World experience in the use of topiramate (literature review)

Nosological classification (ICD-10)

• G40 Epilepsy
• G40.1 Localized (focal) (partial) symptomatic epilepsy and epileptic syndromes with simple partial seizures
• G40.2 Localized (focal) (partial) symptomatic epilepsy and epileptic syndromes with complex partial seizures
• G40.4 Other types of generalized epilepsy and epileptic syndromes
• G40.6 Grand mal seizures, unspecified [with or without petit mal seizures]
• G43 Migraine

Compound

Description of the dosage form

Capsules, 15 mg: hard gelatin No. 2, consisting of a white body and a transparent colorless cap. The cap of the capsule bears the inscription “TOP”. The capsule body bears the inscription “15 mg”.

Capsules, 25 mg: hard gelatin No. 1, consisting of a white body and a transparent colorless cap. The cap of the capsule bears the inscription “TOP”. On the body of the capsule there is the inscription “25 mg”.

Capsules, 50 mg: hard gelatin capsules No. 0, consisting of a white body and a transparent colorless cap. On the cap of the capsule there is an inscription in black ink “TOP”. On the body of the capsule there is an inscription in black ink “50 mg”.

Capsule contents: white or almost white granules.

Pharmacodynamics

Topiramate is an antiepileptic drug belonging to the class of sulfamate-substituted monosaccharides. Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of GABA in relation to certain subtypes of GABA receptors (including GABAA receptors), and also modulates the activity of GABAA receptors themselves, and prevents the activation by kainate of the sensitivity of the kainate/AMPK subtype (α-amino-3-hydroxy-5- Methylisoxazole-4-propionic acid) glutamate receptors do not affect the activity of N-methyl-D-aspartate (NMDA) at the NMDA receptor subtype. These effects of topiramate are dose-dependent at drug plasma concentrations ranging from 1 to 200 µM, with trough activity ranging from 1 to 10 µM. In addition, topiramate inhibits the activity of some carbonic anhydrase isoenzymes. In terms of the severity of this pharmacological effect, topiramate is significantly inferior to acetazolamide, a known inhibitor of carbonic anhydrase, therefore this activity of topiramate is not considered the main component of its antiepileptic activity.

Topamax® (Topamax®)

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

Concomitant use of the drug Topamax® with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect the values ​​of their equilibrium concentrations in plasma, with the exception of certain patients in whom the addition of the drug Topamax® to phenytoin may cause an increase in the concentration of phenytoin in the plasma. plasma. This may be due to the inhibition of a specific polymorphic isoform of the cytochrome P450 enzyme (CYP2Cmeph). 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 steady-state concentration of the latter at doses of topiramate 100-400 mg per day. During and after discontinuation of lamotrigine (average dose 327 mg per day), the equilibrium concentration of topiramate did not change.

Effect of other antiepileptic drugs 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 the following table:

↔ = No effect

** = Increased concentration in isolated patients

↓ = Decrease in plasma concentration

NI = Not studied

AED = antiepileptic drug

Other drug interactions

Digoxin:

In a single-dose study, the area under the breakthrough bleeding curve should be taken into account in patients taking oral contraceptives in combination with Topamax®. Patients taking estrogen-containing contraceptives should be informed of any changes in the timing and nature 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 per day. In patients with manic-depressive psychosis, the use of topiramate in doses up to 200 mg per day did not affect the pharmacokinetics of lithium, however, at higher doses (up to 600 mg per 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 conducted with single and multiple doses of topiramate in healthy volunteers and patients with bipolar disorder yielded similar results. With simultaneous use of topiramate in doses of 250 or 400 mg per day, the AUC of risperidone, taken in doses of 1-6 mg per 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 administration of hydrochlorothiazide (25 mg) and topiramate (96 mg). The results of the studies showed that with simultaneous administration of topiramate and hydrochlorothiazide, there is an increase in the maximum concentration of topiramate by 27% and the area under the curve "conkonkonkoncon" This adverse reaction is not due to a pharmacokinetic interaction.

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 either after starting to take valproic acid and topiramate together, or when the daily dose of topiramate is increased.

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 the following table:

a is expressed as a percentage of the values ​​of maximum plasma concentration and AUC during monotherapy

↔ = No change in maximum plasma concentration and AUC (≤15% of baseline data)

b A 14% increase in AUC was observed with multiple doses of flunarizine alone, which may be due to drug accumulation during steady state.

Pharmacokinetics

Topiramate is absorbed quickly and efficiently. Its bioavailability is 81%. Food intake does not have a clinically significant effect on the bioavailability of topiramate. 13–17% of topiramate is bound to plasma proteins. After a single dose of up to 1200 mg, 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.

