Topamax
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOPTAMAX® (TOPAMAX®)
Composition:
Active ingredient: topiramate;
1 capsule contains 25 mg or 50 mg of topiramate;
Excipients: sucrose, povidone, cellulose acetate, gelatin, purified water, sorbitan monolaurate, sodium lauryl sulfate, titanium dioxide (E 171), shellac glaze solution in ethanol, iron oxide black (E 172), butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide.
Pharmaceutical form. Capsules.
Main physico-chemical properties:
25 mg capsules: hard gelatin capsules of size № 1, consisting of an opaque white body with the marking «25 mg» and a transparent cap with the marking «TOP». The capsule contents are white or almost white granules;
50 mg capsules: hard gelatin capsules of size № 0, consisting of an opaque white body with the marking «50 mg» and a transparent cap with the marking «TOP». The capsule contents are white or almost white granules.
Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs. Topiramate. ATC code N03A X11.
Pharmacological Properties
Pharmacodynamics
Topiramate belongs to the class of sulfamate-substituted monosaccharides. The precise mechanism by which topiramate exerts its anticonvulsant and migraine prophylactic effects is unknown. Electrophysiological and biochemical studies in neuronal cultures have identified three properties that may contribute to the antiepileptic efficacy of topiramate.
Topiramate blocks voltage-gated sodium channels and inhibits the generation of repetitive action potentials during sustained neuronal membrane depolarization. Topiramate enhances the frequency of γ-aminobutyric acid (GABA)-mediated activation of GABAA receptors and increases the ability of GABA to induce chloride ion influx into neurons, indicating that topiramate potentiates the activity of this inhibitory neurotransmitter. This effect is not blocked by flumazenil, a benzodiazepine antagonist. Additionally, topiramate does not increase the duration of ion channel opening, distinguishing it from barbiturates, which modulate GABAA receptors.
Topiramate may modulate a benzodiazepine-insensitive subtype of GABAA receptors, which may explain the significant differences in antiepileptic properties between topiramate and benzodiazepines. Topiramate antagonizes the ability of kainate to activate the kainate/AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) subtype of glutamate receptors, but has no significant effect on the activity of N-methyl-D-aspartate (NMDA) within the NMDA receptor subtype. These effects of topiramate are concentration-dependent within the plasma concentration range of 1 to 200 μmol; minimal activity occurs between 1 and 10 μmol.
In addition, topiramate inhibits the activity of certain isoenzymes of carbonic anhydrase. However, this pharmacological effect of topiramate is considerably weaker than that of acetazolamide—a well-known carbonic anhydrase inhibitor—therefore, this activity is not considered a primary component of its antiepileptic action.
Pharmacokinetics
The pharmacokinetic profile of topiramate, compared to other antiepileptic drugs, is characterized by a long plasma half-life, linear kinetics, predominantly renal clearance, low plasma protein binding, and absence of clinically significant active metabolites.
Topiramate is not a potent inducer of drug-metabolizing enzymes, can be administered independently of food intake, and routine monitoring of plasma concentrations is not required. Clinical studies have not demonstrated a significant correlation between plasma concentrations and either efficacy or adverse reactions.
Absorption. Topiramate is rapidly and effectively absorbed. After oral administration of 100 mg topiramate to healthy volunteers, the mean peak plasma concentration (Cmax) of 1.5 μg/mL was achieved within 2–3 hours (Tmax). Following oral administration of radiolabeled topiramate and measurement of radioactivity in urine, the mean extent of absorption of an oral 100 mg dose of 14C-topiramate was found to be at least 81%. Food does not have a clinically significant effect on the bioavailability of topiramate.
Distribution. Approximately 13–17% of topiramate is bound to plasma proteins. A site with low binding capacity for topiramate on erythrocytes 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 depends on gender: in women, it is approximately 50% of the values observed in men, which is attributed to the higher proportion of adipose tissue in women; however, this difference is not 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 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 via the kidneys. Approximately 66% of the administered dose of 14C-topiramate is excreted unchanged in urine within 4 days. After administration of 50 mg and 100 mg topiramate twice daily, mean renal clearance is approximately 18 mL/min and 17 mL/min, respectively, indicating tubular reabsorption of topiramate in the kidneys. These findings are consistent with studies in rats where co-administration of probenecid resulted in a significant increase in renal clearance of topiramate. After oral administration, the plasma clearance of the drug is 20–30 mL/min.
