Topiramat (Tablets) Instructions for Use

Marketing Authorization Holder

Canonpharma Production, CJS (Russia)

ATC Code

N03AX11 (Topiramate)

Active Substance

Topiramate (Rec.INN registered by WHO)

Dosage Forms

	Topiramate	Film-coated tablets, 25 mg: 7, 10, 14, 28, 30, 56 or 60 pcs.
		Film-coated tablets, 100 mg: 7, 10, 14, 28, 30, 56 or 60 pcs.

Dosage Form, Packaging, and Composition

7 pcs. – contour cell packaging (1) – cardboard packs.
7 pcs. – contour cell packaging (2) – cardboard packs.
7 pcs. – contour cell packaging (4) – cardboard packs.
7 pcs. – contour cell packaging (8) – cardboard packs.
10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
15 pcs. – contour cell packaging (2) – cardboard packs.
15 pcs. – contour cell packaging (4) – cardboard packs.
30 pcs. – contour cell packaging (1) – cardboard packs.
30 pcs. – contour cell packaging (2) – cardboard packs.

7 pcs. – contour cell packaging (1) – cardboard packs.
7 pcs. – contour cell packaging (2) – cardboard packs.
7 pcs. – contour cell packaging (4) – cardboard packs.
7 pcs. – contour cell packaging (8) – cardboard packs.
10 pcs. – contour cell packaging (1) – cardboard packs.
10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.
15 pcs. – contour cell packaging (2) – cardboard packs.
15 pcs. – contour cell packaging (4) – cardboard packs.

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Antiepileptic agent

Pharmacological Action

Antiepileptic drug.

It reduces the frequency of occurrence of repeated action potentials, characteristic of a neuron in a state of persistent depolarization, by blocking sodium channels.

It increases the activity of gamma-aminobutyric acid (GABA) in relation to some subtypes of GABA receptors (including GABA[A] receptors), and also modulates the activity of the receptors themselves; prevents the activation of the kainate-sensitive subtype of kainate/AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors by glutamate, does not affect the activity of N-methyl-D-aspartate (NMDA) in relation to the NMDA receptor subtype.

These effects are dose-dependent at a plasma drug concentration from 1 µmol to 200 µmol, with minimal activity in the range from 1 µmol to 10 µmol.

It inhibits the activity of some carbonic anhydrase isoenzymes; however, this effect is not the main one in the antiepileptic activity of topiramate.

Pharmacokinetics

Absorption Topiramate is absorbed quickly and effectively. Bioavailability is 80%. Food intake does not have a clinically significant effect on bioavailability. C_max in blood plasma is reached in 2 hours.

Distribution 13-17% of topiramate binds to plasma proteins. V_d (after a single oral dose of 1.2 g) is 0.55-0.8 l/kg, depends on gender: in women it is approximately 50% of the values observed in men. It penetrates into breast milk.

Metabolism It is metabolized in the liver by hydroxylation, hydrolysis, glucuronidation with the formation of six pharmacologically inactive metabolites.

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

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

In patients with normal renal function, it may take from 4 to 8 days to achieve a steady-state plasma concentration.

Elimination After multiple doses of 50 and 100 mg twice a day, the T_1/2 of topiramate from plasma averaged 21 hours.

The main route of excretion of unchanged topiramate (70%) and its metabolites is the kidneys.

In renal failure (creatinine clearance less than 60 ml/min) and severe hepatic impairment, plasma and renal clearance are reduced.

Topiramate is effectively removed from plasma by hemodialysis.

Indications

Epilepsy

As monotherapy

Topiramate is used in adults and children over 3 years of age with epilepsy (including patients with newly diagnosed epilepsy).

As part of complex therapy

Topiramate is used in adults and children over 3 years of age with partial or generalized tonic-clonic seizures, as well as for the treatment of seizures in Lennox-Gastaut syndrome.

ICD codes

Dosage Regimen

Orally, regardless of food intake.

Monotherapy.

When used as monotherapy, the possible effect of withdrawal of concomitant anticonvulsant therapy on the frequency of seizures should be taken into account.

In cases where there is no need to abruptly discontinue concomitant anticonvulsant therapy for safety reasons, it is recommended to reduce the dose of the concomitant drug by one third every 2 weeks.

When discontinuing drugs that are inducers of “hepatic” enzymes, topiramate blood concentrations will increase.

In such situations, if clinically indicated, the dose of topiramate may be reduced.