After oral administration, about 20% of the dose taken is metabolized. However, in patients receiving concomitant therapy with antiepileptic drugs that induce enzymes responsible for drug metabolism, the metabolism of topiramate increases up to 50%. Six essentially inactive metabolites have been isolated and identified from human plasma, urine, and feces. The main route of elimination of unchanged topiramate (70%) and its metabolites is the kidneys. After oral administration, plasma clearance of topiramate is 20–30 ml/min. The pharmacokinetics of topiramate is linear, plasma clearance remains constant, and AUC in the dose range from 100 to 400 mg increases in proportion to the dose. In patients with normal renal function, it may take 4 to 8 days to achieve steady-state plasma concentrations. The Cmax value after repeated oral administration of 100 mg of the drug twice a day averaged 6.76 mcg/ml. After multiple doses of 50 and 100 mg twice daily, T1/2 of topiramate from plasma averaged 21 hours.

In patients with moderate to severe renal impairment, the plasma and renal clearance of topiramate is reduced (Cl creatinine <70 ml/min), as a result, the Css of topiramate in the blood plasma may increase compared to patients with normal renal function. In addition, patients with impaired renal function take longer to reach Css of topiramate in the blood. In patients with moderate or severe renal impairment, half the recommended initial and maintenance dose is recommended. Topiramate is effectively eliminated from plasma by hemodialysis. Long-term hemodialysis may result in a decrease in blood concentrations of topiramate below the amount required to maintain anticonvulsant activity. To avoid a rapid fall in plasma concentrations of topiramate during hemodialysis, an additional dose of Topamax may be required. When adjusting the dose, you should take into account:

- duration of hemodialysis;

— the clearance value of the hemodialysis system used;

- effective renal clearance of topiramate in a patient on dialysis.

Plasma clearance of topiramate is reduced by an average of 26% in patients with moderate or severe hepatic impairment. Therefore, patients with hepatic impairment should use topiramate with caution.

In elderly patients without renal disease, the plasma clearance of topiramate does not change.

Pharmacokinetics of topiramate in children under 12 years of age. The pharmacokinetic parameters of topiramate in children, as in adults receiving this drug as adjuvant therapy, are linear, while its clearance does not depend on the dose, and Css in plasma increases in proportion to the dose. One should take into account the fact that in children the clearance of topiramate is increased and its T1/2 is shorter. Therefore, at the same dose per 1 kg of body weight, plasma concentrations of topiramate in children may be lower than in adults. In children, as in adults, antiepileptic drugs that induce liver microsomal enzymes cause a decrease in plasma concentrations of topiramate.

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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Topiramate in severe treatmen-trefractory mania [Abstract] // Proc. 151st Ann Meet American Psychiatric Association. 1998: 121–122. 48. Vieta E. Anticonvulsants and bipolar disorder: impact on mood and body weight // Neuroscience in action: from clinical dilemma to therapeutic breakthrough, Hamburg, Germany, 2223 March 2002 Program and abstract book: P. 40. 49. Fedin A. I., Generalov V.O., Mishnyakova L.P. Topiramate in the treatment of epilepsy in adults. // Bulletin of epileptology. 2006: 1: 3–5. 50. Loiseau P. Tolerability of newer and older antiepileptic drugs: a comparative review // CNS Drugs. 1996: 6: 148–166. 51. Shorvon S., Stefan H. Overview of the Safety of newer antiepileptic drugs // Epilepsia. 1997: 38: Suppl 1: 45–51. 52. Stephen D. Silberstein, Walter Neto, Jennifer Schmitt, David Jacobs, for the MTGR–001 Study Group. Topiramate in the prevention of migraine: results of a large controlled trial (abstract). // Cardiology. 2004: 14: 91. 53. Rudenko A. The pilot study of topiromate for alcohol withdrawal syndrome / E. Krupitsky, A. Rudenko, E. Zvartau, T. Slavina, A Grinenko // Alcohol and Alcoholism. 2003: 38: 5: 508 – 509. 54. Rudenko A.A. Antiglutamatergic drugs in the treatment of alcohol withdrawal syndrome: a double-blind placebo-controlled pilot study of lamotrigine, memantine and topiramate / E.M. Krupitsky, A.A. Rudenko, A.M. Burakov, E.E. Zvartau, T.Yu. Slavina, A.Ya. Grinenko, D.Kh. Crystal. Abstracts of the International Workshop “Pharmacotherapy of Drug Addictions: Basic and Clinical Research”. St. Petersburg 2003: 13–14. 55. Sander J. Practical aspects of the use of topiramate in patients with epilepsy // Epilepsia. 1997: 38: Suppl 1: 56–58. 56. Karlov V.A. Strategy and tactics of epilepsy treatment today // J. neurol. psychiatrist 2004: 104: 8: 28–34. 57. Guberman AH, Besag FMC, Brodie MJ et al. Lamotrigine-associated rash: risk/benefit considerations in adults and children // Epilepsia. 1999:40:985–991. 58. Latini G., Verrotti A., Manco R. et al. Topiramate: its pharmacological properties and therapeutic efficacy in epilepsy // Mini Rev. Med. Chem. 2008: 8:10–23

