Topiromax 25

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOPIROMAX 25 (TOPIROMAX 25) TOPIROMAX 100 (TOPIROMAX 100)

Composition:

Active substance: topiramate;

1 tablet contains topiramate 25 mg or 100 mg;

Excipients: microcrystalline cellulose; lactose monohydrate; pregelatinized starch; sodium starch glycolate (type A); copovidone; talc; colloidal anhydrous silicon dioxide; magnesium stearate;

Coating for film coating application Opadry II White (Topiromax 25): polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide (E 171);

Coating for film coating application Opadry II Yellow (Topiromax 100): polyvinyl alcohol, polyethylene glycol, quinoline yellow (E 104), talc, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

25 mg tablets: film-coated tablets, white, biconvex, round in shape;

100 mg tablets: film-coated tablets, yellow, biconvex, round in shape.

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 exact mechanism of the anticonvulsant and migraine prophylactic action of topiramate is unknown. Three pharmacological properties of topiramate have been identified that may contribute to its antiepileptic efficacy. Topiramate blocks voltage-gated sodium channels and inhibits the generation of sustained repetitive firing of action potentials during prolonged neuronal membrane depolarization. Topiramate enhances the frequency of γ-aminobutyric acid (GABA)-mediated activation of GABA_A 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. In addition, topiramate does not increase the duration of open ion channel time, which distinguishes it from barbiturates that modulate GABA_A receptors.

Topiramate may modulate the benzodiazepine-insensitive subtype of GABA_A receptors due to 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) activity within the NMDA receptor subtype. These effects of topiramate are dose-dependent at plasma concentrations ranging from 1 μmol to 200 μmol, with minimal activity observed between 1 μmol and 10 μmol. Additionally, 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 is not considered a primary component of its antiepileptic activity.

Pharmacokinetics

The pharmacokinetic profile of topiramate, compared to other antiepileptic drugs, is characterized by a long plasma half-life, linear pharmacokinetics, 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 topiramate 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 (C_max) of 1.5 μg/mL was reached within 2–3 hours (T_max). 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 reaches saturation 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 ranges from 0.80 to 0.55 L/kg. The volume of distribution is influenced by sex: it is approximately 50% lower in women than in men, which is attributed to higher body fat content in women; this difference is not considered clinically significant.

Metabolism. In healthy volunteers, topiramate undergoes minimal metabolism (~20%). However, in patients receiving concomitant antiepileptic therapy with drugs known to induce drug-metabolizing enzymes, 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 accounts for less than 3% of 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 dose of ¹⁴C-topiramate is excreted unchanged in urine within 4 days. After administration of 50 mg and 100 mg topiramate twice daily, 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 animal studies in rats where co-administration of probenecid resulted in a marked 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 (AUC) increases proportionally with doses ranging from 100 mg to 400 mg in healthy volunteers. At steady state, plasma concentrations are achieved within 4–8 days in patients with normal renal function. The C_max 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 twice daily, the mean plasma half-life of topiramate 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 (creatinine clearance ≤70 mL/min), both plasma and renal clearance of topiramate are reduced. As a result, for a given dose, higher steady-state plasma concentrations of topiramate are expected in patients with impaired renal function compared to those with normal renal function. 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 hemodialysis may reduce topiramate concentrations 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) dialysis system clearance rate; 3) the patient’s renal clearance of topiramate while on dialysis.

Hepatic impairment. In patients with moderate to severe hepatic impairment, topiramate clearance 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.

Pharmacokinetics in children under 12 years of age.

The pharmacokinetic properties of topiramate in children, as in adults, studied during adjunctive therapy, demonstrate linear kinetics with dose-independent clearance and steady-state plasma concentrations increasing proportionally with dose. However, children have higher clearance rates and shorter half-lives. Therefore, plasma concentrations of topiramate at the same doses in mg/kg may be lower in children compared to adults. As in adults, concomitant use of enzyme-inducing antiepileptic drugs reduces steady-state plasma concentrations of topiramate.

Clinical characteristics.

Indications.

• Monotherapy in the treatment of adults and children aged 6 years and older with partial epileptic seizures with or without secondary generalized seizures, and with primary generalized tonic-clonic seizures.

• Adjunctive therapy in the treatment of adults and children aged 2 years and older with partial epileptic seizures with or without secondary generalized seizures, or with primary generalized tonic-clonic seizures, and in the treatment of seizures associated with Lennox-Gastaut syndrome.

