Topilepsin 25

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOPILEPSIN 25, TOPILEPSIN 50, TOPILEPSIN 100 (TOPILEPSIN 25, TOPILEPSIN 50, TOPILEPSIN 100)

Composition:

Active substance: topiramate;

One tablet contains 25 mg, 50 mg, or 100 mg of topiramate;

Excipients: microcrystalline cellulose, celactose [a mixture of monohydrate lactose and powdered cellulose (75:25)], sodium croscarmellose, stearic acid, hypromellose, titanium dioxide (E 171), talc; colouring agent: azorubine (E 122) (50 mg dosage) or tartrazine (E 102) (100 mg dosage).

Medicinal form. Film-coated tablets.

Main physicochemical properties: film-coated, biconvex tablets of white colour (25 mg dosage), pink colour (50 mg dosage), or yellow colour (100 mg dosage). Marbling on the tablet surface is permissible. Two layers are visible in cross-section (50 mg and 100 mg dosages).

|colour|

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs. Topiramate. ATC code N03A X11.

Pharmacological Properties

Pharmacodynamics. Topiramate belongs to the class of sulfamate-substituted monosaccharides. The precise mechanism by which topiramate exerts its anticonvulsant and migraine prophylactic effects is unknown. Electrophysiological and biochemical studies in neuronal cultures have identified three properties that may contribute to the antiepileptic efficacy of topiramate.

Topiramate blocks voltage-gated sodium channels and inhibits the development of sustained repetitive firing of action potentials during prolonged neuronal membrane depolarization. Topiramate enhances the frequency of activation of γ-aminobutyric acid (GABA) at GABAA receptors and increases the ability of GABA to induce chloride ion influx into neurons, indicating that topiramate potentiates the activity of this inhibitory neurotransmitter. This effect is not blocked by flumazenil, a benzodiazepine antagonist. Additionally, topiramate does not increase the duration of time during which ion channels remain open, differentiating it from barbiturates, which modulate GABAA receptors.

Topiramate may modulate the benzodiazepine-insensitive subtype of GABAA receptors, which may explain the significant differences in antiepileptic properties between topiramate and benzodiazepines. Topiramate antagonizes the ability of kainate to activate the kainate/AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) subtype of glutamate receptors, but has no significant effect on N-methyl-D-aspartate (NMDA) receptor activity within the NMDA receptor subtype. These effects of topiramate are concentration-dependent within plasma concentrations ranging from 1 μmol to 200 μmol, with minimal activity observed between 1 μmol and 10 μmol.

In addition, topiramate inhibits the activity of certain isoenzymes of carbonic anhydrase. However, this pharmacological effect of topiramate is considerably weaker than that of acetazolamide—a well-known carbonic anhydrase inhibitor—and therefore this property is not considered a primary component of its antiepileptic action.

Pharmacokinetics. The pharmacokinetic profile of topiramate, compared to other antiepileptic drugs, is characterized by a long elimination half-life, linear kinetics, predominantly renal clearance, low plasma protein binding, and absence of clinically significant active metabolites.

Topiramate is not a potent inducer of drug-metabolizing enzymes, can be administered independently of food intake, and routine monitoring of plasma concentrations is not required. Clinical studies have not demonstrated a significant correlation between plasma concentrations and either efficacy or adverse reactions.

Absorption. Topiramate is rapidly and effectively absorbed. After oral administration of 100 mg topiramate to healthy volunteers, the mean peak plasma concentration (Cmax) of 1.5 μg/mL was reached within 2–3 hours (Tmax). Following oral administration of radiolabeled topiramate and measurement of radioactivity in urine, the mean extent of absorption of an oral 100 mg dose of 14C-topiramate was found to be at least 81%. Food does not have a clinically significant effect on the bioavailability of topiramate.

Distribution. Approximately 13–17% of topiramate is bound to plasma proteins. A site with low binding capacity for topiramate on erythrocytes has been shown to become saturated at plasma concentrations above 4 μg/mL. The volume of distribution is inversely proportional to dose. After single doses ranging from 100 to 1200 mg, the mean apparent volume of distribution ranged from 0.80 to 0.55 L/kg. The volume of distribution depends on gender: it is approximately 50% lower in women than in men, which is attributed to the higher proportion of body fat in women; however, this difference is not considered clinically significant.

Metabolism. In healthy volunteers, topiramate undergoes minimal metabolism (~20%). However, in patients receiving concomitant therapy with antiepileptic drugs known to induce drug-metabolizing enzymes, the metabolism of topiramate increases up to 50%. Six metabolites formed via hydroxylation, hydrolysis, and glucuronidation have been isolated and identified in human plasma, urine, and feces. Each of these metabolites accounted for less than 3% of the total urinary radioactivity after administration of 14C-topiramate. Studies of two metabolites retaining most of the topiramate structure showed that they exhibit little or no anticonvulsant activity.

