Epimat
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EPIMATE (EPIMATE)
Composition:
Active substance: topiramate;
One film-coated tablet contains topiramate 50 mg or 100 mg;
Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, talc, magnesium stearate, hypromellose, polyethylene glycol, titanium dioxide (E 171), iron oxide yellow (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
50 mg tablets: round, biconvex, film-coated tablets, yellow in color, with a score line on both sides, marked with "10" and "32" on both sides of the break line on one side and "50" on the other side;
100 mg tablets: round, biconvex, film-coated tablets, light yellow in color, with a score line on both sides, marked with "10" and "33" on both sides of the break line on one side and "100" on the other side.
Pharmacotherapeutic group.
Antiepileptic drugs. 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 generation of repetitive action potentials during sustained neuronal membrane depolarization. Topiramate enhances the activity of γ-aminobutyric acid (GABA) at certain subtypes of GABA receptors (including GABAA receptors), and also modulates the ability of GABA receptors 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 prolong the duration of ion channel opening, which differentiates it from barbiturates that modulate GABA receptors.
Since the antiepileptic properties of topiramate differ significantly from those of benzodiazepines, it may modulate a benzodiazepine-insensitive subtype of GABA receptors. Topiramate antagonizes the activation of the kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subtype by kainate, but does not affect the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate are dose-dependent within plasma concentrations ranging from 1 to 200 μmol, with minimal activity observed between 1 and 10 μmol. Additionally, topiramate inhibits the activity of certain carbonic anhydrase isoenzymes. 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.
In animal studies, topiramate demonstrated anticonvulsant activity in rats and mice in models of seizures induced by maximal electroshock, and was effective in rodent models of epilepsy, including tonic and absence-like seizures in spontaneous epileptic rats (SER), as well as tonic and clonic seizures induced by amygdala stimulation or global ischemia. Topiramate only weakly blocks clonic seizures induced by pentetrazol, a GABAA receptor antagonist.
Studies in mice receiving topiramate concomitantly with carbamazepine or phenobarbital showed synergistic anticonvulsant activity, whereas combination with phenytoin demonstrated additive anticonvulsant effects. In adequately controlled additional studies, no correlation was demonstrated between plasma topiramate concentration and clinical efficacy. Evidence of tolerance in humans has not been observed.
Absence seizures
Two small single-group studies were conducted in children aged 4 to 11 years (CAPSS–326 and TOPAMAT‑ABS‑001). One study included 5 children and the other 12 children, but both were prematurely discontinued due to lack of therapeutic response. The doses used in these studies were approximately 12 mg/kg in the TOPAMAT‑ABS‑001 study and up to 400 mg/day (with a maximum of 9 mg/kg/day) in the CAPSS‑326 study. These studies do not provide sufficient evidence to draw conclusions regarding the efficacy or safety of topiramate use in children.
Monotherapy in patients aged 6 to 15 years with newly diagnosed or recently diagnosed epilepsy
A one-year open-label study was conducted in 63 patients aged 6 to 15 years with newly or recently diagnosed epilepsy to evaluate and compare the effects of topiramate (28 patients) and levetiracetam on growth, development, and bone mineralization. Continued growth was observed in both treatment groups, but the topiramate group showed statistically significant reductions in mean annual changes from baseline in body weight and bone mineral density compared to the levetiracetam group. A similar trend was observed for height and growth velocity, although these observations were not statistically significant. Growth-related changes were not clinically significant and did not limit treatment. Other confounding factors cannot be excluded.
Pharmacokinetics.
The pharmacokinetic profile of topiramate, compared to other antiepileptic drugs, is characterized by a long plasma half-life, linear pharmacokinetics, predominantly renal clearance, absence of significant protein binding, and lack of clinically relevant 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 efficacy or adverse reactions.
Absorption. Topiramate is rapidly and readily absorbed. Food intake does not have a clinically significant effect on the bioavailability of topiramate. After oral administration of 100 mg topiramate, 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 a 100 mg oral dose of 14C-topiramate was found to be at least 81%. Food does not have a clinically important effect on topiramate bioavailability.
Distribution. Overall, 13–17% of topiramate is bound to plasma proteins. The volume of distribution is inversely proportional to dose. A gender effect on volume of distribution has been observed, with values in females approximately 50% of those observed in males. This finding is attributed to the higher percentage of body fat in females.
Metabolism. Topiramate is not extensively metabolized (~20%). In patients receiving concomitant therapy with enzyme-inducing antiepileptic drugs, metabolism of topiramate increases to approximately 50%. Six essentially inactive metabolites have been isolated and identified from plasma, urine, and feces. Each of these metabolites accounted for less than 3% of total urinary radioactivity after administration of 14C-topiramate. Studies of two metabolites retaining most of the topiramate structure showed they exhibit little or no anticonvulsant activity.