Linearity. Topiramate exhibits low inter-subject variability in plasma concentrations, making its pharmacokinetic properties predictable. The pharmacokinetics of topiramate are linear: plasma clearance remains constant, and the area under the concentration-time curve increases proportionally with doses ranging from 100 mg to 400 mg in healthy volunteers. In patients with normal renal function, steady-state concentrations are achieved within 4–8 days. The mean Cmax after repeated oral administration of 100 mg topiramate twice daily in healthy volunteers is 6.76 μg/mL. After repeated administration of 50 mg and 100 mg 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 (CLCR ≤ 70 mL/min), plasma and renal clearance of topiramate are reduced. Consequently, higher steady-state plasma concentrations of topiramate are expected at a given dose compared to patients 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 lead to a reduction in topiramate concentration below the level required to maintain anticonvulsant effect. To prevent rapid decreases in plasma topiramate concentrations during hemodialysis, supplemental dosing may be necessary. Dose adjustment should consider: 1) duration of dialysis; 2) clearance rate of the dialysis system used; 3) the patient's renal clearance of topiramate while on dialysis.
Hepatic impairment. In patients with moderate to severe hepatic impairment, clearance of topiramate is reduced by an average of 26%. Therefore, topiramate should be used with caution in patients with hepatic impairment.
Elderly patients. In elderly patients without renal disease, plasma clearance of topiramate is not altered.
Children (under 12 years of age). The pharmacokinetics of topiramate in children, as in adults receiving Topamax® as adjunctive therapy, are linear; clearance is dose-independent, and steady-state plasma concentrations increase proportionally with dose. However, in children, clearance is higher and half-life is shorter. Therefore, plasma concentrations of topiramate following the same dose per kilogram of body weight 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 in children.
Clinical characteristics.
Indications.
As monotherapy for the treatment of adults and children aged 6 years and older with partial-onset seizures with or without secondary generalized seizures and primary generalized tonic-clonic seizures.
As adjunctive therapy for the treatment of adults and children aged 2 years and older with partial-onset seizures with or without secondary generalized seizures or primary generalized tonic-clonic seizures, and for the treatment of seizures associated with Lennox-Gastaut syndrome.
For the prevention of migraine attacks in adults, after careful evaluation of alternative treatment options. Topiramate is not recommended for the treatment of acute conditions.
Contraindications.
Hypersensitivity to any component of the medicinal product.
Migraine prophylaxis in pregnant women and women of childbearing potential who are not using highly effective methods of contraception.
Interaction with other medicinal products and other forms of interaction.
Effect of Topamax® on other antiepileptic drugs.
Combination of Topamax® 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 Topamax® and phenytoin may lead to increased plasma phenytoin concentrations. This may be related to inhibition of a specific polymorphic enzyme isoform (CYP2C19). Therefore, 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 concomitant administration of topiramate at doses of 100 to 400 mg per day with lamotrigine does not affect steady-state plasma concentrations of lamotrigine. Furthermore, no changes in steady-state plasma concentrations of topiramate were observed during or after discontinuation of lamotrigine treatment (mean dose – 327 mg per day).
Topiramate inhibits the enzyme CYP2C19 and may interact with other substances metabolized by this enzyme (e.g., diazepam, imipramine, moclobemide, proguanil, omeprazole).
Effect of other antiepileptic drugs on Topamax®.
Phenytoin and carbamazepine reduce plasma concentrations of Topamax®. Addition or withdrawal of phenytoin or carbamazepine during Topamax® treatment may require adjustment of the Topamax® dose. The dose should be titrated to achieve the desired therapeutic effect. Addition or withdrawal of valproic acid does not cause therapeutically significant changes in plasma concentrations of Topamax® and therefore does not require dose adjustment of Topamax®.
Results of these interactions are presented in Table 1.
Table 1
| Concomitant AED |
AED Concentration |
Topamax® 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.
Interactions with other medicinal products.
Digoxin.
In studies using a single dose, the area under the plasma concentration–time curve (AUC) of digoxin decreased by 12 % when co-administered with Topamax®. The clinical significance of this observation is unknown. When initiating or discontinuing Topamax® in patients receiving digoxin, careful attention should be paid to regular monitoring of serum digoxin concentrations.
Central nervous system (CNS) depressants.
