Topsaver, 50 mg 28 pcs.

Topiramate refers to sulfate-substituted monosaccharides. This active substance blocks sodium channels and inhibits the occurrence of repetitive action potentials against the background of prolonged depolarization of the neuron membrane. It also increases the activity of GABA against some subtypes of GABA receptors.

In addition, inhibits kainat activation of kainat/AMPK (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subtype sensitivity to glutamate and does not affect N-methyl-D-aspartate (NMDA) activity with respect to NMDA receptors. The above 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

Intake

Topiramate is quickly and well absorbed. Food intake has no clinically significant effect on its bioavailability, which is about 80%. The mean C_max after multiple oral doses of 100 mg 2 times/day is 6.76 mcg/ml.

Distribution

The binding to plasma proteins is 13-17%. Mean V_d is 0.55-0.8 L/kg for a single dose of up to 1.2 g. V_d depends on gender: in women the values are 50% of those observed in men, which is associated with higher adipose tissue in women. After a single dose, pharmacokinetics is linear, plasma clearance is constant, AUC in the dose range from 100 mg to 400 mg increases in proportion to the dose. With normal renal function, patients may require 4-8 days to reach C_ss.

Topiramate penetrates into breast milk.

Metabolism

Metabolized about 20% of topiramate. Up to 50% of topiramate is metabolized in patients taking other antiepileptic drugs (PEDs) simultaneously that induce metabolizing enzymes. Six virtually inactive metabolites of topiramate have been isolated from plasma, urine, and human feces.

The unchanged topiramate and its metabolites are primarily excreted via the kidneys. Plasma clearance is about 20-30 ml/min.

The T_1/2 after multiple doses of 50 mg and 100 mg 2 times/day is 21 hours. Efficiently excreted from the blood plasma by hemodialysis.

Pharmacokinetics in special clinical cases

V_d depends on sex: in women these values are 50% of those observed in men, which is associated with higher fatty tissue in women.

In patients with impaired renal function (CK < 60 ml/min), plasma and renal clearance of topiramate is reduced; in patients with end-stage renal failure, plasma clearance of topiramate is reduced.

The plasma clearance of topiramate is not altered in elderly patients in the absence of renal impairment.

The 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. The drug clearance does not depend on 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. Consequently, the plasma concentrations of topiramate at the same dose per kg body weight may be lower in children compared to adults.

Indications

Active ingredient

Composition

Associates:

Lactose monohydrate,

Pregelatinized starch,

partially pregelatinized starch,

Microcrystalline cellulose,

sodium carboxymethyl starch,

Magnesium stearate.

Composition of the shell:

Hypromellose, polysorbate 80, talc, titanium dioxide (E171), iron oxide yellow (E172).

How to take, the dosage

The drug is prescribed orally. The tablet is swallowed whole, without chewing, and is taken regardless of meals. For optimal seizure control, it is recommended to start treatment with a low dose followed by increasing to an effective dose.

In combination therapy

For adults, the minimum effective dose is 200 mg/day. The usual daily dose is 200-400 mg (in 2 doses). Maximum daily dose is 1.6 g. 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. 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 depending on the clinical effect.

In 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 to 3 mg/kg/day for 1-2 weeks, with multiple doses of 2 times/day, until optimal clinical effect is achieved.

Monotherapy

Adults start treatment with 25 mg at night for 1 week. Then the dose is increased by 25-50 mg/day for 1-2 weeks, with a frequency of 2 doses per day. If this dosing regimen is intolerable, the dose is increased by a smaller amount or taken 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.

In children aged 7 years and older, 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/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 recently established partial seizures may be prescribed up to 500 mg/day.

Interaction

Influence of topiramate on other PEPs

There is no effect on concentrations of carbamazepine, valproic acid, phenobarbital, primidone. In individual cases, when used with phenytoin, increased plasma concentrations of phenytoin may occur.

The effect of other PEDs on topiramate

The co-administration of topiramate with phenytoin and carbamazepine may decrease the plasma concentration of topiramate. If phenytoin or carbamazepine is added or withdrawn, it is recommended that the dose of topiramate be adjusted.

The administration of other PEPs that induce liver enzymes decreases the Cmax of topiramate in plasma.

Interaction with other drugs

The AUC of digoxin decreases by 12% when co-administered with topiramate.

Topiramate at a dose of 50-800 mg/day had no significant effect on the effectiveness of norethindrone and at a dose of 50-200 mg/day on the effectiveness of ethinylestradiol. A significant dose-dependent decrease in ethinylestradiol efficacy was observed with topiramate doses of 200-800 mg/day. Patients taking oral contraceptives should inform their physician of any changes in bleeding patterns.