Elimination. Unchanged topiramate and its metabolites are primarily excreted by the kidneys (at least 81% of the dose). Approximately 66% of the dose of 14C-topiramate is excreted unchanged in urine within 4 days. Concomitant administration of 100–400 mg topiramate twice daily with phenytoin or carbamazepine results in a proportional increase in plasma concentrations of topiramate.
Overall, plasma clearance of the drug is approximately 20–30 mL/min after oral administration. Topiramate pharmacokinetics are linear, plasma clearance remains constant, and the area under the concentration-time curve (AUC) increases proportionally with dose. Reaching steady-state plasma concentrations may require 4 to 8 days in patients with normal renal function. After multiple dosing, 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 to 400 mg twice daily concomitantly with phenytoin or carbamazepine demonstrates dose-proportional increases in plasma topiramate concentrations.
Renal impairment. In patients with moderate and severe renal impairment, plasma and renal clearance of topiramate is reduced (CLCR ≤ 70 mL/min). 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 and 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, an additional dose may be required. Dose adjustment should consider: 1) duration of the dialysis period; 2) clearance rate of the dialysis system used; 3) renal clearance value of topiramate in the patient undergoing dialysis.
Hepatic impairment. In patients with moderate to severe hepatic impairment, topiramate clearance is reduced on average by 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 pharmacokinetics of topiramate in children, as in adults, are linear, with dose-independent clearance and steady-state plasma concentrations increasing proportionally with dose. However, children exhibit higher clearance rates and a shorter elimination half-life. Thus, plasma concentrations of topiramate at equivalent mg/kg doses may be lower in children compared to adults. As in adults, concomitant use of enzyme-inducing antiepileptic drugs reduces steady-state plasma concentrations.
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 with 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 with 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 assessment of alternative treatment options.
Topiramate is not indicated for the treatment of acute conditions.
Contraindications.
Hypersensitivity to any component of the medicinal product.
Migraine prophylaxis:
- during pregnancy (see sections "Special precautions", "Use in pregnancy or breastfeeding").
- in women of childbearing potential who are not using highly effective contraception (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Use in pregnancy or breastfeeding").
Epilepsy:
- during pregnancy, if there is no appropriate alternative treatment (see sections "Special precautions", "Use in pregnancy or breastfeeding").
- in women of childbearing potential who are not using highly effective contraception. The only exception is women for whom no appropriate alternative exists, but who are planning pregnancy and are fully informed about the risks of taking topiramate during pregnancy (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Use in pregnancy or breastfeeding").
Interaction with other medicinal products and other forms of interaction.
Effect of topiramate on other antiepileptic drugs.
Concomitant administration of topiramate and 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 increase phenytoin plasma concentration. This may be related to inhibition of a specific polymorphic enzyme isoform (CYP2C19). In each patient receiving phenytoin, plasma phenytoin levels should be monitored if clinical signs or symptoms of toxicity develop.
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 daily. Furthermore, no changes were observed in steady-state topiramate plasma concentrations during or after discontinuation of lamotrigine treatment (mean dose 327 mg daily).
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 topiramate.
Phenytoin and carbamazepine reduce topiramate plasma concentrations. The addition (or discontinuation) of phenytoin or carbamazepine to topiramate therapy may require adjustment of the topiramate dose. The dose should be titrated based on achieving the desired therapeutic effect.
The addition (or discontinuation) of valproic acid does not cause clinically significant changes in topiramate plasma concentration and therefore does not require dose adjustment of topiramate.
Results of these interactions are presented in Table 1.
Table 1
| Adjunctive antiepileptic drug |
Concentration of antiepileptic drug |
Topiramate concentration |
| Phenytoin |
↔** |
↓ |
| Carbamazepine |
↔ |
↓ |
| Valproic acid |
↔ |
↔ |
| Lamotrigine |
↔ |
↔ |
| Phenobarbital |
↔ |
ND |
| Primidone |
↔ |
ND |
↔ = no effect (change ≤ 15 %);
** = increased concentration in individual patients;
- = decreased plasma concentration;
- ND = not studied;
- AED = antiepileptic drug.
Other drug interactions.
Digoxin. In studies using single doses, the area under the plasma concentration–time curve (AUC) of digoxin decreased by 12 % when topiramate was administered concomitantly. The clinical significance of this observation is unknown. When initiating (or discontinuing) topiramate in patients taking digoxin, particular attention should be paid to regular monitoring of serum digoxin concentrations.