Excretion. The primary route of elimination of unchanged topiramate (at least 81% of the dose) and its metabolites in humans is renal. Approximately 66% of the administered dose of 14C-topiramate is excreted unchanged in urine within 4 days. After administration of 50 mg and 100 mg topiramate twice daily, the mean renal clearance is approximately 18 mL/min and 17 mL/min, respectively, indicating tubular reabsorption of topiramate in the kidneys. These findings are consistent with studies in rats, where co-administration of probenecid resulted in a significant increase in renal clearance of topiramate. After oral administration, the plasma clearance of the drug ranges from 20 to 30 mL/min.

Linearity. Topiramate exhibits low inter-subject variability in plasma concentrations, making its pharmacokinetic properties predictable. The pharmacokinetics of topiramate are linear: plasma clearance remains constant, and the area under the concentration-time curve increases proportionally with doses ranging from 100 mg to 400 mg administered to healthy volunteers. In patients with normal renal function, steady-state concentrations are achieved within 4–8 days. The mean Cmax after repeated oral administration of 100 mg topiramate twice daily in healthy volunteers is 6.76 μg/mL. After repeated administration of 50 mg and 100 mg doses twice daily, the mean elimination half-life of topiramate in plasma is approximately 21 hours.

Concomitant use with other antiepileptic drugs. Repeated administration of topiramate at doses of 100–400 mg twice daily concomitantly with phenytoin or carbamazepine demonstrates dose-proportional increases in plasma concentrations of topiramate.

Renal impairment. In patients with moderate to severe renal impairment (CLCR ≤ 70 mL/min), both plasma and renal clearance of topiramate are reduced. As a result, higher steady-state plasma concentrations of topiramate are expected in patients with renal impairment compared to those with normal renal function when the same dose is administered. Patients with known renal impairment may require a longer time to reach steady-state concentrations after each dose. In patients with moderate to severe renal impairment, half of the usual initial and maintenance dose is recommended.

Topiramate is effectively removed from plasma by hemodialysis. Prolonged dialysis may lead to a reduction in topiramate concentration below the level required to maintain anticonvulsant effect. To prevent rapid decreases in plasma topiramate concentrations during hemodialysis, supplemental dosing may be necessary. Dose adjustment should consider: 1) duration of the dialysis session; 2) clearance rate of the dialysis system used; 3) the patient’s renal clearance of topiramate while on dialysis.

Hepatic impairment. In patients with moderate to severe hepatic impairment, the clearance of topiramate is reduced by approximately 26%. Therefore, topiramate should be used with caution in patients with hepatic impairment.

Elderly patients. In elderly patients without renal disease, plasma clearance of topiramate is not altered.

Children (under 12 years of age). The pharmacokinetics of topiramate in children, as in adults receiving topiramate as adjunctive therapy, are linear; clearance is dose-independent, and steady-state plasma concentrations increase proportionally with dose. However, clearance is higher and elimination half-life shorter in children compared to adults. Therefore, plasma concentrations of topiramate following the same dose per kilogram of body weight may be lower in children than in adults. As in adults, concomitant use of enzyme-inducing antiepileptic drugs reduces steady-state plasma concentrations of topiramate in children.

Clinical characteristics.

Indications. As monotherapy for the treatment of adults and children aged 6 years and older with partial-onset seizures with or without secondary generalized seizures, and primary generalized tonic-clonic seizures.

As adjunctive therapy for the treatment of adults and children aged 2 years and older with partial-onset seizures with or without secondary generalized seizures, or primary generalized tonic-clonic seizures, and for the treatment of seizures associated with Lennox-Gastaut syndrome.

For the prevention of migraine attacks in adults, after careful evaluation of alternative treatment options. Topiramate is not recommended for the treatment of acute conditions.

Contraindications. Hypersensitivity to any component of the medicinal product. Migraine prophylaxis in pregnant women and women of childbearing potential who are not using highly effective methods of contraception.

Interaction with other medicinal products and other forms of interaction.

Effect of topiramate on other antiepileptic drugs. Co-administration of topiramate with other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect their steady-state plasma concentrations, except in individual patients where concomitant use of topiramate and phenytoin may lead to increased phenytoin plasma concentrations. This may be related to inhibition of the specific polymorphic isoenzyme CYP2C19. Therefore, in any patient receiving phenytoin who develops clinical signs or symptoms of toxicity, plasma phenytoin levels should be monitored.

Pharmacokinetic interaction studies in patients with epilepsy have shown that concomitant administration of topiramate at doses of 100 to 400 mg per day with lamotrigine does not affect steady-state plasma concentrations of lamotrigine. Furthermore, no changes in steady-state plasma concentrations of topiramate were observed during or after discontinuation of lamotrigine treatment (mean dose 327 mg per day).

Topiramate inhibits the CYP2C19 enzyme and may interact with other substances metabolized by this enzyme (e.g., diazepam, imipramine, moclobemide, proguanil, omeprazole).

