Toreal, 25 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 monotherapy for initial treatment in patients over 2 years old – partial or primary generalized tonic-clonic seizures; in complex therapy in patients over 2 years old – partial or generalized tonic-clonic seizures, as well as seizures against Lennox-Gastaud syndrome.

Migraine: prevention of migraine attacks in adults.

Active ingredient

Composition

How to take, the dosage

Ingestion, swallowing the tablet whole, without chewing, regardless of meals. For optimal seizure control, it is recommended to start treatment with a low dose followed by gradual titration to an effective dose.

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

Parcial or generalized tonic-tonic seizures, and seizures with Lennox-Gastaud 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 starts with 25-50 mg daily at night for 1 week. Then the dose is increased by 25-50 mg daily for 1-2 weeks, with 2 times a day. The dose and frequency of administration are adjusted depending on the clinical effect. In some patients, the effect can be achieved by taking the drug once a day. It is not necessary to monitor the plasma concentration of Toreal® in order to achieve the optimal effect of treatment with the drug. These recommendations apply to all adult patients, including the elderly, in the absence of renal disease.

Combined anticonvulsant therapy in children over 2 years of age

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

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

Epilepsy (including newly diagnosed)

Monotherapy: Generalities

When withdrawing concomitant anticonvulsant medications for the purpose of topiramate monotherapy, the possible effect of this step on seizure frequency must be considered. Where it is not necessary to abruptly withdraw a concomitant anticonvulsant for safety reasons, it is recommended that their doses be reduced gradually, reducing the dose of the concomitant antiepileptic drug by one-third every 2 weeks.

When drugs that are hepatic enzyme inducers are withdrawn, blood concentrations of topiramate will increase. In these situations, the dose of Toreal® may be reduced if clinically indicated.

Monotherapy: adults

The treatment starts with 25 mg at night for 1 week. Then the dose is increased by 25-50 mg per day for 1 to 2 weeks, with 2 doses per day. If this dosing regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of administration are adjusted according to 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 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 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 dosing regimen is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of administration are adjusted depending on the clinical effect. The recommended dose range is 3-6 mg/kg body weight. Children with newly diagnosed partial seizures may be prescribed up to 500 mg per day.

Migraine

The recommended total daily dose of topiramate for the prevention of migraine attacks is 100 mg and is taken in 2 doses. At the beginning of treatment the patient should take 25 mg of Toreal® before sleep for 1 week. Then the dose is increased at 1 week intervals by 25 mg per day. If the patient cannot tolerate this dose escalation regimen, the intervals between dose escalations may be increased or the dose may be increased more gently. Dose selection should be guided by clinical effect. In some patients, positive results are achieved at a daily dose of 50 mg of topiramate. In clinical trials, patients received different daily doses of topiramate, but no more than 200 mg per day.

Special patient groups

Renal failure

Interaction

In concomitant use with topiramate, phenytoin and carbamazepine decrease its plasma concentrations. 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 plasma concentrations of phenytoin was observed.

Concomitant use of a single dose of topiramate and digoxin may decrease the AUC of digoxin.

Concomitant use of an oral contraceptive containing norethindrone and ethinylestradiol had no significant effect on norethindrone clearance, but the plasma clearance of ethinylestradiol was significantly increased. Thus, when topiramate is taken concomitantly with oral contraceptives, their efficacy may be reduced.

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

Concomitant use of topiramate with drugs that predispose to nephrolithiasis may increase the risk of kidney stones.

Special Instructions

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

With caution should be used in renal and hepatic impairment, nephrourolithiasis (including personal and family history), hypercalciuria.

Patients with impaired renal function and patients on hemodialysis require dosing adjustment of topiramate.

Periramate should be withdrawn gradually to minimize the possibility of increased seizure frequency. In clinical trials in adults treated for 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 to prevent migraine. In children in clinical trials, topiramate was gradually withdrawn over 2-8 weeks. If a rapid withdrawal of topiramate is medically necessary, it is recommended to monitor the patient’s condition.

