Toreal - instructions for use, dose, side effects, contraindications

Composition per one tablet
Active substance:
Topiramate	25.0 mg	100.0 mg
Excipients:
Lactose Monohydrate -	28.0 mg	60.3 mg
Corn starch
pregelatinization-
bathroom -	9.0 mg	27.0 mg
Cellulose
microcrystalline -	30.4 mg	89.0 mg
Carboxymethyl starch
sodium -	4.8 mg	15.0 mg
Hypromellose
(hydroxypropyl-
methyl cellulose) -	2.6 mg	8.0 mg
Magnesium stearate	0.2 mg	0.7 mg
Weight of a tablet
(without shell)	100.0 mg	300.0 mg
Sheath:

Ipadra powder and, yellow color [polyvinyl alcohol
the left; polyethylene glycol 4000 (macrogol); talc; ti
the left; polyethylene glycol 4000 (macrogol); talc; ti
tana dioxide; gland
oxide yellow] Coated tablet weight -	3.0 mg 103.0 mg	10.0 mg 310.0 mg

Description:The tablets covered with a cover of yellow color, round, biconcave.

Pharmacotherapeutic group:Anti-epileptic agent.

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.11 Topiramate

Pharmacodynamics:Topiramate refers to sulfate-substituted monosaccharides. It blocks sodium channels and suppresses occurrence of repeated potentials of action against the background of prolonged depolarization of the neuron membrane.Increases the activity of y - aminobutyric acid (GABA) against certain subtypes of GABA receptors. Prevents the activation of kainate / AMPK (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) by kainate with glutamate receptors, without affecting the activity of N-methyl-D-aspartate (NMDA) against NMDA receptors. These effects are dose-dependent. Besides, topiramate inhibits the activity of certain isoenzymes of carbonic anhydrase. This effect is much weaker than that of the acetoazolamide carbonic anhydride inhibitor, and is not the main component of the antiepileptic activity of topiramate.

Pharmacokinetics:

Topiramate is quickly and well absorbed. Eating does not have a clinically significant effect on its bioavailability, which is about 80%. The connection with plasma proteins 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 the topiramate is metabolized. Up to 50% of topiramate is metabolized in patients taking other antiepileptic drugs (PEP) simultaneously, inducing metabolic enzymes.Six practically inactive metabolites of topiramate were isolated from plasma, urine and stool of a human. 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 is linear, the plasma clearance is constant, and the area under the concentration-time curve in the dosage range of 100 to 400 mg increases in proportion to the dose. With normal kidney function, patients may need 4-8 days to achieve an equilibrium plasma concentration. The average value of the maximum concentration after repeated intake of 100 mg of topiramate twice a day is 6.76 μg / ml. Half-life after repeated administration 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 terminal renal failure, the plasma clearance of topiramate decreases. Plasma clearance of topiramate does not change in elderly patients in the absence of renal dysfunction. The plasma clearance of topiramate is reduced in patients with moderate andsevere impairment of liver function.

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 the 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 blood plasma when taking the same doses per kg of body weight may be lower in children than in adults. As in adults, when receiving other PEP, inducing microsomal enzymes of the liver, the equilibrium concentration of topiramate in the blood plasma decreases.

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

Indications:

- monotherapy of epilepsy in children weighing more than 25 kg and adults (including patients with newly established epilepsy);

- Auxiliary therapy in children weighing more than 25 kg and adults with insufficient efficiency of the first-choice PEP with partial or generalized tonic-clonic seizures, as well as with seizures against the background of the Lennox-Gastaut syndrome.

Contraindications:

- hypersensitivity to any of the components of the drug;

- children weighing less than 25 kg;

- pregnancy and lactation period (see also section Application in pregnancy and lactation period);

- Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Carefully:Use with caution in hepatic or renal failure, nephrourolythiasis (including in the past or family history), hypercalciuria.

Pregnancy and lactation:The use of topiramate is contraindicated in pregnancy and lactation. Pregnancy registration data indicate a possible relationship between the use of the drug during pregnancy and congenital malformations developed (craniofacial defects of "hare's lip" / "wolf's mouth"). When taking the drug, women are recommended to use adequate contraception.

Dosing and Administration:

Are common

Inside, swallowing the tablet whole, without chewing, regardless of food intake. For

optimal control of seizures is recommended to begin treatment with low doses with subsequent increase to the effective dose.