Central nervous system (CNS) depressants. The consequences of concomitant use of topiramate with alcohol or other substances that depress CNS function have not been studied. It is not recommended to take topiramate concomitantly with alcohol or with drugs causing CNS depression.
St. John’s wort (Hypericum perforatum). When topiramate is used concomitantly with St. John’s wort preparations, there is a potential risk of reduced plasma concentrations of topiramate and, consequently, reduced efficacy. However, clinical studies of this potential interaction have not been conducted.
Systemic hormonal contraceptives. When combined oral contraceptives containing norethindrone (1 mg) and ethinylestradiol (35 mcg) were used, topiramate at doses of 50–800 mg per day did not significantly affect the efficacy of norethindrone, and at doses of 50–200 mg per day did not affect the efficacy of ethinylestradiol. Doses of topiramate of 200–800 mg per day (in patients with epilepsy) led to dose-dependent decreases in ethinylestradiol concentrations. Significant dose-dependent reductions in ethinylestradiol efficacy were observed at topiramate doses of 200, 400, and 800 mg per day (18 %, 21 %, and 30 %, respectively) when used concomitantly with valproic acid. The clinical significance of these changes is unknown. The risk of reduced contraceptive efficacy and increased breakthrough bleeding should be considered in women taking oral contraceptives together with topiramate. Patients should be advised to report any changes in the duration and pattern of bleeding. Even in the absence of breakthrough bleeding, the efficacy of systemic hormonal contraceptives may be reduced. Women using systemic contraceptives should also be advised to use a barrier method of contraception.
Lithium. It is known that in healthy volunteers, AUC of lithium decreased by up to 18 % during concomitant administration of topiramate at a dose of 200 mg per day. In patients with bipolar disorder, the pharmacokinetics of lithium remained unchanged during concomitant treatment with topiramate at doses of 200 mg per day, whereas with topiramate at doses of 600 mg per day, an increase in lithium AUC of up to 26 % was observed. Monitoring of lithium levels is recommended when used concomitantly with topiramate.
Risperidone. Interaction studies conducted with single doses in healthy volunteers and multiple doses in patients with bipolar disorder showed similar results. When risperidone at doses of 1–6 mg per day was administered concomitantly with topiramate at doses of 100, 250, and 400 mg per day, decreases in risperidone concentrations of 16 % and 33 % in AUC were observed at the 250 and 400 mg per day doses, respectively. However, differences in AUC of the active moiety when risperidone was administered as monotherapy versus in 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 in the pharmacokinetics of 9-hydroxyrisperidone were observed. No clinically significant changes in systemic exposure of active metabolites of either risperidone or topiramate were observed. After adding topiramate at doses of 250–400 mg per day to risperidone treatment at doses of 1–6 mg per day, an increased incidence of adverse reactions was observed (90 % and 54 %, respectively). The most common adverse reactions after adding topiramate to risperidone treatment were somnolence (27 % and 12 %), paresthesia (22 % and 0 %), and nausea (18 % and 9 %, respectively).
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. The study results showed that when topiramate and hydrochlorothiazide were taken concomitantly, Cmax and AUC of topiramate increased by 27 % and 29 %, respectively. The clinical significance of these changes is unknown. When topiramate and hydrochlorothiazide are taken concomitantly, Cmax of topiramate increases by 27 % and AUC of topiramate by 29 %. 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 studies showed a decrease in serum potassium levels with administration of either topiramate or hydrochlorothiazide, which was more pronounced when topiramate and hydrochlorothiazide 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. The study 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 the pharmacokinetics of metformin is unknown. Plasma clearance of topiramate decreases with concomitant administration of metformin following oral administration. The extent of change in clearance is unknown. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unknown.
In cases of 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 decrease in AUCτ,ss of pioglitazone by 15 % was observed without changes in Cmax,ss. The result was not statistically significant. In addition, a decrease in Cmax,ss and AUCτ,ss of the active hydroxymetabolite by 13 % and 16 %, respectively, and a decrease in Cmax,ss and AUCτ,ss of the active ketometabolite by 60 % were observed. The clinical significance of these results has not been established. When prescribing topiramate and pioglitazone concomitantly to patients, their diabetic status should be monitored regularly.
Glyburide. In patients with type 2 diabetes mellitus, concomitant administration of glyburide (5 mg per day) and topiramate (150 mg per day) resulted in a 25 % decrease in AUC24 of glyburide. Systemic exposure to active metabolites 4-trans-hydroxyglyburide and 3-cis-hydroxyglyburide also decreased by 13 % and 15 %, respectively. During concomitant therapy with glyburide, no effect on steady-state pharmacokinetic parameters of topiramate was observed. When prescribing topiramate and glyburide concomitantly, particular attention should be paid to careful monitoring of the diabetic status of these patients.