The concomitant use of Topamax® with alcohol or other CNS depressants has not been studied within clinical trials. It is not recommended to take Topamax® together with alcohol or other CNS depressant drugs.
St. John’s wort (Hypericum perforatum).
Concomitant use of topiramate and St. John’s wort may result in decreased plasma concentrations of topiramate and reduced efficacy. Clinical studies on this interaction have not been conducted.
Oral contraceptives.
In pharmacokinetic drug interaction studies involving healthy volunteers, administration of Topamax® as monotherapy at doses of 50–200 mg per day together with a combined oral contraceptive (norethindrone 1 mg + ethinylestradiol 35 mcg) was not associated with statistically significant changes in mean concentrations (AUC) of either component of the oral contraceptive. In another study, administration of Topamax® at doses of 200, 400, or 800 mg per day as adjunctive therapy to valproic acid treatment in patients with epilepsy was associated with a significant dose-dependent reduction in ethinylestradiol efficacy (18 %, 21 %, and 30 %, respectively). In both studies, Topamax® (administered at doses of 50–200 mg per day to healthy volunteers and 200–800 mg per day to epileptic patients) had no significant effect on norethindrone concentrations. Although dose-dependent decreases in ethinylestradiol concentrations were observed in epileptic patients receiving doses of 200–800 mg per day, no significant dose-dependent changes in ethinylestradiol concentrations were observed in healthy volunteers receiving doses of 50–200 mg per day. The clinical significance of these findings is unknown. The risk of reduced contraceptive efficacy and increased breakthrough bleeding should be considered in women taking combined oral contraceptives concomitantly with Topamax®. Women should be advised to report any changes in the duration and pattern of bleeding while taking estrogen-containing contraceptives. Even in the absence of breakthrough bleeding, contraceptive efficacy may be reduced.
Lithium.
In healthy volunteers, a 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 plasma lithium concentrations is recommended when used concomitantly with topiramate.
Risperidone.
Interaction studies conducted using single doses in healthy volunteers and multiple doses in patients with bipolar disorder showed similar results. Concomitant administration of risperidone at doses of 1–6 mg per day with topiramate at doses of 100, 250, and 400 mg per day resulted in a decrease in risperidone concentrations by 16 % and 33 % AUC for the 250 and 400 mg per day doses, respectively. However, differences in AUC of the active moiety between risperidone monotherapy and combination with topiramate were not statistically significant. Minimal deviations in the pharmacokinetics of the active moiety and active metabolites (risperidone and 9-hydroxyrisperidone) were observed, and no changes in the pharmacokinetics of 9-hydroxyrisperidone were noted. No clinically significant changes in systemic exposure of active metabolites of either risperidone or topiramate were observed. Following addition of 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 therapy were somnolence (27 % and 12 %), paresthesia (22 % and 0 %), and nausea (18 % and 9 %, respectively).
Hydrochlorothiazide.
In a drug 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 co-administration of topiramate and hydrochlorothiazide increased Cmax and AUC of topiramate by 27 % and 29 %, respectively. The clinical significance of these changes is unknown. Prescribing hydrochlorothiazide to patients taking topiramate may require dose adjustment of topiramate. Hydrochlorothiazide pharmacokinetic parameters were not significantly altered during concomitant therapy with topiramate. Clinical laboratory tests showed decreased serum potassium levels with administration of either topiramate or hydrochlorothiazide, with a more pronounced effect when both were used in combination.
Metformin.
In a drug 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. 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 the 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 co-administered 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 Topamax® in patients receiving metformin, their diabetic status should be monitored regularly.
Pioglitazone.
In a drug 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 13 % and 16 % decrease in Cmax,ss and AUCτ,ss of the active hydroxy metabolite, respectively, and a 60 % decrease in Cmax,ss and AUCτ,ss of the active keto metabolite were observed. The clinical significance of these results has not been established. When prescribing Topamax® and pioglitazone concomitantly, patients’ diabetic status should be monitored regularly.
Glibenclamide.
In a drug 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 during concomitant administration 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 Topamax® and glibenclamide concomitantly, patients’ diabetic status should be monitored regularly.
Other types of interactions.
Medicinal products promoting nephrolithiasis.
Concomitant use of Topamax® and other drugs promoting nephrolithiasis may increase the risk of kidney stone formation. During treatment with Topamax®, the use of such drugs should be avoided, as they may cause physiological changes leading to nephrolithiasis.
Valproic acid.
