Toreal, 100 mg 28 pcs.

Pharmacotherapeutic group: antiepileptic drug

ATX code: N03AX11

Pharmacological properties

.Pharmacodynamics

Topiramate refers to sulfate-substituted monosaccharides. It blocks sodium channels and suppresses the occurrence of repetitive action potentials against the background of prolonged depolarization of the neuron membrane. Increases γ – aminobutyric acid (GABA) activity against certain subtypes of GABA receptors. Prevents activation of kainatom kainat/AMPK (alpha-amino-Z-hydroxy-5-methylisoxazole-4-propionic acid) – glutamate receptors, without affecting N-methyl-D-aspartate (NMDA) activity with respect to NMDA – receptors. These effects are dose-dependent. In addition, topiramate inhibits the activity of some carboanhydrase isoenzymes. This effect is much weaker than that of the carboanhydrase inhibitor acetazolamide and is not the main component of the antiepileptic activity of topiramate.

Pharmacokinetics

Topiramate is quickly and well absorbed. Food intake has no clinically significant effect on its bioavailability, which is about 80%. Binding to plasma proteins is 13-17%. Average volume of distribution is 0.55-0.8 l/kg for a single dose up to 1200 mg. This value depends on sex: in women the values are 50% of those 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 concomitantly taking other antiepileptic drugs (PEP) that induce metabolizing enzymes. Six virtually inactive metabolites of topiramate have been isolated from human plasma, urine and feces. The unchanged topiramate and its metabolites are mainly excreted by the kidneys. Plasma clearance is about 20-30 ml/min.

After a single dose, pharmacokinetics is linear, plasma clearance is constant, and the area under the concentration-time curve in the dose range of 100 to 400 mg increases in proportion to the dose. With normal renal function, patients may require 4-8 days to reach equilibrium plasma concentration. The mean maximum concentration after multiple oral doses of 100 mg of topiramate twice daily is 6.76 mcg/ml. The elimination half-life after multiple doses of 50 and 100 mg twice daily is 21 hours.

In patients with impaired renal function (creatinine clearance 70 ml/min), plasma and renal clearance of topiramate is reduced; in patients with terminal renal failure, plasma clearance of topiramate is reduced. Plasma clearance of topiramate is unchanged in elderly patients without renal impairment. Plasma clearance of topiramate is decreased in patients with moderate to severe hepatic impairment.

The pharmacokinetics of topiramate in children, as well as in adults, is linear. Clearance of topiramate is independent of the dose; the equilibrium plasma concentration increases in proportion to the dose. However, children are characterized by higher clearance values and a shorter elimination half-life. Therefore, the plasma concentrations of topiramate at the same dose per kg body weight may be lower in children compared to adults. As in adults, the equilibrium plasma concentrations of topiramate are reduced when taking other PEPs that induce microsomal liver enzymes.

Topiramate is effectively excreted from plasma by hemodialysis. It is presumed to penetrate into breast milk.

Indications

Epilepsy: as a monotherapy for initial treatment in patients over 2 years of age – partial or primary generalized tonic-clonic seizures; as part of complex therapy in patients over 2 years of age – partial or generalized tonic-clonic seizures, as well as seizures associated with Lennox-Gastaut syndrome.

Migraine: prevention of migraine attacks in adults.

Pharmacological effect

Pharmacotherapeutic group: antiepileptic drug

ATX code: N03АХ11

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 γ – aminobutyric acid (GABA) in relation to certain subtypes of GABA receptors. Kainate prevents activation of kainate/AMPK (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptors without affecting the activity of N-methyl-D-aspartate (NMDA) towards 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 a major component of the antiepileptic activity of topiramate.

