Topiramate

Pharmacological properties

A new antiepileptic drug of the sulfamate-substituted monosaccharide class. electrophysiological and biochemical studies on neuron cultures revealed the effects of the drug, which determine its antiepileptic activity. due to blocking the sodium channels of the membrane of neurons, Topiramate blocked action potentials that constantly arise when neurons are maintained in a state of stable depolarization. Topiramate increased the binding of γ-aminobutyric acid (gamma) to gamma receptors, increased the ability of gamma to induce the entry of chlorine ions into neurons, which suggests that Topiramate potentiates the activity of this inhibitory neurotransmitter. since the antiepileptic profile of Topiramate is significantly different from the profile of benzodiazepines, it can modulate the subtype of gamma receptors insensitive to benzodiazepines. Topiramate prevents the activation of the kainate / ampk subtype (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) of the glutamate receptor by the kainate, but does not significantly affect the activity of n-methyl-d-aspartate (nmda) with respect to subtype of nmda receptors. the indicated properties of Topiramate are dose-dependent in the range from 1 to 200 μmol with a minimum activity in the range from 1 to 10 μmol.

In addition, Topiramate inhibits the activity of certain carbonic anhydrase isoenzymes. In terms of the severity of this effect, Topiramate is significantly inferior to acetazolamide; this property of Topiramate is not fundamental in ensuring its antiepileptic activity.

Topiramate has a synergistic anticonvulsant activity with carbamazepine and phenobarbital, and in combination with phenytoin has an additional anticonvulsant effect. In controlled clinical trials, there was no correlation between the level of Topiramate in blood plasma and its clinical efficacy. The development of Topiramate tolerance has not been established.

The pharmacokinetic profile of Topiramate is characterized by a long half-life, a linear nature of the pharmacokinetics, mainly renal clearance, an insignificant degree of binding to blood plasma proteins and the absence of therapeutically active metabolites.

Topiramate does not affect the metabolism of drugs metabolized by microsomal enzymes, it can be taken regardless of food intake, it does not require routine monitoring of plasma concentrations. In clinical studies, no consistent relationship was found between plasma concentration and its effectiveness or side effects.

Topiramate is rapidly and well absorbed, the degree of absorption is at least 81%. Eating does not have a clinically significant effect on the bioavailability of Topiramate. About 13-17% of Topiramate binds to plasma proteins. With a single dose of up to 1200 mg, the average distribution volume is 0.55–0.8 l / kg. The value of distribution volume depends on gender. In women, this value is approximately 50% of the values ​​that are observed in men, which may be due to a higher content of adipose tissue in the body of women. In healthy volunteers, the Topiramate metabolism is not intense (20%), however, in patients who received antiepileptic drugs that induce microsomal enzymes, Topiramate metabolism increased by 50%. Six metabolites have been identified. The pharmacological activity of two of them, which mainly preserve the chemical structure of Topiramate, was tested, and it turned out that they had no anticonvulsant activity or was minimally expressed. The main way to eliminate Topiramate and its metabolites in an unchanged state is the kidneys. After oral administration, the total clearance of the drug in humans is 20-30 ml / min.Individual differences in the plasma concentration of Topiramate in different people are quite insignificant, therefore, the pharmacokinetics of the drug is well predicted. It is linear, the clearance remains constant, and the AUC area increases in proportion to the dose in the range from 100 to 400 mg. In patients with normal renal function, it may take 4 to 8 days to achieve a stable plasma concentration. In healthy volunteers, the average maximum plasma concentration after repeated oral administration at a dose of 100 mg 2 times a day is 6.76 μg / ml. After repeated doses of 50 and 100 mg 2 times a day, the average half-life of Topiramate is about 21 hours. In patients with impaired renal function (creatinine clearance less than 60 ml / min), Topiramate clearance is reduced. Topiramate is excreted during hemodialysis.

In patients with impaired liver function, the clearance of Topiramate is reduced.