• Prevention of migraine attacks in adults after careful assessment of alternative treatment options.

Topiramate is not recommended for the treatment of acute conditions.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Migraine prevention:

• during pregnancy (see sections "Special precautions for use" and "Use in pregnancy or lactation").
• in women of childbearing potential who are not using highly effective contraceptive methods (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Use in pregnancy or lactation").

Epilepsy:

• during pregnancy if there is no appropriate alternative treatment (see sections "Special precautions for use" and "Use in pregnancy or lactation").
• in women of childbearing potential who are not using highly effective contraceptive methods. The only exception is women for whom no appropriate alternative is available, but who plan pregnancy and are fully informed about the risks of taking topiramate during pregnancy (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Use in pregnancy or lactation").

Interaction with other medicinal products and other forms of interaction.

Effect of topiramate on other antiepileptic drugs.

Concomitant 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 plasma concentrations of phenytoin. This may be related to inhibition of a specific polymorphic isoenzyme (CYP2C19). In each patient receiving phenytoin who develops clinical signs or symptoms of intoxication, plasma phenytoin levels should be monitored.

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

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

Effect of other antiepileptic drugs on the medicinal product Topiromax.

Phenytoin and carbamazepine reduce plasma concentrations of topiramate. Addition (or discontinuation) of phenytoin or carbamazepine to topiramate therapy may require adjustment of the latter's dosage. Dosage should be titrated based on achieving the desired therapeutic effect.

Addition (or discontinuation) of valproic acid does not cause therapeutically significant changes in plasma concentrations of topiramate and therefore does not necessitate dose adjustments of topiramate.

The effect of phenobarbital and primidone on topiramate concentration has not been studied.

Table 1.

↔ = no effect (change ≤ 15 %);

** = increased concentration in individual patients;

• = decreased plasma concentration;

ND = not studied;

AED = antiepileptic drug.

Other drug interactions.

Digoxin. It is known that 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 has not been established. When initiating or discontinuing topiramate in patients taking digoxin, particular attention should be paid to regular monitoring of serum digoxin concentrations.

CNS depressants. The effects of concomitant use of topiramate with alcohol or other substances that depress central nervous system (CNS) function have not been studied. It is not recommended to take topiramate concomitantly with alcohol or medications that cause CNS depression.

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

Systemic hormonal contraceptives. The clinical significance of observed changes is unknown. In women taking systemic hormonal contraceptives with the medicinal product Topiromax, a reduced contraceptive effectiveness and increased breakthrough bleeding should be considered. Patients should be advised to report any changes in bleeding patterns. Contraceptive effectiveness may decrease even in the absence of breakthrough bleeding. Women using systemic hormonal contraceptives should be advised to also use a barrier method of contraception.

Lithium. It is known that in healthy volunteers, a decrease (up to 18 %) in lithium AUC was observed during concomitant administration of topiramate at a dose of 200 mg per day. In patients with bipolar disorder, lithium pharmacokinetics remained unchanged during concomitant treatment with topiramate at doses of 200 mg per day, whereas administration of topiramate at doses of 600 mg per day resulted in an increase in lithium AUC of up to 26 %. Monitoring of lithium levels is recommended when used concomitantly with topiramate.

Risperidone. Studies on interaction conducted with single doses in healthy volunteers and multiple doses in patients with bipolar disorder showed similar results. When risperidone (1–6 mg per day) was administered concomitantly with increasing doses of topiramate (100, 250, and 400 mg per day), a decrease in the area under the concentration–time curve (AUC) of risperidone was observed, with reductions of 16 % and 33 % at topiramate doses of 250 mg and 400 mg per day, respectively. However, differences in AUC for total active metabolites when risperidone was administered alone or in combination with topiramate were not statistically significant. Minimal changes were observed in the pharmacokinetics of active metabolites (risperidone + 9-hydroxyrisperidone), and no changes were observed for 9-hydroxyrisperidone. No clinically significant changes in the pharmacokinetics of active metabolites of either risperidone or topiramate were observed. After adding topiramate (250–400 mg per day) to risperidone therapy (1–6 mg per day), an increased frequency of adverse reactions was observed compared to the period before adding topiramate (90 % vs. 54 %, respectively). The most common adverse reactions after adding topiramate to risperidone treatment were somnolence, paresthesia, and nausea.

