World experience in the use of topiramate (literature review)

Topamax, 60 pcs., 25 mg, capsules

The effect of Topamax® on the concentrations of other antiepileptic drugs (AEDs)

Concomitant use of Topamax® with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect their plasma Css values, with the exception of certain patients in whom the addition of Topamax® to phenytoin may cause an increase in plasma phenytoin concentrations . This may be due to inhibition of a specific polymorphic isoform of the enzyme of the cytochrome P450 system (CYP2C19 isoenzyme). Therefore, phenytoin plasma concentrations should be monitored in any patient taking phenytoin who develops clinical signs or symptoms of toxicity.

In a pharmacokinetic study in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the latter's Css at doses of topiramate 100–400 mg/day. During therapy and after discontinuation of lamotrigine (average dose 327 mg/day), Css of topiramate did not change.

Impact of other AEDs on the concentration of Topamax®

Phenytoin and carbamazepine reduce plasma concentrations of Topamax®. The addition or removal of phenytoin or carbamazepine during treatment with Topamax may require a change in the dose of the latter. The dose should be selected based on achieving the desired clinical effect. The addition or removal of valproic acid does not cause clinically significant changes in the plasma concentration of Topamax® and therefore does not require a change in the dose of Topamax®. The results of these interactions are summarized in Table 1.

Table 1

1 - No effect.

** - Increased concentration in isolated patients.

$ - Decreased plasma concentration.

NI - Not studied.

Other drug interactions

Digoxin.

In a single-dose study, the plasma AUC of digoxin decreased by 12% when coadministered with Topamax®. The clinical significance of this observation is unclear. When prescribing or discontinuing Topamax® in patients taking digoxin, special attention should be paid to monitoring the concentration of digoxin in the serum.

CNS depressants.

In clinical studies, the consequences of simultaneous use of Topamax® with alcohol or other substances that depress the functions of the central nervous system have not been studied. It is not recommended to take Topamax® together with alcohol or other drugs that cause depression of central nervous system function.

St. John's wort.

When taking Topamax together with drugs based on St. John's wort
(Hypericum perforatum),
the plasma concentration of topiramate may decrease and, as a result, the effectiveness of the drug may also decrease. Clinical studies of the interaction of Topamax® and drugs based on St. John's wort have not been conducted.

Oral contraceptives.

In a drug interaction study with oral contraceptives using a combination product containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), Topamax® at doses of 50–800 mg per day did not have a significant effect on the effectiveness of norethisterone and at doses of 50–200 mg per day - on the effectiveness of ethinyl estradiol. A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of Topamax® 200–800 mg per day. The clinical significance of the described changes is unclear. The risk of decreased contraceptive effectiveness and increased breakthrough bleeding should be considered in patients taking oral contraceptives in combination with Topamax®. Patients taking estrogen-containing contraceptives should be informed of any changes in the timing and pattern of menstruation. The effectiveness of contraceptives may be reduced even in the absence of breakthrough bleeding.

Lithium.

In healthy volunteers, a decrease in lithium AUC by 18% was observed while taking topiramate at a dose of 200 mg/day. In patients with manic-depressive psychosis, the use of topiramate in doses up to 200 mg/day did not affect the pharmacokinetics of lithium, however, at higher doses (up to 600 mg/day), the AUC of lithium was increased by 26%. When using topiramate and lithium simultaneously, the concentration of the latter in the blood plasma should be monitored.

Risperidone.

Drug interaction studies with single and multiple doses of topiramate in healthy volunteers and patients with bipolar disorder yielded similar results. When coadministered with topiramate at doses of 250 or 400 mg/day, the AUC of risperidone taken in doses of 1–6 mg/day is reduced by 16 and 33%, respectively. At the same time, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed slightly. The change in systemic exposure of risperidone/9-hydroxyrisperidone and topiramate was not clinically significant and this interaction is unlikely to be of clinical significance.

Hydrochlorothiazide.

Drug interactions were assessed in healthy volunteers with the separate and combined use of hydrochlorothiazide (25 mg) and topiramate (96 mg). Study results showed that when topiramate and hydrochlorothiazide were taken concomitantly, the topiramate Cmax increased by 27% and the topiramate AUC increased by 29%. The clinical significance of these studies has not been established. Prescribing hydrochlorothiazide to patients taking topiramate may require a dose adjustment of topiramate. The pharmacokinetic parameters of hydrochlorothiazide were not significantly altered by concomitant therapy with topiramate.

