Pharmacological properties
A new antiepileptic drug of the class of sulfamate-substituted monosaccharides. Electrophysiological and biochemical studies on neuronal cultures have revealed the effects of the drug that determine its antiepileptic activity. Topiramate, by blocking sodium channels in the neuronal membrane, blocked action potentials that constantly arise when neurons are maintained in a state of sustained depolarization. Topiramate increased the binding of γ-aminobutyric acid (GABA) to GABA receptors, enhanced the ability of GABA to cause the entry of chlorine ions into neurons, which suggests that topiramate potentiates the activity of this inhibitory neurotransmitter. Since the antiepileptic profile of topiramate differs significantly from that of benzodiazepines, it can modulate the subtype of GABA receptors that are insensitive to benzodiazepines. Topiramate inhibits kainate activation of the kainate/AMPK (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) glutamate receptor subtype, but does not significantly affect the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These properties of topiramate are dose-dependent in the range of 1 to 200 μM with minimal activity in the range of 1 to 10 μM.
In addition, topiramate inhibits the activity of some carbonic anhydrase isoenzymes. In terms of the severity of this effect, topiramate is significantly inferior to acetazolamide, but this property of topiramate is not the main one in ensuring its antiepileptic activity.
Topiramate has synergistic anticonvulsant activity with carbamazepine and phenobarbital, and in combination with phenytoin has an additive anticonvulsant effect. In controlled clinical studies, no correlation was found between the level of topiramate in the blood plasma and its clinical efficacy. The development of tolerance to topiramate has not been established.
The pharmacokinetic profile of topiramate is characterized by a long half-life, linear pharmacokinetics, predominantly renal clearance, low plasma protein binding, 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, and it does not require routine monitoring of plasma concentrations. In clinical studies, no consistent relationship between plasma concentrations and its efficacy or side effects has been found.
Topiramate is rapidly and well absorbed, the degree of absorption is not less than 81%. Food intake has no clinically significant effect on the bioavailability of topiramate. About 13-17% of topiramate is bound to plasma proteins. With a single dose of up to 1200 mg, the average volume of distribution is 0.55-0.8 l/kg. The value of the volume of distribution depends on gender. In women, this value is approximately 50% of the values observed in men, which may be due to the higher content of adipose tissue in the body of women. In healthy volunteers, the metabolism of topiramate is not intensive (20%), however, in patients receiving therapy with antiepileptic drugs that induce microsomal enzymes, the metabolism of topiramate increased by 50%. Six metabolites have been identified. The pharmacological activity of two of them, which mainly retain the chemical structure of topiramate, was tested, and it turned out that they had no or minimal anticonvulsant activity. The main route of elimination of 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, so the pharmacokinetics of the drug are well predicted. It is linear, the clearance remains constant, and the AUC area increases proportionally to the dose in the range from 100 to 400 mg. In patients with normal renal function, it may take from 4 to 8 days to achieve a stable plasma concentration. In healthy volunteers, the average maximum plasma concentration after multiple oral administration at a dose of 100 mg 2 times a day is 6.76 μg/ml. After multiple doses of 50 and 100 mg twice daily, the average elimination half-life of topiramate is approximately 21 hours. In patients with impaired renal function (creatinine clearance less than 60 ml/min), the clearance of topiramate is reduced. Topiramate is removed by hemodialysis.
In patients with impaired liver function, the clearance of topiramate is reduced.
In elderly people without kidney disease, the clearance of topiramate does not change.
The pharmacokinetics of topiramate in children, as in adults, are linear, however, children have a higher clearance and a shorter half-life.
Indication
As monotherapy or adjunctive therapy for the treatment of partial seizures in adults and children with partial onset seizures, with or without secondary generalized seizures; in adults and children as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome.
Application
Treatment begins with a minimum dose followed by gradual selection of an effective dose. It is taken orally, regardless of meals.
Additional therapy
Adults: initial dose 25-50 mg at night for 1 week. Subsequently, with a weekly or two-week interval, the dose is increased by 25-50 mg, taken in 2 doses. In some patients, the effect can be achieved by 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 doses exceeding 1600 mg/day.
These dosage recommendations can be applied to all adult patients, including the elderly, provided that there is no kidney disease.
Children aged 2 years and older
The recommended daily dose is an average of 5-9 mg per 1 kg of body weight per day, divided into 2 doses. Treatment is started with 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 two-week 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 has proven itself well.
monotherapy
Previously used antiepileptic drugs should be withdrawn gradually, by approximately one-third of the previous dose over 2 weeks.
adults
Dose selection should begin with a dose of 25 mg at night for 1 week. In the future, the dose is increased by 25-50 mg at weekly or two-week intervals (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 well 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 be initiated at a dose of 1-3 mg/kg at night for the first week. The dose may then be increased by 1-3 mg/kg per day at weekly or biweekly intervals until a therapeutic effect is achieved; the daily dose is given in 2 divided doses.