Hydrochlorothiazide. In an interaction study in healthy volunteers, the pharmacokinetics of steady-state concentrations of hydrochlorothiazide (25 mg every 24 hours) and topiramate (96 mg every 12 hours) were evaluated during monotherapy and concomitant administration. Results showed that Cmax and AUC of topiramate increased by 27 % and 29 %, respectively, when administered concomitantly with hydrochlorothiazide. 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. The study showed a reduction in serum potassium levels with either topiramate or hydrochlorothiazide, which was more pronounced when both were used in combination.

Metformin.

In an interaction study in healthy volunteers, the pharmacokinetics of steady-state concentrations of metformin and topiramate in plasma were evaluated during metformin monotherapy and concomitant administration of metformin and topiramate. 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 clearance change is unknown. The clinical significance of the effect of metformin on topiramate pharmacokinetics is unknown.

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

Pioglitazone.

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

Glibenclamide. In an interaction study in patients with type 2 diabetes, the pharmacokinetics of steady-state concentrations of glibenclamide at a dose of 5 mg per day were evaluated during monotherapy and concomitant administration with topiramate at a dose of 150 mg per day. A 25 % decrease 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.

Drugs promoting nephrolithiasis.

Concomitant use of topiramate and other drugs that promote nephrolithiasis may increase the risk of kidney stone formation. During treatment with topiramate, 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 led to hyperammonemia with or without encephalopathy in patients who tolerated monotherapy with these agents well. In most cases, symptoms resolved after discontinuation of one of the drugs. This adverse effect is not related to pharmacokinetic interaction.

Cases of hypothermia, defined as unintentional decrease in body temperature to < 35 °C, associated with concomitant use of valproic acid and topiramate, both with and without hyperammonemia, have been reported. This adverse reaction in patients receiving topiramate and valproic acid concomitantly may occur both at the initiation of topiramate treatment and after an increase in 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 topiramate and warfarin concomitantly.

Additional studies on drug pharmacokinetic interactions.

Additional clinical studies have been conducted to evaluate potential pharmacokinetic interactions between topiramate and other medicinal products. Changes in Cmax and AUC values resulting from interactions are presented in Table 2. 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.

Table 2

Summary of results from additional clinical studies on pharmacokinetic drug interactions.

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

↔ – no effect on Cmax and AUC (less than 15% change from baseline).

ND – not studied.

*DEA – deacetyldiltiazem, DEM – N-dimethyldiltiazem.

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

Special precautions for use.

Pregnancy prevention program.

Topiramate may cause serious congenital malformations and fetal growth retardation when used during pregnancy.

Some data suggest an increased risk of nervous system development disorders in children exposed to topiramate in utero compared to children not exposed to this medicinal product (see section "Use during pregnancy or breastfeeding").

Women of childbearing potential

Before initiating topiramate treatment, women of childbearing potential must be tested for pregnancy. The patient should be fully informed and understand the risks associated with the use of topiramate during pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding"). This includes the necessity of consulting a specialist if the woman plans pregnancy to discuss switching to alternative treatments before discontinuing contraception, as well as seeking immediate medical advice if she becomes pregnant or suspects she may be pregnant.

Female children.

• The prescribing physician must ensure that parents/guardians of female children receiving topiramate understand the necessity of consulting a specialist once the child reaches menarche. At this time, the patient and parents/guardians should be provided with comprehensive information about the risks associated with in utero exposure to topiramate, as well as the need for using highly effective contraceptive methods as soon as feasible. The necessity of continuing topiramate therapy should be re-evaluated, and alternative treatment options should be considered.
• Educational materials regarding these measures are available for healthcare professionals and patients (or parents/guardians).

If rapid discontinuation of topiramate is necessary, clinical monitoring of the patient is recommended (see section "Dosage and administration" for additional information).

As with other antiepileptic drugs, some patients may experience increased 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, disease progression, or paradoxical effects.

Adequate hydration is very important during topiramate use to reduce the risk of nephrolithiasis. Consumption of sufficient fluids before and during physical exertion or exposure to high temperatures may reduce the risk of temperature-dependent adverse reactions (see section "Adverse reactions").

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 ambient temperatures.

Mood disorders/depression.

An 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 has shown 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 increased risk associated with topiramate use.