Concomitant use with topiramate increases mean Cmax and AUC of metformin by 18% and 25%, respectively, while mean total clearance decreases by 20%. Topiramate had no effect on the TCmax of metformin. Plasma clearance of topiramate is decreased by metformin exposure. The clinical significance of metformin effects on topiramate pharmacokinetics is unclear. Carbohydrate metformin therapy should be monitored when prescribing or withdrawing topiramate.

Concomitant administration with hydrochlorothiazide increases Cmax by 27% and AUC of topiramate by 29%.

The concomitant administration of ethanol and other CNS depressants with topiramate is not recommended.

The AUC of pioglitazone was found to decrease by 15%, with no change in Cmax topiramate. For the active hydroxymetabolite pioglitazone, a decrease in Cmax and AUC of 13% and 16%, respectively, was found, and for the active ketometabolite, a decrease in both Cmax and AUC of 60% was found. The clinical significance of these data is unknown.

Topiramate, when used together with other drugs that predispose to nephrolithiasis, in particular carboanhydrase inhibitors (acetazolamide) may increase the risk of nephrolithiasis. Patients should avoid taking these medications while using topiramate because they may create physiologic conditions that increase the risk of renal stone formation.

Special Instructions

Women are advised to use adequate contraception while taking the drug.

Topiramate, like other PEPs, is recommended to be withdrawn with a gradual dose reduction to reduce the potential risk of increased seizure frequency.

Patients with moderate to severe renal impairment may require 10-15 days to reach equilibrium plasma concentrations as opposed to 4-8 days for patients with normal renal function. As in all patients, gradual dose increases should be made according to clinical outcomes (such as seizure control, frequency of side effects), given that patients with moderate to severe renal impairment may take longer to reach steady state after each dose.

In some patients, especially those predisposed to nephrolithiasis, there may be an increased risk of renal stone formation accompanied by symptoms such as renal colic, pain in the side, and kidney area. Adequate hydration is recommended to reduce the risk of renal stone formation.

In patients with impaired liver function, the clearance of topiramate is decreased.

If myopia develops, it is recommended that topiramate be discontinued as quickly as clinically possible and that measures be taken to reduce intraocular pressure.

Hyperchloremic, unrelated to anion deficiency, metabolic acidosis may occur with topiramate use (e.g., decreased plasma hydrocarbonate concentrations below normal levels in the absence of respiratory alkalosis). This decrease in serum hydrocarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carboanhydrase. Therefore, periodic determination of serum hydrocarbonate concentrations is recommended during topiramate treatment.

If body weight decreases during therapy with topiramate, it is advisable to consider prescribing additional nutrition.

Impact on driving and operating machinery

At the time of treatment, it is recommended to refrain from driving and working requiring increased concentration and quick psychomotor reactions.

Contraindications

With caution, the drug should be used in patients with renal or hepatic impairment, nephrourolithiasis (including history), hypercalciuria

Application in patients with hepatic impairment

Precaution should be used in patients with hepatic impairment.

The clearance of topiramate is decreased in patients with hepatic impairment.

Use in impaired renal function

Take with caution in renal impairment.

Patients with moderate to severe renal impairment may require 10-15 days to reach equilibrium plasma concentrations as opposed to 4-8 days for patients with normal renal function. As with all patients, gradual dose increases should be made according to clinical outcomes (such as seizure control, frequency of side effects), given that patients with moderate to severe renal impairment may take longer to reach steady state after each dose.

Side effects

CNS disorders: hyperexcitability, dizziness, headache, speech and vision disorders, psychomotor retardation, ataxia, fatigue, difficulty concentrating, confusion, paresthesia, somnolence, thought disorders, diplopia, anorexia, nystagmus, depression, perversion of taste, agitation, cognitive disorders, emotional lability, apathy, psychotic symptoms, aggressive behavior, suicidal ideas or attempts; additionally in children – personality disorders, increased salivation, hyperkinesia, hallucinations.

In the digestive system: dyspepsia, nausea, abdominal pain, diarrhea, dry lips, increased liver transaminase activity, hepatitis, liver failure.

VIight: possible occurrence of myopia syndrome on the background of increased intraocular pressure with acute decrease in visual acuity and pain in the eye. Myopia, decreased depth of the anterior chamber of the eye, hyperemia of the ocular mucosa and increased intraocular pressure, mydriasis. A possible mechanism of these disorders is an increase in supraciliary effusion, which leads to a forward displacement of the lens and iris, and as a consequence, the development of secondary closed-angle glaucoma.

Dermatological reactions: erythema multiforme, pemphigus, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Others: weight loss, leukopenia, nephrolithiasis, oligohidrosis (mainly in children), metabolic acidosis.

Overdose

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

Treatment: gastric lavage, activated charcoal, symptomatic therapy, hemodialysis.

Pregnancy use

The drug is contraindicated in pregnancy and during lactation (breastfeeding).

Pediatric use

The drug is contraindicated in children under 3 years of age.

The use in children over 3 years is possible according to the dosage regimen.

Similarities