As part of complex therapy

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

Dchildren weighing more than 25 kg: the recommended daily dose is 5-9 mg / kg 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 the frequency of reception 2 times a day, until the optimal clinical effect is achieved.

Monotherapy

Adults: treatment is started 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 frequency of reception 2 times a day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at large intervals. The dose and the frequency of reception are selected depending on the clinical effect. The recommended initial dose of topiramate for monotherapy in adults with newly established 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 kidney function.

Children with a body weight of more than 25 kg: treatment is started 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 reception - 2 times a day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at large intervals. The dose and the frequency of reception are selected depending on the clinical effect. The recommended range of doses is 3-6 mg / kg body weight. Children with newly established partial seizures can be prescribed up to 500 mg per day.

Side effects:

Neurological and psychiatric disorders: increased excitability, dizziness, headache, speech and vision impairment, psychomotor retardation, ataxia, fatigue, difficulty concentrating, confusion, paresthesia, drowsiness, thinking disorders, diplopia, anorexia, nystagmus, depression, perversion of taste sensations, agitation, cognitive disorders, emotional lability , ataxia, apathy, psychotic symptoms, aggressive behavior, suicidal ideation or attempts; In addition, in children - personality disorders, increased salivation, hyperkinesia, hallucinations.

Gastrointestinal disorders: dyspepsia, nausea, abdominal pain, diarrhea, dry lips, increased activity of "liver" transaminases, hepatitis, hepatic insufficiency.

Disorders from the musculoskeletal system: myalgia, incl. chest, muscle cramps, arthralgia.

From the side of the eyes: there may be a myopia syndrome on the background of increased intraocular pressure with acute reduction in visual acuity and pain in the eye area. Myopia, a decrease in the depth of the anterior chamber of the eye, hyperemia of the mucosa eyes and increased intraocular pressure, mydriasis. The possible mechanism of these disorders is an increase in supraciliary eudhotia, which leads to a shift in the lens and iris forward, and as a result, the development of secondary closed-angle glaucoma.

From the skin and mucous membranes: rash, alopecia, itching, decreased face sensitivity, erythema multiforme, pemphigus, Stephen-Johnson syndrome, and toxic epidermal necrolysis.

From the side of the hearing organ and labyrinthine disorders: pain in the ears, ringing in the ears, hearing impairment, in children - dizziness.

Disturbances from the respiratory system: shortness of breath, nosebleeds, nasal congestion, in children - rhinorrhea.

Common violations: fatigue, irritability, weight loss, in children - increased body temperature.

Other: leukopenia, nephrolithiasis, oligohydrosis (mainly in children), metabolic acidosis.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

Symptoms: convulsions, impaired consciousness up to coma, lowering blood pressure, severe metabolic acidosis, increased severity of side effects.

Treatment: gastric lavage, symptomatic therapy. An effective way to remove topiramate from the body is hemodialysis.

Interaction:

Influence of topiramate on other PEPs.

Does not affect the concentration of carbamazepine, phenobarbital, primidone. When used concomitantly with valproic acid AUC Valproic acid is reduced by 11%, topiramate - by 14%. In some cases, when used with phenytoin, an increase in the concentration of phenytoin in the plasma is possible.

The influence of other PEPs on topiramate.

With the combined use of topiramate with phenytoin and carbamazepine, a decrease in the concentration of topiramate in plasma is possible, i.e. When adding or removing phenytoin or carbamazepine, a dose correction for topiramate is recommended.

Other interactions.

Digoxin: the area under the pharmacokinetic curve of digoxin is reduced by 12%,

Oral contraceptives: topiramate in a dose of 50-800 mg / day had no significant effect on the effectiveness of norethisterone and in a dose of 50-200 mg / day - on

efficacy of ethinyl estradiol. Significant dose-dependent reduction in efficacy

Ethinyl estradiol was observed with the administration of topiramate at a dose of 200-800 mg / day. Patients taking oral contraceptives should inform the doctor of any changes in the nature of the bleeding.

Metformin: when used simultaneously with^; topiramate mean values of the maximum concentration and area under the concentration-time curve of metformin are increased by 18% and 25%, respectively, while the average value of the total clearance is reduced by 20%. Topiramate did not affect the time to reach C_m_Oh metformin. Plasma clearance of topiramate under the influence of metformin decreases.The clinical significance of the effects of metformin on the pharmacokinetics of topiramate is not clear. When appointing or canceling topiramate against the background of metformin therapy, it is necessary to monitor the state of carbohydrate metabolism.