Therefore, patients should be monitored for signs of suicidal thoughts and behavior, and appropriate treatment should be initiated. Patients (and caregivers) should seek medical advice at the first sign 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, kidney pain, or flank pain. Risk factors for nephrolithiasis include a history of kidney stones, family history of nephrolithiasis, and hypercalciuria. None of these risk factors can adequately predict the occurrence of stones during topiramate use. Furthermore, the risk is additionally increased in patients taking concomitant medications that promote nephrolithiasis.

Renal function impairment.

Topiramate should be used with caution in patients with renal impairment (CLCR ≤ 70 mL/min) due to reduced plasma and renal clearance of topiramate in such 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 topiramate clearance.

Acute myopia and secondary angle-closure glaucoma.

Cases of acute myopia syndrome associated with secondary angle-closure glaucoma have been reported during topiramate use. Symptoms include sudden decrease in visual acuity and/or eye pain. Ophthalmological examination may reveal myopia, reduced depth of the anterior chamber of the eye, hyperemia (eye redness), and elevated intraocular pressure. Mydriasis may also occur. This syndrome may be related to suprachoroidal effusion causing 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 use has been observed in both children and adults. Treatment involves 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 disturbances.

Visual field defects.

Visual field defects not related to elevated intraocular pressure have been observed in patients receiving topiramate treatment. Clinical trials have reported that most such 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.

Topiramate may cause hyperchloremic, non-anion gap metabolic acidosis (i.e., decreased plasma bicarbonate concentration below normal in the absence of respiratory alkalosis). 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 degree of reduction is usually mild or moderate (on average, 4 mmol/L in adults receiving a 100 mg daily dose and approximately 6 mg/kg body weight daily in children). In some cases, patients have experienced bicarbonate concentrations below 10 mmol/L. Certain conditions or treatments that lead to acidosis (e.g., kidney disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or use of certain medications) may be additional factors enhancing the effect of topiramate on bicarbonate reduction.

Chronic metabolic acidosis increases the risk of kidney stone formation and may potentially lead to osteopenia.

In children, chronic metabolic acidosis may lead to growth retardation. The impact of topiramate on bone-related complications has not been systematically studied in either children or adult patients.

Depending on the underlying condition, appropriate tests, including serum bicarbonate levels, are recommended during topiramate treatment. If symptoms or signs (e.g., Kussmaul breathing, dyspnea, anorexia, nausea, vomiting, excessive fatigue, tachycardia, or arrhythmia) suggestive of metabolic acidosis occur, serum bicarbonate levels should be tested. If metabolic acidosis develops or progresses, dose reduction or discontinuation of topiramate (by dose tapering) is recommended.

Topiramate should be used with caution in patients with risk factors for metabolic acidosis.

Cognitive function impairment.

Cognitive impairments in epilepsy are multifactorial and may be related to the underlying cause of the disease, epilepsy itself, or antiepileptic treatment. Literature reports describe cases of worsening cognitive function in adults receiving topiramate treatment, requiring dose reduction or discontinuation of the drug. However, existing data on the effects of topiramate on cognitive function in children are insufficient, and the relationship requires further study.

Hyperammonemia and encephalopathy.

Hyperammonemia with or without encephalopathy has been reported during topiramate treatment (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 mental status changes during monotherapy with topiramate or adjunctive therapy should be evaluated for hyperammonemic encephalopathy and blood ammonia levels should be measured.

Special dietary considerations. If a patient experiences weight loss during topiramate use, supportive diet or increased caloric intake may be recommended.

The product contains lactose and is therefore not recommended for patients with lactase deficiency, galactosemia, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy.

Risk associated with epilepsy and use of antiepileptic medicinal products.

Women of childbearing potential, particularly those planning pregnancy, and pregnant women should receive specialist counseling regarding potential risks to the fetus from both seizures and antiepileptic treatment. When planning pregnancy, the necessity of antiepileptic drug treatment should be reviewed. Women receiving antiepileptic drugs should avoid abrupt discontinuation of treatment, as this may lead to seizure exacerbation and serious consequences for both the woman and the fetus. Monotherapy should be preferred whenever possible, as the risk of congenital malformations is higher with combination antiepileptic therapy.

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.