Effect of other antiepileptic drugs on topiramate. Phenytoin and carbamazepine reduce plasma concentrations of topiramate. Adding or discontinuing phenytoin or carbamazepine during topiramate treatment may require adjustment of the topiramate dose. The dose should be titrated to achieve the desired therapeutic effect. Adding or discontinuing valproic acid does not cause therapeutically relevant changes in topiramate plasma concentrations and therefore does not require dose adjustment of topiramate.

The results of these interactions are presented below.

↔ = no effect (change ≤ 15 %);

** = increased concentration in individual patients;

• = decreased plasma concentration;

ND = not studied;

AED = antiepileptic drug.

Interactions with other medicinal products.

Digoxin. In single-dose studies, the area under the plasma concentration–time curve (AUC) of digoxin decreased by 12 % when co-administered with topiramate. The clinical significance of this observation is unknown. When initiating or discontinuing topiramate in patients receiving digoxin, careful attention should be paid to regular monitoring of serum digoxin concentrations.

Central nervous system (CNS) depressants. Within clinical trials, the concomitant use of topiramate with alcohol or other substances that depress CNS function has not been studied. It is not recommended to take topiramate together with alcohol or other CNS depressants.

St. John’s wort (Hypericum perforatum). Concomitant use of topiramate and St. John’s wort may reduce plasma concentrations of topiramate and decrease its efficacy. Clinical studies on this interaction have not been conducted.

Oral contraceptives. In pharmacokinetic drug interaction studies involving healthy volunteers, administration of topiramate as monotherapy at doses of 50–200 mg/day concomitantly with a combined oral contraceptive (norethindrone 1 mg + ethinylestradiol 35 mcg) was not associated with statistically significant changes in mean concentrations (AUC) of either component of the oral contraceptive. In another study, administration of topiramate at doses of 200, 400, or 800 mg/day as adjunctive therapy to valproic acid in patients with epilepsy was associated with a significant dose-dependent reduction in ethinylestradiol exposure (18 %, 21 %, and 30 %, respectively). In both studies, topiramate (administered at doses of 50–200 mg/day to healthy volunteers and 200–800 mg/day to patients with epilepsy) had no significant effect on norethindrone concentrations. Although dose-dependent reductions in ethinylestradiol concentrations were observed in patients with epilepsy receiving doses of 200–800 mg/day, no significant dose-dependent changes in ethinylestradiol concentrations were observed in healthy volunteers receiving doses of 50–200 mg/day. The clinical significance of these findings is unknown. The risk of reduced contraceptive efficacy and increased breakthrough bleeding should be considered in women taking combined oral contraceptives concomitantly with topiramate. Patients should be advised to report any changes in duration and pattern of bleeding while taking estrogen-containing contraceptives. Even in the absence of breakthrough bleeding, contraceptive efficacy may be reduced.

Lithium. In healthy volunteers, a reduction (up to 18 %) in lithium AUC was observed during concomitant administration of topiramate at a dose of 200 mg/day. In patients with bipolar disorders, lithium pharmacokinetics remained unchanged during concomitant treatment with topiramate at doses of 200 mg/day, whereas administration of topiramate at doses of 600 mg/day was associated with an increase in lithium AUC of up to 26 %. Monitoring of plasma lithium concentrations is recommended when used concomitantly with topiramate.

Risperidone. Interaction studies conducted with single doses in healthy volunteers and multiple doses in patients with bipolar disorders showed similar results. Concomitant administration of risperidone at doses of 1–6 mg/day with topiramate at doses of 100, 250, and 400 mg/day resulted in reductions in risperidone concentrations of 16 % and 33 % in AUC for the 250 mg and 400 mg daily doses, respectively. However, differences in AUC of the active moiety between risperidone monotherapy and combination with topiramate were not statistically significant. Minimal deviations in the pharmacokinetics of the active moiety and active metabolites (risperidone and 9-hydroxyrisperidone) were observed, and no changes were observed in the pharmacokinetics of 9-hydroxyrisperidone. No clinically significant changes in systemic exposure to active metabolites of either risperidone or topiramate were observed. After adding topiramate at doses of 250–400 mg/day to risperidone treatment at doses of 1–6 mg/day, an increased frequency of adverse reactions was observed (90 % and 54 %, respectively). The most common adverse reactions after adding topiramate to risperidone therapy were somnolence (27 % and 12 %), paresthesia (22 % and 0 %), and nausea (18 % and 9 %, respectively).