The recommended starting dose of Topamax as monotherapy in children aged 2 years and older is 3-6 mg per 1 kg of body weight per day. With a newly diagnosed diagnosis of "partial epileptic seizures", children can be prescribed the drug in a dose of up to 500 mg/day.
Contraindication
Hypersensitivity to the components of the drug, age up to 2 years.
Side effects
Since Topamax is most often used together with other antiepileptic drugs, it is difficult to determine which one caused the side effect.
Adjunctive therapy in adults
Side effects that were recorded in placebo-controlled studies with a rapid dose adjustment period: drowsiness, dizziness, increased excitability, ataxia, increased fatigue, speech disorders, slowed psychomotor reactions, visual impairment, memory difficulties, confusion, paresthesia, diplopia, anorexia, nystagmus, nausea, weight loss, impaired concentration, depression, abdominal pain, asthenia occurred statistically significantly with a frequency of 5% or more.
Much less frequently, taste disturbances, agitation, cognitive impairment, emotional lability, coordination disorders, gait disturbances, apathy, psychosis, aggressive reactions, leukopenia and nephrolithiasis were noted. In isolated cases, thromboembolism was noted, although its relationship with taking the drug has not been proven.
Adjunctive therapy in children
With a frequency of 5% or more, drowsiness, anorexia, increased fatigue, increased excitability, impaired concentration, aggressiveness, weight loss, gait disturbance, ataxia, drooling, nausea, memory impairment, hyperkinesia, dizziness, speech impairment, paresthesia were noted. Emotional lability, agitation, apathy, cognitive impairment, slowed psychomotor reactions, confusion, hallucinations, depression and leukopenia were noted much less frequently.
Monotherapy (in patients of all groups)
With a frequency of 10% or more, paresthesia, headache, dizziness, fatigue, drowsiness, weight loss, nausea, diarrhea were noted.
Special instructions
Antiepileptic drugs, including Topamax, should be withdrawn gradually to minimize the risk of increased seizure frequency. In clinical trials, the dose of the drug was reduced by 100 mg at weekly intervals, and in some patients, withdrawal of the drug was accelerated and proceeded without complications.
In patients with moderate to severe renal impairment, it may take 10 to 15 days to achieve steady-state plasma concentrations, compared with 4 to 8 days in patients with normal renal function. When setting the dose, consideration should be given to therapeutic efficacy (i.e., degree of seizure reduction, absence of side effects) and the fact that patients with impaired renal function may require a longer time to achieve steady-state plasma concentrations of topiramate for each dose.
Patients with a predisposition to nephrolithiasis have an increased risk of kidney stone formation. To reduce this risk, it is necessary to increase the volume of fluid intake accordingly. Risk factors for the development of nephrolithiasis include a history of stone formation and nephrolithiasis, hypercalciuria, and concomitant use of drugs that promote nephrolithiasis.
If the patient loses weight while taking Topamax, increased nutrition is indicated.
The experiment established 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 use of the drug in women who are breastfeeding, it is necessary to decide on the termination of breastfeeding or the withdrawal of the drug. Topamax may cause drowsiness and dizziness, which should be taken into account by persons driving vehicles or working 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 concentrations in the blood plasma, with the exception of individual patients in whom the addition of the drug to phenytoin therapy may cause an increase in the concentration of phenytoin in the blood plasma. This may be the result of inhibition of a specific polymorphic isoform of the enzyme (CYP2CMePH). Thus, in each patient taking phenytoin and developing clinical signs of intoxication, it is necessary to monitor the level of phenytoin in the blood plasma.
Phenytoin and carbamazepine reduce the plasma concentration of topiramate. The addition of phenytoin or carbamazepine to topiramate treatment or their withdrawal may require a change in the dose of the latter. The dose should be set, focusing on achieving the desired therapeutic effect.
The addition or withdrawal of VALPROIC acid does not cause therapeutically significant changes in plasma concentrations of topiramate and, accordingly, does not require a change in the dose of Topamax.
The AUC of digoxin was decreased by 12% when Topamax was coadministered. The clinical significance of this observation is unknown. When Topamax is initiated or discontinued in patients receiving digoxin, special attention should be paid to routine monitoring of serum digoxin concentrations.
It is not recommended to combine Topamax with alcohol or other substances that depress the CNS.
When Topamax was coadministered with a combined oral contraceptive containing norethindrone and ethinyl estradiol, the clearance of norethindrone was not significantly altered, but the clearance of the estrogen component was significantly increased. In such a situation, the effectiveness of the low-dose oral contraceptive may be reduced.
Concomitant use of Topamax with drugs that cause kidney stone formation increases the risk of nephrolithiasis.
Overdose
Perform gastric lavage. In vitro experiments have shown that activated charcoal does not adsorb the drug, so its use in case of overdose is not recommended. Supportive measures are indicated. Hemodialysis is effective, however, in case of acute overdose, including individual cases of taking more than 20 g of the drug, hemodialysis is usually not necessary.
Storage conditions
In a dry place at a temperature not exceeding 25 °C.