Clinical data from pregnancy registries indicate that newborns exposed to topiramate in utero as monotherapy have:

Serious congenital malformations and fetal growth retardation

• An increased risk of congenital malformations (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 three times higher frequency of congenital malformations (4.3%) compared to the control group not taking antiepileptic drugs (1.4%). Data from an observational population-based registry study conducted in Scandinavian countries indicate a 2- to 3-fold increase in the frequency of serious congenital malformations (up to 9.5%) compared to the control group not taking AEDs (3.0%). Additionally, data from other studies indicate an increased risk of teratogenic effects with combination antiepileptic therapy compared to monotherapy. The risk is reported to be dose-dependent; effects were observed with all doses. Women who received topiramate and gave birth to a child with congenital malformations have an increased risk of congenital malformations in subsequent pregnancies exposed to topiramate.
• Increased frequency of low birth weight (<2500 grams) compared to the control group.
• Increased frequency of intrauterine growth retardation (SGA; defined as newborn body weight below the 10th percentile adjusted for gestational age and stratified by sex). In the North American pregnancy registry of women taking antiepileptic drugs, the risk of SGA in children of women receiving topiramate was 18% compared to 5% in children of women without epilepsy not taking AEDs. The long-term consequences of SGA in infants are not established.

Neurodevelopmental disorders

• Data from two observational population-based registry studies conducted on nearly identical datasets in Scandinavian countries indicate that the prevalence of autism spectrum disorders, intellectual disability, or attention deficit hyperactivity disorder (ADHD) in nearly 300 children whose mothers had epilepsy and used topiramate during pregnancy was 2 to 3 times higher than in children of mothers with epilepsy who did not take AEDs during pregnancy. A third observational cohort study conducted in the United States did not find an increased cumulative frequency of these outcomes up to age 8 in approximately 1000 children whose mothers had epilepsy and used topiramate during pregnancy compared to children of mothers with epilepsy who did not receive AEDs.

Use in epilepsy. Topiramate is contraindicated during pregnancy unless there is no appropriate alternative treatment (see sections "Contraindications" and "Special precautions for use").

• Women of childbearing potential must be fully informed about and understand the risks of using topiramate during pregnancy. This includes discussion of the risks of uncontrolled epilepsy for pregnancy.
• If a woman plans pregnancy, efforts should be made to switch to appropriate alternative treatment before discontinuing contraception.
• If a woman becomes pregnant while taking topiramate, she should be referred immediately to a specialist for re-evaluation of topiramate treatment and consideration of alternative treatment options.
• If topiramate is used during pregnancy, the patient should be referred to a specialist for pregnancy evaluation and counseling. Careful prenatal screening should be performed.

Use for migraine prophylaxis. Topiramate is contraindicated for migraine prophylaxis in pregnant women (see sections "Special precautions for use", "Contraindications").

Women of childbearing potential

Topiramate is contraindicated in women of childbearing potential who are not using effective contraceptive methods. The only exception is women with epilepsy for whom no appropriate alternative exists, but who plan pregnancy and are fully informed about the risks associated with taking topiramate during pregnancy (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Use during pregnancy or breastfeeding").

During treatment and for at least 4 weeks after discontinuation of topiramate, at least one highly effective method of contraception (e.g., intrauterine device) or two additional forms of contraception, including a barrier method, should be used (see sections "Contraindications", "Special precautions for use", and "Interaction with other medicinal products and other forms of interaction").

Women of childbearing potential should consider alternative treatment methods.

Before initiating topiramate treatment, women of childbearing potential should undergo a pregnancy test.

The patient must be fully informed and understand the risks associated with using topiramate during pregnancy. This includes the necessity of consulting a specialist if she plans pregnancy and seeking immediate medical advice if she becomes pregnant or suspects she may be pregnant while taking topiramate.

For women with epilepsy, the risk of uncontrolled epilepsy for pregnancy should also be considered (see sections "Contraindications" and "Special precautions for use").

For female children, see section "Special precautions for use".

Period of breastfeeding.

It is known from animal studies that topiramate is excreted in breast milk. Excretion of topiramate into human breast milk has not been studied in controlled trials. Limited observations suggest that topiramate passes into human 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 regarding the necessity of discontinuing breastfeeding or stopping the drug, considering the importance of the drug to 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 vehicles or operating machinery.

Topiramate has a minor or moderate influence on the ability to drive vehicles and operate machinery.

Topiramate acts on the central nervous system and may cause somnolence, dizziness, and other similar symptoms. It may also cause visual disturbances and/or blurred vision. These side effects are generally mild to moderate but may be potentially hazardous for patients driving vehicles or operating machinery, especially when the patient has not yet gained individual experience with the drug.