Hydrochlorothiazide. A drug interaction study in healthy volunteers evaluated the pharmacokinetics of steady-state concentrations of hydrochlorothiazide (25 mg every 24 hours) and topiramate (96 mg every 12 hours) during monotherapy and concomitant administration. The results showed that concomitant administration of topiramate and hydrochlorothiazide increased Cmax and AUC of topiramate by 27 % and 29 %, respectively. The clinical significance of these changes is unknown. Prescribing hydrochlorothiazide to patients taking topiramate may require dose adjustment of topiramate. Pharmacokinetic parameters of hydrochlorothiazide were not significantly altered during concomitant therapy with topiramate. Clinical laboratory tests showed decreased serum potassium levels with administration of either topiramate or hydrochlorothiazide, with a more pronounced effect when both were used in combination.

Metformin. A drug interaction study in healthy volunteers evaluated the pharmacokinetics of steady-state concentrations of metformin and topiramate in plasma during metformin monotherapy and concomitant administration of metformin and topiramate. The results showed that mean Cmax and AUC0-12h of metformin increased by 18 % and 25 %, respectively, while mean CL/F decreased by 20 % when metformin was administered concomitantly with topiramate. Topiramate did not affect tmax of metformin. The clinical significance of the effect of topiramate on metformin pharmacokinetics is unknown. Oral clearance of topiramate from plasma is reduced when administered concomitantly with metformin. The extent of change in clearance is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unknown.

When initiating or discontinuing topiramate in patients receiving metformin, their diabetic status should be monitored regularly.

Pioglitazone. A drug interaction study in healthy volunteers evaluated the pharmacokinetics of steady-state concentrations of topiramate and pioglitazone in plasma during pioglitazone monotherapy and concomitant administration of pioglitazone and topiramate. A 15 % reduction in AUCτ,ss of pioglitazone was observed without changes in Cmax,ss. This result was not statistically significant. Additionally, a 13 % and 16 % reduction in Cmax,ss and AUCτ,ss of the active hydroxymetabolite, respectively, and a 60 % reduction in Cmax,ss and AUCτ,ss of the active ketometabolite were observed. The clinical significance of these results is not established. When prescribing topiramate and pioglitazone concomitantly, patients' diabetic status should be monitored regularly.

Glibenclamide. A drug interaction study in patients with type 2 diabetes evaluated the pharmacokinetics of steady-state concentrations of glibenclamide at a dose of 5 mg/day during monotherapy and concomitant administration with topiramate at a dose of 150 mg/day. A 25 % reduction in AUC24 of glibenclamide was observed when administered concomitantly with topiramate. Systemic exposure to active metabolites 4-trans-hydroxyglibenclamide (M1) and 3-cis-hydroxyglibenclamide (M2) decreased by 13 % and 15 %, respectively. Concomitant treatment with glibenclamide did not affect steady-state concentrations of topiramate.
When prescribing topiramate and glibenclamide concomitantly, patients' diabetic status should be monitored regularly.

Other types of interactions.

Medicinal products promoting nephrolithiasis. Concomitant use of topiramate with other drugs that promote nephrolithiasis may increase the risk of kidney stone formation. During treatment with topiramate, the use of such drugs should be avoided, as they may cause physiological changes leading to nephrolithiasis.

Valproic acid. Concomitant use of topiramate with valproic acid has been associated with hyperammonemia, with or without encephalopathy, in patients who previously tolerated each drug individually. In most cases, symptoms and signs resolved after discontinuation of one of the drugs. This adverse reaction is not related to pharmacokinetic interaction.
Cases of hypothermia (body temperature reduction to < 35 °C) have been reported with concomitant use of valproic acid and topiramate, both with and without hyperammonemia. This adverse reaction in patients receiving both topiramate and valproic acid may occur either at the beginning of topiramate treatment or after an increase in the daily dose.

Warfarin. Decreased prothrombin time/international normalized ratio (PT/INR) has been reported in patients receiving topiramate in combination with warfarin. Therefore, INR should be carefully monitored in patients receiving both topiramate and warfarin.

Additional clinical pharmacokinetic interaction studies. Additional clinical studies were conducted to evaluate potential pharmacokinetic interactions between topiramate and other medicinal products. Changes in Cmax and AUC values resulting from interactions are presented below. The first column lists the medicinal product used during concomitant therapy. The second column describes changes in the concentration of the concomitantly administered medicinal product upon addition of topiramate. The third column (topiramate concentration) indicates the effect of concomitant administration of the medicinal product on topiramate concentration.

a Expressed as a percentage change in Cmax or AUC in plasma compared to monotherapy;

↔ = no effect on Cmax and AUC (less than 15% from baseline values);

ND = not studied;

*DEA = deacetyldiltiazem, DEM = N-demethyldiltiazem;

b AUC of flunarizine increased by 14% in patients receiving flunarizine alone. The increase in effect may be related to its accumulation during attainment of steady-state concentrations.

Special precautions for use.

