Home Coated tongue Topamax instructions for use. Topamax: instructions for use of capsules

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Topamax instructions for use. Topamax: instructions for use of capsules

Topamax (topiramate) is an original drug that is used to treat epilepsy. Its effectiveness and safety have been repeatedly confirmed by numerous clinical trials and many years of practice. Guerrini R. et al proved the effectiveness of Topamax as a monotherapy various forms epilepsy in all patients age groups. The study included patients who had not previously taken antiepileptic drugs or who did not respond to treatment with these drugs. The dosage was selected individually depending on the clinical situation and age of the patient. The study lasted 7 months. During regular drug therapy With Topamax, 44% of patients did not experience a single convulsive episode; in 76%, the frequency of convulsive episodes was significantly reduced. Arroyo S. et al confirmed the effectiveness of Topamax treatment for individuals in whom epilepsy was diagnosed for the first time. The study involved 470 patients of different age groups. After six months of regular pharmacotherapy, complete relief of attacks was achieved in 83% of patients, and after a year – in 76% of patients. Ramsay RE. proved the effectiveness of Topamax in the treatment of elderly patients in whom epilepsy was diagnosed for the first time. All study participants were over 60 years old. The monitoring period was six months. Complete relief of epilepsy attacks was achieved in 52% of patients taking the drug at a dose of 50 mg per day and in 58% of patients taking the drug at a dose of 200 mg per day.

The results of the study are also particularly relevant from the point of view that, in addition to the effective relief of epilepsy attacks in elderly patients, Topamax significantly reduces the likelihood of developing somatic complications associated with an attack. Yu.A. Yakovleva and E.V. Pleshkova proved the ability of Topamax to improve cognitive activity in children. Children took part in the study, the youngest of whom was 6 years old, the oldest was 17 years old. IN clinical trial the positive effect of the drug on speech function, intellectual-mnestic sphere, incl. cognitive functions (memory, attention, concentration, mental activity), emotional sphere. Topamax is quickly and effectively absorbed from the gastrointestinal tract. The presence of food contents in the gastrointestinal tract does not affect the bioavailability of the drug. Elimination from the body occurs through urine. Topiramate should be discontinued gradually to minimize the risk of increased epileptic seizures. If, based on the clinical situation, abrupt discontinuation of the drug is required, the patient should be under constant medical supervision. During medication course There may be an increased incidence of depressive disorders.

Pharmacology

An antiepileptic drug that belongs to the class of sulfamate-substituted monosaccharides.

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of GABA (GABA) in relation to certain subtypes of GABA receptors (including GABA A receptors), and also modulates the activity of GABA A receptors themselves, and prevents the activation by kainate of the sensitivity of the kainate/AMPK subtype (alpha-amino-3 -hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptors does not affect the activity of NMDA in relation to the NMDA receptor subtype. These drug effects are dose-dependent with plasma concentrations of topiramate ranging from 1 µM to 200 µM, with trough activity ranging from 1 µM to 10 µM.

In addition, topiramate inhibits the activity of some carbonic anhydrase isoenzymes. In terms of the severity of this pharmacological effect, topiramate is significantly inferior to acetazolamide, a known carbonic anhydrase inhibitor, therefore this activity of topiramate is not the main component of its antiepileptic activity.

Pharmacokinetics

Suction

After taking the drug orally, topiramate is quickly and effectively absorbed from the gastrointestinal tract. Bioavailability is 81%. Eating has no clinical effect meaningful action on the bioavailability of the drug.

The pharmacokinetics of topiramate is linear, plasma clearance remains constant, and AUC in the dose range from 100 mg to 400 mg increases in proportion to the dose.

After repeated oral administration at a dose of 100 mg 2 times a day, Cmax averages 6.76 mcg/ml.

Distribution

Plasma protein binding is 13-17%.

After a single oral dose of up to 1200 mg, the average Vd is 0.55-0.8 l/kg. The value of V d 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.

In patients with normal renal function, it may take 4 to 8 days to reach steady state.

Metabolism

After oral administration, about 20% of the dose is metabolized.

Six practically inactive metabolites were isolated and identified from human plasma, urine and feces.

Removal

Topiramate (70%) and its metabolites are excreted primarily by the kidneys.

After oral administration, plasma clearance of the drug is 20-30 ml/min.

After repeated doses of the drug, 50 mg and 100 mg 2 times a day, the average T1/2 was 21 hours.

Pharmacokinetics in special clinical situations

The rate of renal excretion of topiramate depends on renal function and is independent of age.

In patients with moderate to severe renal impairment (creatinine clearance ≤ 70 ml/min), the renal and plasma clearance of topiramate is reduced; as a result, the C ss of topiramate in the blood plasma may increase compared to patients with normal function kidney The time to reach C ss of topiramate in the blood plasma in patients with moderate or severe renal impairment ranges from 10 to 15 days. Patients with renal failure In moderate to severe cases, half the recommended initial and maintenance dose is recommended.

In elderly people who do not suffer from kidney disease, the plasma clearance of topiramate does not change.

In patients receiving concomitant therapy with antiepileptic drugs that induce enzymes involved in drug metabolism, the metabolism of topiramate was increased by 50%.

Topiramate is effectively eliminated by hemodialysis. Long-term hemodialysis may result in a decrease in blood concentrations of topiramate below the amount required to maintain anticonvulsant activity. To avoid a rapid fall in plasma concentrations of topiramate during hemodialysis, an additional dose of Topamax may be required. When adjusting the dose, you should take into account:

1) duration of hemodialysis;

2) the clearance value of the hemodialysis system used;

3) effective renal clearance of topiramate in a patient on dialysis.

Plasma clearance of topiramate is reduced by an average of 26% in patients with moderate or severe hepatic impairment. Therefore, patients with hepatic impairment should use topiramate with caution.

In children under 12 years of age, the pharmacokinetic parameters of topiramate are the same as in adults receiving the drug as adjuvant therapy, are linear in nature, while its clearance does not depend on the dose, and C ss in plasma increases in proportion to the dose. It should be taken into account that in children the clearance of topiramate is increased and its T1/2 is shorter. Therefore, 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, antiepileptic drugs that induce liver enzymes cause a decrease in the concentration of topiramate in the blood plasma.

Release form

Hard gelatin capsules, size No. 2, with body white with the inscription "15 mg" and a transparent colorless cap with the inscription "TOP"; the contents of the capsules are white or almost white granules.

	1 caps.
topiramate	15 mg

Excipients: granulated sugar (sucrose, starch syrup) - 45 mg, povidone - 10.4199 mg, cellulose acetate - 5.423 mg.

Composition of the capsule shell: gelatin - 50.8-52.7 mg, water - 9.3-11.2 mg, sorbitan laurate - 0.0252 mg, sodium lauryl sulfate - 0.0252 mg, titanium dioxide (E171) - 0.63 mg, Opacode Black ink S-1-17822/23 black (solution of shellac glaze in ethanol, black iron oxide, n-butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide) - 5-10 mcg.

28 pcs. - polyethylene bottles (1) - cardboard packs.
60 pcs. - polyethylene bottles (1) - cardboard packs.

Dosage

The drug is taken orally, regardless of food intake.

Capsules should be carefully opened and their contents mixed with a small amount (about 1 teaspoon) of some soft food. This mixture should be swallowed immediately without chewing. The drug mixed with food should not be stored until next appointment. Topamax ® capsules can be swallowed whole.

To achieve optimal control epileptic seizures In adults and children, it is recommended to begin treatment with the drug in low doses, followed by titration to effective dose.

Capsules are intended for patients who have difficulty swallowing tablets (for example, children and elderly patients).

Partial or generalized tonic-clonic seizures, as well as seizures associated with Lennox-Gastaut syndrome

Combined anticonvulsant therapy in adults. The minimum effective dose is 200 mg/day. Typically, the total daily dose is from 200 mg to 400 mg and is taken in 2 divided doses. Some patients may need an increase daily dose up to a maximum of 1600 mg. It is recommended to start treatment with a low dose, followed by gradual selection of an effective dose. Dose selection begins with 25-50 mg, taking them at night for 1 week. In the future, at intervals of 1-2 weeks, the dose can be increased by 25-50 mg and taken in 2 doses. When selecting a dose, it is necessary to be guided by the clinical effect. In some patients, the effect can be achieved by taking the drug once a day. To achieve the optimal effect of treatment with Topamax ®, it is not necessary to control its plasma concentration.

Combined anticonvulsant therapy in children over 2 years of age. Recommended total daily dose of Topamax ® as a means complementary therapy ranges from 5 to 9 mg/kg and is taken in 2 doses. Dose titration should begin with 25 mg (or less, based on a starting dose of 1 to 3 mg/kg per day) at night for 1 week. In the future, the dose can be increased at intervals of 1-2 weeks by 1-3 mg/kg and taken in 2 doses. When selecting a dose, it is necessary to be guided by the clinical effect. Daily doses of up to 30 mg/kg are usually well tolerated.

Epilepsy (including newly diagnosed)

When drugs that are inducers of microsomal liver enzymes are discontinued, the concentration of topiramate in the blood will increase. In such situations, if clinically indicated, the dose of Topamax ® can be reduced.

For monotherapy in adults, at the beginning of treatment, Topamax ® is prescribed at a dose of 25 mg at bedtime for 1 week. Then the dose is increased at intervals of 1-2 weeks by 25 mg or 50 mg in 2 doses. If the patient does not tolerate this dose escalation regimen, then the intervals between dose increases can be increased or the dose can be increased more gradually. When selecting a dose, it is necessary to be guided by the clinical effect. The starting dose for topiramate monotherapy in adults is 100 mg/day, and the maximum daily dose should not exceed 500 mg. Some patients with refractory forms of epilepsy tolerate topiramate monotherapy in doses up to 1000 mg/day. These dosing recommendations apply to all adults, including elderly patients without renal disease.

In monotherapy, children over 2 years of age are prescribed Topamax ® in the first week of treatment at a dose of 0.5-1 mg/kg body weight before bedtime. Then the dose is increased at intervals of 1-2 weeks by 0.5-1 mg/kg/day in 2 doses. If the child does not tolerate this dose escalation regimen, the dose can be increased more gradually or the intervals between dose increases can be increased. The dose size and the rate of its increase depend on the clinical effect. The recommended dose range for topiramate monotherapy in children over 2 years of age is 100-400 mg/day. Children with newly diagnosed partial seizures up to 500 mg/day can be prescribed.

For the prevention of migraine attacks, the recommended daily dose of topiramate is 100 mg in 2 divided doses. At the beginning of treatment, 25 mg is prescribed at bedtime for 1 week. Then the dose is increased by 25 mg/day with an interval of 1 week. If this treatment regimen is intolerant, the dose is increased by a smaller amount or at larger intervals. The dose is selected depending on the clinical effect. In some cases positive result achieved with a daily dose of topiramate of 50 mg. In clinical studies, patients received various doses of topiramate, but not more than 200 mg/day.

Special patient groups

In patients with moderate or severe renal impairment, a dose reduction may be necessary. It is recommended to use half the recommended initial and maintenance dose.

Hemodialysis: Because topiramate is removed from the plasma by hemodialysis, an additional dose of Topamax equal to approximately half the daily dose should be administered on hemodialysis days. The additional dose should be divided into two doses taken at the beginning and after completion of the hemodialysis procedure. The additional dose may vary depending on the characteristics of the equipment used during hemodialysis.

Topiramate should be used with caution in patients with hepatic impairment.

Overdose

Symptoms: convulsions, drowsiness, speech and vision disorders, diplopia, thinking disorders, coordination problems, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression. In most cases clinical implications were not severe, but deaths were reported after overdose using a mixture of several drugs, including topiramate. Severe metabolic acidosis may develop.

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 that lasted 20-24 hours. After 3-4 days, the overdose symptoms resolved.

Treatment: if the patient ate food shortly before taking an excessive dose of the drug, it is necessary to immediately rinse the stomach or induce vomiting. In vitro studies have shown that Activated carbon adsorbs topiramate. If necessary, symptomatic therapy should be carried out. Effective way removal of topiramate from the body is hemodialysis. Patients are advised to adequately increase their fluid intake.

Interaction

The effect of Topamax ® on the concentrations of other antiepileptic drugs (AEDs)

Concomitant use of Topamax ® with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect their plasma C ss values, with the exception of certain patients in whom the addition of Topamax ® to phenytoin may cause an increase in the concentration of phenytoin in plasma. This may be due to the inhibition of a specific polymorphic isoform of the cytochrome P450 enzyme (CYP2Cmeph). Therefore, if symptoms of toxicity develop in patients receiving phenytoin, it is necessary to monitor the concentration of phenytoin in the blood plasma.

In a pharmacokinetics study in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the latter's C ss in blood plasma at doses of topiramate 100-400 mg/day. During and after discontinuation of lamotrigine (average dose 327 mg/day), C ss of topiramate did not change.

Effect of other AEDs on plasma concentrations of topiramate

Phenytoin and carbamazepine, when used simultaneously with Topamax ®, reduce the concentration of topiramate in plasma. The addition or removal of phenytoin or carbamazepine during treatment with Topamax ® may require a change in the dose of the latter. The dose is selected depending on the development of the desired clinical effect. Addition or withdrawal of valproic acid does not cause clinical significant changes concentration of topiramate in the blood plasma and, therefore, does not require a change in the dose of Topamax ® .

Interaction with others medicines

In studies conducted with the simultaneous use of Topamax ® in a single dose, the AUC of digoxin decreased by 12%. The clinical significance of this effect has not been established. When prescribing or discontinuing the drug Topamax ® in patients receiving digoxin, it is necessary to monitor the concentration of digoxin in the serum.

In clinical studies, the consequences of combined use of Topamax ® with drugs that depress the functions of the central nervous system, as well as with ethanol, have not been studied. Concomitant use drug Topamax ® with medicines, which have a depressing effect on the central nervous system, and are not recommended with ethanol.

When taking Topamax together with drugs based on St. John's wort (Hypericum perforatum), the plasma concentration of topiramate may decrease and, as a result, the effectiveness of the drug may also decrease. Clinical studies of the interaction of Topamax ® and drugs based on St. John's wort have not been conducted.

With the simultaneous use of an oral contraceptive containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), Topamax ® 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. A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of Topamax ® 200-800 mg/day. The clinical significance of the described changes is unclear. The risk of decreased contraceptive effectiveness and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topamax ® . Patients taking estrogen-containing contraceptives should inform their doctor about any changes in the timing and nature of menstruation. The effectiveness of contraceptives may be reduced even in the absence of breakthrough bleeding.

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

Research drug interactions conducted with single and multiple administrations of topiramate to healthy volunteers and patients with bipolar disorder, gave the same results. With simultaneous use of topiratam in daily doses of 250 mg or 400 mg, the AUC of risperidone, taken in doses of 1-6 mg/day, is reduced by 16% and 33%, respectively. At the same time, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics active substances(risperidone and 9-hydroxyrisperidone) changed slightly. The change in systemic exposure of risperidone/9-hydroxyrisperidone and topiramate was not clinically significant and this interaction is unlikely to be of clinical significance.

Drug interactions were studied in healthy volunteers with the separate and combined administration of hydrochlorothiazide (25 mg) and topiramate (96 mg). The results of the studies showed that when topiramate and hydrochlorothiazide were taken simultaneously, the Cmax of topiramate increased by 27% and its AUC by 29%. The clinical significance of these studies has not been established. When prescribing hydrochlorothiazide to patients taking topiramate, a dose adjustment of topiramate may be required. There were no significant changes in the pharmacokinetic parameters of hydrochlorothiazide during concomitant therapy with topiramate.

Drug interactions were studied in healthy volunteers receiving metformin or a combination of metformin and topiramate. Study results showed that when topiramate and metformin were taken concomitantly, the Cmax and AUC of metformin increased by 18% and 25%, respectively, while the clearance of metformin when administered concomitantly with topiramate decreased by 20%. Topiramate had no effect on metformin plasma Tmax. The clearance of topiramate when co-administered with metformin is reduced. The extent of the observed changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unclear. If Topamax ® is added or discontinued in patients receiving metformin, the patient's condition should be monitored diabetes mellitus.

Drug interactions were studied in healthy volunteers with the separate and combined administration of pioglitazone and topiramate. A decrease in the AUC of pioglitazone by 15% was detected, without changing the Cmax of the drug. These changes were not statistically significant. Also, for the active hydroxymetabolite pioglitazone, a decrease in Cmax and AUC was detected by 13% and by 16%, respectively, and for the active ketometabolite, a decrease in both Cmax and AUC was detected by 60%. The clinical significance of these data is unclear. When patients are co-administered Topamax ® and pioglitazone, the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

A drug interaction study was conducted to examine the pharmacokinetics of glibenclamide (5 mg/day) at steady state, administered alone or concomitantly with topiramate (150 mg/day) in patients with type 2 diabetes mellitus. When topiramate was used, the AUC of glibenclamide decreased by 25%. The level of systemic exposure to active metabolites, 4-trans-hydroxy-glibenclamide and 3-cis-hydroxy-glibenclamide, was also reduced (by 13% and 15%, respectively). Glibenclamide did not affect the pharmacokinetics of topiramate at steady state. A statistically unreliable decrease in the AUC of pioglitazone by 15% was detected with no change in its Cmax. When prescribing topiramate to patients receiving glibenclamide (or prescribing glibenclamide to patients receiving topiramate), the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

When using Topamax ® simultaneously with other drugs that predispose to the development of nephrolithiasis, the risk of kidney stones may increase. During treatment with Topamax ® the use of such drugs should be avoided, as they can cause physiological changes that contribute to the development of nephrolithiasis.

