Toreal, pills 25mg, 28pcs

Composition

Pharmacological action

Pharmacotherapy group: antiepileptic agent

ATX code: N03 AX 11

Pharmacological properties

Pharmacodynamics

Topiramate belongs to the sulfate-substituted monosaccharides. Blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Increases the activity of gamma-aminobutyric acid (GABA) against certain subtypes of GABA receptors. Prevents activation by kainat kainat/AMPK (alpha-amino-Z-hydroxy-5-methylisoxazole-4-propionic acid) receptors for glutamate, without affecting the activity of N-methyl-D-aspartate (NMDA) against NMDA receptors. These effects are dose-dependent. In addition, topiramate inhibits the activity of some carbonic anhydrase isoenzymes. This effect is significantly weaker than that of the carbonic anhydrase inhibitor acetazolamide, and is not the main component of the antiepileptic activity of topiramate.

Pharmacokinetics

Topiramate is rapidly and well absorbed. Food intake does not have a clinically significant effect on its bioavailability, which is about 80%. Plasma protein binding is 13-17%. The average volume of distribution is 0.55-0.8 l / kg for a single dose up to 1200 mg. This indicator depends on gender: in women, these values are 50% of the values observed in men, which is associated with a higher content of adipose tissue in women, about 20% of topiramate is metabolized. Up to 50% of topiramate is metabolized by patients taking concomitantly other antiepileptic drugs (AEDs) that induce metabolizing enzymes. Six practically inactive metabolites of topiramate were isolated from human plasma, urine, and feces. Unchanged topiramate and its metabolites are mainly excreted by the kidneys. Plasma clearance is about 20-30 ml/min.

After a single dose, the pharmacokinetics are linear, plasma clearance is constant, and the area under the concentration-time curve in the dose range from 100 to 400 mg increases proportionally to the dose. With normal renal function, patients may need 4-8 days to reach steady-state plasma concentrations. The average value of the maximum concentration after repeated oral use of 100 mg of topiramate twice a day is 6.76 mcg / ml. The half-life after repeated use of 50 and 100 mg twice a day is 21 hours.

In patients with impaired renal function (creatinine clearance 70 ml/min), the plasma and renal clearance of topiramate decreases; in patients with end-stage renal insufficiency, the plasma clearance of topiramate decreases. Plasma clearance of topiramate does not change in elderly patients in the absence of impaired renal function. Plasma clearance of topiramate decreases in patients with moderate to severe hepatic impairment.

The pharmacokinetics of topiramate in children, as well as in adults, is linear. The clearance of topiramate does not depend on the dose, the equilibrium concentration in blood plasma increases in proportion to the dose. However, children are characterized by higher clearance values and a shorter half-life. Therefore, the concentration of topiramate in the blood plasma when taking the same doses per kg of body weight may be lower in children compared to adults. As in adults, when taking other AEDs that induce microsomal liver enzymes, the equilibrium concentration of topiramate in blood plasma decreases.

Topiramate is effectively removed from the blood plasma during hemodialysis. Presumably penetrates into breast milk.

Indications

Epilepsy: as monotherapy for initial treatment in patients older than 2 years-partial or primary generalized tonic-clonic seizures; as part of complex therapy in patients older than 2 years-partial or generalized tonic-clonic seizures, as well as seizures on the background of Lennox-Gastaut syndrome.

Migraine: prevention of migraine attacks in adults.

Use during pregnancy and lactation

Adequate and strictly controlled clinical studies on the safety of topiramate use during pregnancy have not been conducted.

The use of topiramate during pregnancy can cause damage to the fetus. Data from the pregnancy registry show that intrauterine exposure to topiramate increases the risk of developing congenital malformations (for example, craniofacial defects such as cleft lip/cleft palate, hypospadias, and malformations of various body systems). These malformations were recorded both with topiramate monotherapy and with its use in combination therapy. Compared with the group of patients not taking antiepileptic drugs, data from the register of pregnant women with topiramate monotherapy indicate an increase in the frequency of children born with low body weight (less than 2500 g). No causal relationship has been established.

