foil and aluminum foil, laminated with polyvinylchloride and polyamide film. 30 or 60 tablets in a can of polymeric, sealed insert for induction sealing, sealed with a screw cap, having a device preventing children from opening the can. Free space in the banks is filled with medical cotton. A polyethylene container with silica gel with a warning marking or silica gel is placed in the jar,placed in a paper or polyethylene bag with a perforation with a warning marking. 3 contour mesh packages or each bank together with instruction for use in a pack of cardboard.

Storage conditions:In a dry, protected from light place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001684

Date of registration:02.05.2012

Date of cancellation:2017-09-26

The owner of the registration certificate:NIZHFARM, JSC NIZHFARM, JSC Russia

Manufacturer: & nbsp

MAKIZ-PHARMA, LLC Russia

Information update date: & nbsp26.09.2017

Illustrated instructions

Instructions

Topiramate (Topiramate)