The combined use of topiramate and valproic acid in patients who tolerate each drug separately is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after stopping one of the medications. This adverse event is not due to a pharmacokinetic interaction. 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 after the onset joint reception valproic acid and topiramate, and with an increase daily dose topiramate.

To evaluate potentially possible options drug interactions between topiramate and other drugs have been conducted clinical researches. The results of this interaction are summarized in the table.

Added drug	Concentration of added drug*	Topiramate concentration*
Amitriptyline	increase in Cmax and AUC of nortriptyline (amitriptyline metabolite) by 20%	not studied
Dihydroergotamine (orally and subcutaneously)	**	**
Haloperidol	increase in metabolite AUC by 31%	not studied
Propranolol	increase in C max 4-OH propranolol by 17% (topiramate 50 mg)	increase in Cmax by 9% and 16%, increase in AUC by 9% and 17% (propranolol 40 mg and 80 mg every 12 hours, respectively)
Sumatriptan (orally and subcutaneously)	**	not studied
Pizotifen	**	**
Diltiazem	decrease in AUC of diltiazem by 25% and desacetyldiltiazem by 18% and ** for N-demethyldiltiazem	AUC increase by 20%
Venlafaxine	**	**
Flunarizine	16% increase in AUC (50 mg every 12 hours) 1	**

*expressed as % of Cmax and AUC values for monotherapy
**no changes in Cmax and AUC (≤ 15% of the original data)
1 with repeated administration of flunarizine (monotherapy), an increase in AUC by 14% was observed, which may be due to the accumulation of the drug during the process of reaching equilibrium

Side effects

Frequency determination side effects: very often (≥1/10), often (≥1/100,<1/10), нечасто (≥1/1000 и <1/100), редко (≥1/10 000 и <1/1000) и очень редко (<1/10 000).

From the nervous system: very often - drowsiness, dizziness, paresthesia, in children - apathy, impaired attention; often - nystagmus, lethargy, memory impairment, impaired concentration, tremor, amnesia, hypoesthesia, perversion of taste, impaired thinking, impaired speech, cognitive disorders, apathy, mental impairment, psychomotor impairment, sedative effect; uncommon - loss of taste sensitivity, akinesia, loss of smell, aphasia, apraxia, aura, burning sensation (mainly on the face and extremities), cerebellar syndrome, circadian sleep disorder, impaired motor coordination, complex partial seizures, convulsions, postural dizziness, increased salivation , dysesthesia, dysgraphia, dyskinesia, dysphasia, dystonia, sensation of "pins and needles" in the body, tonic-clonic seizures of the grand mal type, hyperesthesia, hypogeusia, hypokinesia, hyposmia, peripheral neuropathy, parosmia, presyncope, repetitive speech, impaired tactility, stupor , fainting, lack of reactions to stimuli, in children - psychomotor hyperactivity.

Mental disorders: often - slow thinking, confusion, depression, insomnia, aggressive reactions, agitation, disorientation, emotional lability, erectile dysfunction, in children - behavioral changes; infrequently - anorgasmia, sexual dysfunction, crying, sexual arousal disorder, dysphemia, early awakenings in the morning, euphoric mood, auditory and visual hallucinations, hypomanic states, decreased libido, mania, state of panic, paranoid states, perseveration of thinking, impaired reading skills, restlessness , sleep disturbances, suicidal ideas or attempts, tearfulness; very rarely - a feeling of hopelessness.

From the digestive system: very often - decreased appetite, anorexia; often - nausea, diarrhea; uncommon - abdominal pain, constipation, dry mouth, decreased sensitivity in the oral cavity, pancreatitis, increased appetite, gastritis, gastroesophageal reflux, bleeding gums, bad breath, flatulence, glossodynia, pain in the oral cavity, thirst, dyspeptic symptoms ( discomfort in the stomach, discomfort in the epigastric region, heaviness in the stomach), in children - vomiting.

From the musculoskeletal system: often - myalgia, muscle spasms, muscle cramps, muscle pain in the chest area, arthralgia; infrequently - pain in the side, muscle stiffness; very rarely - swelling of the joints, discomfort in the limbs.

From the cardiovascular system: infrequently - bradycardia, rapid heartbeat, flushing, orthostatic hypotension, Raynaud's phenomenon.

From the organ of vision: often - diplopia, blurred vision, dry eyes; uncommon - disturbance of accommodation, amblyopia, blepharospasm, transient blindness, one-sided blindness, increased lacrimation, mydriasis, night blindness, photopsia, presbyopia, scotoma (including atrial fibrillation), decreased visual acuity; very rarely - angle-closure glaucoma, involuntary movements of the eyeballs, swelling of the eyelids, myopia, conjunctival edema, maculopathy.

From the organ of hearing: often - pain in the ears, ringing in the ears, in children - vertigo; infrequently - deafness (including sensorineural and one-sided), discomfort in the ears, hearing impairment.

From the respiratory system: often - difficulty breathing, nosebleeds; infrequently - hoarseness, shortness of breath on exertion, nasal congestion, hypersecretion in the paranasal sinuses, in children - rhinorrhea; very rarely - nasopharyngitis.

From the skin and subcutaneous tissues: often - rash, alopecia, itching, decreased sensitivity of the face; uncommon - lack of sweating, allergic dermatitis, redness of the skin, impaired skin pigmentation, unpleasant skin odor, urticaria; very rarely - erythema multiforme, periorbital edema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the urinary system: often - nephrolithiasis, dysuria, pollakiuria; uncommon - exacerbation of urolithiasis, hematuria, urinary incontinence, frequent urge to urinate, renal colic, pain in the kidney area; very rarely - renal tubular acidosis.

From the hematopoietic system: often - anemia; uncommon - leukopenia, lymphadenopathy, thrombocytopenia, in children - eosinophilia; very rarely - neutropenia.

From the laboratory parameters: infrequently - a decrease in the content of bicarbonates in the blood (on average by 4 mmol/l), crystalluria, leukopenia, hypokalemia (a decrease in the level of potassium in the blood serum below 3.5 mmol/l).

General disorders: very often - fatigue, irritability, weight loss; often - asthenia, anxiety, in children - fever; uncommon - facial swelling, allergic reactions, hyperchloremic acidosis, increased appetite, metabolic acidosis, polydipsia, cold extremities, fatigue, weakness, calcinosis; very rarely - generalized edema, influenza-like illnesses, allergic edema, weight gain.

Indications

Epilepsy:

as monotherapy in adults and children over 2 years of age with epilepsy (including patients with newly diagnosed epilepsy);
as part of complex therapy in adults and children over 2 years of age with partial or generalized tonic-clonic seizures, as well as for the treatment of seizures associated with Lennox-Gastaut syndrome.

prevention of migraine attacks in adults (the use of Topamax ® for the treatment of acute migraine attacks has not been studied).

Contraindications

children under 2 years of age;
hypersensitivity to the components of the drug.

Use with caution in case of renal or liver failure, nephrourolithiasis (including in the past or family history), and hypercalciuria.

Features of application

Use during pregnancy and breastfeeding

There have been no special controlled studies in which Topamax ® was used to treat pregnant women. Topiramate may cause fetal harm when used in pregnant women.

Pregnancy data indicate that infants exposed to topiramate in utero have an increased risk of developing congenital malformations (eg, craniofacial defects such as cleft lip or palate, hypospadias, and developmental anomalies of various body systems). These malformations were recorded both during monotherapy with topiramate and when it was used as part of polytherapy.

Compared with the group of patients not taking antiepileptic drugs, data from pregnancies during monotherapy with Topamax ® indicate an increased likelihood of having children with low body weight (less than 2500 g). The connection between the observed phenomena and the use of the drug has not been established. In addition, pregnancy records and the results of other studies indicate that the risk of developing teratogenic effects with combination treatment with antiepileptic drugs is higher than with monotherapy.

The use of Topamax ® during pregnancy is justified only if the potential benefit of therapy for the mother outweighs the possible risk to the fetus.

When treating and counseling women of childbearing potential, the treating physician must weigh the benefit versus risk of treatment and consider alternative treatment options.

If Topamax ® is used during pregnancy, or if the patient becomes pregnant while taking the drug, she should be warned of the potential risk to the fetus.

A limited number of observations suggest that topiramate is excreted into breast milk in women. If it is necessary to use the drug Topamax ® during lactation, the issue of stopping breastfeeding or stopping taking the drug should be decided.

Use for liver dysfunction

Use with caution in case of liver failure. In patients with moderate to severe liver dysfunction, plasma clearance is reduced.

Use for renal impairment

When prescribing the drug to patients with moderate or severely impaired renal function, it should be taken into account that it may take 10-15 days to achieve an equilibrium state in this category of patients, in contrast to 4-8 days in patients with normal renal function. Since topiramate is removed from the plasma during hemodialysis, on the days of hemodialysis an additional dose of the drug should be prescribed equal to half the daily dose in 2 doses (before and after the procedure).

It should be used with caution in case of renal failure, nephrourolithiasis (including in the past or family history), and hypercalciuria.

Use in children

The drug is contraindicated for use in children under 2 years of age.

special instructions

Topamax ® (like other antiepileptic drugs) should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures. In clinical studies, the dose of the drug was reduced by 50-100 mg once a week - for adults during the treatment of epilepsy and by 25-50 mg - in adults receiving Topamax ® at a dose of 100 mg / day for the prevention of migraine. In children in clinical studies, Topamax ® was gradually withdrawn over 2-8 weeks. If, for medical reasons, rapid discontinuation of the drug Topamax ® is necessary, then it is recommended to carry out appropriate monitoring of the patient’s condition.

As with any disease, dosing schedules should be based on clinical benefit (i.e., degree of seizure control, absence of side effects) and take into account that in patients with renal impairment, it may be necessary to establish a stable plasma concentration for each dose. it will take longer.

During therapy with topiramate, oligohidrosis (decreased sweating) and anhidrosis may occur. Decreased sweating and hyperthermia (increased body temperature) may occur in children exposed to high ambient temperatures. When treating with topiramate, it is very important to adequately increase the volume of fluid intake, which helps reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical activity or elevated temperatures.

An increased incidence of mood disorders and depression has been observed during treatment with topiramate.

When using antiepileptic drugs, including Topamax ® , the risk of suicidal thoughts and behavior increases in patients taking these drugs for any indication.

In double-blind clinical studies, the incidence of suicide-related events (suicidal thoughts, suicide attempts, suicide) was 0.5% in patients receiving topiramate (46 out of 8652 people), which is approximately 3 times higher compared to patients treated with topiramate. those receiving placebo (0.2%; 8 people out of 4045). One case of suicide was reported in a double-blind study of bipolar disorder in a patient receiving topiramate.

Thus, it is necessary to monitor patients for signs of suicidal ideation and prescribe appropriate treatment. Patients (and, if appropriate, caregivers) should be advised to seek immediate medical attention if signs of suicidal thoughts or behavior occur.

Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and associated symptoms such as renal colic. To reduce this risk, an adequate increase in fluid intake is necessary. Risk factors for the development of nephrolithiasis are a history of nephrolithiasis (including family history), hypercalciuria, and concomitant therapy with other drugs that contribute to the development of nephrolithiasis.

Caution should be exercised when prescribing Topamax ® to patients with renal failure (KR<70 мл/мин). Это связано с тем, что у таких пациентов клиренс препарата понижен.

In patients with impaired liver function, Topamax ® should be used with caution due to a possible decrease in the clearance of topiramate.

When using the drug Topamax ®, a syndrome has been described that includes acute myopia with concomitant secondary angle-closure glaucoma. Symptoms include acute loss of visual acuity and/or eye pain. An ophthalmological examination may reveal myopia, flattening of the anterior chamber of the eye, hyperemia (redness) of the eyeball, and increased intraocular pressure. Mydriasis may occur. This syndrome may be accompanied by fluid secretion, leading to forward displacement of the lens and iris with the development of secondary angle-closure glaucoma. Symptoms usually appear 1 month after starting Topamax ® . Unlike primary open-angle glaucoma, which is rarely observed in patients under 40 years of age, secondary angle-closure glaucoma is observed with the use of topiramate in both adults and children. If a syndrome involving myopia associated with angle-closure glaucoma occurs, treatment includes discontinuation of Topamax ® as soon as deemed possible by the treating physician and appropriate measures to lower intraocular pressure. Typically, 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.

When topiramate is used, hyperchloremic, non-anion deficiency, metabolic acidosis (eg, a decrease in plasma bicarbonate concentrations below normal levels in the absence of respiratory alkalosis) may occur. This decrease in serum bicarbonate concentrations is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, a decrease in bicarbonate concentrations occurs at the beginning of the drug, although this effect can occur at any time during treatment with topiramate. The level of decrease in concentration is usually weak or moderate (the average value is 4 mmol/l when used in adult patients at a dose of more than 100 mg/day and about 6 mg/kg/day when used in pediatric practice). In rare cases, patients experienced a decrease in concentration below 10 mmol/l. Certain medical conditions or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory disease, status epilepticus, diarrhea, surgery, ketogenic diet, certain medications) may be additive factors that enhance the bicarbonate-lowering effect of topiramate.

In children, chronic metabolic acidosis can lead to growth retardation. The effects of topiramate on growth and possible complications related to the skeletal system have not been systematically studied in children and adults.

If while taking Topamax ® the patient’s body weight decreases, then the advisability of increased nutrition should be considered.

Impact on the ability to drive vehicles and operate machinery

Topamax ® acts on the central nervous system and may cause drowsiness, dizziness, blurred vision and other symptoms. These adverse effects may pose a danger to patients who drive cars and operate machinery, especially until the patient's response to the drug is established.

In adults and children over 2 years of age:

Epilepsy (including in patients with newly diagnosed epilepsy) - monotherapy;

Partial or generalized tonic-clonic seizures, seizures due to Lennox-Gastaut syndrome - as part of complex therapy.

In adults: prevention of migraine attacks (the use of Topamax® for the treatment of acute migraine attacks has not been studied).

Release form of the drug Topamax

capsules 15 mg; polyethylene bottle (bottle) 28, box (box) 1;

Capsules 15 mg; bottle (bottle) polyethylene 60, box (box) 1;

Capsules 25 mg; polyethylene bottle (bottle) 28, box (box) 1;

Capsules 25 mg; bottle (bottle) polyethylene 60, box (box) 1;

Capsules 50 mg; polyethylene bottle (bottle) 28, cardboard pack 1;

Capsules 50 mg; polyethylene bottle (bottle) 60, cardboard pack 1;

Compound
Capsules 1 capsule.
topiramate 15 mg, 25 mg, 50 mg
excipients for capsules 15 and 25 mg: granulated sugar (sucrose, starch syrup); seen; cellulose acetate
capsule composition: gelatin; purified water; silicon dioxide; sodium lauryl sulfate; titanium dioxide; Opacode ink black S-1-17822/23 (contains iron oxide E172)
excipients for capsules 50 mg: sucrose; povidone; cellulose acetate; gelatin; purified water; silicon dioxide; sodium lauryl sulfate; titanium dioxide; Opacode ink S-1-1788/23 black (contains: shellac glaze solution in ethanol; black iron oxide; n-butyl alcohol; isopropyl alcohol; propylene glycol; ammonium hydroxide)
in a PE bottle 28 or 60 pcs.; 1 bottle in a box.

Pharmacodynamics of the drug Topamax

Topiramate is an antiepileptic drug belonging to the class of sulfamate-substituted monosaccharides.

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of γ-aminobutyric acid (GABA) in relation to certain subtypes of GABA receptors (including GABAA receptors), and also modulates the activity of GABAA receptors themselves, and prevents the activation by kainate of the sensitivity of the kainate/AMPK subtype (α-amino- 3-hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptors does not affect the activity of N-methyl-D-aspartate (NMDA) towards the NMDA receptor subtype. These effects of topiramate are dose-dependent with drug plasma concentrations ranging from 1 µM to 200 µM, with trough activity ranging from 1 µM to 10 µM.

Pharmacokinetics of the drug Topamax

Topiramate is absorbed quickly and efficiently. Bioavailability - 81%. Food intake does not have a clinically significant effect on the bioavailability of topiramate. 13–17% of topiramate is bound to plasma proteins. After a single dose of up to 1200 mg, the average volume of distribution is 0.55–0.8 l/kg. The magnitude of the volume of distribution 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.

After oral administration, about 20% of the dose taken is metabolized. However, in patients receiving concomitant therapy with antiepileptic drugs that induce enzymes responsible for drug metabolism, the metabolism of topiramate increased by up to 50%. Six practically inactive metabolites were isolated and identified from human plasma, urine and feces. The main route of elimination of unchanged topiramate (70%) and its metabolites is the kidneys. After oral administration, plasma clearance of the drug is 20–30 ml/min. The pharmacokinetics of topiramate is linear, plasma clearance remains constant, and the area under the concentration/time curve (AUC) increases proportionally to the dose over the dose range from 100 to 400 mg. In patients with normal renal function, it may take 4 to 8 days to achieve steady-state plasma concentrations. The Cmax value after repeated oral administration at a dose of 100 mg of the drug twice a day averaged 6.76 mcg/ml. After multiple doses of 50 and 100 mg twice daily, T1/2 of topiramate from plasma averaged 21 hours.

In patients with impaired renal function, plasma and renal clearance of topiramate is reduced (Cl creatinine - ≤60 ml/min). In elderly individuals without renal disease, the plasma clearance of topiramate does not change.

Topiramate is effectively eliminated from plasma by hemodialysis.

In patients with moderate to severe hepatic impairment, plasma clearance of topiramate is reduced.