Adult patients at the beginning of monotherapy should take 25 mg of topiramate once a day at bedtime for 1 week.

Then the dose is increased at intervals of 1-2 weeks by 25 or 50 mg (the daily dose is divided into two doses).

If the patient does not tolerate such a dose increase regimen, the intervals between dose increases can be increased, or the dose can be increased more smoothly.

When selecting the dose, one should be guided by the clinical effect.

The recommended dose for topiramate monotherapy in adults is 100 mg per day, and the maximum daily dose is 500 mg.

Some patients with refractory forms of epilepsy tolerate topiramate monotherapy in doses up to 1 g/day.

Children over 3 years of age with monotherapy during the first week of treatment – 0.5-1 mg/kg of body weight per day, at bedtime.

Then the dose is increased at intervals of 1-2 weeks by 0.5-1 mg/kg per day (the daily dose is divided into two doses).

If the child does not tolerate such a dose increase regimen, then the dose can be increased more smoothly or the intervals between dose increases can be increased.

When selecting the dose and the rate of its increase, one should be guided by clinical efficacy.

The recommended dose range for topiramate monotherapy in children over 3 years of age is 3-6 mg/kg per day.

The maximum daily dose for children with recently diagnosed partial seizures does not exceed 500 mg per day.

Use in combination with other anticonvulsants

In adults, the initial dose is 50 mg once a day at night for 1 week.

Further, the dose can be increased by 25-50 mg in 1-2 weeks until an effective dose is reached.

Usually the average daily dose is from 200 mg to 400 mg and is taken in two doses.

Some patients may require an increase in the daily dose to the maximum – 1600 mg.

In some patients, the effect can be achieved by taking the drug once a day.

Combined anticonvulsant therapy in children over 3 years of age.

The recommended total daily dose of topiramate as an adjunctive therapy is from 5 to 9 mg/kg and is taken in two doses.

Dose selection should be started with 25 mg (or less, based on an initial dose of 1 to 3 mg/kg per day), at night, for 1 week.

Further, the dose can be increased by 1-3 mg/kg in 1-2 weeks and taken in two doses.

A daily dose of up to 30 mg/kg is usually well tolerated.

On the days of hemodialysis, Topiramate should be used additionally in a dose equal to 1/2 of the daily dose, in 2 doses (before and after the procedure).

The drug should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures (by 100 mg/week).

Adverse Reactions

Side effects are presented with distribution by frequency and organ systems.

The frequency of side effects was classified as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000 and <1/100), rare (>1/10000 and <1/1000) and very rare (<1/10000).

General disorders very common – increased fatigue, irritability, weight loss; common – asthenia, anxiety, increased body temperature in children; uncommon – facial edema, metabolic acidosis, polydipsia, cold extremities; very rare – generalized edema, flu-like syndrome.

From the central nervous system very common – ataxia (impaired coordination of movements), decreased ability to concentrate, dizziness, paresthesia; common – drowsiness, thinking impairment; rare – nystagmus, emotional lability, tremor, amnesia, taste perversion, speech impairment (aphasia, dysarthria).

From the digestive system very common – decreased appetite; common – nausea, diarrhea, constipation, dyspepsia, dry mouth, gastritis, gastroesophageal reflux; uncommon – flatulence, bad breath, increased salivation, thirst.

From the musculoskeletal system common – arthralgia, muscle spasms, muscle cramps, myalgia, including chest; uncommon – muscle stiffness; very rare – joint swelling, limb discomfort.

Disorders from the cardiovascular system uncommon – bradycardia, palpitations, orthostatic hypotension;

From the senses: From the organ of vision, common – visual impairment, (diplopia), increased lacrimation, mydriasis, night blindness, decreased visual acuity; very rare – conjunctival edema, 1 month after the start of therapy, intraocular hypertension may develop, as a result – myopia, angle-closure glaucoma. From the organ of hearing common – ear pain, ringing in the ears, vertigo in children; uncommon – ear discomfort, hearing impairment, deafness, including sensorineural deafness and unilateral deafness.

From the respiratory system common – difficulty breathing, nosebleeds; uncommon – nasal congestion, hypersecretion in the paranasal sinuses, rhinorrhea in children.

From the skin common – alopecia, itching.

Allergic reactions uncommon – allergic dermatitis, urticaria.

Disorders from the urinary system rare – kidney stone formation (nephrolithiasis), urination disorders.

