Topiramate, 30 pcs., 100 mg, film-coated tablets

Topiramate, 30 pcs., 100 mg, film-coated tablets

Effect of topiramate on concentrations of other AEDs

Concomitant use of topiramate with other AEDs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidone) does not affect their steady-state plasma concentrations, with the exception of certain patients in whom the addition of topiramate to phenytoin may cause an increase in plasma phenytoin concentrations. 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 latter's Css at doses of topiramate 100–400 mg/day. During treatment and after discontinuation of lamotrigine (average dose of topiramate 327 mg/day), Css of topiramate did not change.

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 dose of topiramate.

The results of interaction with AEDs are presented in Table 1.

Table 1

Interaction between topiramate and other AEDs

1 — change in plasma concentration less than 10%;

# - increased concentration in some patients;

$ - decrease in plasma concentration;

NI - not studied.

Other drug interactions

Digoxin:

In a study using a single dose of digoxin, its plasma AUC was decreased by 12% when coadministered with topiramate. The clinical significance of this observation is unclear. When initiating or discontinuing topiramate in patients taking digoxin, special attention should be paid to monitoring serum digoxin concentrations.

CNS depressants:

It is not recommended to use topiramate together with drugs that depress the functions of the central nervous system, incl. with alcohol.

St. John's wort:

when taking topiramate and St. John's wort preparations together, the concentration of topiramate in the blood plasma may decrease, and, as a result, the effectiveness of the drug may also decrease. Clinical studies of the interaction of the drug Topiramate 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 drug containing norethisterone (1 mg) and ethinyl estradiol (35 mcg), topiramate at doses of 50–800 mg/day did not have a significant effect on the effectiveness of norethisterone at doses of 50–200 mg /day - on the effectiveness of ethinyl estradiol. A significant dose-dependent decrease in the effectiveness of ethinyl estradiol was observed at doses of topiramate 200–800 mg/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 topiramate. Patients taking estrogen-containing contraceptives should inform their doctor about 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/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 conducted with single and multiple doses of topiramate in healthy volunteers and patients with manic-depressive psychosis gave the same results. With simultaneous use of topiramate in 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 administration 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.

With simultaneous use of topiramate and metformin, there was an increase in the Cmax and AUC of metformin by 18 and 25%, respectively, while the clearance of metformin decreased by 20%. Topiramate did not affect metformin plasma Tmax. The clearance of topiramate was decreased 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 Topiramate is added or discontinued in patients receiving metformin, the course of diabetes mellitus should be carefully monitored.

With the simultaneous use of pioglitazone and topiramate, a decrease in the AUC of pioglitazone by 15% was detected, without changing the Cmax of pioglitazone. These changes were not statistically significant. Also, for the active hydroxymetabolite pioglitazone, a decrease in Cmax and AUC was 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. In case of co-administration of Topiramate and pioglitazone, the course of diabetes mellitus should be carefully monitored.

When glibenclamide (5 mg/day) was used alone or simultaneously with topiramate (150 mg/day) in patients with type 2 diabetes mellitus, the AUC of glibenclamide decreased by 25%. Systemic exposure to 4-trans-hydroxyglibenclamide and 3-cis-hydroxyglibenclamide was also reduced by 13 and 15%, respectively. Glibenclamide did not affect the pharmacokinetics of topiramate at steady state. When prescribing glibenclamide and topiramate to patients simultaneously, it is necessary to take into account the possible PEF and carefully monitor the patient's condition to assess the course of diabetes mellitus.

Other drugs:

Concomitant use of topiramate with drugs that predispose to nephrolithiasis should be avoided due to an increased risk of kidney stones.

Additional drug interaction studies are presented in Table 2.

table 2

Results of additional studies on interactions between topiramate and various drugs

a - expressed as % of Cmax values ​​in blood plasma and AUC during monotherapy;

1 — no changes in Cmax in blood plasma and AUC (up to 15% of the initial data);

b - with repeated oral administration of flunarizine, an increase in AUC by 14% was observed, which may be due to its accumulation in the process of achieving an equilibrium state;

NI - not studied.

References

1. Gekht, A.B., Milchakova, L.E., Gusev E.I. Experience with Topamax: clinical and pharmacoeconomic aspects. Journal neurol. psychiat., 2005. - T.107. - No. 12. - P. 40-44.
2. Zalyalova, Z.A., Latypova, G.R. Topiramate in the treatment of essential tremor. Journal neurol. psychiat., 2008. - T. 108. - No. 11. - P. 39-42.
3. Karlov, V.A. Strategy and tactics of epilepsy treatment today. Journal neurol. psychiat., 2004. - T. 104. - No. 8. - P. 28-34.
4. Fedin, A.I., Generalov, V.O., Mishnyakova, L.P. Topiramate in the treatment of epilepsy in adults. Bulletin of Epileptology, 2006. - No. 1. - P. 3-5.
5. Arroyo, S., Dodson, W., Privitera, M. et al. Randomized dose controlled study of topiramate as first-line therapy in epilepsy. ActaNeurolScand., 2005. - Vol. 112(4). — P. 214-22.
6. Marson, A., Al-Kharusi, A., Alwaidh, M. et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalized and unclassifiable epilepsy: an unblindedrandomised controlled trial. Lancet, 2007. - Vol. 369(9566). - P. 1016-26.

Special instructions for the use of Topiramate

Adequate and strictly controlled clinical studies of the safety of topiramate during pregnancy have not been conducted, so its use is possible only if the expected benefit to the mother outweighs the potential risk to the fetus. The excretion of topiramate into breast milk has not been studied in controlled studies. A limited number of observations suggest that topiramate is excreted in breast milk. If it is necessary to use topiramate, the issue of stopping breastfeeding should be decided. Topiramate should be discontinued gradually to minimize the possibility of increased seizure frequency. When using topiramate, the risk of kidney stones may increase, especially in patients with a predisposition to nephrolithiasis, as well as when using other drugs that contribute to the development of nephrolithiasis. To reduce the risk of developing nephrolithiasis, you should increase the volume of fluid consumed. If the patient's body weight decreases while taking topiramate, the diet should be adjusted. In patients with impaired liver function, topiramate should be used with caution due to the possible decrease in clearance of this drug. Patients taking topiramate should avoid drinking alcohol. Topiramate should not be used in children under 2 years of age. Topiramate should be prescribed with caution to patients engaged in potentially hazardous activities that require increased attention and speed of psychomotor reactions, since its use may cause drowsiness and dizziness.

Side effects of the drug Topiramate

Often (especially during dose selection) - ataxia, impaired concentration, confusion, dizziness, fatigue, paresthesia, drowsiness, impaired thinking, rarely - agitation, amnesia, anorexia, aphasia, depression, emotional lability, speech disorders, diplopia, nystagmus, visual impairment, taste perversion; in some cases - increased liver function tests, hepatitis, liver failure (when used simultaneously with other drugs), rarely - nausea, nephrolithiasis, weight loss.