Pharmacokinetics of topiramate in children under 12 years of age. The pharmacokinetic parameters of topiramate in children, as well as in adults receiving this drug as adjuvant therapy, are linear, while its clearance does not depend on the dose, and steady-state plasma concentrations increase in proportion to the dose. One should take into account the fact that in children the clearance of topiramate is increased and T1/2 is shorter. Therefore, 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, antiepileptic drugs that induce hepatic enzymes cause a decrease in steady-state plasma concentrations of topiramate.

Using Topamax during pregnancy

There have been no studies in which Topamax® was used to treat pregnant women. However, during pregnancy, Topamax® should be used only if its positive effect on the mother outweighs the potential risk to the fetus.

A limited number of patient observations suggest that topiramate is excreted in breast milk in women. It is necessary to decide whether to stop breastfeeding or stop taking the drug, taking into account its importance to the mother.

Contraindications to the use of Topamax

hypersensitivity to any of the components of the drug;

Children under 2 years of age.

Carefully:

Kidney or liver failure;

Nephrourolithiasis (including in the past or family history);

Hypercalciuria.

Side effects of the drug Topamax

Side effects are given with a distribution by frequency and organ system. The frequency of side effects was classified as follows: very often - ≥1/10, often - ≥1/100,<1/10), нечасто - ≥1/1000 и <1/100, редко - ≥1/10000 и <1/1000 и очень редко - <1/10000.

Infections: very rarely - nasopharyngitis.

From the blood and lymphatic system: often - anemia; uncommon - leukopenia, lymphadenopathy, thrombocytopenia, in children - eosinophilia; very rarely - neutropenia.

From the side of the central nervous system: very often - drowsiness, dizziness, paresthesia, in children - apathy, impaired attention; often - impaired coordination, nystagmus, lethargy, memory impairment, impaired concentration, tremor, amnesia, hypoesthesia, perversion of taste, impaired thinking, speech impairment, cognitive disorders, apathy, mental impairment, psychomotor impairment, sedative effect; uncommon - loss of taste sensitivity, akinesia, loss of smell, aphasia, burning sensation (mainly on the face and limbs), cerebellar syndrome, disturbance of the circadian rhythm of sleep, awkwardness of movements, postural dizziness, increased salivation, dysesthesia, dysgraphia, dyskinesia, dysphasia, goosebumps throughout the body, hyperesthesia, hypogeusia, hypokinesia, hyposmia, peripheral neuropathy, parosmia, presyncope, repetitive speech, disturbance of touch, stupor, fainting, lack of reactions to stimuli, in children - psychomotor hyperactivity.

Mental disorders: often - slow thinking, confusion, depression, insomnia, aggressive reactions, agitation, irritability, disorientation, emotional lability, erectile dysfunction, in children - behavioral changes; uncommon - anorgasmia, sexual dysfunction, apathy, crying, sexual arousal disorder, dysphemia, early morning awakenings, euphoric mood, auditory and visual hallucinations, hypomanic states, decreased libido, mania, state of panic, paranoid states, perseveration of thinking, impaired reading skills , anxiety, sleep disturbances, suicidal ideas or attempts, tearfulness; very rarely - a feeling of hopelessness.

Disorders of the gastrointestinal tract and hepatobiliary system: very often - decreased appetite, anorexia; often - nausea, diarrhea; uncommon - abdominal pain, constipation, dry mouth, decreased sensitivity in the oral cavity, gastritis, gastroesophageal reflux, bleeding gums, bad breath, flatulence, glossodynia, pain in the oral cavity, thirst, dyspeptic symptoms, namely stomach discomfort , discomfort in the epigastric region, heaviness in the stomach, in children - vomiting.

Disorders of the musculoskeletal system and connective tissue: often - myalgia, incl. chest, muscle spasms, muscle cramps, arthralgia; infrequently - pain in the side, muscle stiffness; very rarely: swelling of the joints, discomfort in the limbs.

Cardiovascular system disorders: uncommon - bradycardia, rapid heartbeat, flushing, orthostatic hypotension, Raynaud's phenomenon.

General disorders: very often - fatigue, irritability, weight loss; often - asthenia, anxiety, in children - fever; uncommon - facial swelling, allergic reactions, hyperchloremic acidosis, increased appetite, metabolic acidosis, polydipsia, cold extremities, fatigue, weakness; very rarely - generalized edema, influenza-like illnesses, allergic edema, weight gain.

Ophthalmological disorders: often - diplopia, blurred vision, dry eyes; uncommon - accommodation disturbance, amblyopia, blepharospasm, transient blindness, one-sided blindness, increased lacrimation, mydriasis, night blindness, photopsia, presbyopia, scotoma, incl. flickering, decreased visual acuity; very rarely - angle-closure glaucoma, impaired eye movements, eyelid swelling, myopia, conjunctival edema.

Ear and labyrinth disorders: often - ear pain, tinnitus, in children - vertigo; infrequently - deafness, incl. neurosensory and one-sided, ear discomfort, hearing impairment.

Respiratory system disorders: often - difficulty breathing, nosebleeds; infrequently - hoarseness, shortness of breath during exercise, nasal congestion, hypersecretion in the paranasal sinuses, in children - rhinorrhea.

Disorders of the skin and subcutaneous tissues: often - rash, alopecia, itching, decreased sensitivity of the face; uncommon - lack of sweating, allergic dermatitis, skin redness, skin pigmentation disorders, rashes, facial swelling, unpleasant skin odor, urticaria; very rarely - polymorphic erythema, periorbital edema, Steven-Johnson syndrome, toxic epidermal necrolysis.

Renal and urinary tract disorders: often - nephrolithiasis, dysuria, pollakiuria; uncommon - urolithiasis, hematuria, urinary incontinence, frequent urge to urinate, renal colic, kidney pain; very rarely - renal tubular acidosis.

Changes in laboratory parameters: infrequently - decrease in bicarbonate levels in the blood (on average by 4 mmol/l), crystalluria, leukopenia, hypokalemia (decreased potassium levels in the blood serum<3ммоль/л).

Directions for use and dosage of Topamax

Inside, regardless of food intake.

To achieve optimal control of epileptic seizures in children and adult patients, it is recommended to begin treatment with low doses of the drug, followed by gradual titration to an effective dose.

Capsules are intended for patients who have difficulty swallowing tablets (for example, children and elderly patients). In such cases, the Topamax® capsule should be carefully opened and its contents mixed with a small amount (about 1 teaspoon) of some soft food. This mixture should be swallowed immediately without chewing. Do not store medicine mixed with food until your next dose. Topamax® capsules can be swallowed whole.

Use in combination with other anticonvulsants in adult patients. The minimum effective dose is 200 mg per day. Typically, the total daily dose is from 200 to 400 mg and is taken in 2 divided doses. Some patients may need to increase the daily dose to a maximum of 1600 mg. It is recommended to start treatment with a low dose, followed by gradual selection of an effective dose. Dose selection begins with 25–50 mg, taking them at night for 1 week. In the future, at weekly or 2-week intervals, the dose can be increased by 25–50 mg and taken in 2 doses. When selecting a dose, it is necessary to be guided by the clinical effect. In some patients, the effect can be achieved by taking the drug once a day. To achieve the optimal effect of treatment with Topamax®, it is not necessary to control its plasma concentration.

Combined anticonvulsant therapy in children over 2 years of age. The recommended total daily dose of Topamax® as an additional therapy is from 5 to 9 mg/kg and is taken in 2 divided doses. Dose selection should begin with 25 mg (or less, based on the starting dose of 1 to 3 mg/kg per day), taken at night for 1 week. Subsequently, at weekly or 2-week intervals, the dose can be increased by 1–3 mg/kg and taken in 2 divided doses. When selecting a dose, it is necessary to be guided by the clinical effect. Daily doses of up to 30 mg/kg are usually well tolerated.

Monotherapy, general provisions. When discontinuing concomitant anticonvulsants for the purpose of topiramate monotherapy, the possible impact of this step on seizure frequency must be considered. In cases where it is not necessary to abruptly discontinue concomitant anticonvulsants for safety reasons, it is recommended to reduce their doses gradually, reducing the dose of the concomitant antiepileptic drug by 1/3 every 2 weeks.

When drugs that are inducers of liver enzymes are discontinued, the concentrations of topiramate in the blood will increase. In such situations, if clinically indicated, the dose of Topamax® can be reduced.

Monotherapy in adults. At the beginning - 25 mg of Topamax® before bedtime for 1 week. Then the dose is increased at intervals of 1–2 weeks by 25 or 50 mg (the daily dose is divided into 2 doses). If the patient does not tolerate this dose escalation regimen, then the intervals between dose increases can be increased or the dose can be increased more gradually. When selecting a dose, it is necessary to be guided by the clinical effect.

The starting dose for topiramate monotherapy in adults is 100 mg/day, and the maximum daily dose should not exceed 500 mg. Some patients with refractory forms of epilepsy tolerate topiramate monotherapy in doses up to 1000 mg/day. Dosing recommendations apply to all adults, including elderly patients without renal disease.

Monotherapy in children. Children over 2 years of age should be given topiramate at a dose of 0.5–1 mg/kg body weight at bedtime during the first week of treatment. Then the dose is increased at intervals of 1–2 weeks by 0.5–1 mg/kg/day (the daily dose is divided into 2 doses). If the child does not tolerate this dose escalation regimen, the dose can be increased more gradually or the intervals between dose increases can be increased. The dose size and rate of increase should be determined by the clinical outcome.

Migraine. The recommended total daily dose of topiramate for the prevention of migraine attacks is 100 mg in 2 divided doses. At the beginning of treatment, the patient should take 25 mg of Topamax® at bedtime for 1 week. Then the dose is increased at intervals of 1 week by 25 mg/day. If the patient does not tolerate this dose escalation regimen, then the intervals between dose increases can be increased or the dose can be increased more gradually. When selecting a dose, it is necessary to be guided by the clinical effect.

In some patients, a positive result is achieved with a daily dose of topiramate of 50 mg. In clinical studies, patients received various daily doses of topiramate, but not more than 200 mg/day.

Special instructions when taking Topamax

Antiepileptic drugs, including Topamax®, should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures. In clinical trials, doses were reduced by 50–100 mg at weekly intervals for adults treated for epilepsy and by 25–50 mg in adults receiving 100 mg/day of Topamax® for migraine prophylaxis. In children in clinical studies, Topamax® was gradually withdrawn over 2–8 weeks. If, for medical reasons, rapid discontinuation of Topamax® is necessary, it is recommended to appropriately monitor the patient’s condition.

The rate of excretion through the kidneys depends on renal function and is independent of age. In patients with moderate or severe renal impairment, it may take 10 to 15 days to achieve steady-state plasma concentrations, compared with 4 to 8 days in patients with normal renal function.

As with any disease, dose selection should be based on clinical effect (i.e., degree of seizure control, absence of side effects) and take into account that in patients with impaired renal function, more may be needed to establish a stable plasma concentration for each dose. long time.

When treating with topiramate, it is very important to adequately increase the volume of fluid intake, which can reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical activity or elevated temperatures.

Mood disorders/depression. An increased incidence of mood disorders and depression has been observed during treatment with topiramate.

Suicidal attempts. In double-blind clinical trials using topiramate for approved and investigational indications, suicide attempts occurred with a frequency of 0.003 with topiramate (13 cases among 3999 patients), with a frequency of 0 with placebo (0 cases among 430 patients). There was one completed suicide attempt during a clinical trial of the drug in bipolar disorders.

Nephrolithiasis. Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and associated symptoms such as renal colic. To reduce this risk, an adequate increase in fluid intake is necessary.

Risk factors for the development of nephrolithiasis are a history of nephrolithiasis (including family history), hypercalciuria, and concomitant therapy with drugs that contribute to the development of nephrolithiasis.

Liver dysfunction. In patients with impaired liver function, topiramate should be used with caution due to the possible decrease in clearance of this drug.

Myopia and secondary angle-closure glaucoma. When using the drug Topamax ®, a syndrome has been described that includes acute myopia with concomitant secondary angle-closure glaucoma. Symptoms include acute loss of visual acuity and/or eye pain. An ophthalmological examination may reveal myopia, flattening of the anterior chamber of the eye, hyperemia (redness) of the eyeball, and increased intraocular pressure. Mydriasis may occur. This syndrome may be accompanied by fluid secretion, leading to forward displacement of the lens and iris with the development of secondary angle-closure glaucoma. Symptoms usually appear 1 month after starting Topamax® use. Unlike primary open-angle glaucoma, which is rarely observed in patients under 40 years of age, secondary angle-closure glaucoma is observed with the use of topiramate in both adults and children. If a syndrome involving myopia associated with angle-closure glaucoma occurs, treatment includes discontinuation of Topamax® as soon as deemed possible by the attending physician and appropriate measures aimed at lowering intraocular pressure. Typically, 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.

Metabolic acidosis. When using topiramate, hyperchloremic metabolic acidosis not associated with anion deficiency may occur (for example, a decrease in plasma bicarbonate concentrations below normal levels in the absence of respiratory alkalosis). This decrease in serum bicarbonate concentrations is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, a decrease in bicarbonate concentrations occurs at the beginning of the drug, although this effect can occur at any time during treatment with topiramate. The level of reduction in concentration is usually weak or moderate (average value is 4 mmol/l when used in adult patients at doses above 100 mg per day and about 6 mg/kg/day when used in pediatric practice). In rare cases, patients experience a decrease in bicarbonate concentrations below 10 mmol/L. Certain medical conditions or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory disease, status epilepticus, diarrhea, surgery, ketogenic diet, certain medications) may be additional factors that enhance the bicarbonate-lowering effect of topiramate.

In children, chronic metabolic acidosis can lead to growth retardation. The effect of topiramate on growth and possible complications related to the skeletal system have not been systematically studied in children and adults.

Enhanced nutrition. If a patient loses weight during treatment with Topamax®, then it is necessary to consider the advisability of enhanced nutrition.

Influence on driving a car and working with equipment. Topamax® acts on the central nervous system and may cause drowsiness, dizziness and other symptoms. It can also cause vision problems. These adverse events may pose a danger to patients driving cars and moving machinery, especially during the period until the patient’s individual response to the drug is established.

Catad_pgroup Antiepileptics

Topamax 15, 25 - instructions for use

Registration number:

Tradename:

Topamax ®

International nonproprietary name:

topiramate

Dosage form:

Compound

For 15 mg dosage:
Active substance: topiramate 15 mg.
Excipients: granulated sugar [sucrose, starch syrup] 45.00 mg, povidone 10.4199 mg, cellulose acetate 5.423 mg;
Capsule composition: gelatin 50.8-52.7 mg, water 9.3-11.2 mg, sorbitan laurate 0.0252 mg, sodium lauryl sulfate 0.0252 mg, titanium dioxide (E171) 0.63 mg, Opacode Black ink S-1-17822/23 black (ink composition: shellac glaze solution in ethanol, black iron oxide, n-butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide) 5-10 mcg.

For 25 mg dosage:
Active substance: topiramate 25 mg.
Excipients: granulated sugar [sucrose, starch syrup] 75.00 mg, povidone 17.3665 mg, cellulose acetate 9.038 mg.
Capsule composition: gelatin 64.7-67.0 mg, water 10.0-12.3 mg, sorbitan laurate 0.0312 mg, sodium lauryl sulfate 0.0312 mg, titanium dioxide (E171) 0.78 mg, Opacode Black ink S-1-17822/23 black (ink composition: shellac glaze solution in ethanol, black iron oxide, n-butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide) 5-10 mcg.

Description

15 mg capsules: hard gelatin capsules No. 2, consisting of a white body and a transparent, colorless cap. The cap of the capsule bears the inscription "TOP". On the body of the capsule there is the inscription “15 mg”. The contents of the capsules are white or almost white granules.

25 mg capsules: hard gelatin capsules No. 1, consisting of a white body and a transparent colorless cap. The cap of the capsule bears the inscription "TOP". The capsule body bears the inscription "25 mg". The contents of the capsules are white or almost white granules.

Pharmacotherapeutic group:

antiepileptic drug

ATX code: N03AX11

Pharmacological properties

Pharmacodynamics

Topiramate is an antiepileptic drug belonging to the class of sulfamate-substituted monosaccharides.

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of β-aminobutyric acid (GABA) in relation to certain subtypes of GABA receptors (including GABAA receptors), and also modulates the activity of GABAA receptors themselves, and prevents the activation by kainate of the sensitivity of the kainate/AMPK subtype (β-amino- 3-hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptors does not affect the activity of N-methyl-D-aspartate (NMDA) towards the NMDA receptor subtype. These effects of topiramate are dose-dependent with drug plasma concentrations ranging from 1 µM to 200 µM, with trough activity ranging from 1 µM to 10 µM.

Pharmacokinetics

Topiramate is absorbed quickly and efficiently. Its bioavailability is 81%. Food intake does not have a clinically significant effect on the bioavailability of topiramate. 13–17% of topiramate is bound to plasma proteins. After a single dose of up to 1200 mg, the average volume of distribution is 0.55–0.8 l/kg. The magnitude of the volume of distribution 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.

After oral administration, about 20% of the dose taken is metabolized. However, in patients receiving concomitant therapy with antiepileptic drugs that induce enzymes responsible for drug metabolism, the metabolism of topiramate increases up to 50%. Six essentially inactive metabolites have been isolated and identified from human plasma, urine, and feces. The main route of elimination of unchanged topiramate (70%) and its metabolites is the kidneys. After oral administration, plasma clearance of topiramate is 20–30 ml/min. The pharmacokinetics of topiramate is linear, plasma clearance remains constant, and the area under the concentration-time curve (AUC) increases dose proportionally over the dose range from 100 to 400 mg. In patients with normal renal function, it may take 4 to 8 days to achieve steady-state plasma concentrations. The maximum concentration (Cmax) after repeated oral administration of 100 mg of the drug twice a day averaged 6.76 mcg/ml. After multiple doses of 50 and 100 mg twice daily, the plasma half-life of topiramate averaged 21 hours.