In order to reduce the risk of nephrolithiasis, fluid intake should be increased during treatment.

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

Patients should be monitored during treatment for signs of suicidal ideation and appropriate treatment should be prescribed. Patients (and caregivers, if necessary) should be advised to seek medical attention immediately if signs of suicidal ideation or suicidal behavior appear.

In the event of visual disturbances, including syndrome involving myopia associated with closed-angle glaucoma, topiramate should be discontinued as soon as the treating physician considers it possible. If necessary, measures should be taken to lower intraocular pressure.

In order to avoid the occurrence of metabolic acidosis, necessary tests, including determination of serum bicarbonate concentrations, are recommended during treatment with topiramate. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or discontinue topiramate. In children, chronic metabolic acidosis may lead to growth retardation. The effects of topiramate on growth and possible bone-related complications have not been systematically studied in children and adults.

If body weight decreases with treatment, dietary adjustments should be made.

The concomitant use of other drugs that have a depressant effect on the CNS is not recommended.

Patients should avoid alcohol during treatment.

Impact on driving and operating machinery

Patients engaged in potentially hazardous activities requiring increased attention and rapid psychomotor reactions should be used with caution, since topiramate may cause drowsiness, dizziness, visual disturbances.

Contraindications

Cautions

Cautions should be used with caution in hepatic or renal failure, nephrourolithiasis (including past or family history), hypercalciuria. It should be taken into account that the risk of depression and suicidal syndrome increases when taking the drug. The dose should be reduced or the drug Toreal® should be withdrawn gradually to minimize the likelihood of increased seizure frequency. According to clinical trials, doses were reduced by 50-100 mg at weekly intervals for adults receiving epilepsy therapy and by 25-50 mg in adults receiving 100 mg of topiramate daily for migraine prophylaxis. In children in clinical trials, topiramate was gradually withdrawn over 2-8 weeks. If a rapid withdrawal of Toreal® is medically necessary, appropriate monitoring of the patient is recommended.

Side effects

Nervous system disorders: paresthesias, somnolence, dizziness, attention deficit, memory impairment, amnesia, psychomotor disorders, seizures, improper coordination, tremor, lethargy, hypoesthesia, nystagmus, dysgeusia, balance disorder, articulation disorder, intensional tremor (dynamic), sedation, depressed consciousness, grand mal seizure type seizures, visual field defect, complex partial seizures, speech disorder, psychomotor hyperactivity, syncope, sensory disturbances, salivation, aphasia, repetitive speech, hypokinesia, dyskinesia, postural vertigo, poor sleep quality, burning sensation, loss of sensation, parosmia, cerebellar syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, agueusia dysgraphia, dysphasia, peripheral neuropathy, preconsciousness, dystonia, apraxia, circadian sleep disturbance, hyperaesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli, learning difficulties.

Mental disorders: Depression, slowed thinking, cognitive impairment, insomnia, marked speech disorders, restlessness, confusion, disorientation, aggression, mood lability, anxiety agitation, emotional lability, depressed mood, anger, inadequate behavior, suicidal ideas 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 thought, panic attack, tearfulness, impaired reading skills, flattened emotions, falling asleep disorder, pathological thinking, loss of libido, lethargy, intrasomnic disorder, pathologically increased distractibility, early morning waking, panic response, mania, panic disorder, despair, hypomaniacal state.

Visual side: blurred vision, diplopia, visual disturbances, decreased visual acuity, scotoma, myopia, abnormal eye sensations, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia, unilateral blindness, transient blindness, glaucoma, accommodation disorder, depth perception disorder, atrial fibrillation scotoma, eyelid edema, night blindness, amblyopia, closed-angle glaucoma, maculopathy, oculomotor disorders.

Hematopoietic system disorders: anemia, leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia, neutropenia.

Immune system disorders: hypersensitivity, allergic edema, conjunctival edema.

Metabolic disorders: anorexia, decreased appetite, metabolic acidosis, hypokalemia, increased appetite, polydipsia, hyperchloremic acidosis.