Pharmacokinetics

Topiramate is quickly and well absorbed. Food intake has no clinically significant effect on its bioavailability, which is about 80%. Communication with plasma proteins is 13-17%. The average volume of distribution is 0.55-0.8 l/kg for a single dose of 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 concomitantly taking other antiepileptic drugs (AEDs) that induce metabolizing enzymes. Six practically inactive metabolites of topiramate have been 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. In patients with normal renal function, it may take 4-8 days to reach steady-state plasma concentrations. The mean maximum concentration after repeated oral administration of 100 mg of topiramate twice daily is 6.76 mcg/ml. The half-life after multiple doses of 50 and 100 mg twice daily is 21 hours.

In patients with impaired renal function (creatinine clearance 70 ml/min), plasma and renal clearance of topiramate is reduced; in patients with end-stage renal failure, the plasma clearance of topiramate is reduced. Plasma clearance of topiramate does not change in elderly patients in the absence of renal impairment. Plasma clearance of topiramate is reduced 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 is not dose dependent; the steady-state plasma concentration increases proportionally to the dose. However, children have higher clearance values ​​and a shorter half-life. Therefore, plasma concentrations of topiramate at the same dose per kg body weight may be lower in children compared to adults. As in adults, when taking other AEDs that induce liver microsomal enzymes, the equilibrium concentration of topiramate in the blood plasma decreases.

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

Special instructions

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

It should be used with caution in case of renal and liver failure, nephrourolithiasis (including personal and family history), hypercalciuria.

Patients with impaired renal function and patients on hemodialysis require adjustment of the topiramate dosage regimen.

Topiramate should be discontinued gradually to minimize the potential for increased seizure frequency. In clinical studies in adults for the treatment of epilepsy, doses were reduced by 50-100 mg at intervals of 1 week. and by 25-50 mg in adults receiving topiramate 100 mg/day for migraine prophylaxis. In children in clinical studies, topiramate was gradually withdrawn over 2 to 8 weeks. If prompt discontinuation of topiramate is necessary for medical reasons, it is recommended to monitor the patient’s condition.

To reduce the risk of developing nephrolithiasis during treatment, the volume of fluid consumed should be increased.

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

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

If any disturbances occur on the part of the organ of vision, incl. syndrome involving myopia associated with angle-closure glaucoma, topiramate should be discontinued as soon as deemed possible by the treating physician. 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 carry out the necessary studies, including determination of the concentration of bicarbonates in the serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or discontinue topiramate. In children, chronic metabolic acidosis can lead to growth retardation. The effect of topiramate on growth and possible complications related to the skeletal system have not been systematically studied in children and adults.

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

The simultaneous use of other drugs that have a depressant effect on the central nervous system is not recommended.

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

Impact on the ability to drive vehicles and operate machinery

It should be used with caution in patients engaged in potentially hazardous activities that require increased attention and speed of psychomotor reactions, because Topiramate may cause drowsiness, dizziness, and visual disturbances.

Active ingredient

Topiramate

Composition

1 tab.
topiramate
100 mg

Pregnancy

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

Use of topiramate during pregnancy may cause fetal harm. Pregnancy registry data indicate that fetal exposure to topiramate in utero increases the risk of congenital malformations (e.g., craniofacial defects such as cleft lip/cleft palate, hypospadias, and developmental anomalies of various body systems). These malformations were recorded both during topiramate monotherapy and when it was used as part of combination therapy. Compared with a group of patients not taking antiepileptic drugs, data from the registry of pregnant women with topiramate monotherapy indicate an increase in the frequency of births of children with low body weight (less than 2500 g). A cause-and-effect relationship has not been established.

When treating women of childbearing age, the expected benefits of therapy for the mother should be weighed against the potential risks to the fetus and alternative treatment options should be considered. If topiramate is used during pregnancy or if pregnancy occurs during treatment, the patient should be warned of 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 it during lactation, the issue 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 case of liver or kidney failure, nephrourolithiasis (including in the past or family history), hypercalciuria. It should be borne in mind that when taking the drug, the risk of developing depression and suicidal syndrome increases. The dose of Toreal® should be reduced or discontinued 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 migraine prophylaxis. In children in clinical studies, topiramate was gradually withdrawn over 2 to 8 weeks. If, for medical reasons, rapid discontinuation of the drug Toreal® is necessary, it is recommended to carry out appropriate monitoring of the patient’s condition.