Other types of interactions.
Drugs promoting nephrolithiasis.
Concomitant use of topiramate and other drugs that may 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 led to hyperammonemia with or without encephalopathy in patients who tolerated monotherapy with these drugs well. In most cases, symptoms resolved after discontinuation of one of the drugs. This adverse effect is not related to a pharmacokinetic interaction. Cases of hypothermia, defined as an involuntary decrease in body temperature to < 35 °C, associated with concomitant use of valproic acid and topiramate, with or 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 the daily dose.
Warfarin. Decreases in prothrombin time/international normalized ratio (PT/INR) have 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 of pharmacokinetic drug interactions.
Additional clinical studies were conducted to assess potential pharmacokinetic interactions of topiramate with other drugs. Changes in Cmax and AUC values resulting from interactions are presented in Table 2. The first column lists the drug used during concomitant therapy. The second column describes changes in the concentration of the drug used during concomitant therapy when topiramate is added. The third column (topiramate concentration) indicates the effect of concomitant administration of the drug on topiramate concentration.
Table 2
Summary of results of additional clinical studies of pharmacokinetic drug interactions.
| Added drug |
Concentration of the added drug |
Topiramate concentration |
| Amittryptiline |
↔ 20 % increase in Cmax and AUC of nortriptyline metabolite |
ND |
| Dihydroergotamine (oral and subcutaneous) |
↔ |
↔ |
| Haloperidol |
↔ 31 % increase in metabolite AUC |
ND |
| Propranolol |
↔ 17 % increase in Cmax of 4-OH propranolol (topiramate 50 mg every 12 hours) |
9 % and 16 % increase in Cmax and 9 % and 17 % increase in AUC (propranolol 40 mg and 80 mg every 12 hours, respectively) |
| Sumatriptan (oral and subcutaneous) |
↔ |
ND |
| Pizotifen |
↔ |
↔ |
| Diltiazem |
25 % decrease in AUC of diltiazem and 18 % decrease in DEA, and ↔ for DEM* |
20 % increase in AUC |
| Venlafaxine |
↔ |
↔ |
| Flunarizine |
16 % increase in AUC (topiramate 50 mg every 12 hours)b |
↔ |
aExpressed 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-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.
If rapid discontinuation of topiramate is required, clinical monitoring of the patient is recommended (see section "Dosage and administration" for additional information).
As with other antiepileptic drugs, some patients may experience an increase in seizure frequency or the emergence of new types of seizures during treatment with topiramate. These phenomena may result from overdose, decreased plasma concentrations of concomitantly administered antiepileptic drugs, disease progression, or a paradoxical effect.
Adequate hydration is very important during treatment with topiramate 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-dependent adverse reactions (see section "Adverse reactions").
Pregnancy prevention programme.
Topiramate may cause significant congenital malformations and fetal growth restriction when used in pregnant women. Some data suggest an increased risk of neurodevelopmental disorders in children exposed to topiramate in utero, while other data do not indicate such an increased risk (see section "Use during pregnancy or breastfeeding").
Women of childbearing potential.
Before initiating topiramate therapy in women of childbearing potential, a pregnancy test should be performed.
The patient must be fully informed and understand the risks associated with using 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 transitioning to alternative treatments before discontinuing contraception, as well as immediate consultation with a specialist if she becomes pregnant or suspects she may be pregnant.
Female children.
Physicians should ensure that parents/guardians of female children receiving topiramate understand the need to consult a specialist as soon as menarche occurs. At that 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 necessity of using highly effective contraceptive methods once this becomes relevant. The need for continued treatment with topiramate 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). A patient guide should be provided to all women of childbearing potential receiving topiramate, as well as to parents/guardians of female children. A patient card is supplied with the medication packaging.
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.
An increased incidence of mood disorders and depression has been reported during treatment with topiramate.
Suicide/suicidal thoughts.
Cases of suicidal thoughts and suicidal behaviour have been observed 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 behaviour. The mechanism of this phenomenon is unknown, and available data do not exclude the possibility of an increased risk associated with topiramate use.
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 more frequently than in patients receiving placebo (0.2%; 8 out of 4,045 patients).
Therefore, monitoring for signs of suicidal thoughts and behaviour is recommended, with appropriate treatment initiated if necessary. Patients (and caregivers) should seek medical advice at the first appearance of suicidal thoughts or behaviour.
Serious skin reactions
Serious skin reactions (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)) have been reported in patients receiving topiramate (see section "Adverse reactions"). Patients should be informed about the signs of serious skin reactions. Topiramate should be discontinued if SJS or TEN is suspected.