Hearing and balance: vertigo, tinnitus, ear pain, deafness, unilateral deafness, sensorineural deafness, tinnitus discomfort, hearing loss.

Cardiovascular system disorders: bradycardia, sinus bradycardia, palpitations, orthostatic hypotension, hot flashes, hyperemia, Raynaud’s phenomenon.

Respiratory system disorders: nasopharyngitis, dyspnea, nasal bleeding, nasal congestion, rhinorrhea, cough, dyspnea on exertion, hypersecretion in the paranasal sinuses, dysphonia.

Digestive system disorders: Nausea, diarrhea, vomiting, constipation, upper abdominal pain, dyspepsia, abdominal pain, dry mouth, stomach discomfort, oral paraesthesia, gastritis, abdominal discomfort, pancreatitis, flatulence, gastroesophageal reflux disease, lower abdominal pain Oral hypoesthesia, bleeding gums, abdominal bloating, epigastric discomfort, pain throughout the abdomen, salivary gland hypersecretion, oral pain, bad breath, glossodynia, hepatitis, liver failure.

Skin and subcutaneous tissue disorders: Alopecia, itching, rash, anhidrosis, facial hypoesthesia, urticaria, erythema, generalized itching, macular rash, skin discoloration, allergic dermatitis, facial edema, Stevens-Johnson syndrome, erythema multiforme, unpleasant smelling skin, periorbital edema, localized urticaria, toxic epidermal necrolysis.

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

Urinary system disorders: nephrolithiasis, pollakiuria, dysuria, urinary concretions, urinary incontinence, hematuria, urgent painful urge to urinate, renal colic, renal pain, ureteral concretions, renal tubular acidosis.

Reproductive system: erectile dysfunction, sexual dysfunction.

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

Laboratory findings: decreased body weight, increased body weight, crystalluria, abnormal tandem-walking test, leukopenia, increased liver enzyme activity, hypokalemia, decreased blood hydrocarbonate content.

Overdose

General

Intentionally, swallow the tablet whole, without chewing, regardless of food intake. For optimal seizure control, it is recommended that treatment begin with a low dose followed by increasing to an effective dose.

In 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 starts with 25-50 mg daily at bedtime for 1 week. Then the dose is increased by 25-50 mg daily for 1-2 weeks, with twice-daily dosing. If this dosing regimen is not tolerated, the dose is increased by a smaller amount or at longer intervals. The dose and frequency of administration are adjusted according to the clinical effect.

Children over 3 years of age

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 multiple doses twice a day, until optimal clinical effect is achieved.

Monotherapy

Adults

The treatment starts with 25 mg at night for 1 week. The dose is then increased by 25-50 mg daily for 1 to 2 weeks, with twice-daily dosing. If this dosing regimen is intolerant, the dose is increased by a smaller amount or at longer 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 the elderly with normal renal function.

Children from 3 years old

The treatment starts 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 and the frequency of administration is 2 times a day. If this dosing regimen is intolerant, the dose is increased by a smaller amount or at longer 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 established partial seizures may be prescribed up to 500 mg per day.

Pregnancy use

There are no adequate and strictly controlled clinical safety studies of topiramate in pregnancy.

The use of topiramate in pregnancy may cause fetal damage. Pregnancy registry data show that intrauterine exposure to topiramate increases the risk of fetal birth defects (e.g., craniofacial defects such as cleft lip/wolf’s mouth, hypospadias, and abnormalities of various body systems). These malformations were recorded both with topiramate monotherapy and with its use as part of combination therapy. Compared with the group of patients not taking antiepileptic drugs, the data from the register of pregnant women treated with topiramate monotherapy show an increased frequency of low birth weight babies (less than 2500 g). A causal relationship has not 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.

Limited observations suggest that topiramate is excreted with breast milk. If use during lactation is necessary, discontinuation of breastfeeding should be considered.

Pediatric use

Do not use in children under 2 years of age.

Similarities