In patients with moderate to severe renal impairment, the plasma and renal clearance of topiramate is reduced (creatinine clearance (CC) ≥ 70 ml/min), as a result, the equilibrium concentration of topiramate in the blood plasma may increase compared to patients with normal renal function. In addition, patients with impaired renal function require more time to achieve equilibrium concentrations of topiramate in the blood. In patients with moderate or severe renal impairment, half the recommended initial and maintenance dose is recommended.

Topiramate is effectively eliminated from plasma by hemodialysis. Long-term hemodialysis may result in a decrease in blood concentrations of topiramate below the amount required to maintain anticonvulsant activity. To avoid a rapid fall in plasma concentrations of topiramate during hemodialysis, an additional dose of Topamax may be required. When adjusting the dose, you should take into account:

duration of hemodialysis,
the clearance value of the hemodialysis system used,
effective renal clearance of topiramate in a patient on dialysis.

Plasma clearance of topiramate is reduced by an average of 26% in patients with moderate or severe hepatic impairment. 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 pharmacokinetic parameters of topiramate in children, as well as in adults receiving this drug as adjuvant therapy, are linear, while its clearance does not depend on the dose, and equilibrium plasma concentrations increase in proportion to the dose. However, it should be taken into account that in children the clearance of topiramate is increased and its half-life is shorter. Therefore, 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, antiepileptic drugs that induce liver microsomal enzymes cause a decrease in plasma concentrations of topiramate.

Indications for use

Epilepsy

As a monotherapy:
in adults and children over 2 years of age with epilepsy (including patients with newly diagnosed epilepsy).

As part of complex therapy:
in adults and children over 2 years of age with partial or generalized tonic-clonic seizures, as well as for the treatment of seizures associated with Lennox-Gastaut syndrome.

Migraine

Prevention of migraine attacks in adults. The use of Topamax ® for the treatment of acute migraine attacks has not been studied.

Contraindications

Hypersensitivity to any of the components of this drug, children under 2 years of age.

Use during pregnancy and lactation

Topiramate has shown teratogenic properties in mice, rats and rabbits. In rats, topiramate crossed the placental barrier.

There have been no special controlled studies in which Topamax ® was used to treat pregnant women. Topiramate may cause fetal harm when used in pregnant women. Pregnancy data indicate that infants exposed to topiramate in utero during the first trimester of pregnancy have an increased risk of developing congenital malformations (eg, craniofacial defects such as cleft lip or palate, hypospadias, and developmental anomalies of various body systems). These malformations were recorded both during monotherapy with topiramate and when it was used as part of polytherapy.

Data from one pregnancy registry showed that with topiramate monotherapy, the incidence of significant congenital malformations increased by approximately 3 times compared with a comparison group not taking antiepileptic drugs.

In addition, it has been shown that the risk of developing teratogenic effects associated with taking antiepileptic drugs is higher in the case of combination therapy than in the case of monotherapy.

Compared with the group of patients not taking antiepileptic drugs, data from pregnancies during monotherapy with Topamax ® indicate an increase in the likelihood of having children with low body weight (less than 2500 g). One pregnancy registry showed an increase in the relative number of infants small for gestational age (SGA; defined as birth weight below the 10th percentile, adjusted for gestational age and stratified by sex) among infants exposed to topiramate in utero. The long-term consequences of NGB have not been determined. The cause of decreased birth weight and NGV has not been established.

During topiramate therapy, women of childbearing potential should use reliable methods of contraception.

The use of Topamax ® during pregnancy in women with uncontrolled epilepsy is justified only if the potential benefit of the drug for the mother outweighs the possible risk to the fetus. The use of topiramate for the prevention of migraine attacks is contraindicated during pregnancy, as well as in women with preserved childbearing potential who do not use reliable methods of contraception. When treating and counseling women of childbearing potential, the treating physician must weigh the benefits and risks of treatment and consider alternative treatment options. If Topamax ® is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be warned of the potential risk to the fetus.

A limited number of patient observations suggests that topiramate is excreted into breast milk in women, so the physician should decide whether to breastfeed or discontinue the drug.

In animal studies, no effect of topiramate on fertility was found. The effect of topiramate on fertility in humans has not been established.

Carefully

With renal and liver failure, nephrourolithiasis (including in the past and in family history), hypercalciuria.

Directions for use and doses

Inside, regardless of food intake. To achieve optimal control of epileptic seizures in children and adult patients, it is recommended to begin treatment with low doses of the drug, followed by gradual titration to an effective dose.

Capsules are intended for patients who have difficulty swallowing tablets (for example, children and elderly patients).

Topamax ® capsules should be carefully opened and the contents of the capsules mixed with a small amount (about 1 teaspoon) of some soft food. This mixture should be swallowed immediately without chewing. The drug mixed with food should not be stored until the next dose.

Topamax ® capsules can be swallowed whole.

Partial or generalized tonic-clonic seizures, as well as seizures associated with Lennox-Gastaut syndrome

Use in combination with other anticonvulsants in adult patients

The minimum effective dose is 200 mg per day. Typically, the total daily dose is from 200 mg to 400 mg and is taken in two doses. Some patients may need to increase the daily dose to a maximum of 1600 mg. It is recommended to start treatment with a low dose, followed by gradual selection of an effective dose. Dose selection begins with 25–50 mg, taken at night for 1 week. Subsequently, at weekly or two-week intervals, the dose can be increased by 25–50 mg and taken in two doses. When selecting a dose, it is necessary to be guided by the clinical effect. In some patients, the effect can be achieved by taking the drug once a day. To achieve the optimal effect of treatment with Topamax ®, it is not necessary to control its plasma concentration.
These dosage recommendations apply to all adult patients, including the elderly, unless they have renal disease (see section “Special Instructions”).

Combined anticonvulsant therapy in children over 2 years of age

The recommended total daily dose of Topamax ® as an additional therapy is from 5 to 9 mg/kg and is taken in two doses. Dose titration should begin with 25 mg (or less, based on a starting dose of 1 to 3 mg/kg per day) taken at night for 1 week. Subsequently, at weekly or two-week intervals, the dose can be increased by 1–3 mg/kg and taken in two doses. When selecting a dose, it is necessary to be guided by the clinical effect. Daily doses of up to 30 mg/kg are usually well tolerated.

Epilepsy (including newly diagnosed)

Monotherapy: general provisions

When discontinuing concomitant anticonvulsants for the purpose of topiramate monotherapy, the possible impact of this step on seizure frequency must be considered. In cases where it is not necessary to abruptly discontinue concomitant anticonvulsants for safety reasons, it is recommended to reduce their dosage gradually, reducing the dose of concomitant antiepileptic drugs by one third every 2 weeks.
When drugs that are inducers of microsomal liver enzymes are discontinued, the concentrations of topiramate in the blood will increase. In such situations, if clinically indicated, the dose of Topamax ® can be reduced.

Monotherapy: adults

At the beginning of treatment, the patient should take 25 mg of Topamax ® at bedtime for 1 week. Then the dose is increased at intervals of 1 - 2 weeks by 25 or 50 mg (the daily dose is divided into two doses). If the patient does not tolerate this dose escalation regimen, then the intervals between dose increases can be increased or the dose can be increased more gradually. When selecting a dose, it is necessary to be guided by the clinical effect. The starting dose for topiramate monotherapy in adults is 100 mg per day, and the maximum daily dose should not exceed 500 mg. Some patients with refractory forms of epilepsy tolerate monotherapy with topiramate in doses of up to 1000 mg per day. These dosing recommendations apply to all adults, including elderly patients without renal disease.

Monotherapy: children

Children over 2 years of age should be given topiramate at a dose of 0.5–1 mg/kg body weight at bedtime during the first week of treatment. 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). If the child does not tolerate this dose escalation regimen, the dose can be increased more gradually or the intervals between dose increases can be increased. The dose and rate of increase should be determined by the clinical outcome.
The recommended dose range for topiramate monotherapy in children over 2 years of age is 100–400 mg/day. Children with newly diagnosed partial seizures may be given up to 500 mg per day.

Migraine

The recommended total daily dose of topiramate for the prevention of migraine attacks is 100 mg, taken in 2 divided doses. At the beginning of treatment, the patient should take 25 mg of Topamax ® at bedtime for 1 week. Then the dose is increased at intervals of 1 week by 25 mg per day. If the patient does not tolerate this dose escalation regimen, then the intervals between dose increases can be increased, or the dose can be increased more gradually. When selecting a dose, it is necessary to be guided by the clinical effect.

In some patients, a positive result is achieved with a daily dose of topiramate of 50 mg. In clinical studies, patients received varying daily doses of topiramate, but not more than 200 mg per day.

Special patient groups

Kidney failure
Patients with moderate or severe renal impairment may require a dose reduction. It is recommended to use half the recommended initial and maintenance dose.
Hemodialysis
Since topiramate is removed from plasma during hemodialysis, an additional dose of Topamax ® equal to approximately half the daily dose should be administered on hemodialysis days. The additional dose should be divided into two doses taken at the beginning and after completion of the hemodialysis procedure. The additional dose may vary depending on the characteristics of the equipment used during hemodialysis.
Liver failure
Topiramate should be used with caution in patients with hepatic impairment.

Side effect

Adverse reactions are given with a distribution by frequency and organ system. The frequency of adverse reactions was classified as follows: very often (?1/10), often (?1/100,<1/10), нечасто (?1/1000 и <1/100), редко (?1/10000 и <1/1000) и частота неизвестна (частоту невозможно оценить по имеющимся данным).

The most common adverse reactions (the frequency of which was more than 5% and higher than that in the placebo group for at least one of the indications during controlled clinical trials of topiramate) are: anorexia, decreased appetite, slow thinking, depression, impaired speech fluency, insomnia, disturbances coordination of movements, impaired concentration, dizziness, dysarthria, dysgeusia, hypoesthesia, retardation, memory impairment, nystagmus, paresthesia, drowsiness, tremor, diplopia, blurred vision, diarrhea, nausea, fatigue, irritability and weight loss.

Infections and infestations: very common: nasopharyngitis*.

Blood and lymphatic system disorders: often: anemia; uncommon: leukopenia, lymphadenopathy, thrombocytopenia, eosinophilia; rarely: neutropenia*.

Immune system disorders: often: hypersensitivity; frequency unknown: allergic edema*, conjunctival edema*.

Metabolic and nutritional disorders: often: anorexia, decreased appetite; uncommon: metabolic acidosis, hypokalemia, increased appetite, polydipsia; rarely: hyperchloremic acidosis.

Mental disorders: very often: depression; often: slow thinking, insomnia, impaired speech, anxiety, confusion, disorientation, aggressive reactions, mood disorders, agitation, emotional lability, depressed mood, anger, behavioral disturbances; uncommon: suicidal thoughts, suicide attempts, hallucinations, psychotic disorders, auditory hallucinations, visual hallucinations, apathy, difficulty speaking, sleep disturbances, affective lability, decreased libido, restlessness, crying, dysphemia, euphoric mood, paranoia, perseveration of thinking, panic attacks , tearfulness, impaired reading skills, difficulty falling asleep, flattening of emotions, pathological thinking, loss of libido, lethargy, intrasomnic disorder, absent-mindedness, early awakenings in the morning, panic reactions, high spirits; rarely: mania, panic disorder, feelings of hopelessness*, hypomania.

Central nervous system disorders: very often: paresthesia, drowsiness, dizziness; often: impaired concentration, impaired memory, amnesia, cognitive disorders, impaired thinking, psychomotor impairment, convulsions, impaired coordination of movements, tremor, lethargy, hypoesthesia, nystagmus, dysgeusia, impaired sense of balance, dysarthria, intention tremor, sedation; Uncommon: depressed consciousness, tonic-clonic grand mal seizures, visual field impairment, complex partial seizures, speech impairment, psychomotor hyperactivity, syncope, sensory disturbances, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural vertigo , low quality of sleep, burning sensation, loss of sensitivity, parosmia, cerebral syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, sensation of “pins and needles”; rarely: apraxia, circadian sleep rhythm disorder, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli.

Visual disorders: often: blurred vision, diplopia, visual impairment; uncommon: decreased visual acuity, scotoma, myopia*, strange sensations in the eyes*, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia; rarely: one-sided blindness, transient blindness, glaucoma, impaired accommodation, impaired visual spatial perception, atrial scotoma, eyelid edema*, night blindness, amblyopia; frequency unknown: angle-closure glaucoma*, maculopathy*, ocular motility disorders*.

Hearing and balance disorders: often: vertigo, ringing in the ears, ear pain; uncommon: deafness, one-sided deafness, sensorineural deafness, ear discomfort, hearing impairment.

Cardiovascular system disorders: uncommon: bradycardia, sinus bradycardia, palpitations.

Vascular system disorders: uncommon: hypotension, orthostatic hypotension, hot flashes, hot flashes; rare: Raynaud's phenomenon.

Disorders of the respiratory system, chest and mediastinal organs: often: shortness of breath, nosebleeds, nasal congestion, rhinorrhea, cough*; uncommon: shortness of breath on exertion, hypersecretion in the paranasal sinuses, dysphonia.

Gastrointestinal disorders: very often: nausea, diarrhea; often: vomiting, constipation, pain in the epigastric region, dyspepsia, abdominal pain, dry mouth, stomach discomfort, impaired sensitivity in the oral cavity, gastritis, abdominal discomfort; uncommon: pancreatitis, flatulence, gastroesophageal reflux, pain in the lower abdomen, decreased sensitivity in the oral cavity, bleeding gums, bloating, epigastric discomfort, tenderness in the abdominal area, hypersalivation, oral pain, bad breath, glossodynia .

Disorders of the hepatobiliary system: rarely: hepatitis, liver failure.

Disorders of the skin and subcutaneous tissues: often: alopecia, rash, itching; uncommon: anhidrosis, impaired sensitivity in the facial area, urticaria, erythema, generalized itching, macular rash, skin pigmentation disorder, allergic dermatitis, facial swelling; uncommon: Stevens-Johnson syndrome*, erythema multiforme*, change in skin odor, periorbital edema*, localized urticaria; frequency unknown: toxic epidermal necrolysis*.

Musculoskeletal and connective tissue disorders: often: arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, musculoskeletal chest pain; uncommon: joint swelling*, muscle stiffness, side pain, muscle fatigue; rarely: discomfort in the limbs*.

Renal and urinary tract disorders: often: nephrolithiasis, pollakiuria, dysuria; uncommon: exacerbation of urolithiasis (kidney stones), stress incontinence, hematuria, urinary incontinence, frequent urge to urinate, renal colic, pain in the kidney area; rarely: exacerbation of urolithiasis (stones in the urethra), renal tubular acidosis*.

Disorders of the genital organs and breast: uncommon: erectile dysfunction, sexual dysfunction.

General disorders and disorders caused by the method of application: very often: fatigue; often: increased body temperature, asthenia, irritability, gait disturbances, poor health, anxiety; uncommon: hyperthermia, thirst, flu-like syndrome*, sluggishness, cold extremities, feeling of intoxication, feeling of restlessness; rarely: facial edema, calcification. Changes in laboratory parameters: very often: loss of body weight; often: weight gain*; uncommon: crystalluria, abnormal tandem gait test result, leukopenia, increased activity of liver enzymes in the blood serum, rare: decreased content of bicarbonates in the blood.

Impaired social functioning: uncommon: learning disability.

* – adverse reaction was registered in the post-registration period from spontaneous reports. Frequency calculated based on data from clinical studies.

Special groups:
Children:

Below is a list of adverse reactions that, during controlled clinical trials, were recorded in children 2 or more times more often than in adults: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disturbances, aggressive reactions, apathy, difficulty falling asleep, suicidal thoughts , impaired concentration, lethargy, disruption of the circadian rhythm of sleep, poor quality of sleep, increased lacrimation, sinus bradycardia, poor health, gait disturbances.

The following is a list of adverse reactions that were recorded only in children during controlled clinical trials: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, learning disability.

Overdose

Signs and symptoms of an overdose of Topamax ®: convulsions, drowsiness, speech and vision disturbances, diplopia, impaired thinking, impaired coordination, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression. In most cases, the clinical consequences were not severe, but deaths have been reported following overdose using a mixture of several drugs, including topiramate. An overdose of topiramate can cause severe metabolic acidosis (see section "Special Instructions").

There is a known case of overdose when a patient took a dose of topiramate from 96 to 110 g, which resulted in a coma that lasted 20–24 hours. After 3-4 days, the overdose symptoms resolved.

Treatment

In case of an acute overdose of Topamax ® , if the patient has eaten shortly before, it is necessary to immediately rinse the stomach or induce vomiting. Activated carbon has been shown to adsorb topiramate in in vitro studies. If necessary, symptomatic therapy should be carried out. An effective way to remove topiramate from the body is hemodialysis. Patients are advised to adequately increase their fluid intake.

Interaction with other drugs

The effect of Topamax ® on the concentrations of other antiepileptic drugs (AEDs)

Concomitant use of the drug Topamax ® with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect the values of their equilibrium concentrations in plasma, with the exception of certain patients in whom the addition of the drug Topamax ® to phenytoin may cause an increase in the concentration of phenytoin in the plasma. plasma. This may be due to the inhibition of a specific polymorphic isoform of the cytochrome P450 enzyme (CYP2Cmeph). Therefore, phenytoin plasma concentrations should be monitored in any patient taking phenytoin who develops clinical signs or symptoms of toxicity. In a pharmacokinetic study in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the steady-state concentration of the latter at doses of topiramate 100–400 mg per day. During and after discontinuation of lamotrigine (average dose 327 mg per day), the equilibrium concentration of topiramate did not change.

