Topiramate - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate (sugar milk) - 89.26 mg or 205.9 mg, microcrystalline cellulose - 21.45 mg or 58.50 mg, croscarmellose sodium (impellose) - 1.43 mg or 3.90 mg, silicon dioxide colloid aerosil) - 1.43 mg or 7.80 mg, magnesium stearate - 1.43 mg or 3.90 mg.

composition of the shell: for dosage of 25 mg - Opadrai II white (polyvinyl alcohol (E1203) - 40.0%, titanium dioxide (E 171) - 25.0%, macrogol (polyethylene glycol) (E1521) - 20.2%, talc (E553b) - 14.8%) - 2.962 mg emulsion simethicone 30% (water 50.0-69.5%, polydimethylsiloxane 25.5-33.0%, polyethylene glycol sorbitan tristearate 3.0-7.0%, methyl cellulose - 1.0-5.0%, silica gel - 1.0-5.0%) - 0.038 mg; for dosage of 100 mg - Opaprai II orange (polyvinyl alcohol (E1203) - 40.0%, titanium dioxide (E171) - 22.0%, macrogol (polyethylene glycol) (E1521) - 20.2%, talc (E553b) - 14 , 8%, lacquer aluminum based on the dye sunset yellow (E110) - 3.0%) - 9.875 mg emulsion simethicone 30% (water 50.0-69.5%, polydimethylsiloxane 25.5-33.0 %, polyethylene glycol sorbitan tristearate 3.0-7.0%, methylcellulose 1.0-5.0%, silica gel 1.0-5.0%) 0.125 mg.

Description:Tablets, film-coated,white or white with a grayish shade of color (for a dosage of 25 mg) or orange (for a dosage of 100 mg), round, biconvex. Insignificant roughness of the surface is permissible. Color of tablets on a break - white or white with a yellowish shade.

Pharmacotherapeutic group:Antiepileptic agent.

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.11 Topiramate

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 a background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of y-aminobutyric acid (GABA) for certain subtypes of GABA receptors (including GABA α-receptors), a also modulates the activity of the GABA a receptors themselves, inhibits the activation of kainate sensitivity of the kainate / AMPK subtype (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors to glutamate, does not affect activity N-methyl-O-aspartate (NMDA) with respect to the subtype NMDAreceptors.These effects of topiramate are dose-dependent when the drug concentration in the plasma is from 1 μmol to 200 μmol, with a minimum activity ranging from 1 μmol to 10 μmol. Besides, topiramate inhibits the activity of some isoenzymes of carbonic anhydrase. By the severity of this pharmacological effect topiramate is significantly inferior to acetazolamide, a known inhibitor of coal anhydrase, therefore this activity of topiramate is not considered to be the main component of its antiepileptic activity. In animal studies, it has been established that topiramate has anticonvulsant activity in tests with maximum electric shock in rats and mice. Effective in models of rodent epilepsy, including tonic convulsions, spontaneous epilepsy of rats, tonic-clonic convulsions caused by the excitation of the amygdala or global ischemia. Topiramate is ineffective in clonic convulsions caused by a GABA receptor antagonist - pentylenetetrazole.

With the simultaneous administration of mice with topiramate with carbamazepine or phenobarbital synergistic anticonvulsant effect was noted, with phenytoin - additive.In well-controlled trials of combination topiramate with other anticonvulsants, a correlation between its concentration and clinical efficacy has not been identified. There is no information on addiction to topiramate.

Pharmacokinetics:Compared with other anticonvulsants, topiramate has a long half-life, linearity of pharmacokinetics, preferential renal clearance, low association with plasma proteins and the absence of clinically significant metabolites. Topiramate is not characterized by a powerful inducing effect on microsomal enzymes of the liver, it can be taken regardless of food intake, monitoring of the concentration of topiramate is not required. According to the results of clinical studies, the relationship between the plasma concentration of topiramate and its efficacy and nezhehas not been established.

Absorption

Topiramate is quickly and well absorbed. After oral administration of 100 mg of topiramate, the average maximum concentration in plasma (C_m_Oh) in healthy volunteers is 1.5 mg / ml and is achieved within 2-3 hours (t_max).

After taking 100 mg ¹⁴C-labeled topiramate 81% of radioactivity is found in urine.Eating does not have a clinically significant effect on the bioavailability of topiramate.