Metformin.

Drug interactions were assessed in healthy volunteers receiving metformin or a combination of metformin and topiramate. Study results showed that when topiramate and metformin were taken concomitantly, the Cmax and AUC of metformin increased by 18 and 25%, respectively, while the clearance of metformin when used concomitantly with topiramate decreased by 20%. Topiramate had no effect on metformin plasma Tmax. The clearance of topiramate is reduced when used concomitantly with metformin. The extent of the observed changes in clearance has not been studied. The clinical significance of the effect of metformin on the pharmacokinetics of topiramate is unclear. If Topamax® is added or discontinued in patients receiving metformin, the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

Pioglitazone.

Drug interactions were assessed in healthy volunteers with the separate and simultaneous use of pioglitazone and topiramate. A decrease in the AUC of pioglitazone by 15% was detected, without changing the Cmax of the drug. These changes were not statistically significant. For the active hydroxymetabolite pioglitazone, a decrease in Cmax and AUC was also detected by 13 and 16%, respectively, and for the active ketometabolite, a decrease in both Cmax and AUC was detected by 60%. The clinical significance of these data is unclear. When patients use Topamax® and pioglitazone simultaneously, the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

Glibenclamide.

A drug interaction study was conducted to examine the pharmacokinetics of glibenclamide (5 mg/day) at steady state, administered alone or concomitantly with topiramate (150 mg/day) in patients with type 2 diabetes mellitus. When topiramate was used, the AUC of glibenclamide was reduced by 25%. Systemic exposure to 4-trans-hydroxy-glibenclamide and 3-cis-hydroxy-glibenclamide was also reduced (by 13 and 15%, respectively). Glibenclamide did not affect the pharmacokinetics of topiramate at steady state. A statistically insignificant decrease in the AUC of pioglitazone by 15% was found with no change in Cmax. When prescribing topiramate to patients receiving glibenclamide (or prescribing glibenclamide to patients receiving topiramate), the patient's condition should be carefully monitored to assess the course of diabetes mellitus.

Other drugs.

Concomitant use of Topamax® with drugs that predispose to nephrolithiasis may increase the risk of kidney stones. During treatment with Topamax®, the use of drugs that predispose to nephrolithiasis should be avoided, as they may cause physiological changes that contribute to nephrolithiasis.

Valproic acid.

The combined use of topiramate and valproic acid in patients who tolerate each drug separately is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after stopping one of the medications. This adverse event is not due to a pharmacokinetic interaction. The relationship between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established. When topiramate and valproic acid are taken together, hypothermia (an unintentional decrease in body temperature below 35 °C) may occur in combination with hyperammonemia or independently. This phenomenon can occur both after the start of co-administration of valproic acid and topiramate, and with an increase in the daily dose of topiramate.

Additional drug interaction studies: A number of clinical studies have been conducted to evaluate potential drug interactions between topiramate and other drugs. The results of these interactions are summarized in Table 2.

table 2

* — Expressed as % of Cmax values ​​in blood plasma and AUC during monotherapy.

1 - No changes in plasma Cmax and AUC (<15% of baseline data).

** With multiple doses of flunarizine alone, a 14% increase in AUC was observed, which may be due to drug accumulation during the process of reaching steady state.

NI - not studied.

World experience in the use of topiramate (literature review)

Topiramate belongs to the latest generation of anticonvulsants that replaced or significantly supplemented the effect of drugs from previous years. The list of these drugs traditionally includes barbiturates (phenobarbital, benzonal, hexamidine), hydantoins (difenin), carbamazepines (finlepsin, tegretol) - the first generation; derivatives of valproic acid (Depakine, Valparin, Convulex) – second generation; lamotrigine (Lamictal), levitiracetam (Keppra), oxcarbamazepine (Trileptal) and, finally, topiramate itself - the third generation.

Among the latest generation of drugs, topiramate is perhaps the most studied, and yet the most intriguing drug, due to its unusual sulfate-substituted monosaccharide structure and a unique range of mechanisms of biochemical action, including almost all known types of antiepileptic effects on neurons. This influence is mainly manifested in the activation of the GABAergic and blockade of the glutamateergic systems, which are responsible, respectively, for the basic processes of inhibition and excitation of the central nervous system [1–10].