Indications for Topamax®

epilepsy:

- as a monotherapy in adults and children over 2 years of age with epilepsy (including patients with newly diagnosed epilepsy);

- as part of complex therapy: in adults and children over 2 years of age with partial or generalized tonic-clonic seizures, as well as for the treatment of seizures associated with Lennox-Gastaut syndrome.

migraine:

- prevention of migraine attacks in adults. The use of Topamax® for the treatment of acute migraine attacks has not been studied.

Use during pregnancy and breastfeeding

There have been no special controlled studies in which Topamax® was used to treat pregnant women. Topiramate may cause fetal harm when used in pregnant women. Pregnancy data indicate that infants exposed to topiramate in utero have an increased risk of developing congenital malformations (eg, craniofacial defects such as cleft lip or palate, hypospadias, and developmental anomalies of various body systems). These malformations were recorded both during monotherapy with topiramate and when it was used as part of polytherapy.

Compared with the group of patients not taking antiepileptic drugs, data from pregnancies during monotherapy with Topamax® indicate an increased likelihood of having children with low body weight (less than 2500 g). The connection between the observed phenomena and the use of the drug has not been established.

In addition, pregnancy records and the results of other studies indicate that the risk of developing teratogenic effects with combination treatment with antiepileptic drugs is higher than with monotherapy.

The use of Topamax® during pregnancy is justified only if the potential benefit of the drug for the mother outweighs the possible risk to the fetus. When treating and counseling women of childbearing potential, the treating physician must weigh the benefits and risks of treatment and consider alternative treatment options. If Topamax® is used during pregnancy or the patient becomes pregnant while taking this drug, she should be warned of the potential risk to the fetus.

A limited number of patient observations suggests that topiramate is excreted in breast milk in women, so the physician should decide whether to breastfeed or discontinue the drug.

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.

Side effects

Side effects are given with a distribution by frequency and organ system. The frequency of side effects was classified as follows: very common (≥1/10); frequent (≥1/100, <1/10); uncommon (≥1/1000 and <1/100); rare (≥1/10000 and <1/1000) and very rare (<1/10000).

The most common adverse reactions (the frequency of which was more than 5% and higher than that in the placebo group for at least one of the indications during controlled clinical trials of topiramate) are: anorexia, decreased appetite, slow thinking, depression, impaired speech fluency, insomnia, disturbances coordination of movements, impaired concentration, dizziness, dysarthria, dysgeusia, hypoesthesia, retardation, memory impairment, nystagmus, paresthesia, drowsiness, tremor, diplopia, blurred vision, diarrhea, nausea, fatigue, irritability and weight loss.

Infections and infestations: very often - nasopharyngitis.

From the blood and lymphatic system: often - anemia; uncommon - leukopenia, lymphadenopathy, thrombocytopenia, eosinophilia; rarely - neutropenia*.

From the immune system: often - hypersensitivity; frequency unknown - allergic edema*, conjunctival edema*.

From the side of metabolism and nutrition: often - anorexia, loss of appetite; uncommon - metabolic acidosis, hypokalemia, increased appetite, polydipsia; rarely - hyperchloremic acidosis.

Mental disorders: very often - depression; often - slow thinking, insomnia, impaired speech, anxiety, confusion, disorientation, aggressive reactions, mood disorders, agitation, emotional lability, depressed mood, anger, behavioral disturbances; uncommon - suicidal thoughts, suicide attempts, hallucinations, psychotic disorders, auditory hallucinations, visual hallucinations, apathy, difficulty speaking, sleep disturbances, affective lability, decreased libido, restlessness, crying, dysphemia, euphoric mood, paranoia, perseveration of thinking, panic attacks , tearfulness, impaired reading skills, difficulty falling asleep, flattening of emotions, pathological thinking, loss of libido, lethargy, intrasomnic disorder, absent-mindedness, early awakenings in the morning, panic reactions, high spirits; rarely - mania, panic disorder, feelings of hopelessness*, hypomania.