The effect of other antiepileptic drugs on the concentration of the drug Topamax ®

Phenytoin and carbamazepine reduce plasma concentrations of Topamax®. The addition or removal of phenytoin or carbamazepine during treatment with Topamax ® may require a change in the dose of the latter. The dose should be selected based on achieving the desired clinical effect. The addition or removal of valproic acid does not cause clinically significant changes in the plasma concentration of Topamax ® and, therefore, does not require a change in the dose of Topamax ® .

- = No effect
** = Increased concentration in isolated patients
v = Decrease in plasma concentration
NI = Not studied
AED = antiepileptic drug

Other drug interactions

Digoxin: in a single-dose study, the area under the plasma concentration-time curve of digoxin decreased by 12% when coadministered with Topamax®. The clinical significance of this observation is unclear. When prescribing or discontinuing Topamax ® in patients taking digoxin, special attention should be paid to monitoring the concentration of digoxin in the serum.

CNS depressants: In clinical studies, the effects of co-administration of Topamax ® with alcohol or other substances that depress the functions of the central nervous system have not been studied. It is recommended not to take Topamax ® together with alcohol or other drugs that cause depression of central nervous system function.

St. John's wort
When taking Topamax together with drugs based on St. John's wort (Hypericum perforatum), the plasma concentration of topiramate may decrease and, as a result, the effectiveness of the drug may also decrease. Clinical studies of the interaction of Topamax ® and drugs based on St. John's wort have not been conducted.

Oral contraceptives: In a drug interaction study with oral contraceptives using a combination drug containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), Topamax ® at doses of 50–800 mg per day did not have a significant effect on the effectiveness of norethisterone and at doses of 50–200 mg per day - on the effectiveness of ethinyl estradiol. A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of Topamax ® 200–800 mg per day. The clinical significance of the described changes is unclear. The risk of decreased contraceptive effectiveness and increased breakthrough bleeding should be taken into account in patients taking oral contraceptives in combination with Topamax ® . Patients taking estrogen-containing contraceptives should be informed of any changes in the timing and nature of menstruation. The effectiveness of contraceptives may 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 in 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%. When using topiramate and lithium simultaneously, the concentration of the latter in the blood plasma should be monitored.

Risperidone: Drug interaction studies conducted with single and multiple doses of topiramate in healthy volunteers and patients with bipolar disorder yielded similar results. With simultaneous use of topiramate in doses of 250 or 400 mg per day, the AUC of risperidone taken in doses of 1-6 mg per day is reduced by 16% and 33%, respectively. At the same time, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed slightly. The change in systemic exposure of risperidone/9-hydroxyrisperidone and topiramate was not clinically significant and this interaction is unlikely to be of clinical significance.

Hydrochlorothiazide: drug interactions were assessed in healthy volunteers with separate and combined administration of hydrochlorothiazide (25 mg) and topiramate (96 mg). The results of the study showed that when topiramate and hydrochlorothiazide were taken simultaneously, the maximum concentration of topiramate increased by 27% and the area under the concentration-time curve of topiramate increased by 29%. The clinical significance of these studies has not been established. Prescribing hydrochlorothiazide to patients taking topiramate may require adjustment of the topiramate dose. The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant therapy with topiramate.

Metformin: drug interactions were assessed in healthy volunteers receiving metformin or a combination of metformin and topiramate. The results of the study showed that when topiramate and metformin were taken simultaneously, the maximum concentration and area under the concentration-time curve of metformin increased by 18% and 25%, respectively, while the clearance of metformin when administered simultaneously with topiramate decreased by 20%. Topiramate had no effect on the time to reach maximum metformin plasma concentrations. The clearance of topiramate is reduced when used concomitantly with metformin. The extent of the observed changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unclear. If Topamax ® is added or discontinued in patients receiving metformin, the conditions of patients with diabetes mellitus should be investigated.

Pioglitazone: drug interactions were assessed in healthy volunteers with the separate and simultaneous use of pioglitazone and topiramate. A decrease in the area under the concentration-time curve of pioglitazone by 15% was detected, without changing the maximum concentration of the drug. These changes were not statistically significant. For the active hydroxymetabolite pioglitazone, a decrease in the maximum concentration and the area under the concentration-time curve was also detected by 13% and 16%, respectively, and for the active ketometabolite, a decrease in both the maximum concentration and the area under the concentration-time curve was detected by 60 %. The clinical significance of these data is unclear. When patients use Topamax ® and pioglitazone simultaneously, the conditions of patients with diabetes mellitus should be examined.

Glibenclamide: A drug interaction study was conducted to examine the pharmacokinetics of glibenclamide (5 mg per day) at steady state, administered alone or concomitantly with topiramate (150 mg per day) in patients with type 2 diabetes mellitus.
When topiramate was used, the AUC of glibenclamide decreased by 25%. Systemic exposure to 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. A statistically insignificant decrease in the AUC of pioglitazone by 15% was found with no change in Cmax. When prescribing topiramate to patients receiving glibenclamide (or prescribing glibenclamide to patients receiving topiramate), the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

Other drugs: simultaneous use of Topamax ® with drugs that predispose to nephrolithiasis may increase the risk of kidney stones. During treatment with Topamax ®, the use of drugs that predispose to nephrolithiasis should be avoided, as they may cause physiological changes that contribute to nephrolithiasis.

Valproic acid: The combined use of topiramate and valproic acid in patients who tolerate each drug separately is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after stopping one of the medications. This adverse event is not due to a pharmacokinetic interaction. 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 co-administration of valproic acid and topiramate, and with an increase in the daily dose of topiramate.

Additional drug interaction studies: A number of clinical studies have been conducted to evaluate potential drug interactions between topiramate and other drugs.

The results of these interactions are summarized in the following table:

Added drug	Concentration of added druga	Topiramate concentration a
Amitriptyline	increase in maximum concentration and AUC of nortriptyline metabolite by 20%	not studied
Dihydroergotamine (oral and subcutaneous)	-	-
Haloperidol	increase in metabolite AUC by 31%	not studied
Propranolol	increase in maximum concentration for 4-OH propranolol by 17% (topiramate 50 mg)	increase in maximum concentration by 9% and 16%, increase in AUC by 9 and 17%, (for propranolol 40 mg and 80 mg every 12 hours) respectively
Sumatriptan (oral and subcutaneous)	-	not studied
Pizotifen	-	-
Diltiazem	decrease in AUC of diltiazem by 25% and decrease in desacetyldiltiazem by 18%, and - for N-demethyldiltiazem	AUC increase by 20%
Venlafaxine	-	-
Flunarizine	increase in AUC by 16% (50 mg every 12 hours) b	-

a is expressed as a percentage of the values of maximum plasma concentration and AUC during monotherapy
- = No change in maximum plasma concentration and AUC (? 15% of baseline data)
b A 14% increase in AUC was observed with multiple doses of flunarizine alone, which may be due to drug accumulation during steady state.

special instructions

Antiepileptic drugs, including Topamax ® , should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures. In clinical studies, doses were reduced by 50–100 mg at weekly intervals for adults treated for epilepsy and by 25–50 mg in adults receiving 100 mg of Topamax ® per day for migraine prophylaxis. In children in clinical studies, Topamax ® was tapered gradually over 2–8 weeks. If, for medical reasons, rapid discontinuation of the drug Topamax ® is necessary, then it is recommended to carry out appropriate monitoring of the patient’s condition.

As with other antiepileptic drugs, some patients taking topiramate experience an increase in the frequency of seizures or new types of seizures. This phenomenon may be a consequence of an overdose, a decrease in the concentration of concomitantly used antiepileptic drugs, disease progression, or a paradoxical effect.

As with any disease, dose selection should be based on clinical benefit (i.e., degree of seizure control, absence of side effects) and take into account that in patients with renal impairment, it may be necessary to achieve stable plasma concentrations for each dose. longer time.

During therapy with topiramate, oligohidrosis (decreased sweating) and anhidrosis may occur. Decreased sweating and hyperthermia (increased body temperature) may occur in children exposed to high ambient temperatures. In this regard, when treating with topiramate, it is very important to adequately increase the volume of fluid intake, which can reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical activity or elevated temperatures.

Mood disorders/depression

An increased incidence of mood disorders and depression has been observed during treatment with topiramate.

Suicide attempts

When using antiepileptic drugs, including Topamax®, the risk of suicidal thoughts and behavior increases in patients taking these drugs for any indication.

In double-blind clinical studies, the incidence of suicide-related events (suicidal ideation, suicide attempts, suicide) was 0.5% in patients receiving topiramate (46 of 8652 people), which is approximately 3 times higher than in patients receiving topiramate. those receiving placebo (0.2%; 8 out of 4045 people). One case of suicide was reported in a double-blind study of bipolar disorder in a patient receiving topiramate.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and associated symptoms such as renal colic, kidney pain, or flank pain. To reduce this risk, an adequate increase in fluid intake is necessary. Risk factors for the development of nephrolithiasis are a history of nephrolithiasis (including family history), hypercalciuria, and concomitant therapy with drugs that contribute to the development of nephrolithiasis.

Renal dysfunction

Caution should be exercised when prescribing Topamax ® to patients with renal failure (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 used with caution due to the possible decrease in clearance of this drug.

Myopia and secondary angle-closure glaucoma

Increased intraocular pressure of any etiology in the absence of adequate treatment can lead to serious complications, including loss of vision.

When prescribing topiramate to patients with a history of eye diseases, it is necessary to assess the ratio of the expected benefit to the possible risk of use.

Visual field defects

Visual field defects have been observed in patients taking topiramate, regardless of whether they had elevated intraocular pressure. In clinical studies, most of these cases were reversible, and visual field defects disappeared after discontinuation of topiramate therapy. If vision problems occur while taking topiramate, discontinuation of therapy should be considered.

Metabolic acidosis

When using topiramate, hyperchloremic, not associated with anion deficiency, metabolic acidosis (for example, a decrease in plasma bicarbonate concentrations below normal levels in the absence of respiratory alkalosis) may occur. This decrease in serum bicarbonate concentrations is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, a decrease in the concentration of bicarbonates occurs at the beginning of taking the drug, although this effect can occur at any time during treatment with topiramate. The degree of reduction in concentration is usually weak or moderate (average value is 4 mmol/L when used in adult patients at a dose above 100 mg per day and about 6 mg per day per kg of body weight when used in pediatric practice). In rare cases, patients experienced a decrease in bicarbonate concentrations below 10 mmol/l. Certain diseases or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory disease, status epilepticus, diarrhea, surgery, ketogenic diet, certain medications) may be additional factors that enhance the bicarbonate-lowering effect of topiramate.

In connection with the above, when treating with topiramate, it is recommended to carry out the necessary studies, including determination of the concentration of bicarbonates in the serum. If symptoms of metabolic acidosis occur (eg, deep Kussmaul breathing, dyspnea, anorexia, nausea, vomiting, fatigue, tachycardia or arrhythmia), determination of serum bicarbonate concentrations is recommended. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or discontinue topiramate.

Cognitive impairment

Impairment of cognitive functions in epilepsy is multifactorial in nature and can be caused by the underlying cause of the disease, epilepsy itself or antiepileptic therapy. In adult patients taking topiramate, cases of cognitive impairment requiring dose reduction or discontinuation of therapy have been reported. Data on the effects of topiramate on cognitive function in children are insufficient, and its effects require further study.

Enhanced nutrition

If a patient loses weight during treatment with Topamax ® , then it is necessary to consider the advisability of enhanced nutrition.

Impact on the ability to drive vehicles and machinery

Topamax ® acts on the central nervous system and may cause drowsiness, dizziness, and other symptoms. It can also cause vision problems. These adverse events may pose a danger to patients driving cars and moving machinery, especially during the period until the patient’s response to the drug is established.

Storage conditions

Store in a dry place at a temperature not exceeding 25°C.
Keep out of the reach of children.

Best before date

2 years.
Do not use after the expiration date indicated on the package.

Release form

Capsules 15 mg and 25 mg.
28 or 60 capsules in a bottle made of high-density polyethylene. The bottle, along with instructions for medical use, is placed in a cardboard box.

Conditions for dispensing from pharmacies

On prescription.

Manufacturer:

Production:
Janssen-Ortho LLC, Puerto Rico,
State Road, 933 km 0.1 Mamie Ward, Gurabo.

Primary packaging:
Silag AG, Switzerland,
or
Janssen-Cilag S.p.A., Italy
Cologno Monzese, Milan,
st. M. Buonarotti, 23.

Secondary packaging and release quality control:
Silag AG, Switzerland,
Hochstrasse 201, CH-8205, Schaffhausen
or
Janssen-Cilag S.p.A., Italy
Cologno Monzese, Milan,
st. M. Buonarotti, 23
or
JSC "Biocom", Russia,
355016, Stavropol,
Chapaevsky proezd, 54

Marketing authorization holder and organization receiving claims:
Johnson & Johnson LLC, Russia,
121614, Moscow, st. Krylatskaya, 17/2.

Compound

Active substance: topiramate 15 mg, 25 mg or 50 mg.

Excipients: granulated sugar (sucrose, starch syrup), povidone, cellulose acetate.

One 15 mg capsule contains from 28.1 mg to 41.2 mg of sucrose.

One 25 mg capsule contains from 46.8 mg to 68.6 mg of sucrose. One 50 mg capsule contains from 93.7 mg to 137.2 mg of sucrose.

Capsule composition: gelatin, purified water, sorbitan monolaureate, sodium lauryl sulfate, titanium dioxide (E171), Opacode Black ink S-1-17822/23 (contains: shellac glaze solution in ethanol, black iron oxide (E172), n-butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide).

Description

Hard gelatin capsules with a white body and a transparent, colorless cap. The cap of the capsule bears the inscription "TOP". Capsule contents: white or almost white granules.

15 mg capsules: hard gelatin capsules No. 2, the capsule body is marked “15 mg”.

25 mg capsules: hard gelatin capsules No. 1, the capsule body is marked “25 mg”.

50 mg capsules: hard gelatin capsules No. 0, the capsule body is marked “50 mg”.

Pharmacotherapeutic group

P Other antiepileptic drugs.

ATX code: N03AX11.

Pharmacological properties

Pharmacodynamics

Topiramate is an antiepileptic drug belonging to the class of sulfamate-substituted monosaccharides.

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of γ-aminobutyric acid (GABA) in relation to certain subtypes of GABA receptors (including GABAA receptors), and also modulates the activity of GABAA receptors themselves, and prevents the activation by kainate of the sensitivity of the kainate/AMPK subtype (α-amino-3- hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptors does not affect the activity of N-methyl-D-aspartate (NMDA) towards the NMDA receptor subtype. These effects of topiramate are dose-dependent with drug plasma concentrations ranging from 1 µM to 200 µM, with trough activity ranging from 1 µM to 10 µM.

In addition, topiramate inhibits the activity of some carbonic anhydrase isoenzymes. In terms of the severity of this pharmacological effect, topiramate is significantly inferior to acetazolamide, a known inhibitor of carbonic anhydrase, therefore this activity of topiramate is not considered the main component of its antiepileptic activity.

Pharmacokinetics

Suction

Topiramate is rapidly and completely absorbed. Following oral administration of a 100 mg dose of topiramate to healthy volunteers, the mean peak plasma concentration (Cmax) is 1.5 mcg/mL and is reached within 2–3 hours (Tmax). The degree of absorption of an oral dose of 100 mg of topiramate is at least 81%. Food intake does not have a significant effect on the bioavailability of topiramate.

Distribution

13–17% of topiramate is bound to plasma proteins. The volume of distribution varies inversely with the dose. The mean apparent volume of distribution is 0.80 to 0.55 L/kg for a single dose of 100 to 1200 mg. The sex of the patient influences the volume of distribution: rates in women are 50% lower than rates in men. This effect is explained by a higher percentage of adipose tissue in the female body without clinical consequences.

Metabolism

The drug is metabolized up to 50% in patients receiving concomitant antiepileptic therapy with known inducers of drug-metabolizing enzymes. 6 metabolites are formed by hydroxylation, hydrolysis and glucuronidation. Each metabolite is less than 3% from the total radioactivity excreted after taking 14C-topiramate. Two metabolites structurally similar to topiramate exhibit little anticonvulsant activity.

Removal

In humans, unchanged topiramate and its metabolites are excreted by the kidneys (at least 81% of the dose taken). Approximately 66% of 14C-topiramate is excreted unchanged in urine within 4 days. When administered twice as a 50 mg or 100 mg dose of topiramate, the average renal clearance is 18 ml/minute and 17 ml/minute, respectively. Renal tubular reabsorption of topiramate was established. In studies in rats, it was found that when topiramate was combined with probenecid, there was a significant increase in the renal clearance of topiramate. After oral administration, plasma clearance of topiramate is 20–30 ml/minute.

The pharmacokinetics of topiramate is linear: plasma clearance is constant, the area under the concentration-time curve increases proportionally after single doses of 100-400 mg are administered to healthy volunteers.

In patients with normal renal function, steady-state plasma concentrations are achieved within 4–8 days. The average Cmax value after oral administration to healthy volunteers of repeated doses of 100 mg 2 times a day is 6.76 μg/ml. Following multiple doses of 50 mg and 100 mg of topiramate twice daily, the mean plasma half-life is approximately 21 hours.

When topiramate is coadministered in doses of 100 mg to 400 mg twice daily with phenytoin or carbamazepine, a proportional increase in plasma concentrations of topiramate is observed.