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 prior history of kidney stones, family history of nephrolithiasis, and hypercalciuria (see "Metabolic acidosis" and its consequences below). None of these risk factors adequately predict the occurrence of kidney stones during topiramate treatment. 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 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 associated with secondary angle-closure glaucoma have been reported during treatment with topiramate. Symptoms include sudden decrease in visual acuity and/or eye pain. Ophthalmologic examination may reveal some or all of the following: myopia, mydriasis, reduced depth of the anterior chamber of the eye, hyperemia (eye redness), choroidal detachment, retinal pigment epithelial detachment, macular striae, and elevated intraocular pressure. Mydriasis may also occur. This syndrome may be related to suprachoroidal effusion, leading to lens and iris displacement and development of secondary angle-closure glaucoma. Symptoms usually 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. Treatment includes rapid 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. Most cases reported during clinical trials were reversible and resolved after discontinuation of treatment. Visual defects at any time during therapy should prompt consideration of discontinuing the drug.
Metabolic acidosis and its consequences.
Topiramate may cause hyperchloremic, non-anion gap metabolic acidosis (i.e., decreased plasma bicarbonate concentration below normal in the absence of respiratory alkalosis). The reduction in serum bicarbonate concentration results from topiramate's inhibition of carbonic anhydrase in the kidneys. Most often, the reduction in bicarbonate occurs early in treatment, although this effect may appear 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 levels below 10 mmol/L. Certain conditions or treatments that lead to acidosis (e.g., kidney disease, severe respiratory disorders, epileptic status, diarrhoea, surgery, ketogenic diet, or use of certain medications) may be additional factors that enhance topiramate's effect on reducing bicarbonate concentration.
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 bone-related complications has not been systematically studied in either children or adults. An open-label one-year study was conducted in children aged 6 to 15 years (see subsection "Pharmacodynamics").
Depending on the underlying condition, appropriate monitoring, including serum bicarbonate levels, is recommended during topiramate treatment. If symptoms or signs (e.g., Kussmaul breathing, dyspnoea, anorexia, nausea, vomiting, excessive fatigue, tachycardia, or arrhythmia) suggestive of metabolic acidosis occur, serum bicarbonate levels should be measured. If metabolic acidosis develops or progresses, dose reduction or discontinuation of topiramate (via dose tapering) is recommended.
Topiramate should be used with caution in patients with risk factors for metabolic acidosis.
Cognitive 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, requiring dose reduction or discontinuation of treatment. However, existing data on the effects of topiramate on cognitive function in children are insufficient, and further study is needed.
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 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 or adjunctive therapy with topiramate should be evaluated for hyperammonemic encephalopathy, and blood ammonia levels should be measured.
Special dietary considerations.
During treatment with topiramate, some patients may lose body weight; therefore, body weight monitoring is recommended. If weight loss occurs during treatment with Epimat, supportive diet or increased nutritional intake should be considered.
Lactose intolerance.
The medicinal product contains lactose monohydrate. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.
Use during pregnancy or breastfeeding.
Pregnancy. Risk associated with epilepsy and use of antiepileptic drugs in general. Women of childbearing potential, especially those planning pregnancy, and pregnant women should consult a specialist regarding the potential risk to the fetus from both seizures and antiepileptic drug use. 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 unborn child. Monotherapy should be preferred when possible, as the risk of congenital malformations is higher with combination antiepileptic therapy, depending on the specific antiepileptic drugs used.
Risk associated with topiramate use. Topiramate showed teratogenic activity 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 blood and maternal blood.
Pregnancy registry data indicate that newborns whose mothers used topiramate as monotherapy have an increased risk of major congenital malformations and fetal growth restriction:
- Increased risk of congenital malformations (craniofacial defects, including cleft lip/palate, hypospadias, and abnormalities in 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 (1.4%) not taking antiepileptic drugs. Data from a study conducted in Northern European countries showed 2–3 times higher prevalence of major congenital malformations (up to 9.5%) compared to the control group not taking antiepileptic drugs (3.0%). Furthermore, 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 at 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 restriction (SGA; defined as newborn weight below the 10th percentile adjusted for gestational age and stratified by sex). In the North American Antiepileptic Drug Pregnancy Registry, the risk of SGA in children of women who received topiramate was 18% compared to 5% in children of women with epilepsy not receiving antiepileptic drugs. Long-term outcomes of SGA infants are not established.