Concomitant administration of topiramate with valproic acid has been associated with hyperammonemia, with or without encephalopathy, in patients who tolerated each drug well when used separately. In most cases, symptoms and signs resolved after discontinuation of one of the drugs. This adverse reaction is not related to a pharmacokinetic interaction.
Cases of hypothermia (body temperature reduction to < 35 °C) have been reported during concomitant use of valproic acid and topiramate, both with and without hyperammonemia. This adverse reaction in patients receiving both topiramate and valproic acid may occur either at the beginning of topiramate treatment or after an increase in the daily dose.
Warfarin.
Decreased prothrombin time/international normalized ratio (PT/INR) has been reported in patients receiving topiramate in combination with warfarin. Therefore, INR should be closely monitored in patients receiving topiramate and warfarin concomitantly.
Additional pharmacokinetic drug interaction studies.
Additional clinical studies have been conducted to evaluate potential pharmacokinetic interactions between topiramate and other medicinal products. Changes in Cmax and AUC parameters 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.
| Concomitant drug |
Concentration of concomitant drug |
Concentration of Topamax®a |
| Amitriptyline |
↔ 20 % increase in Cmax and AUC of nortriptyline metabolite |
ND |
| Dihydroergotamine (oral and subcutaneous) |
↔ |
↔ |
| Haloperidol |
↔ 31 % increase in AUC of metabolite |
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 |
| Velafaxine |
↔ |
↔ |
| Flunarizine |
16 % increase in AUC (topiramate 50 mg every 12 hours)b |
↔ |
Expressed as a percentage change in Cmax or AUC values in blood 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 additional information in section "Dosage and administration").
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 topiramate use to reduce the risk of nephrolithiasis. Adequate fluid intake before and during physical exertion or exposure to high temperatures may reduce the risk of temperature-related adverse reactions (see section "Adverse reactions").
Women of childbearing potential.
Topiramate may cause fetal malformations and fetal growth restriction (small for gestational age and low birth weight) when administered during pregnancy. Data from the North American Antiepileptic Drug Pregnancy Registry showed approximately three times higher prevalence of major congenital malformations (4.3%) with topiramate monotherapy compared to the reference group not taking antiepileptic drugs (1.4%). In addition, data from other studies indicate an increased risk of teratogenic effects associated with the use of antiepileptic drugs in combination therapy compared to monotherapy.
Before initiating topiramate treatment, women of childbearing potential should undergo a pregnancy test and be advised to use a highly effective method of contraception (see section "Interaction with other medicinal products and other forms of interaction"). The patient should be fully informed about the risks associated with the use of topiramate during pregnancy (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Oligohidrosis. Cases of oligohidrosis (reduced sweating) associated with topiramate use have been reported. Reduced sweating and hyperthermia (elevated body temperature) may occur primarily in young children exposed to high environmental temperatures.
Mood disorders/depression. Increased incidence of mood disorders and depression has been reported during treatment with topiramate.
Suicide/suicidal thoughts. Cases of suicidal thoughts and suicidal behavior have been reported in patients treated with antiepileptic drugs for various indications. A meta-analysis of placebo-controlled trials of antiepileptic drugs showed a small increased risk of suicidal thoughts and behavior. The mechanism of this phenomenon is unknown, and available data do not exclude the possibility of increased risk associated with topiramate use.
In double-blind, controlled trials, suicidal adverse reactions (suicidal thoughts, suicide attempts, and completed suicides) were observed in 0.5% of patients receiving topiramate (46 out of 8652 patients), approximately three times higher than in patients receiving placebo (0.2%; 8 out of 4045 patients).
Therefore, monitoring for signs of suicidal thoughts and behavior is recommended in patients receiving this treatment. Patients (and their caregivers) should seek medical advice at the first appearance of suicidal thoughts or behavior.
Nephrolithiasis. Some patients, particularly those predisposed to nephrolithiasis, may have an increased risk of kidney stone formation and related symptoms such as renal colic, kidney pain, or flank pain. Risk factors for nephrolithiasis include prior history of kidney stones, family history of nephrolithiasis, and hypercalciuria (see "Metabolic acidosis" below). None of these risk factors can adequately predict the occurrence of stones during topiramate 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 these patients. Dosage recommendations for patients with known renal impairment are provided in the section "Dosage and administration".