From the side of the central nervous system: very often - paresthesia, drowsiness, dizziness; often - impaired concentration, memory impairment, amnesia, cognitive disorders, impaired thinking, psychomotor impairment, convulsions, impaired motor coordination, tremor, lethargy, hypoesthesia, nystagmus, dysgeusia, impaired sense of balance, dysarthria, intention tremor, sedation; uncommon - depressed consciousness, tonic-clonic grand mal seizures, visual field impairment, complex partial seizures, speech impairment, psychomotor hyperactivity, fainting, sensory disturbances, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness , low quality of sleep, burning sensation, loss of sensitivity, parosmia, cerebral syndrome, dysesthesia, hypogeusia, stupor, clumsiness, aura, ageusia, dysgraphia, dysphasia, peripheral neuropathy, presyncope, dystonia, pins and needles sensation; rarely: apraxia, circadian sleep rhythm disorder, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli.

From the organ of vision: often - blurred vision, diplopia, visual impairment; uncommon - decreased visual acuity, scotoma, myopia*, strange sensations in the eyes*, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsia, mydriasis, presbyopia; rarely - one-sided blindness, transient blindness, glaucoma, impaired accommodation, impaired visual spatial perception, atrial scotoma, eyelid edema*, night blindness, amblyopia; frequency unknown: angle-closure glaucoma*, maculopathy*, ocular motility disorders*.

From the organ of hearing and balance: often - vertigo, ringing in the ears, pain in the ear; uncommon: deafness, one-sided deafness, sensorineural deafness, ear discomfort, hearing impairment.

From the cardiovascular system: infrequently - bradycardia, sinus bradycardia, palpitations.

From the vascular system: infrequently - hypotension, orthostatic hypotension, hot flashes, hot flushes; rarely - Raynaud's phenomenon.

From the respiratory system, chest and mediastinal organs: often - shortness of breath, nosebleeds, nasal congestion, rhinorrhea, cough *; infrequently - shortness of breath on exertion, hypersecretion in the paranasal sinuses, dysphonia.

From the gastrointestinal tract: very often - nausea, diarrhea; often - vomiting, constipation, pain in the epigastric region, dyspepsia, abdominal pain, dry mouth, stomach discomfort, impaired sensitivity in the oral cavity, gastritis, abdominal discomfort; uncommon - pancreatitis, flatulence, gastroesophageal reflux, pain in the lower abdomen, decreased sensitivity in the oral cavity, bleeding gums, bloating, discomfort in the epigastric region, tenderness in the abdominal area, hypersalivation, pain in the oral cavity, bad breath, glossodynia .

From the hepatobiliary system: rarely - hepatitis, liver failure.

From the skin and subcutaneous tissues: often - alopecia, rash, itching; uncommon - anhidrosis, impaired sensitivity in the facial area, urticaria, erythema, generalized itching, macular rash, skin pigmentation disorder, allergic dermatitis, facial swelling; uncommon - Stevens-Johnson syndrome*, erythema multiforme*, change in skin odor, periorbital edema*, localized urticaria; frequency unknown - toxic epidermal necrolysis*.

From the musculoskeletal system and connective tissue: often - arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, musculoskeletal pain in the chest; uncommon: joint swelling*, muscle stiffness, side pain, muscle fatigue; rarely: discomfort in the limbs*.

From the kidneys and urinary tract: often - nephrolithiasis, pollakiuria, dysuria; uncommon - exacerbation of urolithiasis (kidney stones), stress urinary incontinence, hematuria, urinary incontinence, frequent urge to urinate, renal colic, pain in the kidney area; rarely - exacerbation of urolithiasis (stones in the urethra), renal tubular acidosis*.

From the genital organs and breast: uncommon - erectile dysfunction, sexual dysfunction.

General disorders and disorders caused by the method of application: very often - fatigue; often - increased body temperature, asthenia, irritability, gait disturbances, poor health, anxiety; uncommon - hyperthermia, thirst, flu-like syndrome*, slowness, cold extremities, feeling of intoxication, feeling of anxiety; rarely - facial swelling, calcification.

Changes in laboratory parameters: very often - loss of body weight; often - weight gain*; infrequently - crystalluria, abnormal result of the tandem gait test, leukopenia, increased activity of liver enzymes in the blood serum, rarely - a decrease in the content of bicarbonates in the blood.

Impaired social functioning: uncommon - learning disability.

*adverse reaction was registered in the post-registration period from spontaneous reports. Frequency calculated based on data from clinical studies.

Special groups:

Children

A list of adverse reactions that, during controlled clinical trials, were recorded in children 2 or more times more often than in adults: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disorders, aggressive reactions, apathy, difficulty falling asleep, suicidal thoughts, disorder concentration, lethargy, disruption of the circadian rhythm of sleep, poor quality of sleep, increased lacrimation, sinus bradycardia, poor health, gait disturbances.