Dosage and Administration

Treatment should be initiated at the lowest dose, with subsequent gradual titration to an effective dose. The dose of the drug and the rate of its escalation should be adjusted according to the therapeutic response. The drug can be taken independently of food intake.

Monitoring of topiramate plasma concentration is not necessary for optimizing therapy with the drug. In rare cases, concomitant therapy with phenytoin and topiramate may require adjustment of the phenytoin dose to achieve optimal clinical effect. Addition or discontinuation of phenytoin or carbamazepine during concomitant therapy with topiramate may require adjustment of the topiramate dose.

Antiepileptic drugs, including topiramate, should be discontinued gradually to minimize the risk of seizure occurrence or increased seizure frequency, regardless of whether seizures or epilepsy are present in the patient's history. Daily doses should be reduced by 50–100 mg at weekly intervals in adult patients with epilepsy, and by 25–50 mg in adults who have been receiving topiramate at doses up to 00 mg daily for migraine prophylaxis. Discontinuation of topiramate in children should be performed gradually over 2–8 weeks.

Female children and women of reproductive age.

Topiramate treatment should be initiated and supervised by a physician experienced in the treatment of epilepsy or migraine.

Alternative treatment options should be considered in female children and women of reproductive age. The need for topiramate treatment in these patient groups should be reviewed at least annually (see sections "Contraindications", "Special precautions", and "Use in pregnancy or breastfeeding").

Epilepsy.

Monotherapy.

When discontinuing concomitant antiepileptic drugs to switch to topiramate monotherapy, the potential impact of this step on seizure frequency should be considered. If there is no safety-related necessity for immediate discontinuation of concomitant antiepileptic agents, a sequential reduction of their doses by approximately one-third of the previous dose over 2 weeks is recommended. After discontinuation of drugs with enzyme-inducing properties affecting drug metabolism, topiramate levels increase. In such cases, the topiramate dose may be reduced if clinically indicated.

Adults. The dose should be titrated according to clinical response. Treatment should be initiated at a dose of 25 mg of topiramate at night for one week. Thereafter, the dose may be increased by 25–50 mg at weekly or two-weekly intervals, administered in two divided doses. If the patient does not tolerate dose escalation, smaller increments or longer intervals between dose increases may be used.

The recommended initial target dose of Topiramax in monotherapy for adults is 100–200 mg daily, divided into two doses, with a maximum recommended dose of 500 mg daily. Some patients with refractory forms of epilepsy tolerate monotherapy with Topiramax at a dose of 1000 mg daily. These dosage recommendations may be applicable to all adult patients, including elderly patients, in the absence of 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 be initiated at a dose of 0.5–1 mg/kg body weight of topiramate at night for the first week. Thereafter, the dose may be increased by 0.5–1 mg/kg body weight daily at weekly or two-weekly intervals, with the daily dose divided into two administrations. If the child does not tolerate the dose titration schedule, smaller increments or longer intervals between dose increases may be used.

The recommended initial target dose of Topiramax in monotherapy for children aged 6 years and older is 100 mg daily, depending on clinical response (approximately 2 mg/kg body weight daily for children aged 6–16 years). If lower doses are required, other topiramate formulations allowing such dosing should be used.

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 is initiated at a dose of 25–50 mg of the drug at night for one week. Lower starting doses have been reported, but have not been systematically studied. Thereafter, the dose may be increased by 25–50 mg at weekly or two-weekly intervals, divided into two doses. Dose titration should be guided by therapeutic effect. In some patients, efficacy may be achieved with once-daily administration.

The minimum effective dose is 200 mg. The maintenance dose ranges from 200 to 400 mg daily, administered in two divided doses.

These dosage recommendations may be applicable to all adult patients, including elderly individuals, provided there is no renal impairment (see section "Special precautions").

Children aged 2 years and older.

The recommended daily dose of Topiramax for adjunctive therapy is on average 5–9 mg/kg body weight, divided into two doses. Treatment should be initiated with dose titration by administering 25 mg (or less, based on a dosing range of 1–3 mg/kg body weight daily) at night for one week. Thereafter, the dose may be increased by 1–3 mg/kg body weight daily at weekly or two-weekly intervals, administered in two divided doses, until therapeutic effect is achieved. Dose titration should be guided by therapeutic effect. A dose of 30 mg/kg body weight daily has been well established in clinical trials.

Migraine.

Adults.