Hepatic function impairment. Topamax® 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 Topamax®. Symptoms include sudden decrease in visual acuity and/or eye pain. Ophthalmologic 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 anterior displacement of the lens and iris, leading to secondary angle-closure glaucoma. Symptoms typically occurred within the first month of Topamax® 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 Topamax® and appropriate measures to reduce intraocular pressure.
Elevated intraocular pressure of any etiology, if untreated, may lead to serious complications, including permanent vision loss.
It should be determined 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. In clinical trials, most cases were reversible and resolved after discontinuation of treatment. The necessity of discontinuing the drug should be considered if visual defects occur at any time during therapy.
Metabolic acidosis. Hyperchloremic, non-anion gap metabolic acidosis (i.e., decreased plasma bicarbonate concentration below normal in the absence of respiratory alkalosis) may occur during topiramate use. The reduction in serum bicarbonate concentration is due to inhibition of carbonic anhydrase by topiramate in the kidneys. In most cases, the decrease in bicarbonate concentration occurs early in treatment, although this effect may appear at any time during topiramate therapy. The reduction is usually mild or moderate (on average, 4 mmol/L in adults receiving 100 mg daily and about 6 mg/kg body weight daily in children). In some cases, patients experienced bicarbonate concentrations below 10 mmol/L. Certain conditions or treatments that lead to acidosis (e.g., kidney disease, severe respiratory diseases, epileptic status, diarrhea, surgical procedures, ketogenic diet, 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 (see "Nephrolithiasis").
In children, chronic metabolic acidosis may lead to growth retardation. The impact of topiramate on complications related to bone tissue has not been systematically studied in either children or adult patients.
Depending on the underlying condition, appropriate monitoring, including serum bicarbonate levels, is recommended during topiramate treatment. Serum bicarbonate level testing is recommended if symptoms or signs (such as Kussmaul breathing, dyspnea, anorexia, nausea, vomiting, excessive fatigue, tachycardia, or arrhythmia) indicating metabolic acidosis are present. 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 impairment. Cognitive disturbances in epilepsy are multifactorial and may be related to the underlying cause of the disease, epilepsy itself, or antiepileptic treatment. Publications report cases of worsening cognitive function in adults receiving topiramate treatment, requiring dose reduction or discontinuation of the drug. However, available data on the effect of topiramate on cognitive function in children are insufficient, and the relationship of such effects to drug use requires further study.
Hyperammonemia and encephalopathy.
Hyperammonemia with or without encephalopathy has been reported during treatment with topiramate (see section "Adverse reactions"). The risk of hyperammonemia with topiramate use is dose-dependent. Hyperammonemia is reported more frequently when topiramate is used concomitantly with valproic acid (see section "Interaction with other medicinal products and other forms of interaction").
Patients who develop unexplained lethargy or changes in mental status during monotherapy with topiramate or adjunctive therapy should be evaluated for hyperammonemic encephalopathy and blood ammonia levels should be measured.
Dietary considerations. During treatment with topiramate, some patients may lose body weight; therefore, body weight monitoring is recommended. If weight loss occurs during Topamax® treatment, the need for supportive diet or increased nutrition should be considered.
Sucrose intolerance. The product contains sucrose. Patients with rare hereditary conditions of sucrose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take Topamax®.
Use during pregnancy or breastfeeding.
Pregnancy
Risk associated with epilepsy and use of antiepileptic medicinal products. Women of childbearing potential should consult a specialist. When planning pregnancy, the need for antiepileptic drug treatment should be reviewed. Women receiving antiepileptic drugs should avoid abrupt discontinuation of treatment, as this may lead to seizure exacerbation and cause serious consequences for both the woman and the fetus. Monotherapy should be preferred 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.
Registry pregnancy data indicate that newborns whose mothers used topiramate as monotherapy have:
- an increased risk of congenital malformations (craniofacial defects, including cleft lip/palate, hypospadias, and anomalies of various organ systems) due to topiramate use during the first trimester of pregnancy. Data from the North American Antiepileptic Drug Pregnancy Registry (NAAED) indicate nearly three times higher frequency of congenital malformations (4.3%) compared to the control group (1.4%) not taking antiepileptic drugs. 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 had 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 birth weight below the 10th percentile adjusted for gestational age and stratified by sex). Long-term outcomes of SGA infants are not established.