Hydrochlorothiazide: at simultaneous reception there is an increase in the maximum the concentration of topiramate by 27% and the area under the curve "concentration-time" of topiramate by 29%.

Means that depress the central nervous system (CNS): Not recommended osimultaneous reception with topiramate of ethanol and other means, depressing the central nervous system,

Pioglitazone: revealed a decrease in the area under the curve "concentration-time" pioglitazone by 15%, without changing the maximum concentration of the drug. For active hydroxymetabolite of pioglitazone, a decrease in the maximum concentration and area under the concentration-time curve by 13% and 16% respectively, and for active ketometabolite, a decrease in both the maximum concentration and the area under the concentration-time curve by 60% was revealed. The clinical significance of this data is unknown.

Other means: topiramate, when combined with other drugs predisposing to nephrolithiasis,in particular with carbonic anhydrase inhibitors

(acetazolamide) may increase the risk of nephrolithiasis. During application of topiramate patients should avoid taking such drugs, as they can create physiological conditions that increase the risk of kidney stones.

The table presents the results of the drug interaction between topiramate and other drugs.

Drug to be added	Concentration of the added drug¹	Concentration of topiramate¹
Haloperidol	Increase AUC²metabolite by 31%	Not investigated
Propranolol	Increase in the maximum concentration for 4-OH propranolol by 17% (topiramate 50 mg)	Increase in maximum concentration by 9% and 16%, increase AUC 9% and 17% (for propranolol 40 mg and 80 mg every 12 hours), respectively
Diltiazem	Decrease AUC diltiazem by 25% and deacetylldithiasem by 18%, no changes in the maximum concentration and AUC N-detylldithiazema	Increase AUC by 20%

¹% change from maximum concentration values and increase AUC with monotherapy.

²AUC - area under the curve "concentration-time"

Special instructions:

Topiramate, like other PEPs, is recommended to be canceled, gradually reducing the dose, in order to reduce the potential risk of increasing the frequency of seizures.

Renal insufficiency: Patients with moderate and severe impairment

kidney function may need 10-15 days to achieve an equilibrium state of plasma concentration unlike 4-8 days for patients with normal renal function. As with all patients, a gradual increase in dose should be made according to clinical outcomes (such as seizure control, the incidence of side effects), given that patients with moderate or severe renal failure may need more time to reach a stable state after each dose.

Nephrolithiasis: in some patients, especially predisposed to nephrolithiasis, the risk of kidney stones may increase, accompanied by symptoms such as renal colic, side pain and kidney problems. It is recommended to conduct adequate hydration to reduce the risk of kidney stones.

Liver failure: In patients with impaired liver function, the clearance of topiramate is reduced.

Myopia and secondary closed angle glaucoma: when developing myopia, it is recommended to cancel topiramate as quickly as clinically possible and take measures aimed at reducing intraocular pressure.

Metabolic acidosis: when topiramate is used, hyperchloremic, non-anion-deficient, metabolic acidosis may occur (for example, a decrease in the bicarbonate concentration in the plasma below the normal level in the absence of respiratory alkalosis). This decrease in serum bicarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carboanhydrase. In this regard, in the treatment of topiramate it is recommended to periodically determine the concentration of bicarbonates in the blood serum.

Diet: with a decrease in body weight during therapy with topiramate, it is advisable to consider the possibility of supplementary feeding.

Depression: when topiramate is used, there is an increased incidence of mood disorders and depression.

Suicide attempts: the use of antiepileptic drugs may increase the risk of suicidal and suicidal thoughts.With the purpose of early detection of behavioral disorders, which may be harbingers of suicidal thoughts and actions, it is recommended to monitor the mental state of patients.

Effect on the ability to drive transp. cf. and fur:During treatment it is recommended to abstain from driving a car and work that requires an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets coated with a coating, 25 mg and 100 mg.

Packaging:For 14 or 28 tablets in cans of polymer with the control of the first autopsy. 1 can of polymer with the instruction for use is placed in a pack of cardboard.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:2 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LS-002228

Date of registration:01.12.2011

The owner of the registration certificate:LEKKO, ZAO LEKKO, ZAO Russia

Manufacturer: & nbsp

LEKKO, ZAO Russia

Information update date: & nbsp09.09.2015

Illustrated instructions

Instructions

Torale® (Toreal®)