Distribution

About 13-17% of topiramate binds to plasma proteins. Places of binding of topiramate on erythrocytes are saturated at its concentration in plasma more than 4 mg / ml. The volume of distribution is inversely proportional to the dose. After a single dose of 100-1200 mg, the average volume of distribution is 0.55-0.8 l / kg. The size of the distribution depends on the sex: in women it is approximately 50% of the values observed in men, which is associated with a higher content of adipose tissue in women; this circumstance has no clinical significance.

Metabolism

After ingestion, healthy volunteers metabolize about 20% of the dose. However, in patients taking concomitant therapy with anticonvulsants - inducers of microsomal liver enzymes, the metabolism of topiramate is increased to

50 %. From the plasma, urine and human feces, six metabolites were formed and identified, formed by hydroxylation, hydrolysis, and glucuronation. The amount of each metabolite does not exceed 3% of the total radioactivity detected after administration ¹⁴C-topiramate.Two metabolites with the greatest structural similarity to topiramate have practically no anticonvulsant activity.

Excretion

Unchanged topiramate and its metabolites are excreted by the kidneys (at least 81% of the dose taken). Within 4 days with urine, about 66% of unchanged ¹⁴C-topiramate. After taking 50 and 100 mg of topiramate twice a day, the average renal clearance is 18 and 17 ml / min, respectively. Topiramate is subjected to tubular reabsorption, which is confirmed by the results of a study in rats with simultaneous administration of probenecid: there was a marked increase in renal clearance of topiramate. After oral administration, the plasma clearance of topiramate is approximately 20-30 ml / min.

Topiramate has a low interindividual variation of plasma concentrations, i.e. has predictable pharmacokinetics. With a single admission of healthy volunteers in doses of 100-400 mg, the pharmacokinetics of topiramate is linear, plasma clearance remains constant, and the area under the "concentration-time" curve (AUC) increases in proportion to the dose. The time to reach the equilibrium concentration in patients with normal renal function is 4-8 days. Average C_m_Ohafter repeated ingestion of 100 mg in healthy volunteers is 6.76 μg / ml. The average plasma half-life after repeated administration of 50 and 100 mg of topiramate twice daily is 21 hours.

With simultaneous application of topiramate in doses of 100-400 mg twice daily with phenytoin or carbamazepine, the concentration of the first in plasma increased in proportion to the dose.

In patients with impaired renal function of medium and severe degree (creatinine clearance (CC) <70 ml / min), the plasma and renal clearance of topiramate decreases. In this regard, in such patients, an increase in the equilibrium concentration of topiramate in the blood plasma is possible compared with patients with normal renal function. In addition, patients with impaired renal function to achieve an equilibrium concentration of topiramate in the plasma takes more time. Patients with impaired renal function of medium and severe degree are recommended to take half of the recommended initial and maintenance dose.

Topiramate is well excreted from the plasma by hemodialysis. Long-term hemodialysis can lead to a decrease in the concentration of topiramate in the blood below the level necessary to maintain anticonvulsant activity.To avoid a rapid decrease in plasma topiramate concentration during hemodialysis, an additional dose of topiramate may be required. When adjusting the dose should be taken into account:

1) duration of hemodialysis,

2) clearance of the hemodialysis system used,

3) effective renal clearance of topiramate in a patient on dialysis.

In patients with moderate or severe hepatic insufficiency, the plasma clearance of topiramate is reduced by an average of 26%. Therefore, patients with hepatic impairment should be treated topiramate carefully.

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

Pharmacokinetics of topiramate in children under 12 years old

The pharmacokinetics of topiramate in children, as well as in adults taking it as part of combination therapy, is linear, with the clearance of topiramate independent of the dose, and the equilibrium concentrations in the plasma increase in proportion to the dose increase. However, in children the clearance of topiramate is increased, and the half-life is shorter. In this regard, at the same dose, based on 1 kg of body weight, the concentrations of topiramate in plasma in children may be lower than in adults.In children, as in adults, anticonvulsant drugs inducing microsomal enzymes of the liver cause a decrease in the concentrations of topiramate in plasma.

Indications:

Epilepsy

As a means of monotherapy: in adults and children older than 6 years with partial (with secondary generalization or without) or primary generalized tonic-clonic seizures.

As part of complex therapy: in adults and children older than 3 years with partial (with or without secondary generalization) or generalized tonic-clonic seizures, and also for the treatment of convulsions against the background of the Lennox-Gastaut syndrome.

Migraine

Prevention of migraine attacks in adults. Application of topiramate preparations for treatment of acute migraine attacks has not been studied.

Contraindications:

- Hypersensitivity to the components of the drug.

- Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

- Breastfeeding period.

- Pregnancy.

- Children up to 3 years (as part of complex therapy).