Neurodevelopmental disorders
Data from two observational population-based pregnancy registry studies, primarily from the same Scandinavian dataset, suggest that the prevalence of autism spectrum disorders, intellectual disability, or attention deficit hyperactivity disorder (ADHD) may be 2–3 times higher in nearly 300 children of mothers with epilepsy exposed to topiramate in utero, compared to children of mothers with epilepsy not using antiepileptic drugs. A third observational cohort study conducted in the United States did not show an increased cumulative frequency of these outcomes up to 8 years in approximately 1000 children of mothers with epilepsy exposed to topiramate in utero, compared to children of mothers with epilepsy not receiving antiepileptic drugs.
Use in epilepsy.
Topiramate is contraindicated during pregnancy except when no suitable alternative treatment is available (see sections "Contraindications" and "Special precautions for use"). The woman must be fully informed about the risks of using topiramate during pregnancy and understand them. This includes discussing the risks of uncontrolled epilepsy during pregnancy. If a woman plans pregnancy, efforts should be made to transition to an 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 options. If topiramate is used during pregnancy, the patient should be referred to a specialist for pregnancy evaluation and counselling.
Use for migraine prophylaxis.
Topiramate is contraindicated for migraine prophylaxis in pregnant women (see sections "Contraindications" and "Special precautions for use").
Women of childbearing potential (all indications)
Topiramate is contraindicated in women of childbearing potential unless they use highly effective contraceptive methods. The only exception is a woman with epilepsy for whom no suitable alternative exists, but who plans pregnancy and is fully informed about the risks associated with topiramate use during pregnancy (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").
During treatment and for at least 4 weeks after discontinuation of topiramate, at least one highly effective contraceptive method (e.g., intrauterine device) or two complementary contraceptive methods, including a barrier method, should be used (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction", and "Special precautions for use").
Alternative treatment options should be considered for women of childbearing potential.
Before initiating topiramate treatment in women of childbearing potential, a pregnancy test should be performed.
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 the woman plans pregnancy, as well as immediate consultation with a specialist if she becomes pregnant or suspects she may be pregnant during topiramate treatment.
For women with epilepsy, the risks of uncontrolled epilepsy during pregnancy should also be considered (see sections "Contraindications" and "Special precautions for use").
Female children – see section "Special precautions for use".
Lactation. It is known from animal studies that topiramate is excreted into breast milk. 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 neonates/infants include diarrhoea, 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 to the mother (see section "Special precautions for use").
Fertility. Animal studies did not reveal any harmful effect 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 negligible 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 similar symptoms. It may also cause visual disturbances and/or blurred vision. These adverse effects 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.
It is recommended to initiate treatment with the lowest dose, followed by titration to an effective dose to avoid dose-dependent adverse effects. The dose and rate of dose escalation should be individualized according to the therapeutic response. Tablets should not be broken. Epimat should be taken independently of food intake, with sufficient fluid. The drug should be discontinued gradually to minimize the risk of increased frequency and severity of seizures. In clinical studies, 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/day for migraine prophylaxis. In these studies, topiramate dose reduction was performed gradually over 2–8 weeks.
Monitoring of plasma topiramate concentrations is not necessary for optimizing therapy. 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 topiramate therapy may require dose adjustment of the drug.
Monotherapy for epilepsy.
General recommendations. When discontinuing concomitant antiepileptic drugs (AEDs) to initiate topiramate monotherapy, the impact of these drugs on seizure control should be considered. If there is no safety-related need for rapid discontinuation of concomitant AEDs, a stepwise reduction of their doses by approximately one-third of the previous dose every 2 weeks is recommended.
After discontinuation of drugs with enzyme-inducing properties, topiramate levels increase. The patient's clinical status may require a reduction in topiramate dose.
Adults. Dose titration should begin with 25 mg at night for 1 week. Thereafter, the dose should be increased by 25–50 mg/day at 1–2 week intervals, divided into two doses. If the patient does not tolerate this dose escalation regimen, smaller increments or longer intervals before increasing the dose may be used. The recommended initial target dose for topiramate monotherapy in adults is 100–200 mg/day in two divided doses. The maximum recommended dose is 500 mg/day, divided into two doses. Some patients with refractory forms of epilepsy have tolerated monotherapy with topiramate at doses up to 1000 mg/day. These dosage recommendations apply to all adults, including elderly patients, provided they have no renal impairment.
Children aged 6 years and older. Dose selection and titration should be based on clinical response. Treatment in children aged 6 years and older should begin with 0.5–1 mg/kg body weight at night for 1 week. The dose should then be increased by 0.5–1 mg/kg body weight/day every 1–2 weeks, divided into two doses. If the child does not tolerate this dose escalation, smaller increments or longer intervals before increasing the dose may be used. The recommended initial target dose for topiramate monotherapy in children aged 6 years and older is 100 mg/day, depending on clinical response (approximately 2 mg/kg body weight/day for children aged 6–16 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 at a dose of 25–50 mg at night for 1 week. Thereafter, the dose should be increased by 25–50 mg/day at 1–2 week intervals, divided into two doses. In some patients, efficacy may be achieved with once-daily dosing. The minimum effective dose is 200 mg. The usual maintenance dose is 200–400 mg/day in two divided doses.