In the elderly, without kidney disease, the clearance of Topiramate does not change.

The pharmacokinetics of Topiramate in children, as in adults, is linear, but in children there is a higher clearance and a shorter half-life.

Indications

As monotherapy or adjunctive therapy for the treatment of adults and children with partial epileptic seizures that are accompanied or not accompanied by secondary generalized seizures; in adults and children as adjunctive therapy for seizures associated with Lennox-gastout syndrome.

Application

Treatment begins with a minimum dose, followed by a gradual selection of an effective dose. taken orally, regardless of food intake.

Adjunctive therapy

Adults: in an initial dose of 25-50 mg at night for 1 week. Subsequently, with a weekly or fortnightly interval, the dose is increased by 25-50 mg, taking in 2 doses. In some patients, the effect can be achieved when taking the drug 1 time per day.

The minimum effective dose is 200 mg. The usual maintenance dose is 200-400 mg / day in 2 divided doses. Some patients tolerate a dose exceeding 1600 mg / day.

These dosage recommendations can be applied to all adult patients, including the elderly, provided that there are no kidney diseases.

Children 2 years and older

The recommended daily dose is on average 5–9 mg per 1 kg of body weight per day, divided into 2 doses. Treatment begins with the appointment of a dose of 25 mg or lower, at the rate of 1-3 mg per 1 kg of body weight per day at night for 1 week. Subsequently, with a weekly or fortnightly interval, the dose is increased by 1-3 mg / kg, divided into 2 doses, until a therapeutic effect is achieved. In clinical studies, the use of the drug at a dose of 30 mg / kg per day is well established.

Monotherapy

Previously used antiepileptic drugs should be canceled gradually, approximately one third of the previous dose within 2 weeks.

Adults

Dose selection should begin with the appointment of a dose of 25 mg at night for 1 week. In the future, the dose is increased by 25-50 mg with a weekly or two-week interval (the dose is divided into 2 doses) until a therapeutic effect is achieved. The recommended dose of Topamax for monotherapy in adults is 100-200 mg / day, the maximum recommended dose is 500 mg / day. Some patients with refractory forms of epilepsy tolerate Topamax monotherapy at a dose of 1000 mg / day. These dosage recommendations can be applied to all adult patients, including the elderly, in the absence of kidney disease.

Children

Treatment of children aged 2 years and older should begin with a dose of 1-3 mg / kg at night during the first week.In the future, the dose can be increased by 1-3 mg / kg per day with a weekly or two-week interval until a therapeutic effect is achieved; the daily dose is taken in 2 divided doses.

The recommended initial dose of Topamax for monotherapy in children aged 2 years and older is 3–6 mg per 1 kg of body weight per day. With the recently established diagnosis of "partial seizures" children can be prescribed a dose of up to 500 mg / day.

Contraindications

Hypersensitivity to the drug, up to 2 years old.

Side effects

Since topamax is most often used together with other antiepileptic drugs, it is difficult to establish which of them caused the development of a side effect.

Complementary therapy in adults

Side effects that were recorded in placebo-controlled studies with a quick dose selection period: statistically significant with a frequency of 5% or more, drowsiness, dizziness, increased irritability, ataxia, increased fatigue, speech disorders, slowing of psychomotor reactions, visual impairment, difficulty remembering, confusion, paresthesia, diplopia, anorexia, nystagmus, nausea, weight loss, impaired concentration, depression, abdominal pain, asthenia.

Disturbance of taste sensations, agitation, cognitive impairment, emotional lability, impaired coordination, gait, apathy, psychosis, aggressive reactions, leukopenia and nephrolithiasis were much less common. In some cases, thromboembolism was noted, although its relationship with the drug was not proven.

Additional therapy in children

With a frequency of 5% or more, drowsiness, anorexia, increased fatigue, increased irritability, impaired attention concentration, aggressiveness, weight loss, impaired gait, ataxia, salivation, nausea, memory impairment, hyperkinesia, dizziness, speech impairment, paresthesia were noted. Emotional lability, agitation, apathy, cognitive impairment, a slowdown in psychomotor reactions, confusion, hallucinations, depression, and leukopenia were significantly less common.