- Children up to 6 years of age (as a monotherapy).

- Preventing migraine attacks during pregnancy or in women of childbearing age who do not use reliable methods of contraception.

Carefully:Renal / hepatic insufficiency, nephrourolythiasis (including in the past and in family history), hypercalciuria.

Pregnancy and lactation:

In mice, rats and rabbits topiramate is teratogen. Penetrates through the placental barrier of rats.

According to the UK Pregnancy Registry and the Register of Pregnancy, "Antiepileptic Drugs in North America" in infants exposed to intrauterine exposure to topiramate monotherapy in the first trimester, the risk of developing congenital malformations (eg, facial skull defects such as cleft of the upper lip or palate, hypospadias and abnormalities development of various body systems). According to the same registry, when using topiramate as a monotherapy during pregnancy, the frequency of severe congenital malformations was three times higher than in peers whose mothers did not take anticonvulsants. In addition, in the treatment group of topiramate compared with the control group, the probability of giving birth to children with a low body weight (<2500 g) is increased.

In addition, pregnancy records and other studies indicate that the risk of developing teratogenic effects in combination therapy with anticonvulsants is higher than with monotherapy.

Women of childbearing age are recommended to use reliable methods of contraception, and also to select alternative methods of treatment.

Topiramate penetrates into the breast milk of animals. The ability to penetrate human milk has not been studied. Based on the results of limited observations, a high content of topiramate in breast milk is established.

In view of the fact that many medicines penetrate into breast milk, it is necessary either to stop taking topiramate, or stop breastfeeding, and the importance of the drug to the mother (see "Special instructions") should be taken into account.

Dosing and Administration:

The drug is taken orally, without chewing, regardless of food intake. For optimal control of epileptic seizures, it is recommended to begin treatment with low doses with subsequent increase to an effective dose. When choosing a dose and the rate of its increase, one should be guided by the clinical response of the patient. Monitoring the concentration of topiramate to optimize drug therapy is not required. In rare cases, correction of doses of phenytoin or carbamazepine may be required when combined with topiramate.

To avoid the development of the syndrome of "withdrawal" or an increase in the number of seizures in patients, regardless of the history of seizures or epilepsy, anticonvulsant therapy, including topiramate, should be lifted gradually. In clinical studies, adult patients with epilepsy were reduced by 50-100 mg per week; patients receiving topiramate in a dose up to 100 mg / day for the prevention of migraine, the dose was reduced by 25-50 mg per week. In clinical studies in children, the withdrawal of topiramate was carried out for 2-8 weeks.

As part of complex therapy

Adults: the minimum effective dose is 200 mg / day. The average daily dose is 200 - 400 mg, the frequency of reception is 2 times / day. The maximum daily dose is 1600 mg. Treatment begins with a dose of 25 to 50 mg 1 time / day at night for 1 week. Then the dose is increased by 25 to 50 mg at intervals of 1 or 2 weeks before the effective dose is selected, the frequency of administration is 2 times / day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at large intervals. The dose and the frequency of reception are selected depending on the clinical effect. These dose recommendations apply to all adult patients, including the elderly, in the absence of kidney disease (see p.section "Special instructions").

Children from 3 years: the recommended daily dose is 5 to 9 mg / kg, divided into 2 divided doses. Treatment begins with 25 mg / day (or less, at a rate of 1 - 3 mg / kg of body weight per day), the drug is taken at night for 1 week. Then the dose is increased by 1-3 mg / kg / day for 1 to 2 weeks with a frequency of 2 times a day until the optimal clinical effect is achieved. The daily dose to 30 mg / kg is usually well tolerated.

Monotherapy

If cancellation of concomitant anticonvulsants with the aim of initiating monotherapy with topiramate, it is necessary to take into account the possible influence of this step on the frequency of seizures. In cases where, for safety reasons, the need for a sharp abolition of concomitant anticonvulsant drugs is not available, a dose of these drugs should be reduced by one-third every 2 weeks.

With the elimination of inducers of microsomal liver enzymes, the concentration of topiramate in plasma increases. In such situations, in the presence of clinical indications, a reduction in the dose of topiramate may be required.

Adults: treatment is started with 25 mg 1 time / day at night for 1 week. Then the dose is increased at intervals of 1 to 2 weeks by 25-50 mg / day with a frequency of reception 2 times / day.If this dosage regimen is intolerant, the dose is increased by a smaller amount or at large intervals. The dose and the frequency of reception are selected depending on the clinical effect. The recommended initial dose of topiramate for monotherapy in adults with newly established epilepsy is 100 mg / day, the maximum daily dose should not be more than 500 mg. These doses are recommended for all adults, including elderly patients without kidney disease.