For prophylaxis of migraine attacks in adults, the recommended daily dose of topiramate is 100 mg, divided into two doses. Treatment should be initiated at 25 mg in the evening for one week. Thereafter, the dose should be increased by 25 mg daily at weekly intervals after each dose increment. Smaller dose increments or longer intervals between increases may be used if the patient does not tolerate the specified titration schedule.

In some patients, a positive outcome is achieved with a daily dose of topiramate of 50 mg. Clinical studies have shown that patients received daily doses of topiramate up to 200 mg daily. Such dosing may be effective for some patients, but should be prescribed cautiously to prevent an increased incidence of adverse effects. Dose titration should be guided by therapeutic efficacy.

Special patient groups.

Renal impairment. Topiramate should be used with caution in patients with impaired renal function (CLCR ≤ 70 mL/min), as plasma and renal clearance of topiramate is reduced in such patients. These patients require a longer time to reach steady state after each dose. It is recommended to use half the usual initial and maintenance dose.

Topiramate is eliminated from plasma during hemodialysis. Patients with end-stage renal disease should receive an additional dose of topiramate on hemodialysis days, approximately half of the daily dose. The additional dose should be divided into two administrations and given before and after the hemodialysis procedure. The additional dose may vary depending on the characteristics of the hemodialysis equipment used.

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

Elderly patients. Dose adjustment is not required for elderly patients in the absence of 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-Gastau 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.

Cases of topiramate overdose have been reported.

Symptoms and signs of overdose: seizures, somnolence, speech and visual disturbances, diplopia, cognitive impairment, coordination disturbances, lethargy, stupor, arterial hypotension, abdominal pain, agitation, dizziness, and depression. In most cases, clinical manifestations were not severe, but fatal outcomes have been recorded following overdose involving multiple drugs, including topiramate.

Topiramate overdose may cause severe metabolic acidosis (see "Special precautions").

Treatment. In acute topiramate overdose, if ingestion was recent, immediate gastric lavage or induction of emesis is necessary. In vitro studies have shown that activated charcoal adsorbs topiramate. If required, symptomatic therapy is recommended, and patients should be encouraged to drink plenty of fluids. Hemodialysis is an effective method for eliminating topiramate from the body.

Adverse Reactions

The most commonly observed adverse reactions are anorexia, decreased appetite, bradypsychia, depression, expressive speech disturbances, insomnia, coordination disturbances, attention concentration impairment, dizziness, dysarthria, taste distortion, hypesthesia, lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, blurred vision, diarrhea, nausea, fatigue, irritability, and weight loss.

Adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and not known (cannot be estimated from available data).

Infections and infestations: very common – nasopharyngitis*.

Blood and lymphatic system disorders: common – anemia; uncommon – eosinophilia, leukopenia, lymphadenopathy, thrombocytopenia; rare – neutropenia*.

Immune system disorders: common – hypersensitivity; not known – allergic edema*.

Metabolism and nutrition disorders: common – anorexia, decreased appetite; uncommon – hypokalemia, metabolic acidosis, increased appetite, polydipsia; rare – hyperchloremic acidosis, hyperammonemia*, hyperammonemic encephalopathy*.

Psychiatric disorders: very common – depression; common – bradypsychia, insomnia, expressive speech disturbances, anxiety, confusion, disorientation, aggression, mood disturbances, restlessness, mood swings, depressed mood, irritability, abnormal behavior; uncommon – suicidal ideation, suicide attempt, hallucinations, psychotic disorders, auditory hallucinations, visual hallucinations, apathy, spontaneous speech disturbances, sleep disorders, affective lability, decreased libido, agitation, crying, dysphemia, euphoric mood, paranoia, perseveration, panic attack, tearfulness, reading impairment, primary insomnia, emotional blunting, unusual thinking, loss of libido, indifference, intrasomniac disorder, distractibility, early awakening, panic reactions, elevated mood; rare – mania, panic-type disorders, feelings of despair*, hypomania.

Nervous system disorders: very common – dizziness, paresthesia, somnolence; common – attention concentration impairment, memory impairment, amnesia, cognitive disorders, cognitive dysfunction, psychomotor disorders, convulsions, coordination disturbances, tremor, lethargy, hypesthesia, nystagmus, dysgeusia, balance disorders, dysarthria, intention tremor, sedation; uncommon – impaired consciousness, grand mal seizure, visual field defect, complex partial seizures, speech disturbances, psychomotor hyperactivity, syncope, sensory disturbances, hypersalivation, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness, poor sleep quality, burning sensation, sensitivity disturbances, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, "pins and needles" sensation; rare – apraxia, sleep-wake cycle disturbances, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli.

