TOPIRAMAT (Topiramate)

     Chemical name : 2,3:4,5 - Di-O- izopropiliden- beta-D- fruktopiranozy sulfamat

     Description : The white crystalline powder bitter taste. Well soluble in acetone, chloroform, dimetilsulfokside, ethanol.

     Pharmacology : The drugs act-protivoepilepticheskoe.

Lock sodium channels and suppresses the emergence of re-building actions in the face of a prolonged membrane depolarization token. It increases the frequency of activating GABA receptors GAMKA- increases GAMK- induced flow of chlorine ions inside token, potentsiruet brake GAMKergicheskuyu transfer. It prevents activation kainatom subtype kainat / AM PC (alpha-amino? 3-hydroxy? 5-metilizoksazol? 4-propionic acid) receptors glutamatnyh and oppressing the incident glutamatergicheskuyu neyrotransmissiyu. Decreases activity by some izofermentov karboangidrazy.

In tests in vitro and in vivo showed no genotoxic and mutagennogo action. Carcinogenicity Study in giving mice 20, 75 and 300 mg / kg within 21 months showed that a 300 mg / kg accompanied by credible increased frequency in individuals of both sexes bladder tumors (mostly gladkomyshechnyh of gistomorfologicheski unique to the mouse.) Level topiramata plasma in mice receiving 300 mg / kg, approximately 50-100% equilibrium concentration observed in patients with monotherapies topiramatom in the recommended dose of 400 mg and equilibrium concentrations of 150-200% in patients receiving 400 mg topiramata in combination with fenitoinom. It found cancer-causing in rats that received over two years dose to 120 mg / kg (about 3 times higher MRDCH mg / m 2).

Data on the potential carcinogenicity in humans are not available.

In studies on animals (mice, rats and rabbits) registered teratogenic effect. Introduction to doses 20, 100 and 500 mg / kg pregnant mice during organogeneza increased frequency of dangerous malformations (mainly kraniofatsialnyh defects). At doses of 500 mg / kg decreased body weight and skeletal ossifikatsii from embryos, and reduced allowances pregnant body mass index.

Introduction topiramata in doses of 400 mg / kg or more pregnant rats during organogeneza an increase in the frequency of limb deformities (ektrodaktiliya, mikromeliya, Amelia) of the descendants. Clinical signs of maternal toxicity occurred at doses of 400 mg / kg or more, at doses of 100 mg / kg and decreased body weight allowances for females. Embriotoksichnost (decrease weight embryo, the increase in the structural biases) seen in small doses (20 mg / kg).

Do rabbits receiving Topiramate in doses of 35 mg / kg or more, increased embrio / foetal deaths; At doses of 120 mg / kg was pronounced teratogenic effects (primarily ribs and vertebralnye deformities). The signs of maternal toxicity (decrease body weight increases, clinical signs and / or fatality observed at doses of 35 mg / kg and above.

For the descendants of rats receiving Topiramate in doses of 200 mg / kg during the period of pregnancy and during breast feeding, revealed reduced vitality and slow physical development; At doses 2 mg / kg and above, the reduction of body weight in the period before and / or after termination of breastfeeding.

Study embrio / foetal development and post-natal offspring of rats receiving Topiramate showed slower physical development at doses of 400 mg / kg and continued (hard) to reduce body weight at doses 30 mg / kg or more.

In rats Topiramate crosses the placental barrier and excreted milk.

Rapidly absorbed from the digestive tract, bioavailability of 81% and does not depend on the meals. Linking plasma proteins, 13-17%. The average allocation for single doses up to 1200 mg of 0,55-0,8 l / kg, depending on the sex of patients (women 2 times lower than that of men). Cmax (after repeated administered orally 100 mg 2 times a day) of 6.76 ug / ml. Time Cmax after receiving a dose of 400 mg to 2 hours For patients with normal renal function equilibrium concentration in plasma achieved over 4-8 days (expressed in the face of the functional kidney in 10-15 days). Pharmacokinetics is linear (concentration in plasma is proportional to dose) in the range of 200-800 mg doses per day. Biotransformiruetsya education 6 inactive metabolites. Write mainly kidneys (70% unchanged). T1 / 2 to 21 h. The plasma clearance 20-30 mL / min. Patients who are violating kidney function (creatinine clearance below 60 ml / min) and renal plasma clearance down; In violation of the functions of the liver decreased plasma clearance.