These dosage recommendations apply to all adults, including elderly patients, provided they have no renal impairment.
Children aged 2 years and older. The recommended total daily dose of topiramate for adjunctive therapy is on average 5–9 mg/kg body weight/day, divided into two doses. Dose titration begins with 25 mg (or less, within the range of 1–3 mg/kg body weight/day) at night for 1 week. The dose should be increased by 1–3 mg/kg body weight/day at weekly or biweekly intervals (administered in two doses) until therapeutic effect is achieved.
In clinical studies, a dose of 30 mg/kg body weight/day has proven effective.
Migraine.
Adults. The recommended daily dose of topiramate for migraine prophylaxis is 100 mg, divided into two doses. Dose titration should begin with 25 mg at night for 1 week. Thereafter, the dose should be increased by 25 mg/day at weekly intervals. If the patient does not tolerate this dose escalation regimen, smaller increments or longer intervals before increasing the dose may be used. In some patients, a positive outcome is achieved with a daily dose of topiramate of 50 mg/day. Patients have received daily doses of topiramate up to 200 mg/day. This dose may provide benefits for some patients; however, it is recommended to use it with caution due to increased frequency of adverse effects.
Children. Topiramate is not recommended for treatment or prophylaxis of migraine attacks in children due to insufficient data on safety and efficacy.
General dosage recommendations for special patient populations.
Renal 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.
Patients with diagnosed kidney disease may require a longer time to reach steady-state concentrations at each dose. Patients with end-stage renal disease should receive an additional dose of topiramate equal to approximately half the daily dose on hemodialysis days, as topiramate is removed from plasma by hemodialysis. The additional dose should be divided into two administrations and taken before and after the hemodialysis procedure. The additional dose may vary depending on the hemodialysis equipment used.
Hepatic impairment.
Topiramate should be used with caution in patients with moderate to severe hepatic impairment due to reduced clearance of topiramate.
Elderly patients.
Dose adjustment is not necessary in elderly patients with normal renal function.
Female children and women of reproductive potential.
Treatment with topiramate should be initiated and monitored by a physician experienced in the treatment of epilepsy or migraine.
Alternative treatment options should be considered for female children and women of reproductive potential. The need for topiramate treatment in these patients should be reviewed at least annually (see sections "Contraindications", "Special precautions", and "Use during pregnancy or breastfeeding").
Children.
Monotherapy for epilepsy. Indicated for 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). Indicated for children aged 2 years and older.
Migraine. Topiramate is not recommended for 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 disorder, blurred vision, diplopia, cognitive impairment, lethargy, coordination disturbances, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. In most cases, clinical manifestations were not severe, but fatal outcomes have been reported following overdose involving multiple drugs, including topiramate. Topiramate overdose may cause severe metabolic acidosis (see section "Special precautions").
Treatment. In acute topiramate overdose, if ingestion was recent, gastric lavage or induction of emesis should be performed immediately. Activated charcoal has been shown to adsorb topiramate. Symptomatic therapy should be administered as needed. Hemodialysis is an effective method for removing topiramate from the body. Patients are advised to increase fluid intake.
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. These studies evaluated the use of 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 or recently diagnosed epilepsy or migraine prophylaxis. Most adverse reactions were of mild to moderate severity. The adverse reactions observed during clinical trials and in the post-marketing period are listed in Table 3 below. 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 common 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 disorder, attention disturbance, dizziness, dysarthria, taste disturbance, hypoesthesia, lethargy, memory impairment, nystagmus, paresthesia, somnolence, tremor, diplopia, blurred vision, diarrhea, nausea, fatigue, irritability, and weight decreased.