When treating women of childbearing age, the expected benefit of therapy to the mother and the potential risk to the fetus should be weighed, and alternative treatment options should be considered. If topiramate is used during pregnancy or if pregnancy occurs during treatment, the patient should be warned about the potential risk to the fetus.

A limited number of observations suggest that topiramate is excreted in breast milk. If it is necessary to use during lactation, the question of stopping breastfeeding should be decided.

Use in children

Do not use in children under 2 years of age.

Contraindications

• hypersensitivity to any of the components of the drug;
• children under 2 years of age;
• pregnancy and in women with preserved childbearing potential, who do not use reliable methods of contraception, and during breastfeeding;
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution

It should be used with caution in patients with hepatic or renal insufficiency, nephrourolithiasis (including in the past or family history), hypercalciuria. It should be borne in mind that taking the drug increases the risk of developing depression and suicidal syndrome. Reduce the dose or discontinue Toreal® gradually to minimize the likelihood of an increase in the frequency of seizures. According to clinical studies, doses were reduced by 50-100 mg at weekly intervals for adults in the treatment of epilepsy and by 25-50 mg in adults receiving 100 mg of topiramate per day for the prevention of migraines. In children in clinical trials, topiramate was gradually discontinued for 2-8 weeks. If rapid withdrawal of Toreal® is medically necessary, appropriate monitoring of the patient’s condition is recommended.

Side effects

Nervous system disorders:  paresthesia, drowsiness, dizziness, attention disorders, memory disorders, amnesia, psychomotor disorders, convulsions, poor coordination, tremor, lethargy, hypesthesia, nystagmus, dysgeusia, balance disorders, articulation disorders, intentional tremors (dynamic), sedation, depression of consciousness, convulsions like large convulsive seizures, visual field defect, complex partial seizures, speech disorder, psychomotor disability hyperactivity, syncope, sensory disturbances, drooling, aphasia, repetitive speech, hypokinesia, dyskinesia, postural vertigo, poor sleep quality, burning sensation, loss of sensation, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphy, dysphasia, peripheral neuropathy, pre-syncope, dystonia, apraxia, circadian rhythm disorder sleep rhythm disorders, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli, learning difficulties.

Mental disorders:  depression, slow thinking, cognitive disorders, insomnia, severe speech disorders, anxiety, confusion, disorientation, aggression, mood lability, anxious arousal, emotional lability, depressive mood, anger, inappropriate behavior, suicidal ideation or attempts, auditory and visual hallucinations, psychotic disorder, apathy, lack of spontaneous speech, sleep disorders, affective lability, decreased libido, anxiety, tearfulness, dysphemia, euphoria, paranoid states, perseveration of thinking, panic attack, tearfulness, impaired reading skills, flattening of emotions, falling asleep disorder, abnormal thinking, loss of libido, lethargy, intrasomnic disorder, pathologically increased distractibility, early morning awakenings, panic reaction, mania, panic disorder, feelings of despair, hypomanic state.

From the side of the visual organ:  blurred vision, diplopia, visual impairment, decreased visual acuity, scotoma, myopia, abnormal eye sensations, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia, unilateral blindness, transient blindness, glaucoma, accommodation disorders, visual depth perception disorders, atrial scotoma, eyelid edema, night blindness, amblyopia, angle-closure glaucoma, maculopathy, oculomotor disorders.

From the hematopoietic system:  anemia, leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia, neutropenia.

From the immune system: hypersensitivity, allergic edema, conjunctival edema.

From the side of metabolism: anorexia, decreased appetite, metabolic acidosis, hypokalemia, increased appetite, polydipsia, hyperchloremic acidosis.

From the side of the organ of hearing and balance: vertigo, tinnitus, ear pain, deafness, unilateral deafness, sensorineural deafness, tinnitus discomfort, hearing impairment.