Laboratory parameters uncommon – in the blood an increase in the number of leukocytes, platelets (leukopenia, thrombocytopenia), in children in the blood – an increase in the number of eosinophils (eosinophilia), a decrease in the concentration of bicarbonate, the concentration of potassium in the blood, detection of crystals in the urine (crystalluria); very rare – (a decrease in the number of neutrophils (neutropenia).

Contraindications

Hypersensitivity, pregnancy, lactation period.

Topiramate in this dosage form (tablets), due to difficulties with swallowing, is not recommended for use in children under 3 years of age.

With caution. In renal and hepatic insufficiency, nephrourolithiasis (including in the past and in family history), hypercalciuria.

Use in Pregnancy and Lactation

Due to the lack of clinical data, it is not used for the treatment of pregnant women.

Topiramate is excreted in breast milk in women.

The use of the drug is contraindicated in women during breastfeeding.

If it is necessary to take the drug during lactation, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Use with caution in renal insufficiency, nephrourolithiasis (including in the past and in family history), hypercalciuria.

Pediatric Use

Topiramate in this dosage form (tablets), due to difficulties with swallowing, is not recommended for use in children under 3 years of age.

Special Precautions

Topiramate should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures.

In clinical trials, doses were reduced by 50-100 mg at weekly intervals for adults in the treatment of epilepsy.

In children in clinical studies, Topiramate was gradually discontinued over 2-8 weeks.

If, for medical reasons, rapid discontinuation of Topiramate is necessary, then appropriate monitoring of the patient’s condition is recommended.

The rate of renal excretion depends on renal function and does not depend on age.

In patients with moderate or severe renal impairment, it may take 10 to 15 days to achieve steady-state plasma concentrations, as opposed to 4-8 days in patients with normal renal function.

As with any disease, the dose selection regimen should be guided by the clinical effect (i.e., the degree of seizure control, absence of side effects) and take into account that in patients with impaired renal function, a longer time may be required to establish a stable plasma concentration for each dose.

Nephrolithiasis. In some patients, especially those predisposed to nephrolithiasis, the risk of kidney stone formation and the appearance of associated symptoms, such as renal colic, may increase.

To reduce this risk, adequate increase in fluid intake is necessary.

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

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

Myopia and secondary angle-closure glaucoma .

When using topiramate, a syndrome has been described that includes acute myopia with concomitant secondary angle-closure glaucoma.

Symptoms include acute decrease in visual acuity and/or eye pain.

Ophthalmological examination may reveal myopia, flattening of the anterior chamber of the eye, hyperemia (redness) of the eyeball, and increased intraocular pressure.

Mydriasis may be observed.

Symptoms usually appear within 1 month after starting topiramate.

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

Treatment includes discontinuation of topiramate and appropriate measures aimed at reducing intraocular pressure.

Metabolic acidosis.

When using topiramate, hyperchloremic, non-anion gap, metabolic acidosis may occur (for example, a decrease in plasma bicarbonate concentration below the normal level in the absence of respiratory alkalosis).

Such a decrease in serum bicarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase.

The decrease in concentration is usually mild or moderate (the average value is 4 mmol/L when used in adult patients at a dose above 100 mg per day and about 6 mg per day per kg of body weight when used in pediatric practice).

In rare cases, patients have experienced a decrease in bicarbonate concentration below 10 mmol/L.

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

In view of the above, when treating with topiramate, it is recommended to conduct the necessary studies, including determining the concentration of bicarbonate in the serum.

If metabolic acidosis occurs and persists, it is recommended to reduce the dose or discontinue topiramate.

Enhanced nutrition.

If the patient loses weight during treatment with Topiramate, then the advisability of enhanced nutrition should be considered.

Topiramate acts on the central nervous system and can cause drowsiness, dizziness, visual impairment and other symptoms.

Therefore, during the treatment period, caution should be exercised when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Overdose symptoms intensification of dose-dependent side effects.

Treatment in case of acute overdose, it is necessary to immediately perform gastric lavage.

If necessary, symptomatic therapy should be carried out.

An effective way to remove topiramate from the body is hemodialysis.

Drug Interactions

Effect of topiramate on concentrations of other antiepileptic drugs (AEDs)

Concomitant administration of topiramate with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect their steady-state plasma concentrations, except for individual patients in whom the addition of topiramate to phenytoin may cause an increase in phenytoin plasma concentration.

In each patient taking phenytoin and who develops clinical signs or symptoms of toxicity, phenytoin plasma concentrations should be monitored.

In a pharmacokinetic study in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the steady-state concentration of the latter at topiramate doses of 100-400 mg per day.