Table 3
| System organ class/frequency |
Adverse reactions |
| Infections and infestations |
|
| Very common |
Nasopharyngitis* |
| Blood and lymphatic system disorders |
|
| Common |
Anaemia |
| Uncommon |
Leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia |
| Rare |
Neutropenia* |
| Immune system disorders |
|
| Common |
Hypersensitivity |
| Not known |
Allergic oedema* |
| Metabolism and nutrition disorders |
|
| Common |
Anorexia, decreased appetite |
| Uncommon |
Metabolic acidosis, hypokalaemia, increased appetite, polydipsia |
| Rare |
Hyperchloraemic acidosis, hyperammonaemia*, hyperammonaemic encephalopathy* |
| Psychiatric disorders |
|
| Very common |
Depression |
| Common |
Bradypsychia, insomnia, expressive speech disorder, anxiety, confusion, disorientation, aggression, mood disturbance, restlessness, mood swings, depressive mood, irritability, unusual behaviour |
| Uncommon |
Suicidal ideation, suicide attempt, hallucinations, psychotic disorders, auditory hallucinations, visual hallucinations, apathy, spontaneous speech disorder, sleep disorder, affective lability, decreased libido, agitation, crying, dysphemia, euphoric mood, paranoia, perseveration, panic attack, tearfulness, reading disorder, 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 |
Paraesthesia, somnolence, dizziness |
| Common |
Attention disturbance, memory impairment, amnesia, cognitive disorder, mental impairment, psychomotor function disorder, seizures, coordination disorder, tremor, lethargy, hypaesthesia, nystagmus, dysgeusia, balance disorder, dysarthria, intention tremor, sedation |
| Uncommon |
Consciousness depression, grand mal seizure, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbances, hypersalivation, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness, poor sleep quality, burning sensation, sensation disorder, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, tingling sensation |
| Rare |
Apraxia, sleep-wake cycle disturbance, hyperaesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli |
| Eye disorders |
|
| Common |
Blurred vision, diplopia, visual disturbances |
| Uncommon |
Reduced visual acuity, scotoma, acute myopia*, unusual eye sensations*, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia |
| Rare |
Unilateral blindness, transient blindness, glaucoma, accommodation disorder, altered depth perception, flickering scotoma, eyelid oedema*, night blindness, amblyopia |
| Not known |
Angle-closure glaucoma*, maculopathy*, eye movement disorders*, conjunctival oedema*, uveitis |
| Ear and labyrinth disorders |
|
| Common |
Vertigo, tinnitus, ear pain |
| Uncommon |
Deafness, unilateral deafness, sensorineural deafness, ear discomfort, hearing impairment |
| Cardiac disorders |
|
| Uncommon |
Bradycardia, sinus bradycardia, palpitations |
| Vascular disorders |
|
| Uncommon |
Arterial hypotension, orthostatic hypotension, hyperaemia, flushing |
| Rare |
Raynaud's phenomenon |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
Dyspnoea, epistaxis, nasal congestion, rhinorrhoea, cough* |
| Uncommon |
Dyspnoea on exertion, paranasal sinus hypersecretion, dysphonia |
| Gastrointestinal disorders |
|
| Very common |
Nausea, diarrhoea |
| Common |
Vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, discomfort in stomach, paraesthesia of oral mucosa, gastritis, abdominal discomfort |
| Uncommon |
Pancreatitis, flatulence, gastroesophageal reflux disease, lower abdominal pain, hypaesthesia of oral mucosa, gingival 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, rash, pruritus |
| Uncommon |
Anhidrosis, facial hypaesthesia, urticaria, erythema, generalized pruritus, macular rash, skin discoloration, allergic dermatitis, facial oedema |
| Rare |
Stevens-Johnson syndrome*, erythema multiforme*, unusual skin odour, periorbital oedema*, 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 |
Nephrolithiasis, pollakiuria, dysuria, nephrocalcinosis* |
| Uncommon |
Urinary stones, urinary incontinence, haematuria, 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 disturbance, unusual sensations, malaise |
| Uncommon |
Hyperthermia, thirst sensation, influenza-like illness*, lethargy, cold extremities, feeling of intoxication, anxious feeling |
| Rare |
Facial oedema |
| Investigations |
|
| Very common |
Decreased body weight |
| Common |
Increased body weight* |
| Uncommon |
Presence of crystals in urine, abnormal tandem gait test result, decreased white blood cell count, increased liver enzyme levels |
| Rare |
Decreased blood bicarbonate levels |
| Social behaviour disorders |
|
| Rare |
Inability to learn |
*Adverse reactions reported during the post-marketing period (spontaneous reports). Their frequency was calculated based on data from clinical trials.
Congenital malformations and fetal growth restriction (see sections "Special precautions" and "Use during pregnancy or breastfeeding").
Safety profile characteristics in children.
Adverse reactions observed in children at least 2 times more frequently than in adults during double-blind controlled studies: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disorders, aggression, apathy, primary insomnia, suicidal ideation, attention disturbance, lethargy, sleep-wake cycle rhythm disorders, poor sleep quality, increased lacrimation, sinus bradycardia, unusual sensations, gait disturbance.
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 ºC.
Keep out of reach of children.
Packaging.
10 tablets per blister; 10 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Torrent Pharmaceuticals Ltd.
Manufacturer's address and location of operations.
Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana Gujarat 382721, India.