From the cardiovascular system: bradycardia, sinus bradycardia, rapid heartbeat, orthostatic hypotension, hot flashes, hyperemia, Raynaud’s phenomenon.

Respiratory system disorders: nasopharyngitis, dyspnoea, nosebleeds, nasal congestion, rhinorrhea, cough, shortness of breath during exercise, hypersecretion in the paranasal sinuses, dysphonia.

From the digestive system: nausea, diarrhea, vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, stomach discomfort, oral paresthesia, gastritis, abdominal discomfort, pancreatitis, flatulence, gastroesophageal reflux disease, lower abdominal pain, oral hypesthesia, bleeding gums, bloating, epigastric discomfort, soreness all over the body abdominal pain, salivary gland hypersecretion, oral pain, bad breath, glossodynia, hepatitis, liver failure.

Skin and subcutaneous tissue disorders: alopecia, pruritus, rash, anhidrosis, facial hypesthesia, urticaria, erythema, generalized pruritus, macular rash, skin discoloration, allergic dermatitis, facial edema, Stevens-Johnson syndrome, erythema multiforme, skin odor, periorbital edema, localized urticaria, toxic epidermal necrolysis.

Musculoskeletal disorders: arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, muscle pain in the chest, joint swelling, muscle stiffness, side pain, muscle fatigue, discomfort in the extremities.

From the urinary system: nephrolithiasis, pollakiuria, dysuria, urinary stones, urinary incontinence under stress, hematuria, urgent painful urge to urinate, renal colic, pain in the kidney area, ureteral stones, renal tubular acidosis.

From the side of the reproductive system: erectile dysfunction, sexual dysfunction.

General reactions: fatigue, pyrexia, asthenia, irritability, gait disturbance, unusual sensations, malaise, hyperthermia, thirst, flu-like state, inertia, cold extremities, feeling intoxicated, anxiety, facial edema, calcification.

From the side of laboratory parameters: weight loss, weight gain, crystalluria, abnormal tandem gait test, leukopenia, increased activity of liver enzymes, hypokalemia, decrease in the content of bicarbonates in the blood.

Interaction

When used concomitantly with topiramate, phenytoin and carbamazepine reduce its concentration in blood plasma. This is due to the induction under the influence of phenytoin and carbamazepine of enzymes involved in the metabolism of topiramate. In some cases, when using topiramate, an increase in the concentration of phenytoin in blood plasma was observed.

With simultaneous use of a single dose of topiramate and digoxin, a decrease in the AUC of digoxin may occur.

When an oral contraceptive containing norethindrone and ethinyl estradiol was used simultaneously, topiramate did not significantly affect the clearance of norethindrone, but the plasma clearance of ethinyl estradiol increased significantly. Thus, when taking topiramate with oral contraceptives at the same time, their effectiveness may be reduced.

In patients taking metformin, pioglitazone, glibenclamide, with simultaneous use or withdrawal of topiramate, fluctuations in plasma glucose levels may occur. With these combinations, plasma glucose levels should be monitored.

Concomitant use of topiramate with drugs predisposing to the development of nephrolithiasis may increase the risk of kidney stones.

How to take, course of use and dosage

Inside, by swallowing the tablet whole, without chewing, regardless of food intake. For optimal seizure control, it is recommended to start treatment with low doses, followed by gradual titration to the effective dose.

Toreal ® tablets are not recommended to be divided into parts.

Partial or generalized tonic-tonic seizures, as well as seizures associated with Lennox-Gastaut syndrome

Use in combination with other anticonvulsants in adult patients

The minimum effective dose is 200 mg / day. Usually, the total daily dose is 200-400 mg (in 2 doses). Some patients may need to increase the daily dose to a maximum of 1600 mg. Treatment begins with 25-50 mg daily at night for 1 week. Then the dose is increased by 25-50 mg per day for 1-2 weeks, with a multiplicity of 2 times a day. The dose and frequency of use are selected depending on the clinical effect. In some patients, the effect can be achieved by taking the drug 1 time a day. To achieve the optimal effect of treatment with Toreal®, it is not necessary to monitor its concentration in plasma. These guidelines apply to all adult patients, including the elderly, who do not have kidney disease.