PatientsWithrenal failure

Plasma and renal clearance of topiramate is reduced in patients with impaired renal function (CLCR

Patients with liver failure

Plasma clearance of topiramate is reduced by an average of 26% in patients with moderate or severe hepatic impairment.

Elderly patients

Plasma clearance of topiramate remains unchanged in elderly patients in the absence of underlying renal disease.

Children under 12 years old

The pharmacokinetics of topiramate in children, as in adults receiving adjunctive therapy, is linear, with dose-independent clearance and steady-state plasma concentrations increasing proportionally to the dose. Children have a higher clearance and shorter half-life, so plasma concentrations of topiramate at the same mg/kg doses may be lower in children compared to adults. As in adults, induction of liver enzymes by antiepileptic drugs reduces steady-state plasma concentrations.

Indications for use

Epilepsy

As a monotherapy:

initial therapy in patients over 2 years of age with partial or primary generalized tonic-clonic seizures.

As part of complex therapy:

in adults and children aged 2 to 16 years with partial or generalized tonic-clonic seizures, as well as in patients 2 or more years old with seizures associated with Lennox-Gastaut syndrome.

Migraine

For patients 12 years of age and older for the prevention of migraine headaches.

Contraindications

Hypersensitivity to any of the components of this drug.

Prevention of migraine in women of childbearing age who do not use effective methods of contraception.

Use during pregnancy and lactation

There have been no specific controlled studies in which Topamax® was used to treat pregnant women.

Using Topamax® during pregnancy may cause harm to the fetus. Pregnancy registry data indicate that fetal exposure to topiramate in utero increases the risk of congenital malformations (e.g., craniofacial defects such as cleft lip/cleft palate, hypospadias, and developmental anomalies of various body systems). These malformations were recorded both during topiramate monotherapy and when it was used as part of combination therapy.

In addition, the pregnancy registry and the results of other studies indicate that the risk of teratogenic effects with combination treatment with antiepileptic drugs may be higher than with monotherapy.

Compared with the group of patients not taking antiepileptic drugs, data from the registry of pregnant women with monotherapy with Topamax® indicate an increase in the frequency of births of children with low body weight (less than 2500 g). One pregnancy registry showed an increase in the relative number of small-for-gestational age (SGA; defined as birth weight below the 10th percentile adjusted for gestational age and stratified by sex) among infants exposed to topiramate in utero. The long-term consequences of NGB have not been determined. A cause-and-effect relationship for low birth weight and NGB has not been established.

Topamax® should be used during pregnancy only if the potential benefit outweighs the possible risk to the fetus. When treating and counseling women of childbearing potential, the treating physician must weigh the benefits versus risks of treatment and consider alternative treatment options. If Topamax® is used during pregnancy or if the patient becomes pregnant while taking Topamax®, she should be warned of the potential risk to the fetus.

A limited number of patient observations suggest that topiramate is excreted in breast milk in women, so the physician should decide whether to breastfeed or discontinue the drug, taking into account the significance of the drug to the mother.

Prescription for migraine prevention

Topiramate is contraindicated for the prevention of migraine in women during pregnancy and in women of reproductive age if they are not using effective methods of contraception (see sections “Interaction with other drugs”, “Other drug interactions”, “Contraindications”).

Carefully

With renal and liver failure, nephrourolithiasis (including in the past and in family history), hypercalciuria.

Directions for use and dosage

Monotherapy for epilepsy

Adults and children 10 years and older:

Table 1

Children aged 2 to 9 years:

The dose depends on the child's weight. Initial dosage is 25 mg/day taken at night for the first week. Based on tolerability, the daily dose can be increased to 50 mg/day (25 mg twice daily) during the second week. In the future, taking into account tolerability, it is possible to increase the dose by 25–50 mg/day every week. It is advisable to achieve the minimum maintenance dose within 5–7 weeks. Further increases in the maintenance dose (based on tolerability and clinical response) can be made by 25–50 mg/day weekly. The total daily dose should not exceed the maximum maintenance dose for each weight range (Table 2).

table 2

* Divided into 2 doses.

Complementary therapy for epilepsy

Adults (17 years and older)

The recommended dosage for adults with partial seizures or Lennox-Gastaut syndrome is 200 to 400 mg/day (in two divided doses) and 400 mg/day (in two divided doses) for primary generalized tonic-clonic seizures. The initial dose is from 25 to 50 mg/day, followed by achieving an effective dose by adding 25–50 mg/day weekly. Titration with 25 mg/day increments every week may delay the time to reach an effective dose. Doses greater than 400 mg/day have not been shown to improve clinical response in adults with partial-onset seizures.

Children aged 2 to 16 years:

The recommended dosage in patients with partial seizures, primary generalized tonic-clonic seizures or seizures associated with Lennox-Gastaut syndrome is about 5-9 mg/kg/day, divided into 2 doses. Initial dose is 25 mg/day (or less in the range of 1–3 mg/kg/day) taken at night for the first week. It is recommended to increase the dose by 1-3 mg/kg/day (in two divided doses) at intervals of 1 or 2 weeks until an optimal clinical response is achieved. Dose titration is based on clinical outcome. The total daily dose should not exceed 400 mg/day.

Special patient groups

Renal dysfunction

Considering that plasma and renal clearance of topiramate are reduced in patients with impaired renal function (C.L.CR≤ 70 ml/min), topiramate should be administered to such patients with caution. Patients with known renal impairment may take longer to reach steady state after each dose. Half the initial and maintenance dose is recommended (see section "Pharmacological properties").

Liver dysfunction

In patients with moderate to severe hepatic impairment, Topamax should be administered with caution, given the reduced clearance of topiramate.

Elderly patients

For the treatment of elderly patients, no dose adjustment is required if they do not have impaired renal function.

Method of administration

Topamax® can be taken with or without food.

Topamax® is available in capsule form for oral administration.

Topamax® capsules can be swallowed whole or opened carefully and mixed with a small amount (about 1 teaspoon) of a soft food. This food/drug mixture should be taken orally immediately without chewing. Do not store medicine mixed with food until your next dose.

Special patient groups

Kidney failure

In patients with moderate or severe renal impairment (creatinine clearance

Since topiramate is removed from plasma during hemodialysis, an additional dose of Topamax equal to approximately half the daily dose should be administered on hemodialysis days. The additional dose should be divided into two doses taken at the beginning and after completion of the hemodialysis procedure. The additional dose may vary depending on the characteristics of the equipment used during hemodialysis.

Liver failure

Topiramate should be used with caution in patients with hepatic impairment.

Side effect

The section lists adverse reactions recorded during clinical trials and during post-marketing use of the drug Topamax®. Adverse reactions are given with a distribution by frequency and organ system. The frequency of side effects was classified as follows: very common (≥1/10 prescriptions), frequent (≥1/100 and

Often:nasopharyngitis*.

Blood and lymphatic system disorders:

often:anemia;

uncommon: leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia;

rarely: neutropenia*.

Immune system disorders:

often:hypersensitivity;

very rarely:allergic edema*.

Metabolic and nutritional disorders:

often:anorexia, loss of appetite;

uncommon: metabolic acidosis, hypokalemia, increased appetite, polydipsia;

rarely: hyperchloremic acidosis, hyperammonemia, hyperammonemic encephalopathy.

Mental disorders:

Often:depression;

often: slow thinking, insomnia, severe speech impairment, anxiety, confusion, disorientation, aggression, mood lability, anxious arousal, emotional lability, depressed mood, anger, inappropriate behavior;

uncommon: suicidal ideation or attempts, auditory and visual hallucinations, psychotic disorder, anorgasmia, apathy, lack of spontaneous speech, sleep disturbances, affective lability, anxiety, tearfulness, sexual arousal disorder, dysphemia, euphoric mood, paranoid states, perseveration of thinking, panic attack , tearfulness, impaired reading skills, initial insomnia, flattening of emotions, pathological thinking, loss of libido, lethargy, intrasomnic disorder, pathologically increased distractibility, early awakenings in the morning, decreased orgasmic sensations, panic reaction, high spirits;

rarely: mania, panic disorder, feelings of despair*, hypomanic state.

Nervous system disorders:

very often: paresthesia, drowsiness, dizziness;

often: impaired attention, memory impairment, amnesia, cognitive disorders, decreased mental activity, psychomotor impairment, convulsions, poor coordination, tremor, lethargy, hypoesthesia, nystagmus, dysgeusia, imbalance, articulation disorder, intentional tremor (dynamic), sedation;

Uncommon: depressed level of consciousness, grand mal seizures, visual field defect (loss), complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbances, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness, poor quality of sleep, burning sensation, loss of sensitivity, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, crawling sensation;

rarely: apraxia, circadian sleep rhythm disorder, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli.

Violations by op ghana view:

often: blurred vision, diplopia, visual impairment;

uncommon: decreased visual acuity, scotoma, myopia*, pathological sensations in the eyes, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia;

rarely: one-sided blindness, transient blindness, glaucoma, impaired accommodation, impaired visual depth perception, atrial scotoma, eyelid edema*, night blindness, amblyopia;

very rare: angle-closure glaucoma*, maculopathy*, impaired eye movements*, conjunctival edema*.

Hearing and labyrinth disorders:

often:vertigo, ringing in the ears, ear pain;

uncommon: deafness, one-sided deafness, sensorineural deafness, ear discomfort, hearing impairment.

Cardiac disorders:

uncommon: bradycardia, sinus bradycardia, palpitations.

Vascular disorders:

uncommon: orthostatic hypotension, flushing, hyperemia;

rare: Raynaud's phenomenon.

Disorders of the respiratory system, chest organs and mediastinum:

often: dyspnea, nosebleeds, nasal congestion, rhinorrhea, cough;

uncommon: dyspnea on exertion, hypersecretion in the paranasal sinuses, dysphonia.

Gastrointestinal disorders:

Often:nausea, diarrhea;

often: vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, stomach discomfort, oral paresthesia, gastritis, abdominal discomfort;

Uncommon: pancreatitis, flatulence, gastroesophageal reflux disease, lower abdominal pain, oral hypoesthesia, bleeding gums, bloating, epigastric discomfort, tenderness throughout the abdomen, salivary gland hypersecretion, oral pain, halitosis, glossodynia .

Disorders of the liver and biliary tract th :

rarely: hepatitis, liver failure.

Disorders of the skin and subcutaneous tissues:

often:alopecia, itching, rash;

uncommon: anhidrosis, facial hypoesthesia, urticaria, erythema, generalized itching, macular rash, skin discoloration, allergic dermatitis, facial edema;

rarely: Stevens-Johnson syndrome*, erythema multiforme*, unpleasant skin odor, periorbital edema*, localized urticaria;

very rare: toxic epidermal necrolysis*.

Musculoskeletal and connective tissue disorders:

often: arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, muscle pain in the chest;

uncommon: joint swelling*, muscle stiffness, flank pain, muscle fatigue;

rarely: discomfort in the limbs.

Renal and urinary disorders sch their ways:

often:nephrolithiasis, pollakiuria, dysuria;

uncommon: urinary calculi, urinary incontinence, stress incontinence, hematuria, painful urinary urgency, renal colic, pain in the renal area;

rarely: ureteral stones, renal tubular acidosis*.

Disorders of the genital organs and breast:

infrequently:erectile dysfunction, sexual dysfunction.

General disorders and disorders at the injection site:

Often:fatigue;

often: pyrexia, asthenia, irritability, gait disturbance, unusual sensations, malaise;

uncommon: hyperthermia, generalized edema, thirst, flu-like state*, inertia, cold extremities, feeling of intoxication, feeling of anxiety;

rarely: facial swelling, calcification.

Influence on the results of laboratory and instrumental studies:

Often: weight loss;

often:weight gain;

uncommon: crystalluria, abnormal tandem gait test, leukopenia, increased liver enzyme levels, hypokalemia;

rarely: decrease in the content of bicarbonates in the blood.

Impact on social factors:

infrequently:learning difficulties.

*adverse reactions were identified based on an analysis of spontaneous reports during post-marketing use of the drug. Their frequency was calculated based on clinical trial data.

Overdose

Signs and symptoms of an overdose of Topamax®: convulsions, drowsiness, speech and vision disturbances, diplopia, impaired thinking, impaired coordination, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression. In most cases, the clinical consequences were not severe, but deaths have been reported following overdose using a mixture of several drugs, including topiramate. An overdose of topiramate can cause severe metabolic acidosis (see section "Special Instructions").

There is a known case of overdose when a patient took a dose of topiramate from 96 to 110 g, which resulted in a coma that lasted 20–24 hours. After 3–4 days, the patient’s condition returned to normal.

Treatment.

In case of an acute overdose of Topamax®, if the patient has eaten shortly before, it is necessary to immediately rinse the stomach or induce vomiting. Activated carbon has been shown to adsorb topiramate in in vitro studies. If necessary, symptomatic therapy should be carried out. An effective way to remove topiramate from the body is hemodialysis. Patients are advised to adequately increase their fluid intake.

Interaction with other drugstami

Effect of the drug Topamax® on the concentration of othergeeantiepilepticdrugs(PEP)

Concomitant use of Topamax® with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect the values of their steady-state plasma concentrations, with the exception of certain patients in whom the addition of Topamax® to phenytoin may cause an increase in the concentration of phenytoin in the plasma. plasma. This may be due to the inhibition of a specific polymorphic isoform of the enzyme of the cytochrome P450 system (cytochrome isoenzyme CYP2C19). Therefore, phenytoin plasma concentrations should be monitored in any patient taking phenytoin who develops clinical signs or symptoms of toxicity. In a pharmacokinetic study in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the steady-state concentration of the latter at doses of topiramate 100–400 mg per day. During and after discontinuation of lamotrigine (average dose 327 mg per day), the equilibrium concentration of topiramate did not change.

Effect of other antiepileptic drugs on Topamax drug concentrations®

Phenytoin and carbamazepine reduce plasma concentrations of Topamax®. The addition or removal of phenytoin or carbamazepine during treatment with Topamax® may require a change in the dose of the latter. The dose should be selected based on achieving the desired clinical effect. The addition or removal of valproic acid does not cause clinically significant changes in the plasma concentration of Topamax® and, therefore, does not require a change in the dose of Topamax®.

↔ = No effect

** = Increased concentration in isolated patients

↓ = Decrease in plasma concentration

NI = Not studied

P E P = Antiepileptic drug

Other drug interactions

Digoxin: In a single-dose study, the area under the plasma concentration-time curve of digoxin decreased by 12% when coadministered with Topamax®. The clinical significance of this observation is unclear. When prescribing or discontinuing Topamax® in patients taking digoxin, special attention should be paid to monitoring serum digoxin concentrations.

CNS depressants: The effects of co-administration of Topamax with alcohol or other CNS depressants have not been studied in clinical studies. It is recommended not to take Topamax® with alcohol or other drugs that cause depression of central nervous system function.

St. John's wort(Hypericum perforatum)

With the simultaneous use of topiramate and St. John's wort, there is a risk of reducing the concentration of topiramate in the blood plasma and reducing its effectiveness. No clinical studies have been conducted to evaluate this interaction.

Oral contraceptives: In a drug interaction study with oral contraceptives using a combination product containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), Topamax® at doses of 50-200 mg per day did not have a significant effect on the effectiveness of norethisterone and ethinyl estradiol. A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of Topamax® 200–800 mg per day. The clinical significance of the described changes is unclear. The risk of decreased contraceptive effectiveness and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topamax®. Patients taking estrogen-containing contraceptives should be informed of any changes in the timing and nature of menstruation. The effectiveness of contraceptives may be reduced even in the absence of breakthrough bleeding.

Lithium: In healthy volunteers, a 18% decrease in lithium AUC was observed when co-administering topiramate 200 mg daily. In patients with manic-depressive psychosis, the use of topiramate in 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%. When using topiramate and lithium simultaneously, the concentration of the latter in the blood plasma should be monitored.

Risperidone: Drug interaction studies conducted with single and multiple doses of topiramate in healthy volunteers and manic-depressive patients yielded similar results. With simultaneous use of topiramate at doses of 100, 250 or 400 mg per day, the AUC of risperidone taken in doses of 1-6 mg per day is reduced by 16% and 33%, respectively. At the same time, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed slightly. The change in systemic exposure of risperidone/9-hydroxyrisperidone and topiramate was not clinically significant and this interaction is unlikely to be of clinical significance. When topiramate was added to riperidone (at a dosage of 1–6 mg/day), treatment-related adverse events were reported more frequently than before the administration of topiramate (250–400 mg/day) (90% and 54%, respectively). The most common adverse events after adding topiramate to risperidone therapy were: drowsiness (27% and 12%), paresthesia (22% and 0%), nausea (18% and 19%).

Hydrochlorothiazide: Drug interactions were assessed in healthy volunteers with the separate and coadministration of hydrochlorothiazide (25 mg every 24 hours) and topiramate (96 mg every 12 hours). The results of the study showed that when topiramate and hydrochlorothiazide were taken simultaneously, the maximum concentration of topiramate increased by 27% and the area under the concentration-time curve of topiramate increased by 29%. The clinical significance of these studies has not been established. Prescribing hydrochlorothiazide to patients taking topiramate may require a dose adjustment of topiramate. The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant therapy with topiramate. The results of clinical laboratory studies indicate a decrease in serum potassium after taking topiramate or hydrochlorothiazide, which was significantly more significant when taking topiramate or hydrochlorothiazide together.