If rapid discontinuation of topiramate is required, clinical monitoring of the patient is recommended (see additional information in the section "Dosage and administration").
As with other antiepileptic drugs, some patients may experience an increase in seizure frequency or the emergence of new seizure types during treatment with topiramate. These phenomena may result from overdose, decreased plasma concentrations of concomitantly administered antiepileptic drugs, progression of the underlying disease, or a paradoxical effect.
Adequate hydration is very important during topiramate therapy to reduce the risk of nephrolithiasis. Sufficient fluid intake before and during physical exertion or exposure to high temperatures may reduce the risk of temperature-related adverse reactions (see section "Adverse reactions").
Women of childbearing potential. Topiramate may cause fetal malformations and fetal growth restriction (small for gestational age and low birth weight) when administered during pregnancy. Data from the North American Antiepileptic Drug Pregnancy Registry showed approximately a threefold higher prevalence of major congenital malformations (4.3%) with topiramate monotherapy compared to the reference group not taking antiepileptic drugs (1.4%). Furthermore, data from other studies indicate an increased risk of teratogenic effects associated with the use of antiepileptic drugs in combination therapy compared to monotherapy.
Before initiating topiramate therapy, women of childbearing potential should undergo a pregnancy test and be advised to use a highly effective method of contraception (see section "Interaction with other medicinal products and other forms of interaction"). The patient should be fully informed about the risks associated with the use of topiramate during pregnancy (see sections "Contraindications" and "Pregnancy and breastfeeding").
Oligohidrosis. Cases of oligohidrosis (reduced sweating) associated with topiramate use have been reported. Reduced sweating and hyperthermia (elevated body temperature) may occur primarily in young children exposed to high environmental temperatures.
Mood disorders/depression. Increased incidence of mood disorders and depression has been reported during treatment with topiramate.
Suicide/suicidal thoughts. Cases of suicidal thoughts and suicidal behavior have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of placebo-controlled trials of antiepileptic drugs showed a small increased risk of suicidal thoughts and behavior. The mechanism of this phenomenon is unknown, and available data do not exclude the possibility of an increased risk associated with the use of topiramate.
In double-blind controlled trials, suicidal adverse reactions (suicidal thoughts, suicide attempts, and suicide cases) were observed in 0.5% of patients receiving topiramate (46 out of 8,652 patients), approximately three times higher than in patients receiving placebo (0.2%; 8 out of 4,045 patients).
Therefore, monitoring for signs of suicidal thoughts and behavior is recommended in patients receiving this treatment. Patients (and their caregivers) should seek medical advice at the first appearance of suicidal thoughts or behavior.
Nephrolithiasis. Some patients, particularly those predisposed to nephrolithiasis, may have an increased risk of kidney stone formation and associated symptoms such as renal colic, renal pain, or flank pain. Risk factors for nephrolithiasis include a history of kidney stones, family history of nephrolithiasis, and hypercalciuria (see "Metabolic acidosis" below). None of these risk factors can adequately predict the occurrence of stones during topiramate use. Additionally, the risk is further increased in patients taking concomitant medications that promote nephrolithiasis.
Renal function impairment. Topiramate should be used with caution in patients with impaired renal function (CLCR ≤ 70 mL/min) due to reduced plasma and renal clearance of topiramate in these patients. Dosage recommendations for patients with known renal impairment are provided in the section "Dosage and administration".
Hepatic function impairment. Topiramate should be used with caution in patients with hepatic impairment due to the potential for reduced clearance of topiramate.
Acute myopia and secondary angle-closure glaucoma. Cases of acute myopia associated with secondary angle-closure glaucoma have been reported during topiramate use. Symptoms include sudden decrease in visual acuity and/or eye pain. Ophthalmologic examination may reveal myopia, shallow anterior chamber, hyperemia (eye redness), and elevated intraocular pressure. Mydriasis may also be observed. This syndrome may be related to suprachoroidal effusion causing forward displacement of the lens and iris, leading to secondary angle-closure glaucoma. Symptoms typically occur within the first month of topiramate treatment. Unlike primary open-angle glaucoma, which is rarely observed in patients under 40 years of age, secondary angle-closure glaucoma associated with topiramate has been reported in both children and adults. Management includes prompt discontinuation of topiramate and appropriate measures to reduce intraocular pressure.
Elevated intraocular pressure of any etiology, if untreated, may lead to serious complications, including permanent vision loss.
Consideration should be given to whether topiramate can be prescribed to patients with a history of visual disorders.
Visual field defects. Visual field defects not related to elevated intraocular pressure have been observed in patients receiving topiramate. In clinical trials, most cases were reversible and resolved after discontinuation of treatment. If visual defects occur at any time during therapy, discontinuation of the drug should be considered.
Metabolic acidosis. Hyperchloremic, non-anion gap metabolic acidosis (i.e., decreased plasma bicarbonate concentration below normal in the absence of respiratory alkalosis) may occur during topiramate use. Decreased serum bicarbonate concentration results from topiramate's inhibition of carbonic anhydrase in the kidneys. In most cases, the reduction in bicarbonate concentration occurs early in treatment, although this effect may manifest at any time during topiramate therapy. The reduction is usually mild to moderate (on average, 4 mmol/L in adults receiving 100 mg/day and about 6 mg/kg/day in children). In some cases, patients experienced bicarbonate levels below 10 mmol/L. Certain conditions or treatments that lead to acidosis (e.g., kidney disease, severe respiratory disorders, epileptic status, diarrhea, surgery, ketogenic diet, or use of certain medications) may be additional factors that enhance the effect of topiramate on bicarbonate reduction.
Chronic metabolic acidosis increases the risk of kidney stone formation and may potentially lead to osteopenia (see "Nephrolithiasis").
In children, chronic metabolic acidosis may lead to growth retardation. The impact of topiramate on complications related to bone tissue has not been systematically studied in either children or adults.
Depending on the underlying condition, appropriate monitoring, including serum bicarbonate levels, is recommended during topiramate treatment. If symptoms or signs suggestive of metabolic acidosis (such as Kussmaul breathing, dyspnea, anorexia, nausea, vomiting, excessive fatigue, tachycardia, or arrhythmia) occur, serum bicarbonate levels should be measured. If metabolic acidosis develops or progresses, dose reduction or discontinuation of topiramate (through dose tapering) is recommended.
Topiramate should be used with caution in patients with risk factors for metabolic acidosis.
Cognitive function impairment. Cognitive disturbances in epilepsy are multifactorial and may be related to the underlying cause of the disease, epilepsy itself, or antiepileptic treatment. Published reports describe cases of worsening cognitive function in adults receiving topiramate, requiring dose reduction or discontinuation of treatment. However, data on the effects of topiramate on cognitive function in children are insufficient, and the relationship of such effects to drug use requires further study.
Hyperammonemia and encephalopathy. Hyperammonemia with or without encephalopathy has been reported during treatment with topiramate (see section "Adverse reactions"). The risk of hyperammonemia with topiramate use is dose-dependent. Hyperammonemia is reported more frequently when topiramate is used concomitantly with valproic acid (see section "Interaction with other medicinal products and other forms of interaction").
Patients who develop unexplained lethargy or changes in mental status during monotherapy with topiramate or adjunctive therapy should be evaluated for hyperammonemic encephalopathy and ammonia levels in blood should be measured.
Dietary considerations. During topiramate treatment, some patients may lose body weight; therefore, body weight monitoring is recommended. If weight loss occurs during topiramate use, the need for a supportive diet or increased caloric intake should be considered.