Children from 6 years: treatment starts with a dose of 0.5-1 mg / kg per night for 1 week. Then the dose is increased by 0.5-1 mg / kg / day for 1 to 2 weeks, the frequency of administration is 2 times / day. If this dosage regimen is intolerant, the dose is increased by a smaller amount or at large intervals. The dose and the frequency of reception are selected depending on the clinical effect. The recommended range of doses is 100-400 mg / day. Children with newly established partial seizures can be prescribed up to 500 mg / day.

Migraine

The recommended total daily dose of topiramate for prevention of migraine attacks is 100 mg, taken in 2 divided doses. At the beginning of treatment, the patient should take 25 mg of topiramate before bedtime for 1 week. Then the dose is increased with an interval of 1 week for 25 mg / day.If the patient does not tolerate such a regime of increasing the dose, then it is possible to increase the intervals between dose increases, or to increase the dose more smoothly. When choosing a dose, it is necessary to be guided by the clinical effect. In some patients, a positive result is achieved with a daily dose of topiramate 50 mg. In clinical trials, patients received various daily doses of topiramate, but not more than 200 mg / day.

Special patient groups

Renal insufficiency: Patients with moderate or severe renal failure are recommended to use half of the recommended initial or maintenance dose.

Hemodialysis: In days of hemodialysis topiramate should be prescribed additionally in a dose equal to half the daily dose, in 2 doses (before and after the procedure of hemodialysis).

Liver failure: Patients with hepatic insufficiency topiramate should be used with caution.

Elderly: In elderly patients with normal renal function, dose adjustment is not required.

Side effects:

The most common adverse reactions (with a frequency> 5% compared with the placebo group, observed in at least 1 double-blind controlled study): anorexia, decreased appetite, mental retardation, depression, slurred speech, insomnia, impaired coordination of movements, attention disturbance, dizziness, dysarthria, taste disorders, hypoesthesia, lethargy, memory loss, nystagmus, paresthesia, drowsiness, tremor, diplopia, impaired vision , diarrhea, nausea, fatigue, irritability, weight loss.

Children

Unwanted reactions, which were> 2 times more frequent in children than in adults, as a result of double-blind clinical trials: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, impaired behavior, aggression, apathy, sleep disturbance, suicidal ideation, impaired attention, drowsiness, violation of the daily rhythm of sleep, poor sleep quality, increased lacrimation, sinus bradycardia, general unsatisfactory condition, gait disturbance. Undesirable reactions that arise in clinical studies exclusively in children: eosinophilia, psychomotor agitation, vertigo, vomiting, hyperthermia, fever, learning disability.

Side effects are given with a frequency distribution and organ systems. The incidence of side effects was classified as follows: very often (>1/10), often (>1/100, <1/10), infrequently (>1/1000, <1/100); rarely (>1/10000, <1/1000); very rarely (<1/10000), including isolated cases.

Infections: very often - nasopharyngitis.

From the side of the blood and lymphatic system: often - anemia; infrequently - leukopenia, thrombocytopenia, lymphadenopathy eosinophilia; rarely - neutropenia.

From the nervous system: very often - drowsiness, dizziness, paresthesia; disorder of coordination, nystagmus, lethargy, memory impairment, attention deficit disorder, tremor, amnesia, hypoesthesia, taste taste distortion, loss of taste sensitivity, impaired thinking, speech impairment, cognitive disorders, mental disorders, psychomotor disorders, seizures, intentional tremor, sedative effect; infrequently - aphasia, tonic-clonic seizures by type "grand mal", complex partial seizures, a burning sensation (predominantly on the face and limbs), cerebellar syndrome, clumsiness, postural dizziness, increased salivation, dysesthesia, dyskinesia, dyskinesia, dysphasia, "goose bumps" in the body, hypogesia, hypokinesia,peripheral neuropathy, parosmia, pre-fainting condition, recurring speech, loss of sensitivity, aura, dystonia, stupor, fainting, in children - psychomotor hyperactivity; rarely - apraxia, hyperaesthesia, hyposphresia, anosmia, essential tremor, akinesia, unresponsive to stimuli in children - a circadian rhythm sleep disorder.