Metformin: Drug interactions were assessed in healthy volunteers receiving metformin or a combination of metformin and topiramate. The results of the study showed that when topiramate and metformin were taken simultaneously, the maximum concentration and area under the concentration-time curve of metformin increased by 18% and 25%, respectively, while the clearance of metformin when administered simultaneously with topiramate decreased by 20%. Topiramate had no effect on the time to reach maximum metformin plasma concentrations. The clinical significance of the effect of topiramate on the pharmacokinetics of metformin is unclear. The clearance of topiramate when co-administered with metformin is reduced. The extent of the observed changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unclear. If Topamax® is added or discontinued in patients receiving metformin, the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

Pioglitazone: Drug interactions were assessed in healthy volunteers when pioglitazone and topiramate were administered separately and together. A decrease in the area under the concentration-time curve of pioglitazone by 15% was detected, without changing the maximum concentration of the drug. These changes were not statistically significant. Also, for the active hydroxymetabolite pioglitazone, a decrease in the maximum concentration and the area under the concentration-time curve was detected by 13% and 16%, respectively, and for the active ketometabolite, a decrease in both the maximum concentration and the area under the concentration-time curve was detected by 60%. The clinical significance of these data is unclear. When patients are co-administered Topamax® and pioglitazone, the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

Glibenclamide: A drug interaction study was conducted to examine the pharmacokinetics of glibenclamide (5 mg daily) at steady state, administered alone or concomitantly with topiramate (150 mg daily) in patients with type 2 diabetes mellitus. When topiramate was used, the AUC of glibenclamide decreased by 25%. Systemic exposure to 4-trans-hydroxy-glibenclamide and 3-cis-hydroxy-glibenclamide was also reduced (by 13% and 15%, respectively). Glibenclamide did not affect the pharmacokinetics of topiramate at steady state. A statistically insignificant decrease in the AUC of pioglitazone by 15% was found in the absence of changes in Cmax. When prescribing topiramate to patients receiving glibenclamide (or prescribing glibenclamide to patients receiving topiramate), the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

Other drugs: Concomitant use of Topamax® with drugs that predispose to nephrolithiasis may increase the risk of kidney stones. During treatment with Topamax®, the use of drugs that predispose to nephrolithiasis should be avoided, as they may cause physiological changes that contribute to nephrolithiasis.

Valproic acid: The combined use of topiramate and valproic acid in patients who tolerate each drug separately is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after discontinuation of one of the drugs (see section "Special instructions" and "Side effects"). This adverse reaction is not due to a pharmacokinetic interaction.

With the combined use of topiramate and valproic acid, cases of hypothermia, defined as a spontaneous decrease in body temperature to

Additional drug interaction studies: for poten assessment A number of clinical studies have been conducted to evaluate possible drug interactions between topiramate and other drugs.

The results of these interactions are summarized in the following table:

Added drug	Concentration of added druga	Topiramate concentration
Amitriptyline	increase in maximum concentration and AUC of nortriptyline metabolite by 20%	not studied
Dihydroergotamine (oral and subcutaneous)	↔	↔
Haloperidol	increase in metabolite AUC by 31%	not studied
Propranolol	increase in maximum concentration for 4-OH propranolol by 17% (topiramate 50 mg)	increase in maximum concentration by 9% and 16%, increase in AUC by 9 and 17%, respectively (for propranolol 40 mg and 80 mg every 12 hours)
Sumatriptan (oral and subcutaneous)	↔	not studied
Pizotifen	↔	↔
Diltiazem	25% reduction in diltiazem AUC and 18% reduction in desacetyldiltiazem, and ↔ for N-demethyldiltiazem	AUC increase by 20%
Venlafaxine	↔	↔
Flunarizine	16% increase in AUC (50 mg every 12 hours)b	↔

a is expressed as a percentage of the values of maximum plasma concentration and AUC during monotherapy

↔ = No change in maximum plasma concentration and AUC (≤15% of baseline data).

b A 14% increase in AUC was observed with multiple doses of flunarizine alone, which may be due to drug accumulation during steady state.

Precautionary measures

If prompt discontinuation of topiramate is necessary, clinical monitoring of the patient's condition is recommended.

As with other antiepileptic drugs, some patients may experience an increase in the frequency of seizures or the development of new types of seizures while using topiramate. These phenomena may be the result of an overdose, a decrease in the plasma concentration of antiepileptic drugs used simultaneously, progression of the disease, or a paradoxical effect.

In patients with or without a history of seizures or epilepsy, antiepileptic drugs, including Topamax®, should be withdrawn gradually to minimize the possibility of an increase in the frequency of seizures. In clinical trials, dosages were reduced by 50–100 mg at weekly intervals for adults treated for epilepsy and by 25–50 mg in adults receiving 100 mg of Topamax® per day for migraine prophylaxis. In children in clinical studies, Topamax® was tapered gradually over 2–8 weeks. If, for medical reasons, rapid discontinuation of Topamax® is necessary, it is recommended to appropriately monitor the patient’s condition.

The rate of excretion through the kidneys depends on renal function and is independent of age. In patients with moderate or severe renal impairment, 10 or more may be needed to achieve steady-state plasma concentrations. before 15 days, as opposed to 4–8 days in patients with normal renal function.

As with any disease, dose selection should be based on clinical effect (i.e., degree of seizure control, absence of side effects) and take into account that in patients with impaired renal function, it may be necessary to achieve stable plasma concentrations for each dose. longer time.

Oligohidrosis

There have been reports of oligohidrosis (decreased sweating) and anhidrosis associated with the use of topiramate. Decreased sweating and hyperthermia (increased body temperature) can occur, especially in young children, in conditions of elevated ambient temperatures.

When using topiramate, adequate fluid replacement is very important. Replenishing fluid loss can reduce the risk of nephrolithiasis (see below). Adequate fluid replacement before and during activities such as exercise or exposure to high temperatures can reduce the risk of heat-related complications.

Mood disorders/depression

An increased incidence of mood disorders and depression has been observed during treatment with topiramate.

Suicide attempts

When using antiepileptic drugs, including Topamax®, the risk of suicidal thoughts and behavior increases in patients taking these drugs for any indication. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs showed an increased risk of suicidal ideation and behavior (0.43% with antiepileptic drugs versus 0.24% with placebo). The mechanism of this risk is unknown. In double-blind clinical studies, the incidence of suicide-related events (suicidal idealization, suicide attempts, suicide) was 0.5% in patients receiving topiramate (46 of 8652 people) compared with 0.2% in patients receiving topiramate. those receiving placebo (8 people out of 4045). One case of suicide was reported in a double-blind study of bipolar disorder in a patient receiving topiramate. Therefore, it is necessary to monitor patients for suicidal thoughts and behavior and prescribe appropriate treatment. Patients (and, if necessary, caregivers) should be advised to immediately seek medical help if signs of suicidal idealization or suicidal behavior occur.

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and associated symptoms such as renal colic, kidney pain, and flank pain. To reduce this risk, an adequate increase in fluid intake is necessary. Risk factors for the development of nephrolithiasis are a history of nephrolithiasis (including family history), hypercalciuria, and concomitant therapy with drugs that contribute to the development of nephrolithiasis. None of these risk factors reliably predict stone formation during topiramate treatment.

Liver dysfunction

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

Kidney failure

Patients with moderate or severe renal impairment may require a dose reduction. It is recommended to use half the usual initial and maintenance doses.

Hemodialysis

Since Topamax® is removed from plasma during hemodialysis, an additional dose of Topamax® equal to approximately half the daily dose should be administered on hemodialysis days. The additional dose should be divided into two doses taken at the beginning and after completion of the hemodialysis procedure. The additional dose may vary depending on the characteristics of the equipment used during hemodialysis.

Myopia and secondary closed anglebglaucoma

When using the drug Topamax®, a syndrome has been described that includes acute myopia with concomitant secondary angle-closure glaucoma. Symptoms include acute loss of visual acuity and/or eye pain. An ophthalmological examination may reveal myopia, flattening of the anterior chamber of the eye, hyperemia (redness) of the eyeball, and increased intraocular pressure. Mydriasis may occur. This syndrome may be accompanied by fluid secretion, leading to forward displacement of the lens and iris with the development of secondary angle-closure glaucoma. Symptoms usually appear 1 month after starting Topamax®. Unlike primary open-angle glaucoma, which is rarely observed in patients under 40 years of age, secondary angle-closure glaucoma is observed with the use of topiramate in both adults and children. If a syndrome involving myopia associated with angle-closure glaucoma occurs, treatment includes discontinuation of Topamax® as soon as deemed possible by the treating physician and appropriate measures to lower intraocular pressure. Typically, 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.

Visual field defects

Visual field defects were observed in patients receiving topiramate regardless of increased intraocular pressure. In clinical trials, most of these effects were reversible after discontinuation of topiramate. Discontinuation of topiramate should be considered if visual impairment occurs at any time while taking the drug.

Metabolic acidosis

When using topiramate, hyperchloremic, not associated with anion deficiency, metabolic acidosis (for example, a decrease in plasma bicarbonate concentrations below normal levels in the absence of respiratory alkalosis) may occur. This decrease in serum bicarbonate concentrations is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, a decrease in the concentration of bicarbonates occurs at the beginning of taking the drug, although this effect can occur at any time during treatment with topiramate. The level of reduction in concentration is usually weak or moderate (average value is 4 mmol/L when used in adult patients at a dose above 100 mg per day and about 6 mg per day per kg of body weight when used in pediatric practice). In rare cases, patients experienced a decrease in bicarbonate concentrations below 10 mmol/l. Certain diseases or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory disease, status epilepticus, diarrhea, surgery, ketogenic diet, certain medications) may be additional factors that enhance the bicarbonate-lowering effect of topiramate.

In children, chronic metabolic acidosis can lead to growth retardation.

The effect of topiramate on growth and possible complications related to the skeletal system have not been systematically studied in children and adults.

In connection with the above, when treating with topiramate, it is recommended to carry out the necessary studies, including determination of the concentration of bicarbonates in the serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or discontinue topiramate (by gradually reducing the dose).

Cognitive impairment

Cognitive impairment in epilepsy is caused by many factors and may be associated with the underlying cause of the disease, epilepsy itself, or antiepileptic treatment. There are reports in the literature of cases of deterioration in cognitive function in adults treated with topiramate, which required dose reduction or discontinuation of treatment. Existing research data are insufficient to assess the effects of topiramate on cognitive function in children. This problem requires further study.

Hyperammonemia and encephalopathy

When using topiramate, the development of hyperammonemia with or without encephalopathy was observed (see section “Side effects”). The risk of developing hyperammonemia with topiramate is dose-dependent. Hyperammonemia is more often observed with simultaneous use of topiramate and valproic acid (see section "Other drug interactions"). Clinical symptoms of hyperammonemic encephalopathy often include severe impairment of consciousness and/or cognitive function and lethargy. In most cases, hyperammonemic encephalopathy regresses when therapy is discontinued. In patients who have developed unexplained lethargy or changes in mental status of unknown origin, receiving topiramate as monotherapy or as part of combination therapy, it is recommended to take into account the possibility of hyperammonemic encephalopathy and determine the concentration of ammonia in the blood.

Instructions for use

Topamax instructions for use

Dosage form

Hard gelatin capsules No. 1, consisting of a white body and a transparent colorless cap. The cap of the capsule bears the inscription "TOP". The capsule body bears the inscription "25 mg". The contents of the capsules are white or almost white granules.

Compound

Active substance: topiramate 25 mg.

Excipients: granulated sugar [sucrose, starch syrup] 75.00 mg, povidone 17.3665 mg, cellulose acetate 9.038 mg.

Capsule composition: gelatin 64.7-67.0 mg, water 10.0-12.3 mg, sorbitan laurate 0.0312 mg, sodium lauryl sulfate 0.0312 mg, titanium dioxide (E171) 0.78 mg, Opacode ink Black S-1-17822/23 black (ink composition: shellac glaze solution in ethanol, black iron oxide, n-butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide) 5-10 mcg.

Pharmacodynamics

Topiramate is an antiepileptic drug belonging to the class of sulfamate-substituted monosaccharides.

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of α-aminobutyric acid (GABA) in relation to certain subtypes of GABA receptors (including GABAA receptors), and also modulates the activity of GABAA receptors themselves, and prevents the activation by kainate of the sensitivity of the kainate/AMPK subtype (β-amino-3- hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptors does not affect the activity of N-methyl-D-aspartate (NMDA) towards the NMDA receptor subtype. These effects of topiramate are dose-dependent with drug plasma concentrations ranging from 1 µM to 200 µM, with trough activity ranging from 1 µM to 10 µM.

In addition, topiramate inhibits the activity of some carbonic anhydrase isoenzymes. In terms of the severity of this pharmacological effect, topiramate is significantly inferior to acetazolamide, a known inhibitor of carbonic anhydrase, therefore this activity of topiramate is not considered the main component of its antiepileptic activity.

Pharmacokinetics

The magnitude of the volume of distribution 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.

The main route of elimination of unchanged topiramate (70%) and its metabolites is the kidneys. After oral administration, plasma clearance of topiramate is 20-30 ml/min. 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 over the dose range from 100 to 400 mg.

In patients with normal renal function, it may take 4 to 8 days to achieve steady-state plasma concentrations. The maximum concentration (Cmax) after repeated oral administration of 100 mg of the drug twice a day averaged 6.76 mcg/ml. After multiple doses of 50 and 100 mg twice daily, the plasma half-life of topiramate averaged 21 hours.

In patients with moderate to severe renal impairment, plasma and renal clearance of topiramate is reduced (creatinine clearance (CC)< 70 мл/мин), как следствие возможно повышение равновесной концентрации топирамата в плазме крови по сравнению с пациентами, имеющими нормальную функцию почек. Кроме того, пациентам с нарушениями функции почек требуется больше времени для достижения равновесной концентрации топирамата в крови. Пациентам со средней или тяжелой почечной недостаточностью рекомендуется применение половины рекомендованной начальной и поддерживающей дозы.

When adjusting the dose, you should take into account:

1) duration of hemodialysis,

2) the clearance value of the hemodialysis system used,

3) effective renal clearance of topiramate in a patient on dialysis.

Plasma clearance of topiramate is reduced by an average of 26% in patients with moderate or severe hepatic impairment. 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 pharmacokinetic parameters of topiramate in children, as in adults receiving this drug as adjuvant therapy, are linear, while its clearance does not depend on the dose, and equilibrium plasma concentrations increase in proportion to the dose.

However, it should be taken into account that in children the clearance of topiramate is increased and its half-life is shorter. Therefore, 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, antiepileptic drugs that induce liver microsomal enzymes cause a decrease in plasma concentrations of topiramate.

Side effects

Adverse reactions are given with a distribution by frequency and organ system. The frequency of adverse reactions was classified as follows: very often (?1/10), often (?1/100,<1/10), нечасто (?1/1000 и <1/100), редко (?1/10000 и <1/1000), очень редко (<1/10000, включая отдельные случаи) и частота неизвестна (частоту невозможно оценить по имеющимся данным).

Infections and infestations: very common: nasopharyngitis*.

Disorders of the blood and lymphatic system: often: anemia; uncommon: leukopenia, lymphadenopathy, thrombocytopenia, eosinophilia; rarely: neutropenia*.

Immune system disorders: often: hypersensitivity; frequency unknown: allergic edema*, conjunctival edema*.

Metabolic and nutritional disorders: often: anorexia, decreased appetite; uncommon: metabolic acidosis, hypokalemia, increased appetite, polydipsia; rarely: hyperchloremic acidosis; hyperammonemia, hyperammonemic encephalopathy.

Mental disorders: very often: depression; often: slow thinking, insomnia, impaired speech, anxiety, confusion, disorientation, aggressive reactions, mood disorders, agitation, emotional lability, depressed mood, anger, behavioral disturbances; uncommon: suicidal thoughts, suicide attempts, hallucinations, psychotic disorders, auditory hallucinations, visual hallucinations, apathy, difficulty speaking, sleep disturbances, affective lability, decreased libido, restlessness, crying, dysphemia, euphoric mood, paranoia, perseveration of thinking, panic attacks , tearfulness, impaired reading skills, difficulty falling asleep, flattening of emotions, pathological thinking, loss of libido, lethargy, intrasomnic disorder, absent-mindedness, early awakenings in the morning, panic reactions, high spirits; rarely: mania, panic disorder, feelings of hopelessness*, hypomania.

Disorders of the central nervous system: very often: paresthesia, drowsiness, dizziness; often: impaired concentration, impaired memory, amnesia, cognitive disorders, impaired thinking, psychomotor impairment, convulsions, impaired coordination of movements, tremor, lethargy, hypoesthesia, nystagmus, dysgeusia, impaired sense of balance, dysarthria, intention tremor, sedation; Uncommon: depressed consciousness, tonic-clonic grand mal seizures, visual field impairment, complex partial seizures, speech impairment, psychomotor hyperactivity, syncope, sensory disturbances, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural vertigo , low quality of sleep, burning sensation, loss of sensitivity, parosmia, cerebral syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, sensation of “pins and needles”; rarely: apraxia, circadian sleep rhythm disorder, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli.

Visual disturbances: often: blurred vision, diplopia, visual impairment; uncommon: decreased visual acuity, scotoma, myopia*, strange sensations in the eyes*, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia; rarely: one-sided blindness, transient blindness, glaucoma, impaired accommodation, impaired visual spatial perception, atrial scotoma, eyelid edema*, night blindness, amblyopia; frequency unknown: angle-closure glaucoma*, maculopathy*, ocular motility disorders*.

Hearing and balance disorders: often: vertigo, tinnitus, ear pain; uncommon: deafness, one-sided deafness, sensorineural deafness, ear discomfort, hearing impairment.

Cardiovascular system disorders: uncommon: bradycardia, sinus bradycardia, palpitations.