Thus, topiramate is an activator of the turnover of the biogenic amino acid GABA (γ-aminobutyric acid - GABA), the main inhibitory transmitter of the neural system, through positive selective modulation of GABAA receptors. Topiramate opens voltage-dependent chloride and bicarbonate ion entry channels, which activates the benzodiazepine and barbiturate sites of GABAA, acting similarly to benzodiazepines and barbiturates. At the same time, the drug inhibits the action of glutamate (a nonessential amino acid), a basic excitatory neurotransmitter. Topiramate blocks voltage-dependent channels for the entry of sodium and calcium ions, thereby inactivating two main glutamate receptors - kainate (affinity for kainate acid) and AMPA (affinity for α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) , responsible for excitation processes in the synaptic system. At the same time, topiramate does not increase or slightly decreases the activity of the third type of glutamate receptors - NMDA (N-methyl-D-aspartate-dependent), which mediates the excitatory effect of glutamate and is a prolongator of excitation processes in neurons. The inhibitory effect on glutamate metabolism, like that of topiramate, is the basis for the neuromodulatory effect of carbamazepine and valproic acid derivatives.

In addition to the noted effect, topiramate selectively affects the system of carbonic anhydrase enzymes (CA), blocking CA II (cytoplasmic carbonic anhydrase) and CA IV (cytoplasmic membrane carbonic anhydrase). These enzymes have a nonspecific diuretic effect due to the deactivation of kidney carbonic anhydrases, reduce the formation of cerebrospinal fluid and intracranial pressure and suppress the activity of glutamate receptors by eliminating interneuronal sodium and calcium ions, which helps to weaken excitatory processes in the central nervous system. A similar mechanism of action, in a more dramatic form, is inherent in the drug acetazolamide (diacarb), which blocks all carbonic anhydrases.

It is worth noting that GABA is formed from glutamate through glutamate decarboxylase, and glutamate itself is a derivative of glutamine, one of twenty amino acids that enter the body with food. However, glutamine and its derivatives do not cross the blood-brain barrier, and all glutamate in the CNS is synthesized in neurons.

Clinical use of topiramate began in 1995, first as an adjunctive drug and then as a primary treatment for the treatment and prevention of epileptic seizures in almost all types of paroxysmal conditions. This was facilitated by the pharmacokinetics of topiramate: bioavailability of 81% independent of food intake, linear dependence of blood concentration on daily dosage, constant plasma clearance independent of dose, stable concentration leveling time for 5–8 days. The half-life (T1/2) is 21 hours; when utilized by liver enzymes, topiramate forms inactive metabolites, which are excreted mainly through the kidneys. Such features mean the possibility of use at any age with once or twice a day, ease of dose selection without the use of plasma monitoring, the absence of a cumulative effect and the possibility of quickly cleansing the body by hemodialysis [10–12].

Research into the effectiveness of topiramate as monotherapy began with a number of studies from 1997–2002. In different groups of patients ranging from 22 to 292 people, topiramate was prescribed at a dose of 100 to 1,600 mg for the treatment of partial and generalized seizures for 3 to 13 months. It turned out that after 6 months of treatment, the proportion of respondents (DR) with a reduction of attacks > 50% was 46–58%, DR with a reduction > 75% was 25–37%, DR with a reduction of 100% was 11–13%. At the same time, a more pronounced therapeutic effect of topiramate was found in initially identified patients - DR with a reduction of 100% of seizures to 60%, and in cases of resistance to previously carried out treatment of generalized seizures - DR with a reduction of 100% reached 35%. Moreover, a dosage of 1,000 mg was noticeably more effective than 100 mg [13–18].