Excipients. The medicinal product contains lactose. If the patient has known intolerance to certain sugars, consultation with a physician is necessary before taking this medicinal product.

The product contains the colorants azorubine (E 122) and tartrazine (E 102), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy.

Risk associated with epilepsy and use of antiepileptic medicinal products. Women of childbearing potential should consult a specialist. The need for antiepileptic drug treatment should be reviewed before planning pregnancy. Women receiving antiepileptic drugs should avoid abrupt discontinuation of treatment, as this may lead to seizure exacerbation and cause serious consequences for both the woman and the fetus. Monotherapy should be preferred when possible, as the risk of congenital malformations is higher with combination therapy of antiepileptic drugs.

Risk associated with topiramate use. Topiramate has demonstrated teratogenic effects in mice, rats, and rabbits. In rats, topiramate crosses the placental barrier.

In humans, topiramate crosses the placenta, and similar concentrations are found in umbilical cord and maternal blood.

Registry data indicate that newborns whose mothers used topiramate as monotherapy have:

• an increased risk of congenital malformations (craniofacial defects, including cleft lip/palate, hypospadias, and anomalies of various organ systems) due to topiramate use during the first trimester of pregnancy. Data from the North American Antiepileptic Drug Pregnancy Registry (NAAED) indicate nearly a threefold higher frequency of congenital malformations (4.3%) compared to the control group (1.4%) not taking antiepileptic drugs. Furthermore, data from other studies indicate an increased risk of teratogenic effects with combination therapy of antiepileptic drugs compared to monotherapy. The risk is reported to be dose-dependent; effects were observed at all doses. Women who received topiramate and had a child with congenital malformations have an increased risk of congenital malformations in subsequent pregnancies with topiramate exposure.
• increased frequency of low birth weight (< 2500 grams) compared to the control group.
• increased frequency of intrauterine growth restriction (SGA; defined as birth weight below the 10th percentile adjusted for gestational age and stratified by sex). Long-term outcomes of SGA infants are not established.

Use in epilepsy. Women of childbearing potential are advised to consider alternative treatment options. When treating with topiramate, women of childbearing potential should use highly effective contraceptive methods (see section "Interaction with other medicinal products and other forms of interaction"). During pregnancy, topiramate should be prescribed only after thorough patient counseling about the known risks of uncontrolled epilepsy to pregnancy and the potential effects of the drug on the fetus. Planning pregnancy requires consultation with a physician to reassess treatment and consider alternative therapies. Careful prenatal monitoring is necessary if topiramate is used during the first trimester of pregnancy.