Eye disorders: common – diplopia, blurred vision, visual disturbances; uncommon – decreased visual acuity, scotoma, acute myopia*, unusual eye sensations*, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia; rare – monocular blindness, transient blindness, glaucoma, accommodation disorders, altered depth perception, flickering scotoma, eyelid edema*, night blindness, amblyopia; not known – angle-closure glaucoma*, maculopathy*, eye movement disorders*, conjunctival edema*, uveitis.

Ear and labyrinth disorders: common – vertigo, tinnitus, ear pain; uncommon – deafness, unilateral hearing loss, sensorineural deafness, ear discomfort, hearing disturbances.

Cardiac disorders: uncommon – bradycardia, sinus bradycardia, palpitations.

Vascular disorders: uncommon – flushing, arterial hypotension, orthostatic hypotension, hyperthermia; rare – Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders: common – dyspnea, epistaxis, nasal congestion, rhinorrhea, cough*; uncommon – exertional dyspnea, paranasal sinus hypersecretion, dysphonia.

Gastrointestinal disorders: very common – nausea, diarrhea; common – vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, gastric discomfort, paresthesia of oral mucosa, gastritis, abdominal discomfort; uncommon – pancreatitis, flatulence, gastroesophageal reflux disease, lower abdominal pain, hypesthesia of oral mucosa, gum bleeding, abdominal distension, epigastric discomfort, abdominal tenderness, hypersalivation, oral cavity pain, bad breath, glossodynia.

Hepatobiliary disorders: rare – hepatitis, hepatic failure.

Skin and subcutaneous tissue disorders: common – alopecia, pruritus, rash; uncommon – anhidrosis, facial hypesthesia, urticaria, erythema, generalized pruritus, macular rash, skin discoloration, allergic dermatitis, facial edema; rare – Stevens-Johnson syndrome*, erythema multiforme*, unusual skin odor, periorbital edema*, localized urticaria; not known – toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: common – arthralgia, muscle spasms, myalgia, muscle twitching, muscle weakness, musculoskeletal chest pain; uncommon – joint swelling*, musculoskeletal stiffness, flank pain, muscle fatigue; rare – discomfort in limbs*.

Renal and urinary disorders: common – dysuria, nephrolithiasis, frequent urination (pollakiuria), nephrocalcinosis*; uncommon – urinary crystals, hematuria, urinary incontinence, incontinence, urinary urgency, renal colic, kidney pain; rare – urinary tract stones, renal tubular acidosis*.

Reproductive system and breast disorders: uncommon – erectile dysfunction, sexual dysfunction.

General disorders and administration site conditions: very common – increased fatigue; common – pyrexia, asthenia, irritability, gait disturbances, unusual sensations, malaise; uncommon – hyperthermia, thirst, influenza-like illness*, lethargy, cold extremities, feeling of intoxication, anxiousness; rare – facial edema.

Investigations: very common – weight loss; common – weight gain*; uncommon – presence of crystals in urine, abnormal tandem gait test result, decreased white blood cell count, increased liver enzymes; rare – decreased blood bicarbonate level.

Social behavior: rare – inability to learn.

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

Congenital malformations and fetal growth restriction (see sections "Special Warnings and Precautions for Use" and "Pregnancy and Lactation").

Safety profile in pediatric patients.

Adverse reactions observed in children at a frequency ≥ 2 times higher than in adults during double-blind controlled trials: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disturbances, aggression, apathy, primary insomnia, suicidal ideation, attention concentration impairment, lethargy, sleep-wake cycle disturbances, poor sleep quality, increased lacrimation, sinus bradycardia, unusual sensations, gait disturbances.

Adverse reactions observed only in children during double-blind controlled trials: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, and inability to learn.

Shelf life. 3 years.

Storage conditions.

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

Packaging.

Topiramax 25: 10 tablets per blister; 1 or 3 blisters per cardboard box.

Topiramax 100: 10 tablets per blister; 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. LLC "Pharma Start", Ukraine.

Manufacturer's address and location of business activity.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

If adverse effects occur or if you have any questions regarding the safety of this medicinal product, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333.