Monotherapy (in patients of all groups)

With a frequency of 10% or more, paresthesia, headache, dizziness, increased fatigue, drowsiness, weight loss, nausea, diarrhea were noted.

special instructions

Antiepileptic drugs, in particular topamax, should be discontinued gradually to minimize the risk of an increase in the frequency of seizures. in clinical trials, the dose of the drug was reduced by 100 mg at weekly intervals, in some patients, drug withdrawal was accelerated and passed without complications.

In patients with moderate or severe renal failure, it may take 10 to 15 days to achieve a stable plasma concentration, in contrast to 4-8 days in patients with normal renal function. When establishing a dose, therapeutic efficacy (i.e., the degree of reducing the frequency of seizures, the absence of side effects) and the fact that patients with impaired renal function to achieve a stable concentration of Topiramate in blood plasma for each dose may need a longer time.

In patients with a tendency to nephrolithiasis, the risk of kidney stones is increased. To reduce this risk, a corresponding increase in fluid intake is necessary. Risk factors for the development of nephrolithiasis are the formation of stones and a history of nephrolithiasis, hypercalciuria, and the simultaneous use of drugs that promote nephrolithiasis.

In patients with liver pathology, the drug should be used with caution.

In case the patients body weight decreases while taking Topamax, enhanced nutrition is indicated.

In the experiment, the presence of Topamax teratogenic effects.During pregnancy, Topamax should be used only if the expected positive effect for the expectant mother outweighs the potential risk to the fetus. In the case of the use of the drug in women who are breastfeeding, it is necessary to decide whether to stop breastfeeding or to discontinue the drug. Topamax can cause drowsiness and dizziness, which should be considered by persons who drive vehicles or work with potentially dangerous mechanisms.

Interactions

The combination of topamax with other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect the level of their constant plasma concentrations, with the exception of some patients in whom the addition of the drug to phenytoin therapy can cause an increase in the concentration of phenytoin in blood plasma. this may be due to inhibition of a specific polymorphic isoform of the enzyme (cyp2cmeph). Thus, in every patient who takes phenytoin and who develop clinical signs of intoxication, it is necessary to control the level of phenytoin in the blood plasma.

Phenytoin and carbamazepine reduce the concentration of Topiramate in blood plasma. Addition of phenytoin or carbamazepine to Topiramate treatment or their withdrawal may require a change in the doses of the latter. The dose should be established, focusing on achieving the necessary therapeutic effect.

Addition or withdrawal of valproic acid does not cause therapeutically significant changes in the concentration of Topiramate in blood plasma and, accordingly, does not require a change in the dose of Topamax.

Digoxin AUC while taking Topamax was reduced by 12%. The clinical significance of this observation has not been elucidated. When prescribing or canceling Topamax in patients taking digoxin, special attention should be paid to routine monitoring of serum digoxin concentration.

It is not recommended to combine Topamax with alcohol or other substances that depress the central nervous system.

With the simultaneous use of Topamax with an oral combined contraceptive containing norethindrone and ethinyl estradiol, the clearance of norethindrone did not change significantly, however, the clearance of the estrogen component increased significantly. In such a situation, the effectiveness of low-dose oral contraceptives may be reduced.

The simultaneous use of Topamax with drugs that cause the formation of calculi in the kidneys increases the risk of nephrolithiasis.

Overdose

Perform gastric lavage. in vitro experiments revealed that activated carbon does not adsorb the drug, so it is not recommended to use it in case of overdose. supporting activities are shown. hemodialysis is effective, however, in case of acute overdose, including some cases of taking more than 20 g of the drug, hemodialysis is usually not necessary.

Storage conditions

In a dry place at temperatures up to 25 ° C.