Vascular system disorders: uncommon: hypotension, orthostatic hypotension, hot flashes, hot flashes; rare: Raynaud's phenomenon.

Disorders of the respiratory system, chest and mediastinal organs: often: shortness of breath, nosebleeds, nasal congestion, rhinorrhea, cough*; uncommon: shortness of breath on exertion, hypersecretion in the paranasal sinuses, dysphonia.

Gastrointestinal disorders: very common: nausea, diarrhea; often: vomiting, constipation, pain in the epigastric region, dyspepsia, abdominal pain, dry mouth, stomach discomfort, impaired sensitivity in the oral cavity, gastritis, abdominal discomfort; uncommon: pancreatitis, flatulence, gastroesophageal reflux, pain in the lower abdomen, decreased sensitivity in the oral cavity, bleeding gums, bloating, epigastric discomfort, tenderness in the abdominal area, hypersalivation, oral pain, bad breath, glossodynia .

Disorders of the hepatobiliary system: rarely: hepatitis, liver failure.

Disorders of the skin and subcutaneous tissues: often: alopecia, rash, itching; uncommon: anhidrosis, impaired sensitivity in the facial area, urticaria, erythema, generalized itching, macular rash, skin pigmentation disorder, allergic dermatitis, facial swelling; uncommon: Stevens-Johnson syndrome*, erythema multiforme*, change in skin odor, periorbital edema*, localized urticaria; frequency unknown: toxic epidermal necrolysis*.

Musculoskeletal and connective tissue disorders: common: arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, musculoskeletal chest pain; uncommon: joint swelling*, muscle stiffness, side pain, muscle fatigue; rarely: discomfort in the limbs*.

Renal and urinary tract disorders: often: nephrolithiasis, pollakiuria, dysuria; uncommon: exacerbation of urolithiasis (kidney stones), stress incontinence, hematuria, urinary incontinence, frequent urge to urinate, renal colic, pain in the kidney area; rarely: exacerbation of urolithiasis (stones in the urethra), renal tubular acidosis*.

Genital and breast disorders: uncommon: erectile dysfunction, sexual dysfunction.

General disorders and disorders caused by the method of application: very often: fatigue; often: increased body temperature, asthenia, irritability, gait disturbances, poor health, anxiety; uncommon: hyperthermia, thirst, flu-like syndrome*, sluggishness, cold extremities, feeling of intoxication, feeling of restlessness; rarely: facial edema, calcification.

Changes in laboratory parameters: very often: loss of body weight; often: weight gain*; uncommon: crystalluria, abnormal tandem gait test result, leukopenia, increased activity of liver enzymes in the blood serum, rare: decreased content of bicarbonates in the blood.

Impaired social functioning: uncommon: learning impairment.

* - adverse reaction was registered in the post-registration period from spontaneous reports. Frequency calculated based on data from clinical studies.

Special groups:

Selling Features

prescription

Special conditions

Antiepileptic drugs, including Topamax®, should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures. In clinical studies, doses were reduced by 50-100 mg at weekly intervals for adults treated for epilepsy and by 25-50 mg in adults receiving 100 mg of Topamax® per day for migraine prophylaxis. In children in clinical studies, Topamax® was gradually withdrawn over 2-8 weeks. If, for medical reasons, rapid discontinuation of Topamax® is necessary, it is recommended to appropriately monitor the patient’s condition.

During therapy with topiramate, oligohidrosis (decreased sweating) and anhidrosis may occur. Decreased sweating and hyperthermia (increased body temperature) may occur in children exposed to high ambient temperatures. In this regard, when treating with topiramate, it is very important to adequately increase the volume of fluid intake, which can reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical activity or elevated temperatures.

Mood disorders/depression

An increased incidence of mood disorders and depression has been observed during treatment with topiramate.

Suicide attempts

When using antiepileptic drugs, including Topamax®, the risk of suicidal thoughts and behavior increases in patients taking these drugs for any indication.

Nephrolithiasis

Renal dysfunction

Caution should be exercised when prescribing Topamax® to patients with renal failure (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 used with caution due to the possible decrease in clearance of this drug.

Myopia and secondary angle-closure glaucoma

Unlike primary open-angle glaucoma, which is rarely observed in patients under 40 years of age, secondary angle-closure glaucoma is observed with the use of topiramate in both adults and children.

If a syndrome involving myopia associated with angle-closure glaucoma occurs, treatment includes discontinuation of Topamax® as soon as deemed possible by the attending physician and appropriate measures aimed at lowering intraocular pressure. Typically, 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.

When prescribing topiramate to patients with a history of eye diseases, it is necessary to assess the ratio of the expected benefit to the possible risk of use.

Visual field defects

Metabolic acidosis

Cognitive impairment

Hyperammonemia and encephalopathy

When using topiramate, the development of hyperammonemia with or without encephalopathy was observed (see section "Side effects"). The risk of developing hyperammonemia with topiramate is dose-dependent.

Hyperammonemia is more often observed with simultaneous use of topiramate and valproic acid (see section "Other drug interactions").

Clinical symptoms of hyperammonemic encephalopathy often include severe impairment of consciousness and/or cognitive function and lethargy.

In most cases, hyperammonemic encephalopathy regresses when therapy is discontinued.

In patients with developed lethargy or unexplained changes in mental status receiving topiramate as monotherapy or as part of combination therapy, it is recommended to take into account the possibility of hyperammonemic encephalopathy and determine the level of ammonia in the blood.

Enhanced nutrition

If a patient loses weight during treatment with Topamax®, then it is necessary to consider the advisability of enhanced nutrition.

Impact on the ability to drive vehicles. Wed and fur.:

Topamax® acts on the central nervous system and may cause drowsiness, dizziness, and other symptoms. It can also cause vision problems. These adverse events may pose a danger to patients driving cars and moving machinery, especially during the period until the patient’s response to the drug is established.

Indications

Epilepsy

As a monotherapy: in adults and children over 2 years of age with epilepsy (including patients with newly diagnosed epilepsy).

As part of complex therapy: in adults and children over 2 years of age with partial or generalized tonic-clonic seizures, as well as for the treatment of seizures associated with Lennox-Gastaut syndrome.

Prevention of migraine attacks in adults. The use of Topamax® for the treatment of acute migraine attacks has not been studied.

Contraindications

Hypersensitivity to any of the components of this drug, children under 2 years of age.

Carefully:

With renal and liver failure, nephrourolithiasis (including in the past and in family history), hypercalciuria.

Pregnancy and lactation:

Topiramate has shown teratogenic properties in mice, rats and rabbits. In rats, topiramate crossed the placental barrier.

There have been no special controlled studies in which Topamax® was used to treat pregnant women. Topiramate may cause fetal harm when used in pregnant women. Pregnancy data indicate that infants exposed to topiramate in utero during the first trimester of pregnancy have an increased risk of developing congenital malformations (eg, craniofacial defects such as cleft lip or palate, hypospadias, and developmental anomalies of various body systems). These malformations were recorded both during monotherapy with topiramate and when it was used as part of polytherapy. Data from one pregnancy registry showed that with topiramate monotherapy, the incidence of significant congenital malformations increased by approximately 3 times compared with a comparison group not taking antiepileptic drugs.

In addition, it has been shown that the risk of developing teratogenic effects associated with taking antiepileptic drugs is higher in the case of combination therapy than in the case of monotherapy.

Compared with the group of patients not taking antiepileptic drugs, data from pregnancies during monotherapy with Topamax® indicate an increased likelihood of having children with low body weight (less than 2500 g). One pregnancy registry showed an increase in the relative number of infants small for gestational age (SGA; defined as birth weight below the 10th percentile, adjusted for gestational age and stratified by sex) among infants exposed to topiramate in utero. The long-term consequences of NGB have not been determined. The cause of decreased birth weight and NGV has not been established.

During topiramate therapy, women of childbearing potential should use reliable methods of contraception. Use of Topamax® during pregnancy in women with uncontrolled epilepsy

Justified only when the potential benefit of the drug for the mother outweighs the possible risk to the fetus.

The use of topiramate for the prevention of migraine attacks is contraindicated during pregnancy, as well as in women with preserved childbearing potential who do not use reliable methods of contraception. When treating and counseling women of childbearing potential, the treating physician must weigh the benefits and risks of treatment and consider alternative treatment options. If Topamax® is used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be warned of the potential risk to the fetus.

A limited number of patient observations suggests that topiramate is excreted into breast milk in women, so the physician should decide whether to breastfeed or discontinue the drug.

In animal studies, no effect of topiramate on fertility was found. The effect of topiramate on fertility in humans has not been established.

Drug interactions

The effect of Topamax® on the concentrations of other antiepileptic drugs (AEDs)

Concomitant use of the drug Topamax® with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect the values of their equilibrium concentrations in plasma, with the exception of certain patients in whom the addition of the drug Topamax® to phenytoin may cause an increase in the concentration of phenytoin in the plasma. plasma. This may be due to the inhibition of a specific polymorphic isoform of the cytochrome P450 enzyme (CYP2Cmeph). Therefore, phenytoin plasma concentrations should be monitored in any patient taking phenytoin who develops clinical signs or symptoms of toxicity. In a pharmacokinetic study in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the steady-state concentration of the latter at doses of topiramate 100-400 mg per day. During and after discontinuation of lamotrigine (average dose 327 mg per day), the equilibrium concentration of topiramate did not change.

Effect of other antiepileptic drugs on the concentration of Topamax®

The addition or removal of valproic acid does not cause clinically significant changes in the plasma concentration of Topamax® and, therefore, does not require a change in the dose of Topamax®.

Other drug interactions

Digoxin: In a single-dose study, the plasma area under the concentration-time curve of digoxin decreased by 12% when coadministered with Topamax®. The clinical significance of this observation is unclear. When prescribing or discontinuing Topamax® in patients taking digoxin, special attention should be paid to monitoring serum digoxin concentrations. CNS depressants: The effects of co-administration of Topamax with alcohol or other CNS depressants have not been studied in clinical studies. It is recommended not to take Topamax® with alcohol or other drugs that cause depression of central nervous system function.

St. John's wort

When taking Topamax® and drugs based on St. John's wort (Hypericum perforatum) together, the plasma concentration of topiramate may decrease and, as a result, the effectiveness of the drug may also decrease. Clinical studies of the interaction of Topamax® and drugs based on St. John's wort have not been conducted.

Oral contraceptives: In a drug interaction study with oral contraceptives using a combination product containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), Topamax® at doses of 50-800 mg per day did not have a significant effect on the effectiveness of norethisterone and doses 50-200 mg per day - for the effectiveness of ethinyl estradiol. A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of Topamax® 200-800 mg per day. The clinical significance of the described changes is unclear. The risk of decreased contraceptive effectiveness and increased breakthrough bleeding should be taken into account in patients taking oral contraceptives in combination with Topamax®. Patients taking estrogen-containing contraceptives should be informed of any changes in the timing and nature of menstruation. The effectiveness of contraceptives may be reduced even in the absence of breakthrough bleeding.

Risperidone: Drug interaction studies conducted with single and multiple doses of topiramate in healthy volunteers and patients with bipolar disorder yielded similar results. With simultaneous use of topiramate in doses of 250 or 400 mg per day, the AUC of risperidone, taken in doses of 1-6 mg per day, is reduced by 16% and 33%, respectively. At the same time, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed slightly. The change in systemic exposure of risperidone/9-hydroxyrisperidone and topiramate was not clinically significant and this interaction is unlikely to be of clinical significance.

Hydrochlorothiazide: Drug interactions were assessed in healthy volunteers with the separate and coadministration of hydrochlorothiazide (25 mg) and topiramate (96 mg). The results of the study showed that when topiramate and hydrochlorothiazide were taken simultaneously, the maximum concentration of topiramate increased by 27% and the area under the concentration-time curve of topiramate increased by 29%. The clinical significance of these studies has not been established. Prescribing hydrochlorothiazide to patients taking topiramate may require adjustment of the topiramate dose. The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant therapy with topiramate.

Metformin: Drug interactions were assessed in healthy volunteers receiving metformin or a combination of metformin and topiramate. The results of the study showed that when topiramate and metformin were taken simultaneously, the maximum concentration and area under the concentration-time curve of metformin increased by 18% and 25%, respectively, while the clearance of metformin when administered simultaneously with topiramate decreased by 20%. Topiramate had no effect on the time to reach maximum metformin plasma concentrations. The clearance of topiramate is reduced when used concomitantly with metformin. The extent of the observed changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unclear. If Topamax® is added or discontinued in patients receiving metformin, the conditions of patients with diabetes mellitus should be investigated.

Pioglitazone: Drug interactions were assessed in healthy volunteers with the separate and concomitant use of pioglitazone and topiramate. A decrease in the area under the concentration-time curve of pioglitazone by 15% was detected, without changing the maximum concentration of the drug. These changes were not statistically significant. For the active hydroxymetabolite pioglitazone, a decrease in the maximum concentration and the area under the concentration-time curve was also detected by 13% and 16%, respectively, and for the active ketometabolite, a decrease in both the maximum concentration and the area under the concentration-time curve was detected by 60 %. The clinical significance of these data is unclear. When patients use Topamax® and pioglitazone simultaneously, the conditions of patients with diabetes mellitus should be examined.

A statistically insignificant decrease in the AUC of pioglitazone by 15% was found in the absence of changes in Cmax. When prescribing topiramate to patients receiving glibenclamide (or prescribing glibenclamide to patients receiving topiramate), the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

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 either after starting to take valproic acid and topiramate together, or when the daily dose of topiramate is increased.

Additional drug interaction studies: A number of clinical studies have been conducted to evaluate potential drug interactions between topiramate and other drugs.
Topamax® capsules should be carefully opened and the contents of the capsules mixed with a small amount (about 1 teaspoon) of some soft food. This mixture should be swallowed immediately without chewing. The drug mixed with food should not be stored until the next dose.

Topamax® capsules can be swallowed whole.

Partial or generalized tonic-clonic seizures, as well as seizures associated with Lennox-Gastaut syndrome

Use in combination with other anticonvulsants in adult patients

It is recommended to start treatment with a low dose, followed by gradual selection of an effective dose. Dose selection begins with 25-50 mg, taking them at night for 1 week. In the future, at weekly or two-week intervals, the dose can be increased by 25-50 mg and taken in two doses. When selecting a dose, it is necessary to be guided by the clinical effect. In some patients, the effect can be achieved by taking the drug once a day. To achieve the optimal effect of treatment with Topamax®, it is not necessary to control its plasma concentration.

Combined anticonvulsant therapy in children over 2 years of age

Dose titration should begin with 25 mg (or less, based on a starting dose of 1 to 3 mg/kg per day) taken at night for 1 week. Subsequently, at weekly or two-week intervals, the dose can be increased by 1-3 mg/kg and taken in two doses. When selecting a dose, it is necessary to be guided by the clinical effect. Daily doses of up to 30 mg/kg are usually well tolerated.

Epilepsy (including newly diagnosed)

Monotherapy: general provisions

When drugs that are inducers of microsomal liver enzymes are discontinued, the concentrations of topiramate in the blood will increase. In such situations, if clinically indicated, the dose of Topamax® can be reduced.

Monotherapy: adults

When selecting a dose, it is necessary to be guided by the clinical effect. The starting dose for topiramate monotherapy in adults is 100 mg per day, and the maximum daily dose should not exceed 500 mg. Some patients with refractory forms of epilepsy tolerate monotherapy with topiramate in doses of up to 1000 mg per day. These dosing recommendations apply to all adults, including elderly patients without renal disease.

Monotherapy: children

Children over 2 years of age should be given topiramate at a dose of 0.5-1 mg/kg body weight at bedtime during the first week of treatment. 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). If the child does not tolerate this dose escalation regimen, the dose can be increased more gradually or the intervals between dose increases can be increased. The dose and rate of increase should be determined by the clinical outcome. The recommended dose range for topiramate monotherapy in children over 2 years of age is 100 - 400 mg/day. Children with newly diagnosed partial seizures may be given up to 500 mg per day.

The recommended total daily dose of topiramate for the prevention of migraine attacks is 100 mg, taken in 2 divided doses. At the beginning of treatment, the patient should take 25 mg of Topamax® at bedtime for 1 week. Then the dose is increased at intervals of 1 week by 25 mg per day. If the patient does not tolerate this dose escalation regimen, then the intervals between dose increases can be increased, or the dose can be increased more gradually. When selecting a dose, it is necessary to be guided by the clinical effect.

In some patients, a positive result is achieved with a daily dose of topiramate of 50 mg. In clinical studies, patients received varying daily doses of topiramate, but not more than 200 mg per day.

Special patient groups

1. Kidney failure

Patients with moderate or severe renal impairment may require a dose reduction. It is recommended to use half the recommended initial and maintenance dose.

2. Hemodialysis

3. Liver failure

Topiramate should be used with caution in patients with hepatic impairment.

Overdose

Signs and symptoms of an overdose of Topamax®: convulsions, drowsiness, speech and vision disturbances, diplopia, impaired thinking, impaired coordination, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression. In most cases, the clinical consequences were not severe, but deaths have been reported following overdose using a mixture of several drugs, including topiramate. An overdose of topiramate can cause severe metabolic acidosis (see section "Special Instructions").

In case of an acute overdose of Topamax®, if the patient has eaten shortly before, it is necessary to immediately rinse the stomach or induce vomiting. Activated carbon has been shown to adsorb topiramate in in vitro studies. If necessary, symptomatic therapy should be carried out. An effective way to remove topiramate from the body is hemodialysis. Patients are advised to adequately increase their fluid intake.

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Topamax 15, 25 - instructions for use

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