Use for migraine prophylaxis. Topiramate is contraindicated for migraine prophylaxis in pregnant women and in women of childbearing potential who are not using highly effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction", "Contraindications").

Breastfeeding period. Excretion of topiramate into breast milk has been demonstrated in animal studies. Excretion of topiramate into human breast milk has not been studied in controlled trials. Limited observations suggest that topiramate passes into breast milk in significant amounts. Effects observed in breastfed newborns/infants include diarrhea, somnolence, irritability, and inadequate weight gain.

Since most medicinal products pass into breast milk, a decision must be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug for the mother (see section "Special precautions for use").

Fertility. Animal studies did not reveal any harmful effects of topiramate on fertility. The effect of topiramate on human fertility has not been established.

Ability to affect reaction speed when driving or operating machinery. Topiramate has a minor or moderate effect on the ability to drive and operate machinery.

Topiramate acts on the central nervous system and may cause somnolence, dizziness, and other symptoms. It may also cause visual disturbances and/or blurred vision. These adverse effects may be potentially hazardous for patients driving or operating machinery, particularly when the patient has not yet gained individual experience with the drug.

Dosage and Administration.

Treatment is recommended to begin with a low dose, followed by gradual titration to an effective dose. The dose and rate of dose escalation should be individualized based on clinical response.

Monitoring plasma concentrations of topiramate is not necessary for optimizing treatment with topiramate. In rare cases, co-administration of topiramate with phenytoin may require adjustment of the phenytoin dose to achieve optimal clinical effect. Adding or discontinuing phenytoin or carbamazepine as adjunctive therapy during treatment with topiramate may require adjustment of the topiramate dose.

The medicinal product can be taken independently of food intake.

Discontinuation of antiepileptic drugs, including topiramate, should be performed gradually to minimize the risk of seizure occurrence or increased seizure frequency, regardless of whether patients have a history of epileptic seizures. In clinical trials, daily doses were reduced by 50–100 mg weekly in adults with epilepsy, and by 25–50 mg weekly in adults receiving topiramate at doses up to 100 mg daily for migraine prophylaxis. In pediatric clinical trials, topiramate was discontinued gradually over 2–8 weeks.

Epilepsy monotherapy. When discontinuing concomitant antiepileptic drugs to transition to topiramate monotherapy, the potential impact of this step on seizure frequency should be considered. If safety considerations do not require immediate discontinuation of the concomitant antiepileptic drug, it is recommended to gradually reduce its dose by one-third every 2 weeks.

When discontinuing enzyme-inducing antiepileptic drugs, plasma concentrations of topiramate will increase. In such cases, if clinically indicated, the topiramate dose may be reduced.

Adults. The dose should be titrated according to clinical response. Treatment should begin with a nightly dose of 25 mg for 1 week, followed by weekly or biweekly increments of 25 or 50 mg daily (the daily dose administered in two divided doses). If the patient does not tolerate this titration regimen, the intervals between dose increases may be extended or smaller dose increments used.

The recommended initial target dose level for topiramate monotherapy in adults is 100–200 mg daily, divided into two doses. The maximum recommended dose is 500 mg daily, divided into two doses. Some patients with refractory forms of epilepsy tolerate monotherapy with topiramate at a dose of 1000 mg daily. These dosage recommendations apply to all adult patients, including elderly individuals, provided they do not have renal disease.

Children (aged 6 years and older). The dose for children should be titrated according to clinical response. Treatment in children aged 6 years and older should begin with a nightly dose of 0.5–1 mg/kg for 1 week, followed by weekly or biweekly increments of 0.5–1 mg/kg daily (the daily dose administered in two divided doses). If the child does not tolerate this titration regimen, the intervals between dose increases may be extended or smaller dose increments used.

The recommended initial target dose of topiramate for monotherapy in children aged 6 years and older is 100 mg daily, depending on clinical response (approximately 2 mg/kg body weight daily for children aged 6 to 16 years).

Adjunctive therapy for epilepsy (partial seizures with or without secondary generalization, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome).

Adults. Treatment should begin with a nightly dose of 25–50 mg for 1 week. Lower starting doses have been reported, but have not been systematically studied. Subsequently, the dose should be increased weekly or biweekly by 25–50 mg daily (the daily dose administered in two divided doses). In some patients, efficacy may be achieved with once-daily dosing.

In clinical trials of topiramate as adjunctive therapy, the minimal effective dose was 200 mg daily. The usual daily dose is 200–400 mg in two divided doses.

These dosage recommendations apply to all adult patients, including elderly individuals, provided they do not have renal disease (see section "Special Warnings and Precautions for Use").