List of adverse reactions that were recorded only in children during controlled clinical trials: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, learning disability.

Topamax

Use during pregnancy and breastfeeding

There have been no specific controlled studies in which Topamax® was used to treat pregnant women.
Topiramate may cause fetal harm when used in pregnant women. Pregnancy data indicate that infants exposed to topiramate in utero have an increased risk of developing congenital malformations (eg, craniofacial defects such as cleft lip or palate, hypospadias, and developmental anomalies of various body systems). These malformations were recorded both during monotherapy with topiramate and when it was used as part of polytherapy.

Compared with the group of patients not taking antiepileptic drugs, data from pregnancies during monotherapy with Topamax® indicate an increased likelihood of having children with low body weight (less than 2500 g). The connection between the observed phenomena and the use of the drug has not been established. In addition, pregnancy records and the results of other studies indicate that the risk of developing teratogenic effects with combination treatment with antiepileptic drugs is higher than with monotherapy.

The use of Topamax® during pregnancy is justified only if the potential benefit of therapy for the mother outweighs the possible risk to the fetus.

When treating and counseling women of childbearing potential, the treating physician must weigh the benefit versus risk of treatment and consider alternative treatment options.

If Topamax® is used during pregnancy, or if the patient becomes pregnant while taking the drug, she should be warned of the potential risk to the fetus.

A limited number of observations suggest that topiramate is excreted into breast milk in women. If it is necessary to use the drug Topamax® during lactation, the issue of stopping breastfeeding or stopping taking the drug should be decided.

Use for liver dysfunction

Use with caution in case of liver failure. In patients with moderate to severe liver dysfunction, plasma clearance is reduced.

Use for renal impairment

When prescribing the drug to patients with moderate or severely impaired renal function, it should be taken into account that it may take 10-15 days to achieve an equilibrium state in this category of patients, in contrast to 4-8 days in patients with normal renal function. Since topiramate is removed from the plasma during hemodialysis, on the days of hemodialysis an additional dose of the drug should be prescribed equal to half the daily dose in 2 doses (before and after the procedure).

It should be used with caution in case of renal failure, nephrourolithiasis (including in the past or family history), and hypercalciuria.

Use in children

The drug is contraindicated for use in children under 2 years of age.

special instructions

Topamax® (like other antiepileptic drugs) should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures. In clinical studies, the dose of the drug was reduced by 50-100 mg once a week - for adults during the treatment of epilepsy and by 25-50 mg - in adults receiving Topamax® at a dose of 100 mg / day for the prevention of migraine. In children in clinical studies, Topamax® was gradually withdrawn over 2-8 weeks. If, for medical reasons, rapid discontinuation of Topamax® is necessary, it is recommended to appropriately monitor the patient’s condition.

As with any disease, dosing schedules should be based on clinical benefit (i.e., degree of seizure control, absence of side effects) and take into account that in patients with renal impairment, it may be necessary to achieve a stable plasma concentration for each dose. it will take longer.

During therapy with topiramate, oligohidrosis (decreased sweating) and anhidrosis may occur. Decreased sweating and hyperthermia (increased body temperature) may occur in children exposed to high ambient temperatures. When treating with topiramate, it is very important to adequately increase the volume of fluid intake, which helps reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical activity or elevated temperatures.

An increased incidence of mood disorders and depression has been observed during treatment with topiramate.

When using antiepileptic drugs, including Topamax®, the risk of suicidal thoughts and behavior increases in patients taking these drugs for any indication.

In double-blind clinical studies, the incidence of suicide-related events (suicidal thoughts, suicide attempts, suicide) was 0.5% in patients receiving topiramate (46 out of 8652 people), which is approximately 3 times higher compared to patients treated with topiramate. those receiving placebo (0.2%; 8 people out of 4045). One case of suicide was reported in a double-blind study of bipolar disorder in a patient receiving topiramate.

Thus, it is necessary to monitor patients for signs of suicidal ideation and prescribe appropriate treatment. Patients (and, if appropriate, caregivers) should be advised to seek immediate medical attention if signs of suicidal thoughts or behavior occur.

Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of developing kidney stones and associated symptoms such as renal colic. To reduce this risk, an adequate increase in fluid intake is necessary. Risk factors for the development of nephrolithiasis are a history of nephrolithiasis (including family history), hypercalciuria, and concomitant therapy with other drugs that contribute to the development of nephrolithiasis.