Side Effects

From the nervous system: paresthesia, drowsiness, dizziness, impaired attention, memory impairment, amnesia, psychomotor disturbances, convulsions, poor coordination, tremor, lethargy, hypoesthesia, nystagmus, dysgeusia, imbalance, articulation disorder, intentional tremor (dynamic), sedation, depression of consciousness, convulsions of the grand mal convulsive type seizures, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbances, drooling, aphasia, repetitive speech, hypokinesia, dyskinesia, postural vertigo, poor sleep quality, burning sensation, sensory loss, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, apraxia, circadian sleep disorder, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli, learning difficulties.

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

From the organ of vision: blurred vision, diplopia, visual impairment, decreased visual acuity, scotoma, myopia, pathological sensations in the eyes, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia, one-sided blindness, transient blindness, glaucoma, impaired accommodation, impaired visual depth perception, atrial fibrillation 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.

Metabolism: anorexia, loss of appetite, metabolic acidosis, hypokalemia, increased appetite, polydipsia, hyperchloremic acidosis.

On the part of the organ of hearing and balance: vertigo, tinnitus, ear pain, deafness, one-sided deafness, sensorineural deafness, discomfort in the ears, hearing impairment.

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

From the respiratory system: nasopharyngitis, dyspnea, epistaxis, nasal congestion, rhinorrhea, cough, shortness of breath on exertion, 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 hypoesthesia, bleeding gums, bloating abdomen, discomfort in the epigastric region, pain throughout the abdomen, hypersecretion of the salivary glands, pain in the oral cavity, bad breath, glossodynia, hepatitis, liver failure.

From the skin and subcutaneous tissues: alopecia, itching, rash, anhidrosis, facial hypoesthesia, urticaria, erythema, generalized itching, macular rash, skin discoloration, allergic dermatitis, facial swelling, Stevens-Johnson syndrome, erythema multiforme, unpleasant skin odor, periorbital edema, localized urticaria, toxic epidermal necrolysis.

From the musculoskeletal system: arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, muscle pain in the chest, joint swelling, muscle stiffness, flank pain, muscle fatigue, discomfort in the extremities.

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

From 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 of intoxication, anxiety, facial swelling, calcinosis.

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

Interaction

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

When a single dose of topiramate and digoxin are used simultaneously, the AUC of digoxin may decrease.

When administered concomitantly with an oral contraceptive containing norethindrone and ethinyl estradiol, topiramate did not significantly affect the clearance of norethindrone, but the plasma clearance of ethinyl estradiol was significantly increased. Thus, when topiramate is taken concomitantly with oral contraceptives, their effectiveness may be reduced.

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

When topiramate is used simultaneously with drugs that predispose to the development of nephrolithiasis, the risk of kidney stones may increase.

Overdose

General

Orally, swallow the tablet whole, without chewing, regardless of food intake. For optimal seizure control, it is recommended to start treatment at low doses and then increase to an 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 dosage frequency of 2 times a day. If this dosage regimen is intolerable, the dose is increased by a smaller amount or at larger intervals. The dose and frequency of administration are selected depending on the clinical effect.

Children over 3 years old

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

Monotherapy

Adults

Treatment begins with 25 mg at night for 1 week. Then the dose is increased by 25-50 mg per day for 1-2 weeks, with a dosage frequency of 2 times a day. If this dosage regimen is intolerable, the dose is increased by a smaller amount or at larger intervals. The dose and frequency of administration 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, with a maximum recommended dose of 500 mg/day. These doses are recommended for all adults, including older adults with normal renal function.

Children from 3 years old

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

Storage conditions

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

Shelf life

2 years

Manufacturer

Pharmstandard-Leksredstva, Russia