Topiramate Canon pills 100mg, 28pcs

Composition

of 1 tab. topiramate 100 mg

Auxiliary substances:

lactose monohydrate,

microcrystalline cellulose,

pregelatinized starch,

sorbitol,

colloidal silicon dioxide,

magnesium stearate.

Composition of the film shell:

Opadray II (Series 85) – partially hydrolyzed polyvinyl alcohol, macrogol-3350, titanium dioxide E 171, talc, iron oxide yellow dye E 172. Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, sorbitol, colloidal silicon dioxide, magnesium stearate.

Pharmacological action

The drug belongs to the class of sulfate-substituted monosaccharides.

Topiramate reduces the frequency of action potentials that are characteristic of a neuron in a state of persistent depolarization, which indicates the dependence of the blocking effect of the drug on sodium channels on the state of the neuron. This Active ingredient potentiates the activity of GABA against certain subtypes of GABA receptors (including GABAA receptors), modulates the activity of GABAA receptors themselves, and also prevents kainate from activating the sensitivity of kainate / AMPK receptors to glutamate and does not affect the activity of N-methyl-D-aspartate against NMDA receptors. These effects of topiramate are dose-dependent at plasma concentrations of topiramate ranging from 1 µm to 200 µm, with minimal activity ranging from 1 µm to 10 µm.

In addition, topiramate inhibits the activity of some carbonic anhydrase isoenzymes, but this effect in topiramate is weaker than in acetazolamide and, apparently, is not the main one in the antiepileptic activity of topiramate.

Pharmacokinetics

After oral use, topiramate is absorbed quickly and effectively. Bioavailability – 81%. Food intake does not have a clinically significant effect on the bioavailability of topiramate. Binding to plasma proteins is 13-17%. After a single dose of up to 1.2 g, the average Vd is 0.55-0.8 l / kg.

The value of Vd depends on gender: in women, it is approximately 50% of the values observed in men, which is associated with a higher content of adipose tissue in the body of women. The pharmacokinetics of topiramate are linear. Plasma clearance remains constant, while AUC increases in proportion to the dose in the dose range from 100 to 400 mg.

Css in plasma is reached after 4-8 days. After repeated oral use at a dose of 100 mg 2 times/day, Cmax averages 6.76 mcg / ml. After oral use, about 20% of the dose is metabolized. 6 practically inactive metabolites were identified in human plasma, urine, and feces.

It is mainly excreted by the kidneys in unchanged form (70%) and in the form of metabolites. Plasma clearance is 20-30 ml/min. After repeated use in doses of 50 mg and 100 mg 2 times/day, the average T1 / 2 of topiramate from plasma is 21 hours.

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 topiramate.

Use in patients with liver function disorders

Use with caution in patients with impaired liver function due to a possible decrease in the clearance of topiramate.