Caution should be exercised when prescribing Topamax® to patients with renal failure (creatinine clearance <70 ml/min). This is due to the fact that in such patients the clearance of the drug is reduced.

In patients with impaired liver function, Topamax should be used with caution due to a possible decrease in the clearance of topiramate.

When using the drug Topamax®, a syndrome has been described that includes acute myopia with concomitant secondary angle-closure glaucoma. Symptoms include acute loss of visual acuity and/or eye pain. An ophthalmological examination may reveal myopia, flattening of the anterior chamber of the eye, hyperemia (redness) of the eyeball, and increased intraocular pressure. Mydriasis may occur. This syndrome may be accompanied by fluid secretion, leading to forward displacement of the lens and iris with the development of secondary angle-closure glaucoma. Symptoms usually appear 1 month after starting Topamax®. Unlike primary open-angle glaucoma, which is rarely observed in patients under 40 years of age, secondary angle-closure glaucoma is observed with the use of topiramate in both adults and children. If a syndrome involving myopia associated with angle-closure glaucoma occurs, treatment includes discontinuation of Topamax® as soon as deemed possible by the attending physician and appropriate measures aimed at lowering intraocular pressure. Typically, these measures lead to normalization of intraocular pressure.

Increased intraocular pressure of any etiology in the absence of adequate treatment can lead to serious complications, including loss of vision.

When topiramate is used, hyperchloremic, non-anion deficiency, metabolic acidosis (eg, a decrease in plasma bicarbonate concentrations below normal levels in the absence of respiratory alkalosis) may occur. This decrease in serum bicarbonate concentrations is a consequence of the inhibitory effect of topiramate on renal carbonic anhydrase. In most cases, a decrease in bicarbonate concentrations occurs at the beginning of the drug, although this effect can occur at any time during treatment with topiramate. The level of decrease in concentration is usually weak or moderate (the average value is 4 mmol/l when used in adult patients at a dose of more than 100 mg/day and about 6 mg/kg/day when used in pediatric practice). In rare cases, patients experienced a decrease in concentration below 10 mmol/l. Certain medical conditions or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory disease, status epilepticus, diarrhea, surgery, ketogenic diet, certain medications) may be additive factors that enhance the bicarbonate-lowering effect of topiramate.

In children, chronic metabolic acidosis can lead to growth retardation. The effects of topiramate on growth and possible complications related to the skeletal system have not been systematically studied in children and adults.

In connection with the above, when treating with topiramate, it is recommended to carry out the necessary studies, including determination of the concentration of bicarbonate in the serum. If metabolic acidosis occurs and persists, it is recommended to reduce the dose or stop taking Topamax®.

If, while taking Topamax®, the patient’s body weight decreases, then the advisability of increased nutrition should be considered.

Impact on the ability to drive vehicles and operate machinery

Topamax® acts on the central nervous system and may cause drowsiness, dizziness, blurred vision and other symptoms. These adverse effects may pose a danger to patients who drive cars and operate machinery, especially until the patient's response to the drug is established.

Interaction

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.

Experience with the use of topiramate in children and adults

In the last decade, many new original antiepileptic drugs (AEDs) have been synthesized, which are included in the daily clinical practice of both pediatric and adult epileptologists. The main goal of modern pharmacology in the treatment of epilepsy is to create an “ideal” drug that suppresses not only seizures, but also has a true antiepileptogenic effect with a maximum efficacy/tolerability ratio. The increase in the number of AEDs significantly expands the possibilities in the treatment of epilepsy, especially in drug-resistant forms, and at the same time puts the doctor in a difficult position in choosing an adequate drug. The situation gets worse with the advent of each new drug, since patients with drug-resistant epilepsy may experience transient improvement after taking each of the newly prescribed AEDs, and this creates the illusion of their effectiveness. At the same time, only the accumulation of experience in the use of these drugs makes it possible to expand the group of AEDs. New drugs showed better tolerability, lower potential for interaction with other AEDs; in addition, they are easier to use. One such drug is topiramate (Topamax).

Topamax belongs to the class of sulfamate-substituted monosaccharides. The action of the drug is due to several mechanisms: blockade of voltage-dependent calcium and sodium channels (preventing the activation of GABAergic transmission), suppression of excitation mediators (glutamate), inhibition of carbonic anhydrase. Thus, the imbalance of the inhibitory GABAergic and excitatory glutamatergic systems is corrected. Thanks to this effect, the range of use of the drug for various forms of epilepsy, both in the form of mono- and as part of complex therapy, is expanding.