Combined anticonvulsant therapy in children over 2 years of age

The recommended total daily dose of Toreal® as an adjunct therapy is 5 to 9 mg / kg of body weight and is taken in 2 divided doses. Treatment begins with a dose of 25 mg (or less, based on an initial dose of 1 to 3 mg/kg per day) at night for 1 week. Then the dose is increased by 1-3 mg / kg / day for 1-2 weeks, with a multiplicity of 2 times a day, until the optimal clinical effect is achieved.

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

Epilepsy (including newly diagnosed ones)

Monotherapy: general provisions

When discontinuing concomitant anticonvulsant medications for the purpose of topiramate monotherapy, it is necessary to consider the possible impact of this step on the frequency of seizures. In cases where it is not necessary to abruptly cancel the concomitant anticonvulsant drug for safety reasons, it is recommended to reduce their doses gradually, reducing the dose of the concomitant antiepileptic drug by one-third every 2 weeks.

When drugs that are inducers of liver enzymes are discontinued, topiramate concentrations in the blood will increase. In such situations, if there are clinical indications, the dose of Toreal® can be reduced.

Monotherapy: adults

Treatment begins with 25 mg per night for 1 week. Then the dose is increased by 25-50 mg per day for 1-2 weeks, with a multiplicity of 2 times a day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of use are selected depending on the clinical effect. The recommended starting dose of topiramate for monotherapy in adults with newly diagnosed epilepsy is 100 mg / day, the maximum recommended dose is 500 mg / day. These doses are recommended for all adults, including the elderly with normal renal function.

Monotherapy: children

In children over 2 years of age, treatment begins with a dose of 0.5-1 mg/kg of body weight at night for 1 week. Then the dose is increased by 0.5-1 mg / kg / day for 1-2 weeks, the frequency of use is 2 times a day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of use are selected depending on the clinical effect. The recommended dose range is 3-6 mg / kg of body weight. Children with newly diagnosed partial seizures can be prescribed up to 500 mg per day.

Migraines

The recommended total daily dose of topiramate for the prevention of migraine attacks is 100 mg and is taken in 2 divided doses. At the beginning of treatment, the patient should take 25 mg of Toreal® at bedtime for 1 week. Then the dose is increased at intervals of 1 week by 25 mg per day. If the patient does not tolerate this mode of increasing the dose, then you can increase the intervals between dose increases, or increase the dose more smoothly. When selecting the dose, it is necessary to be guided by the clinical effect. In some patients, a positive result is achieved with a daily dose of topiramate 50 mg. In clinical trials, patients received various daily doses of topiramate, but not more than 200 mg per day.

Special patient groups

Kidney failure

Patients with moderate or severe renal insufficiency may need to reduce the dose. It is recommended to use half of the recommended starting dose and maintenance dose.

Hemodialysis

Since topiramate is removed from the plasma during hemodialysis, an additional dose of Toreal® should be administered on the days of hemodialysis, equal to approximately half the daily dose. The additional dose should be divided into two doses taken at the beginning and after completion of the hemodialysis procedure. The additional dose may vary depending on the characteristics of the equipment used for hemodialysis.

Liver failure

Topiramate should be used with caution in patients with hepatic insufficiency.

Overdose

General information

Inside, by swallowing the tablet whole, without chewing, regardless of food intake. For optimal seizure control, it is recommended to start treatment with low doses and then increase to the effective dose.

As part of complex therapy.