Children (aged 2 years and older). The recommended total daily dose of topiramate as adjunctive therapy is approximately 5–9 mg/kg body weight daily in two divided doses. Treatment should begin with a nightly dose of 25 mg (or lower, calculated as 1–3 mg/kg daily) for 1 week, followed by weekly or biweekly increments of 1–3 mg/kg daily (the daily dose administered in two divided doses) until therapeutic effect is achieved. In clinical trials, doses up to 30 mg/kg daily were studied and generally well tolerated.

Migraine.

Adults. The recommended total daily dose of topiramate for migraine prophylaxis is 100 mg, divided into two doses. Treatment should begin with 25 mg in the evening for 1 week, followed by weekly increments of 25 mg daily, with a 1-week interval after each dose increase. If the patient does not tolerate this titration regimen, the intervals between dose increases may be extended.

In some patients, clinical response is achieved with 50 mg of topiramate daily. In clinical trials, patients received up to 200 mg of topiramate daily. This dosage may be effective in some patients, but should be prescribed cautiously to minimize the risk of increased adverse reactions.

Special patient groups.

Renal impairment. Since plasma and renal clearance of topiramate are reduced in patients with impaired renal function (CLCR ≤ 70 mL/min), topiramate should be administered with caution in such patients. Patients with known renal impairment may require a longer time to reach steady-state after each dose. It is recommended to use half the usual initial and maintenance dose (see section "Pharmacological Properties").

Topiramate is removed from plasma during hemodialysis; therefore, in patients with end-stage renal disease, an additional dose of topiramate—approximately half the usual daily dose—is recommended on hemodialysis days. This additional dose should be divided into two doses and administered at the beginning and after completion of the hemodialysis procedure. The additional dose may vary depending on the characteristics of the dialysis system used (see section "Pharmacological Properties").

Hepatic impairment. Topiramate should be administered with caution in patients with moderate to severe hepatic impairment due to reduced clearance of topiramate.

Elderly patients. Dose adjustment is not required for elderly patients unless they have renal impairment.

Children.

Monotherapy for epilepsy. For use in children aged 6 years and older.

Adjunctive therapy (partial seizures with or without secondary generalization, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome). For use in children aged 2 years and older.

Migraine. Topiramate is not recommended for the treatment or prophylaxis of migraine in children due to insufficient data on safety and efficacy.

Overdose.

Symptoms. Cases of topiramate overdose have been reported. Signs and symptoms of topiramate overdose include seizures, somnolence, speech difficulties, blurred vision, diplopia, cognitive disturbances, coordination impairment, lethargy, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. In most cases, no severe clinical consequences occurred, but fatal cases have been reported following overdose involving multiple drugs, including topiramate. Topiramate overdose may cause severe metabolic acidosis (see "Special Warnings and Precautions for Use").

Treatment. In acute topiramate overdose, if ingestion was recent, gastric lavage or induction of emesis should be performed immediately. In vitro studies have shown that activated charcoal adsorbs topiramate. Symptomatic treatment should be administered as needed, and patients are advised to maintain adequate fluid intake. Hemodialysis is an effective method for removing topiramate from the body.

Adverse Reactions

The safety profile of topiramate was evaluated based on data from the clinical trial database involving 4111 patients (3182 receiving topiramate and 929 receiving placebo) who participated in 20 double-blind studies, and 2847 patients who participated in 34 open-label studies, using topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures, partial seizures, seizures associated with Lennox-Gastaut syndrome, as well as monotherapy for the treatment of newly diagnosed or recently diagnosed epilepsy or migraine prophylaxis. Most adverse reactions were of mild to moderate severity. The table below lists adverse reactions observed during clinical trials and in the post-marketing period. Adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), and not known (cannot be estimated from available data).

The most commonly observed adverse reactions with an incidence > 5% and occurring at a higher frequency than in the placebo group during topiramate clinical trials were: anorexia, decreased appetite, bradypsychia, depression, expressive speech disorder, insomnia, coordination disturbances, attention disturbances, dizziness, dysarthria, taste disturbance, hypoesthesia, lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, blurred vision, diarrhea, nausea, fatigue, irritability, and weight decreased.

*Adverse reactions reported in the post-marketing period (spontaneous reports). Their frequency was determined based on clinical trial data.

Congenital malformations and fetal growth restriction (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

Special safety profile in children.

Adverse reactions observed in children at least twice as frequently as in adults during double-blind controlled studies: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disorders, aggression, apathy, primary insomnia, suicidal thoughts, difficulty concentrating, lethargy, sleep-wake cycle disturbances, poor sleep quality, increased lacrimation, sinus bradycardia, unusual sensations, gait disturbances.

Unwanted reactions observed only in children during double-blind controlled studies: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, and learning disability.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Film-coated tablets, 25 mg, 50 mg, or 100 mg, pack of 10x3 in blisters in a box.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, 100.

(Limited Liability Company "FARMEKS GROUP")