Topamax is characterized by linear pharmacokinetics and rapid absorption; at doses up to 200 mg/day it is not metabolized in the liver. Since the half-life is approximately 21 hours, the optimal dose is 1-2 times a day, regardless of meals. Topamax has no effect on the concentration of other AEDs, which, in turn, do not affect its therapeutic activity. The disadvantages of Topamax include slow titration. The “therapeutic window” of the drug is very wide - from 2 to 10 mg/kg/s. In children, the clearance of topiramate is increased and the half-life is shorter. Therefore, at the same dose per 1 kg of body weight, plasma concentrations of Topamax in children may be lower. In this regard, it is necessary to select higher doses compared to adults - up to 15 mg/kg/s. It should be emphasized that Topamax is classified in the third group of AEDs in terms of potential teratogenic effects, i.e., it has minimal teratogenicity (LE Leppic, 2001).

Publications by domestic authors note the promise of using the drug in the treatment of children and adults. Foreign doctors have extensive experience in using Topamax in the form of mono- and add-therapy with sufficient monitoring of pediatric and adult patients. Also, double-blind studies were conducted abroad to compare the effectiveness of Topamax, carbamazepine and valproate (Privitera M. et al., 2003; etc.).

The purpose of this study was to evaluate the effectiveness and safety of Topamax in children and adults as initial therapy, mono- and polytherapy.

An open randomized study included 199 patients (100 men and 99 women) aged 2 to 50 years who received Topamax for 6–36 months (Table 1). All patients were subjected to dynamic clinical observation, EEG, MRI (in several cases CT), and, if necessary, polygraphic sleep recording was performed.

In the majority of patients, the disease debuted in childhood - 66.7% (Table 2).

When analyzing risk factors, the following data were obtained. Hereditary complications were noted in 15 patients, perinatal pathology - in 79, traumatic brain injury - in 19 patients, neuroinfections - in 12, cerebral dysplasia - in 22, cysts - in 7, brain tumors - in 4, mesial temporal sclerosis - in 4, vascular diseases - in 3, tuberous sclerosis - in 1, others (Sturge-Weber disease, Randu-Osler disease, etc.) - in 6; Risk factors were not identified in 27 patients. The data presented show that perinatal pathology is one of the main risk factors for the occurrence of epilepsy.

According to the forms of the disease, patients were distributed as follows: symptomatic/cryptogenic epilepsy - 159 patients, idiopathic: rolandic epilepsy - 3, epilepsy with generalized convulsive seizures - 2, childhood absence epilepsy - 4, juvenile absence epilepsy - 4, juvenile myoclonic epilepsy - 7 patients. It was not possible to classify the form of the disease in 20 people.

Mental disorders of a paroxysmal nature were observed in the analyzed group before taking Topamax in 9 patients, delayed psycho-speech development was diagnosed in 10 children, dysphoria was noted in 18 cases, depression in 16, cognitive impairment was observed in 23 patients, intellectual impairment of varying severity was noted in 15 cases.

The following features were identified in the women included in this study: a connection with the onset of menstruation at the onset of the disease - in 18 patients, catamenial epilepsy was diagnosed in 6. Pregnancy took place in 2, childbirth - in one case (the child is healthy). Hormonal disorders in the form of dysmenorrhea and/or polycystic ovary syndrome were diagnosed in 17 women, 9 of them before taking AEDs and 8 after the start of treatment (7 patients were simultaneously receiving valproate).

The dose of Topamax ranged from 2 to 15 mg per 1 kg of body weight per day. Monotherapy was administered to 48 patients; in 151 cases the drug was used as an additional drug.

In 40 patients (20.1%), the drug was discontinued due to ineffectiveness or negative effects: aggravation of seizures in the form of their frequency and/or severity, the appearance of seizures of another type, the addition of waking seizures to sleep attacks (total 14 cases - 7%) . In 12 cases (6%), the drug was discontinued due to severe side effects such as excitability, lethargy, speech impairment due to the formation of kidney stones, the development of cystitis with hematuria, weight loss of more than 10 kg, as well as unusual disorders: severe insomnia, psycho-emotional disorders (melancholy), skin pigmentation.

133 patients continued to receive Topamax; of these, 54 (40.6%) were used as monotherapy and 79 (59.4%) as polytherapy. In 65 cases (48.9%) remission was achieved, in 22 (16.5%) seizures were stopped by 50% or more.

The study identified the reasons that served as the basis for prolonging the use of Topamax in 46 patients (34.6%), in whom, according to generally accepted criteria, significant improvement (cessation or significant reduction in seizures) was not observed. A positive effect of the drug on other factors was established, namely: elimination of secondary generalization of seizures or the transition of complex partial seizures into simple ones (17 patients), easier recovery from a seizure (10 people), or a combination of several factors (19 patients).