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

Effect of topiramate on concentrations of other antiepileptic drugs (AEDs)At the same time, when used simultaneously 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. co-use of topiramate with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect the values of their steady-state plasma concentrations, with the exception of individual patients in whom the addition of topiramate to phenytoin may cause an increase in the concentration of phenytoin in plasma. In every patient who takes phenytoin and develops clinical signs or symptoms of toxicity, it is necessary to monitor the concentration of phenytoin in plasma. In a study of pharmacokinetics in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the steady-state concentration of the latter at doses of topiramate 100-400 mg per day. During therapy and after discontinuation of lamotrigine (mean dose 327 mg / day), the steady-state concentration of topiramate did not change. The effect of other antiepileptic drugs on the concentration of topiramata Fenytoin and carbamazepine reduces the concentration of topiramate in plasma. The addition or withdrawal of phenytoin or carbamazepine during treatment with topiramate may require a change in the dose of the latter. The dose should be selected based on achieving the necessary clinical effect. The addition or withdrawal of valproic acid does not cause clinically significant changes in the plasma concentration of Topiramate and, therefore, does not require a change in the dose of Topiramate. Other drug interactions Digoxin: In the study, when Topiramate was co-administered with a single dose of digoxin, the plasma digoxin AUC decreased by 12%. When Topiramate is used or discontinued in patients taking digoxin, special attention should be paid to routine monitoring of serum digoxin concentrations. It is not recommended to take Topiramate together with alcohol or other drugs that cause CNS depression. Oral contraceptives: A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of Topiramate 200-800 mg per day. The risk of reduced effectiveness of contraceptives and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topiramate. Patients taking estrogen-containing contraceptives should be informed of any changes in the timing and nature of menstruation. The effectiveness of contraceptives can be further reduced in the absence of breakthrough bleeding. Lithium preparations: When topiramate and lithium preparations are used simultaneously, the concentration of lithium in the blood plasma should be monitored. Risperidone: When topiramate is co-administered at 250 or 400 mg / day, the AUC of risperidone taken at 1-6 mg / day decreases by 16% and 33%, respectively. The total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed slightly. Hydrochlorothiazide: With simultaneous use of topiramate and hydrochlorothiazide, the maximum concentration of topiramate increases by 27% and the AUC of topiramate increases by 29%. The use of hydrochlorothiazide in patients taking topiramate may require dose adjustment of topiramate. The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant topiramate therapy. Metformin: When topiramate and metformin were co-administered, the maximum concentration and AUC of metformin increased by 18% and 25%, respectively, while the clearance of metformin when co-administered with topiramate decreased by 20%. Topiramate did not affect the time to reach the maximum concentration of metformin in blood plasma. Topiramate clearance decreases when co-administered with metformin. The degree of detected changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unclear. If Topiramate is added or discontinued in patients receiving metformin, special attention should be paid to a thorough investigation of the condition of patients with diabetes mellitus. Pioglitazone: In clinical trials, the AUC of pioglitazone decreased by 15%, without changing the maximum concentration of the drug. These changes were not statistically significant. When Topiramate and pioglitazone are used together in patients, special attention should be paid to a thorough investigation of the condition of patients with diabetes mellitus. Glibenclamide: A drug interaction study was conducted to study the pharmacokinetics of glibenclamide (5 mg per day) at steady state, used alone or simultaneously with topiramate (150 mg per day) in patients with type 2 diabetes mellitus. When topiramate was used, the AUC of glibenclamide decreased by 25%. The level of systemic exposure to active metabolites was also reduced. Glibenclamide did not affect the pharmacokinetics of topiramate at steady state. When using topiramate in patients receiving glibenclamide (or using glibenclamide in patients receiving topiramate), the patient’s condition should be carefully monitored to assess the course of diabetes mellitus. Other medications: Concomitant use of Topiramate with medications predisposing to nephrolithiasis may increase the risk of kidney stones. Valproic acid: The combined use of topiramate and valproic acid in patients who tolerate each drug well separately is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after discontinuation of one of the drugs. This adverse event is not caused by a pharmacokinetic interaction. The association between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established. Additional drug interaction studies have shown:Amitriptyline: when amitriptyline is co-administered with topiramate, the maximum concentration and AUC of the nortriptyline metabolite increases by 20%; Haloperidol: when haloperidol is co-administered with topiramate, the AUC of haloperidol increases by 31%;Diltiazem: when diltiazem is co-administered with topiramate, the AUC of diltiazem decreases by 25%, the AUC of topiramate increases by 20%.

How to take it, course of use and dosage

Individual, depending on the indications, the patient’s age, kidney function and the effectiveness of the therapy.

Overdose

Symptoms: seizures, drowsiness, speech and vision disorders, diplopia, thinking disorders, coordination disorders, dizziness, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression, metabolic acidosis. In most cases, the clinical consequences were not severe, but deaths were reported after overdose using a mixture of several drugs, including topiramate. There is a known case of overdose of topiramate in a dose of up to 110 g, which led to coma within 20-24 hours, and then after 3-4 days — full recovery.

Treatment: there is no specific antidote to the drug, and if necessary, symptomatic therapy is performed. It is necessary to immediately induce vomiting and flush the stomach, increase water intake. In vitro studies have shown that activated carbon adsorbs topiramate. Hemodialysis is the most effective way to remove topiramate from the body. Patients are advised to increase their fluid intake appropriately.

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

Children as prescribed by a doctor, Adults as prescribed by a doctor

Indications

Migraine, Epilepsy