During therapy and after discontinuation of lamotrigine (average dose 327 mg per day), the steady-state concentration of topiramate did not change.

Effect of other antiepileptic drugs on topiramate concentration

Phenytoin and carbamazepine reduce topiramate plasma concentrations.

Addition or withdrawal of phenytoin or carbamazepine during treatment with topiramate may require a change in the dose of the latter.

The dose should be selected based on achieving the desired clinical effect.

Addition or withdrawal of valproic acid does not cause clinically significant changes in Topiramate plasma concentration and, therefore, does not require a change in the Topiramate dose.

Other drug interactions

Digoxin in a study with simultaneous administration of Topiramate using a single dose of digoxin, the AUC of digoxin in plasma decreased by 12%.

When starting or discontinuing Topiramate in patients taking digoxin, special attention should be paid to routine monitoring of digoxin serum concentration.

It is not recommended to take Topiramate together with alcohol or other drugs that cause depression of the CNS function.

Oral contraceptives A significant dose-dependent decrease in the efficacy of ethinylestradiol was observed at Topiramate doses of 200-800 mg per day. The risk of decreased contraceptive efficacy and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topiramate. Patients taking estrogen-containing contraceptives should be informed to report any changes in the timing and nature of menstruation. Contraceptive efficacy may be further reduced in the absence of breakthrough bleeding.

Lithium preparations When Topiramate and lithium preparations are used concomitantly, the plasma lithium concentration should be monitored.

Risperidone With the concomitant use of Topiramate at doses of 250 or 400 mg per day, the AUC of risperidone taken at doses of 1-6 mg per day decreases by 16% and 33%, respectively. The overall pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed insignificantly.

Hydrochlorothiazide When Topiramate and hydrochlorothiazide are taken concomitantly, the maximum concentration of Topiramate increases by 27% and the AUC of Topiramate by 29%. The use of hydrochlorothiazide in patients taking Topiramate may require adjustment of the Topiramate dose. The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered with concomitant Topiramate therapy.

Metformin When Topiramate and metformin are taken concomitantly, the maximum concentration and AUC of metformin increase by 18% and 25%, respectively, while the clearance of metformin when used concomitantly with Topiramate decreased by 20%. Topiramate did not affect the time to reach the maximum plasma concentration of metformin. The clearance of Topiramate decreases when used concomitantly with metformin. The extent of the identified changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of Topiramate is unclear. If Topiramate is added or discontinued in patients receiving metformin, special attention should be paid to a thorough examination of the condition of patients with diabetes mellitus.

Pioglitazone Clinical trials revealed a 15% decrease in the AUC of pioglitazone, without a change in the maximum concentration of the drug. These changes were not statistically significant. When Topiramate and pioglitazone are used concomitantly, special attention should be paid to a thorough examination of the condition of patients with diabetes mellitus.

Glibenclamide A drug interaction study was conducted to investigate the pharmacokinetics of glibenclamide (5 mg/day) at steady state, used alone or concomitantly with Topiramate (150 mg/day) in patients with type 2 diabetes mellitus. When Topiramate was used, the AUC of glibenclamide decreased by 25%. The level of systemic exposure to active metabolites was also reduced. Glibenclamide did not affect the pharmacokinetics of Topiramate at steady state. When Topiramate is used in patients receiving glibenclamide (or when glibenclamide is used in patients receiving Topiramate), the patient’s condition should be carefully monitored to assess the course of diabetes mellitus.

Other drugs Concomitant use of Topiramate with drugs that predispose to nephrolithiasis may increase the risk of kidney stone formation.

Valproic acid: Combined use of Topiramate and valproic acid in patients who tolerate each drug well individually is accompanied by hyperammonemia with or without encephalopathy. In most cases, the symptoms and signs disappear after discontinuation of one of the drugs. This adverse event is not caused by a pharmacokinetic interaction. The relationship between hyperammonemia and the use of Topiramate alone or in combination with other drugs has not been established.

Additional drug interaction studies have shown Amitriptyline: when amitriptyline is used concomitantly with Topiramate, the maximum concentration and AUC of the metabolite nortriptyline increase by 20%;

Haloperidol when haloperidol is used concomitantly with Topiramate, the AUC of haloperidol increases by 31%;

Diltiazem when diltiazem is used concomitantly with Topiramate, the AUC of diltiazem decreases by 25%, and the AUC of Topiramate increases by 20%.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life. 2 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.