     Application : Partsialnye or toniko- klonicheskie Generalized seizures as monotherapies and in combination with other convulsants means; Complementary therapy in the treatment of tachycardia associated with Lennox-Gastaut syndrome (adults and children); First illness epilepsy (in adults and children over 2 years ).

     Contraindications : Giperchuvstvitelnost.

     Restrictions on the use : Pregnancy, breast-feeding, child age (safety and efficacy of the use of children under 2 years of age are not identified).

     Application of pregnancy and breastfeeding : Perhaps if the expected effect of treatment outweighs the potential risk to the fetus (adequate and controlled studies on the use during pregnancy did not take place). At the time of treatment should stop breastfeeding.

     Side Effects : From the nervous system and sensory organs : the increased fatigability, ataxy breach of thinking and concentration, emotional lability, sputannost consciousness, dizziness, paresteziya, gipesteziya, drowsiness; Seldom-excitation, amnesia speech, depression, diplopia and other violations view, conjunctivitis, eye, the speech, a perversion of taste sensations.

For part of the digestive tract : anorexia, gingivitis, nausea.

Other : reducing weight, pain in the abdomen, fever, hemorrhagic, dispnoe, swelling, nasal bleeding, stone, hematuria, prurit, tinnit, dismenoreya, decreasing libido, impotence.

     Networking : Phenytoin and carbamazepine lower topiramata content in the blood. Topiramate reduces AUC digoxin (12%), the level fenitoina plasma and effectiveness of oral contraceptives. The simultaneous use of drugs, predisposing to stone, may increase the risk of kidney stones education.

     Overdosing : Symptoms : increased side effects.

Treatment : washing stomach or vomiting induction, maintenance therapy. In severe cases, a kidney dialysis possible.

     Dosing and Administration : The inside (of eating). Adults with monotherapies : initial dose of 25 mg-1 once a day (at night) for 1 week and then increased the dose of 25-50 mg / day (divided into 2 admission) at intervals of 1-2 weeks before clinical performance; Recommended dose : 100 mg / day, the maximum daily 500 mg (for some patients with epilepsy refrakternymi forms-1000 mg / day). Children over 2 years : in the first week of treatment-0,5-1 mg / kg at night, then increase the dose to 0,5-1 mg / kg / day (divided into 2 admission) at intervals of 1-2 weeks; The recommended dose - 3-6 mg / kg / day (for children with newly diagnosed partial seizures, and 500 mg / day).

In combination with other drugs convulsants : adults, 25-50 mg per night for one week, then increase the dose of 25-50 mg every 1-2 weeks and take in 2 admission; The minimum effective dose of 200 mg / day, the average daily, 200-400 mg, 1600 mg maximum. Children over 2 years : 1-3 mg / kg / day for one night during the week and then increase the dose of 1-3 mg / kg at intervals of 1-2 weeks and take in 2 admission; The recommended daily intake, 5-9 mg / kg.

     Precautions : Patients in hemodialysis, in the days of the meeting to give more doses (approximately 1 / 2 daily dose) before and after the procedure. Lifting a gradually reducing the dosage of 100 mg with weekly intervals.

Patients who are at risk stone to raise adequate amount of fluids. To use caution in patients with liver function violation (by the possibility of reducing the clearance topiramata). There may be cases of secondary zakrytougolnoy glaucoma in children and adults. If a significant loss of body weight in the treatment topiramatom be nutritional or use of nutritional supplements.

It should not be used in conjunction with the drivers and people with occupations related to higher concentration. Do not take with alcohol or drugs, oppressive central nervous system.

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