Use in epilepsy. Women of childbearing potential are advised to consider alternative treatment methods. When treating women of childbearing potential with topiramate, highly effective methods of contraception should be used (see section "Interaction with other medicinal products and other forms of interaction"). During pregnancy, Topamax® should be prescribed only after thorough patient counseling regarding the known risks of uncontrolled epilepsy for pregnancy and the potential effects of the drug on the fetus. When planning pregnancy, consultation with a physician is necessary to reassess treatment and consider alternative therapies. Careful prenatal monitoring is required if Topamax® is used during the first trimester of pregnancy.
Use for migraine prophylaxis. Topiramate is contraindicated for migraine prophylaxis in pregnant women and in women of childbearing potential who are not using highly effective methods of contraception (see sections "Interaction with other medicinal products and other forms of interaction", "Contraindications").
Breastfeeding period
During animal studies, excretion of topiramate into breast milk was detected. Excretion of topiramate into human breast milk has not been studied in controlled trials. Limited observations suggest that topiramate passes into breast milk in significant amounts. Effects observed in breastfed newborns/infants include diarrhea, somnolence, irritability, and inadequate weight gain.
Since most medicinal products pass into breast milk, a decision must be made regarding the necessity of discontinuing breastfeeding or discontinuing 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 effects of topiramate on fertility. The effect of topiramate on human fertility has not been established.
Ability to influence reaction speed when driving or operating machinery.
Topamax® has a negligible or moderate influence on the ability to drive or operate machinery.
Topamax® acts on the central nervous system and may cause drowsiness, dizziness, and other 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
Treatment should be initiated at a low dose with gradual titration to an effective dose. The dose and rate of dose escalation should be individualized according to clinical response.
Monitoring plasma concentrations of topiramate is not necessary for optimizing treatment with TOPAMAX®. In rare cases, when topiramate is prescribed as adjunctive therapy with phenytoin, dosage adjustment of phenytoin may be required to achieve optimal clinical effect. The addition or discontinuation of phenytoin or carbamazepine as adjunctive therapy in patients treated with TOPAMAX® may require adjustment of the TOPAMAX® dose.
TOPAMAX® capsules may be swallowed whole or the capsule may be carefully opened and its contents sprinkled onto a small amount (one teaspoon) of soft food. The medication/mixture should be swallowed immediately without chewing. The mixture of capsule contents with food should not be stored for later use.
The drug may be taken independently of food intake.
Antiepileptic drugs, including topiramate, should be discontinued gradually to minimize the potential for seizure occurrence or increased seizure frequency, regardless of whether patients have a history of epileptic seizures. In clinical trials, daily doses were reduced by 50–100 mg at weekly intervals in adults with epilepsy, and by 25–50 mg in adults receiving topiramate at doses up to 100 mg daily for migraine prophylaxis. In pediatric clinical trials, topiramate discontinuation was conducted gradually over 2–8 weeks.
Epilepsy monotherapy.
When discontinuing concomitant antiepileptic drugs to transition to topiramate monotherapy, the potential impact of this change on seizure frequency should be considered. Unless safety concerns require immediate discontinuation of the concomitant antiepileptic drug, it is recommended to gradually reduce its dose by one-third every 2 weeks.
When discontinuing enzyme-inducing antiepileptic drugs, plasma concentrations of topiramate will increase. In such cases, if clinically indicated, the dose of TOPAMAX® may be reduced.
Adults.
The dose should be titrated according to clinical response. Treatment should be initiated at 25 mg at night for 1 week, followed by weekly or biweekly increments of 25 or 50 mg per day (the daily dose is administered in two divided doses). If the patient does not tolerate this titration regimen, the intervals between dose increases may be extended or smaller dose increments may be used.
The recommended initial target dose of TOPAMAX® for monotherapy in adults is 100–200 mg daily, divided into two doses. The maximum recommended dose is 500 mg daily, divided into two doses. Some patients with refractory epilepsy tolerate monotherapy with TOPAMAX® at a dose of 1000 mg daily. These dosage recommendations apply to all adult patients, including elderly patients, provided they do not have renal impairment.
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 0.5–1 mg/kg at night for 1 week, followed by weekly or biweekly increments of 0.5–1 mg/kg per day (the daily dose is administered in two divided doses). If the child does not tolerate this titration regimen, the intervals between dose increases may be extended or smaller dose increments may be used.
The recommended initial target dose of TOPAMAX® for monotherapy in children aged 6 years and older is 100 mg daily, depending on clinical response (approximately 2 mg/kg body weight daily for children aged 6 to 16 years).