Adults

The minimum effective dose is 200 mg / day. The usual daily dose is 200-400 mg (in 2 doses). The maximum daily dose is 1600 mg. Treatment begins with 25-50 mg daily at night for 1 week. Then the dose is increased by 25-50 mg per day for 1-2 weeks, with a multiplicity of 2 times a day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of use are selected depending on the clinical effect.

Children over 3 years of age

The recommended daily dose is 5-9 mg / kg of body weight, divided into 2 doses. Treatment begins with a dose of 25 mg per night for 1 week. Then the dose is increased by 1-3 mg / kg / day for 1-2 weeks, with a multiplicity of 2 times a day, until the optimal clinical effect is achieved.

Monotherapy

Adults

Treatment begins with 25 mg per night for 1 week. Then the dose is increased by 25-50 mg per day for 1-2 weeks, with a multiplicity of 2 times a day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of use are selected depending on the clinical effect. The recommended starting dose of topiramate for monotherapy in adults with newly diagnosed epilepsy is 100 mg / day, the maximum recommended dose is 500 mg / day. These doses are recommended for all adults, including the elderly with normal renal function.

Children from 3 years of age

Treatment begins with a dose of 0.5-1 mg/kg of body weight at night for 1 week. Then the dose is increased by 0.5-1 mg / kg / day for 1-2 weeks, the frequency of use is 2 times a day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of use are selected depending on the clinical effect. The recommended dose range is 3-6 mg / kg of body weight. Children with newly diagnosed partial seizures can be prescribed up to 500 mg per day.

Special instructions

The use of topiramate for the treatment of acute migraine attacks has not been studied.

It should be used with caution in patients with renal and hepatic insufficiency, nephrourolithiasis (including personal and family history), hypercalciuria.

Patients with impaired renal function and patients on hemodialysis need to adjust the dosage regimen of topiramate.

Topiramate should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures. In clinical studies in adults treated with epilepsy, doses were reduced by 50-100 mg at 1-week intervals. and by 25-50 mg in adults receiving topiramate at a dose of 100 mg / day for the prevention of migraines. In children in clinical trials, topiramate was gradually discontinued for 2-8 weeks. If a rapid withdrawal of topiramate is medically necessary, it is recommended to monitor the patient’s condition.

To reduce the risk of developing nephrolithiasis during treatment, you should increase the amount of fluid consumed.

With the use of topiramate, sweating and hyperthermia may decrease, especially in young children, in conditions of elevated ambient temperature. Adequate replacement of fluid loss before and during activities such as exercise or exposure to high temperatures can reduce the risk of overheating-related complications.

During the treatment period, it is necessary to monitor the condition of patients in order to detect signs of suicidal idealization and prescribe appropriate treatment. Patients (and, if necessary, caregivers) should be advised to seek immediate medical attention if signs of suicidal ideation or suicidal behavior appear.

If visual disturbances occur, including a syndrome involving myopia associated with angle-closure glaucoma, topiramate should be discontinued as soon as the attending physician considers it possible. If necessary, measures should be taken to reduce intraocular pressure.

To avoid the occurrence of metabolic acidosis, during treatment with topiramate, it is recommended to conduct the necessary studies, including determining the concentration of bicarbonates in serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or stop taking topiramate. In children, chronic metabolic acidosis can lead to growth retardation. The effect of topiramate on growth and possible bone-related complications has not been systematically studied in children and adults.

If the body weight decreases during treatment, the diet should be adjusted.

Concomitant use of other drugs that have a depressing effect on the central nervous system is not recommended.

During the treatment period, the patient should avoid drinking alcohol.

Influence on the ability to drive motor vehicles and manage mechanisms

It should be used with caution in patients engaged in potentially dangerous activities that require increased attention and speed of psychomotor reactions, since topiramate can cause drowsiness, dizziness, and visual disturbances.

Form of production

Tablets

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25 °C

Shelf life

2 years

Active ingredient

Topiramate

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as prescribed by a doctor, for children as prescribed by a doctor

Indications

Epilepsy