Further study of the effectiveness of topiramate was developed in the use of the drug in childhood epilepsy, especially in its most severe forms. The latter include West syndrome (West - “infantile” spasm or “Saalam” convulsions with characteristic partial paroxysms in the form of “nods”), Lennox-Gastaut (Lennox-Gastaut - polymorphic seizures with severe encephalopathy and developmental delay), Rett (Rett - generalized tonic-clonic seizures, motor stereotypies, pronounced psychophysical regression, respiratory disorders in girls), Landau-Kleffner (Lan-dau-Kleffner - partial motor seizures, aphasia, autism with aggressiveness), Dravet syndrome (Dravet - severe myoclonic epilepsy of infancy ). In the majority of children (60–86%), topiramate reduced the number of seizures in >50%, and D. Ormrod and K. McClellan achieved remission in 31% of cases. Better control was achieved over atypical absence seizures, atonic, clonic and generalized tonic-clonic seizures, as well as breathing disorders [19–27].

The effectiveness of Topamax was further studied in long-term studies using a double-blind, randomized method in adult patients with partial and generalized epilepsy.

In partial epilepsy, long-term treatment with topiromate for 1 to 5 years resulted in a >50% reduction in seizures in 27–52% of cases, with complete reduction occurring in only 0–10% of patients [28–31].

More significant results were achieved when topiramate was used in adult patients with generalized seizures. A decrease in the number of paroxysmal states with full-blown convulsive states by > 50% was observed in 45–60% of cases, stable remission with complete disappearance of seizures was achieved in 20–35% of patients. All observations were characterized by a simplification and reduction in the duration of prodromal symptoms, a reduction in the structure and a reduction in the time of paroxysmal states, the disappearance of post-convulsant disorders, as well as the relief of concomitant productive mental disorders. Topiramate has especially been indicated for use in severe conditions such as juvenile myoclonic epilepsy and idiopathic generalized epilepsy [32–38].

Topiramate is also used in combination with other antiepileptic drugs, and topiramate itself does not affect these drugs, but its combination with carbamazepine, phenytoin (diphenin), felbamate leads to a decrease in the concentration of topiramate in the blood. This is due to the activation of liver enzymes by carbamazepine and other indicated drugs, the acceleration of topiramate utilization and a decrease in blood concentrations by more than 50%. In such cases, it is recommended to increase the dose of topiramate to 400 mg [34, 39].

In addition to the anticonvulsant effect, topiramate also exhibits other effects. These include neuroprotective effects, psychotropic activity, effects on body weight, treatment of migraines and the possibility of use in drug-dependent conditions.

The neuroprotective effect was identified in models of various CNS lesions, such as middle cerebral artery embolism, perinatal hypoxia, non-traumatic chest compression, bilateral occlusion of the carotid arteries, which is associated with activation of the GABAergic system. Topiramate has been successfully used to treat essential tremor, and in patients with epilepsy taking the drug, a slowdown in the rate of epileptic personality changes and intellectual-mnestic decline was noted [40–44].

The psychotropic effect of topiramate is also due to its effect on the GABAergic and glutamateergic systems and is determined by a general nonspecific balanced sedative-activating effect, acting primarily on dysthymic disorders in epilepsy. The ability of topiramate to smooth out bipolar affective disorders, especially with their rapid cyclicity, has also been revealed, and it, still in rare cases, is used as a mood stabilizer in both depression and mania [39, 45–48].

A special property of topiramate is weight loss. This phenomenon is based on a selective reduction in the formation and accumulation of lipids in adipose tissue and is observed in approximately 17% of patients at high dosages of the drug. Thus, taking topiramate at a dose of 200 mg caused a decrease in body weight by 1 kg, and at a dose of 800 mg - by 6 kg. Weight loss is perceived ambiguously and is interpreted by some authors as an undesirable side effect, and by others as a positive effect in cases of concomitant endocrine diseases accompanied by obesity. The ability to reduce body weight of topiramate is dose-dependent and is completely reversible with a decrease in drug intake [24, 49–51].

Along with this, there are reports of non-specific use of topiramate in healthy people without epileptic disorders as a means for weight loss. In particular, athletes began to use it to quickly reduce body weight before competitions [www.SciTecLibrary.ru, www.Ironworld.ru].

There are indications of the possibility of using topiramate for migraine. Thus, a 26-week randomized, double-blind, placebo-controlled study was conducted in 487 patients. Topiramate at a dose of 100–200 mg reduced the frequency of migraine attacks by >50% in more than half of patients [52].