Side effects that were transient in nature were observed in 36 patients (27%) in the form of excitability (11 patients), retardation, slow speech (6 patients), loss of body weight by 3–10 kg (17 patients), parasthesia (2 patients) . They stopped on their own or when the dose of Topamax was adjusted.

Topamax is an AED with different mechanisms of action: like carbamazepines, it affects sodium channels, like valproates, it affects calcium channels, like benzodiazepines and valproates, it has a GABAergic effect, like acetazolamide it inhibits carbonic anhydrase; Its antiglutamate effect cannot be ruled out either. Thanks to these mechanisms, the drug has a broad-spectrum antiepileptic effect. It is no coincidence that the greatest attention at the last European (Vienna, 2004) and international (Paris, 2005) congresses on the treatment of epilepsy was focused on Topamax along with oxcarbazepine and levetiracetam. There is already significant experience in using Topamax in Russia. According to our data, Topamax treatment is carried out in at least 600 patients. A large number of studies concern childhood epilepsy. In our observation, 25% of patients were pre-pubertal, and the onset of the disease at this age was noted in 75% of patients. And although we do not have experience with the use of Topamax in children of a younger age group, there are reports in the literature of the successful use of Topamax from the age of four months (A. Grinspan et al., 2005).

The effect of Topamax, defined in the literature by the number of respondents responding to therapy with a cessation or reduction of seizures by more than 50%, is assessed differently. For example, according to a study by M. Bujand et al (2004), complete cessation of seizures was noted in 39%, and according to J. Kruja et al (2004) - in only 4.3%, YH Yi et al (2005) - in 22.2%. At the same time, the number of patients whose number of seizures was reduced by more than 50% was 56–58%. In general, such a high percentage of positive results does not correspond to modern data, according to which, despite the introduction of new AEDs, the number of pharmacoresistant patients is at least 1/4 - 1/3 of observations (W. Loscher, D. Schmidt, 2002; D. Schmidt, W Loscher, 2004). Such a discrepancy requires special analysis and most likely requires long-term prospective observation for an objective assessment. As for the spread of the data presented, the result may depend on whether Topamax was used for resistant forms as the first drug or as an additional drug. However, even in the latter case, the result (complete cessation of seizures) ranges from 4.3% (J. Kruja et al., 2004) to 39% (M. Bujand et al., 2004). Only long-term prospective observations can be of value, since the effectiveness of the drug often decreases over time. But information about the duration of prospective observation is not always provided. There may be influence of other factors or their combinations. Thus, according to some data, Topamax, used as the first drug in the elderly, caused the cessation of seizures in 77.3% of patients; no improvement was recorded in only 9.1% of cases (Y. Chinvarun et al., 2005).

The results of our observations confirm the effectiveness of Topamax in the treatment of epilepsy. At least this is obvious for symptomatic/cryptogenic epilepsy, since this particular group of patients was quite representative - 159 people. Noteworthy is the fact that the effectiveness of Topamax was high both in mono- and polytherapy (40.6% and 59.4%, respectively), especially since Topamax was not the first choice drug in all cases. Thus, in 12 patients, it replaced previously prescribed valproate due to planned pregnancy or the presence of side effects such as dysmenorrhea and polycystic ovary syndrome. Moreover, in 4 patients whose seizures were not completely controlled with valproate, treatment became successful after they were switched to Topamax. S. Rielke and A. Schreinea (2005), who have experience in transferring therapy from valproate to Topamax in 65 patients aged 12 years and older, noted positive results in 73% of patients, including cessation of seizures in 48%.

Recently, due to increased attention to the treatment of epilepsy in women, the importance of the problem of replacing valproates with modern AEDs will apparently increase. One of the difficult methodological problems is assessing the effectiveness of drugs, in particular AEDs. We analyzed data on patients who did not give up Topamax, although the frequency of their attacks did not change. For the first time, the criterion of effectiveness was not considered to be a reduction in the frequency of seizures, but the possibility of simplifying and facilitating recovery from an attack. Thus, Topamax was effective in 43.7% of cases in accordance with generally accepted methods and in 66.8% taking this factor into account.

The effectiveness of AEDs, in particular Topamax, according to the results of this study was 66.8%, in 40.6% as monotherapy and in 59.4% as additive. Topamax can not only reduce the frequency of attacks, but also help ease their course and recover from an attack. In children, a larger dose per 1 kg of body weight is required than in adults. The drug has a high efficacy/tolerability rate in both children and adults.

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V. A. Karlov , Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Medical Sciences N. V. Freidkova MGMSU, Children's City Morozov Clinical Hospital, Moscow