Adjunctive therapy for epilepsy (partial seizures with or without secondary generalization, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome).
Adults.
Treatment should be initiated at 25–50 mg at night for 1 week. Lower starting doses have been reported, but have not been systematically studied. Subsequently, the dose should be increased weekly or biweekly by 25–50 mg per day (the daily dose is administered in two divided doses). In some patients, efficacy may be achieved with once-daily dosing.
In clinical trials of topiramate as adjunctive therapy, the minimum effective dose was 200 mg daily. The usual daily dose ranges from 200–400 mg, administered in two divided doses.
These dosage recommendations apply to all adult patients, including elderly patients, provided they do not have renal impairment (see section "Special Warnings and Precautions for Use").
Children (aged 2 years and older).
The recommended total daily dose of TOPAMAX® (topiramate) as adjunctive therapy is approximately 5–9 mg/kg body weight daily, divided into two doses. Treatment should be initiated at 25 mg (or lower, based on 1–3 mg/kg body weight daily) at night for 1 week, followed by weekly or biweekly increments of 1–3 mg/kg body weight daily (the daily dose is administered in two divided doses) until therapeutic effect is achieved. Doses up to 30 mg/kg body weight daily have been studied in clinical trials and were generally well tolerated.
Migraine.
Adults.
The recommended total daily dose of topiramate for migraine prophylaxis is 100 mg, divided into two doses. Treatment should be initiated at 25 mg in the evening for 1 week, followed by weekly increments of 25 mg per day after each dose increase. If the patient does not tolerate this titration regimen, the intervals between dose increases may be extended.
In some patients, clinical response is achieved with 50 mg of topiramate daily. In clinical trials, patients received up to 200 mg of topiramate daily. This dosage may be effective in some patients, but should be prescribed with caution to minimize the risk of increased adverse reactions.
Special patient groups.
Renal impairment.
Since plasma and renal clearance of topiramate are reduced in patients with impaired renal function (CLCR ≤ 70 mL/min), topiramate should be administered with caution in such patients. Patients with known renal impairment may require a longer time to reach steady-state after each dose. It is recommended to use half the usual initial and maintenance doses (see section "Pharmacological Properties").
Topiramate is removed from plasma during hemodialysis; therefore, in patients with end-stage renal disease, an additional dose of TOPAMAX®—approximately half the usual daily dose—should be administered on hemodialysis days. This additional dose should be divided into two doses and administered at the beginning and after completion of the hemodialysis procedure. The additional dose may vary depending on the characteristics of the dialysis system used (see section "Pharmacological Properties").
Hepatic impairment.
TOPAMAX® should be administered with caution in patients with moderate to severe hepatic impairment due to reduced topiramate clearance.
Elderly patients.
Dose adjustment is not required in elderly patients unless they have renal impairment.
Children.
Monotherapy for epilepsy. For use in children aged 6 years and older.
Adjunctive therapy (partial seizures with or without secondary generalization, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome). For use in children aged 2 years and older.
Migraine. TOPAMAX® is not recommended for the treatment or prophylaxis of migraine in children due to insufficient data on safety and efficacy.
Overdose.
Symptoms.
Cases of topiramate overdose have been reported. Signs and symptoms of TOPAMAX® overdose include seizures, somnolence, speech disturbances, blurred vision, diplopia, cognitive impairment, coordination disturbances, lethargy, stupor, hypotension, abdominal pain, agitation, dizziness, and depression. In most cases, no severe clinical consequences occurred, but fatal cases have been reported following overdose involving multiple drugs, including topiramate.
Topiramate overdose may cause severe metabolic acidosis (see "Special Warnings and Precautions for Use").
Treatment.
In acute topiramate overdose, if ingestion was recent, gastric lavage or induction of emesis should be performed immediately. In vitro studies have shown that activated charcoal adsorbs topiramate. Symptomatic therapy should be administered as needed, and patients are advised to drink plenty of fluids. Hemodialysis is an effective method for removing topiramate from the body.
Adverse reactions
The safety profile of topiramate was evaluated based on data from the clinical trial database involving 4111 patients (3182 receiving topiramate and 929 receiving placebo) who participated in 20 double-blind studies, and 2847 patients who participated in 34 open-label studies, using topiramate as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures, partial-onset 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. The adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), and not known (cannot be estimated from available data).