Topiramate has a positive effect on drug addiction, which has been shown in a number of studies. Thus, the effect of topiramate at a dose of 100 mg, 25 mg 4 times a day was studied in 127 patients with alcohol withdrawal syndrome. Topiramate statistically significantly reduced anxiety, depressive symptoms, sleep disorders, relieved the desire for alcohol, and also stopped tremor and astheno-vegetative disorders. According to the researcher, the basis was the antiglumatoergic mechanism of action of topiramate [53, 54].

There are reports of the ability of topiramate to reduce cravings for alcohol not only in the periods between alcohol intakes, but also during binge drinking. B. Johson (2003), director of research on alcoholism and drug addiction at the University of Texas, noted the significant effectiveness of topiramate, outstripping the effect of naltrexone and acaprosate [www.Inopressa.ru].

In Russia, topiramate is represented by the following trade names: Toreal - tablets 25 and 100 mg No. 28 (ZAO Lekko FF, Russia), Maksitopir - tablets 50 and 100 mg No. 10 (Actavis hf, Iceland), Topsaver 25 and 100 mg No. 28 ( Pliva Hrvatska doo, Croatia) and Topamax capsules 15, 25 and 50 mg No. 60, tablets 25 and 100 mg No. 28 (Janssen Cilag Pharmaceutica NV, Belgium).

It is important to consider that the prescription of an antiepileptic drug is usually a permanent, sometimes lifelong factor in which economic characteristics come to the fore.

If we compare the most common drugs - Topsaver and Topamax - according to their pharmacoeconomic indicators under the conditions that the daily effective maintenance dose of topiramate is 200 mg per day, and the most convenient form is 100 mg tablet No. 28, then the following results are obtained. The cost of a daily dose of Topsaver ranges from 73.98 to 93.57 rubles, with an average of 83.78 rubles. – the first ten offers in the Moscow pharmacy chain, and monthly from 2,219.40 to 2,807.10 rubles, on average 2,513.40 rubles. For Topamax, these figures will range from 165.21 to 185.00 rubles, with an average of 175.11 rubles. – daily dose, from 4,956.30 to 5,550.00 rubles, on average 5,253.30 rubles. – monthly (www.apteka.mos.ru).

The difference of more than two undoubtedly speaks in favor of Topsaver, which can become a leading drug not only for epilepsy, but also for other conditions. Particularly significant is the fact that the cost of a monthly dose of the Croatian drug is lower than the psychologically acceptable amount of 3,000 rubles/month.

As for side effects, at the initial stages of starting to take topiramate, dizziness, fatigue, difficulty thinking, headache and confusion most often appear. In most cases, this occurs with rapid increases in topiramate doses.

In this regard, treatment should begin with 25-50 mg per day and then slowly titrate the dose by 25-50 mg in weekly increments until reaching 200 mg per day. Usually this dose is divided into two doses of 100 mg. For monotherapy, the effective dose is 200 mg, although in some patients it may be 100 mg per day. When topiramate is combined with other anticonvulsants, especially carbamazepine and phenytoin, the effective dose is at least 400 mg per day.

For most patients, the daily effective dose is in the range of 200–600 mg, and the maximum tolerated dose in some patients is 1600 mg per day [55].

It is important to note that topiramate does not have a number of serious side effects characteristic of other antiepileptic drugs. Thus, the absence of any effect on the hormonal system in women and the risk of developing polycystic ovary syndrome, characteristic of valproate, significantly expands the possibilities of using topiramate in women, especially of reproductive age. This drug also has virtually no risk of allergic reactions, which can become a serious clinical problem during lamotrigine therapy [55–58].

In conclusion, we can emphasize the main features of the drug topiramate.

1. Topiramate has the entire spectrum of antiepileptic activity and includes the action of all known anticonvulsants.

2. Topiramate can be used as monotherapy for any type of seizure and at any age.

3. Topiramate is effective even in the most unfavorable types of epilepsy and in cases of resistance to most anticonvulsants.

4. Topiromate is easy to administer and has linear pharmacokinetics, although it requires caution when gradually increasing (titrating) the dosage.

5. Side effects during topiromate therapy are not too serious and are dose-dependent, which makes it possible to get rid of undesirable effects by adjusting the dosage of the drug.

6. Topiromate, along with the antiepileptic effect, has a number of somatotropic, neurotropic and psychotropic properties, which not only facilitates the course of diseases with paroxysmal conditions, but also allows its use for disorders that are far from epilepsy.

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