The most commonly observed adverse reactions with an incidence > 5% and occurring at a higher frequency than in the placebo group during topiramate clinical trials were: anorexia, decreased appetite, bradylalia, depression, expressive speech disorder, insomnia, disturbance in coordination, difficulty with concentration, 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/site and frequency |
Adverse reactions |
| Infections and infestations |
|
| Very common |
Nasopharyngitis* |
| Blood and lymphatic system disorders |
|
| Common |
Anemia |
| Uncommon |
Leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia |
| Rare |
Neutropenia* |
| Immune system disorders |
|
| Common |
Hypersensitivity |
| Not known |
Allergic edema* |
| Metabolism and nutrition disorders |
|
| Common |
Anorexia, decreased appetite |
| Uncommon |
Metabolic acidosis, hypokalemia, increased appetite, polydipsia |
| Rare |
Hyperchloremic acidosis, hyperammonemia*, hyperammonemic encephalopathy* |
| Psychiatric disorders |
|
| Very common |
Depression |
| Common |
Bradypsychia, insomnia, expressive speech disorder, anxiety, confusion, disorientation, aggression, mood disturbance, restlessness, mood swings, depressed mood, irritability, unusual behavior |
| 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 impairment, primary insomnia, emotional blunting, unusual thinking, loss of libido, indifference, intrasomnic 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 disorders, mental disturbance, psychomotor function disorder, convulsions, coordination disorder, tremor, lethargy, hypoesthesia, 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, salivation, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness, poor sleep quality, burning sensation, sensitivity disturbance, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, "pins and needles" sensation |
| Rare |
Apraxia, sleep-wake cycle disturbance, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, unresponsiveness to stimuli |
| Eye disorders |
|
| Common |
Blurred vision, diplopia, visual disturbances |
| Uncommon |
Decreased 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 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 deafness, sensorineural deafness, ear discomfort, hearing impairment |
| Cardiac disorders |
|
| Uncommon |
Bradycardia, sinus bradycardia, palpitations |
| Vascular disorders |
|
| Uncommon |
Arterial hypotension, orthostatic hypotension, hyperemia, flushing |
| Rare |
Raynaud's phenomenon |
| Respiratory, thoracic and mediastinal disorders |
|
| Common |
Dyspnea, epistaxis, nasal congestion, rhinorrhea, cough* |
| Uncommon |
Dyspnea on exertion, paranasal sinus hypersecretion, dysphonia |
| Gastrointestinal disorders |
|
| Very common |
Nausea, diarrhea |
| Common |
Vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, stomach discomfort, paraesthesia of oral mucosa, gastritis, abdominal discomfort |
| Uncommon |
Pancreatitis, flatulence, gastroesophageal reflux disease, lower abdominal pain, hypoesthesia 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 hypoesthesia, 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 |
Nephrolithiasis, polyuria, dysuria, nephrocalcinosis* |
| Uncommon |
Urinary stones, urinary incontinence, hematuria, incontinence, urinary urgency, renal colic, kidney pain |
| Rare |
Urinary tract stones, renal tubular acidosis* |
| Reproductive system disorders |
|
| Uncommon |
Erectile dysfunction, sexual dysfunction |
| General disorders |
|
| 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, feeling of anxiety |
| Rare |
Facial swelling |
| 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 behavior disorders |
|
| Rare |
Inability to learn |
*Adverse reactions reported in the post-marketing period (spontaneous reports). Their frequency was determined based on clinical trial data.
Congenital malformations and fetal growth restriction (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
Safety profile characteristics in children.
Adverse reactions observed in children at ≥ 2 times higher frequency than in adults during double-blind controlled studies: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disorders, aggression, apathy, primary insomnia, suicidal ideation, difficulty concentrating, lethargy, sleep-wake cycle disturbance, poor quality of sleep, 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 with tightly closed cap to protect from moisture at a temperature not exceeding 25 °C. Keep out of the reach and sight of children.
Packaging.
28 capsules in a high-density polyethylene bottle with a child-resistant cap; 1 bottle in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
Responsible for batch release:
Janssen-Cilag S.p.A.
Janssen Cilag S.p.A.
Manufacturer's address and place of business.
Via C. Janssen, 04100 Borgo S. Michele, Latina, Italy
Via C. Janssen, 04100 Borgo S. Michele, Latina, Italy.