Mental disorders: very often - depression, often - delayed thinking, confusion, insomnia, agitation, anxiety, irritability, disorientation, mood disturbance, emotional lability, anger; infrequent - apathy, erectile dysfunction, sexual dysfunction, impaired sexual arousal, dyspharmia, early waking up in the morning, euphoria, auditory and visual hallucinations, hypomaniacal conditions, decreased libido, panic attacks, paranoia, perseveration of thinking, violation of reading skills, sleep disorders, suicidal thoughts, suicidal attempts, tearfulness; rarely - mania, anorgasmia, a feeling of despair, a decrease in sensations during orgasm, in children - apathy, crying.

From the side of the organ zrennya: often - blurred vision, diplopia, impaired vision; infrequently - blepharospasm, myopia, photopsy, presbyopia, scotoma, decreased visual acuity, increased lacrimation, mydriasis, photophobia; rarely - a violation of accommodation, glaucoma, amblyopia, edema of the eyelids, ciliary scotoma, visual agnosia, one-sided blindness, transient blindness, night blindness; frequency unknown - angle-closure glaucoma, impaired mobility of the eyes, maculopathy,

From the side of the organ of hearing and balance: often - vertigo, pain in the ears, ringing in the ears; infrequently - deafness, incl. sensory and one-sided, discomfort in the ears, hearing loss.

From the cardiovascular system: infrequently - a bradycardia, sensation of palpitation, incl. sinus, "tides" of blood, hypotension, incl. orthostatic; rarely - the phenomenon of Raynaud.

From the respiratory system: often - shortness of breath, nasal congestion, epistaxis, cough, in children - rhinorrhea; infrequently - dysphonia, shortness of breath with physical exertion, hypersecretion in the paranasal sinuses.

From the gastrointestinal tract and the hepatobiliary system: very often - nausea, diarrhea; often - decreased appetite, anorexia, constipation,pain in the epigastric region, dryness of the oral mucosa, dyspepsia, abdominal discomfort, paresthesia in the oral cavity, gastritis; infrequently - pancreatitis, flatulence, gastroesophageal reflux, pain in the lower abdomen, hypoesthesia in the oral cavity, bleeding gums, bad breath, glossodynia, oral pain, polydipsia, increased appetite, hypersecretion of the salivary glands, discomfort in the epigastric region; rarely - hepatitis, hepatic insufficiency, increased activity of hepatic enzymes.

From the musculoskeletal system and connective tissue: often - myalgia, muscle spasms, muscle cramps, muscle weakness, arthralgia, musculoskeletal pain in the chest area; infrequently - stiffness of muscles, swelling of the joints, pain in the side, muscle fatigue; rarely - discomfort in the extremities, discomfort in the lumbar region.

From the side of the kidneys and urinary system: often - nephrolithiasis, dysuria, pollakiuria; rarely - concrements in the urine, hematuria, urinary incontinence, frequent urge to urinate, renal colic, pain in the kidney area; rarely - concrements of ureters, renal tubular acidosis.

From the skin and subcutaneous tissues: often - skin rash, alopecia, itchy skin; infrequently - anhidrosis, facial skin hypoesthesia, urticaria, erythema, generalized itching, macular rash, skin pigmentation disorder, rashes, edema of the face; infrequently - polymorphic erythema, paraorbital edema, unpleasant skin odor, Stephen-Johnson syndrome; very rarely - generalized edema; frequency unknown - toxic epidEternal necrolysis.

Laboratory indicators: infrequently - crystalluria, rarely - a decrease in the content of hydrocarbonates in the blood.

Other: very often - weight loss; often - asthenia, weight gain; infrequently - metabolic acidosis, cold extremities, calcification; rarely - flu-like diseases.

Overdose:

Symptoms: convulsions, impaired consciousness up to coma, speech and vision impairment, diplopia, impaired thinking, impaired coordination, lethargy, stupor, lowering of blood pressure, abdominal pain, dizziness, agitation and depression, severe metabolic acidosis. In most cases, the clinical consequences were not severe, but there were lethal outcomes after an overdose with a combination of medications that included topiramate. Overdose of topiramate can cause severe metabolic acidosis (see section "Special instructions").

Treatment: gastric lavage, symptomatic therapy. In studies in vitro it was shown that Activated carbon adsorbs topiramate. An effective way to remove topiramate from the body is hemodialysis. Patients are advised to adequately increase the amount of fluid consumed.

Interaction:

The effect of topiramate on the concentration of other anti-epileptic drugs (PEP)

Simultaneous reception of topiramate with other PEP (phenytoin, carbamazepine, valproic acid, phenobarbital, primidon) does not affect their concentration in the plasma, except for individual patients in whom the addition of topiramate to phenytoin may cause an increase in plasma concentration in the plasma. This may be due to the fact that topiramate inhibits a specific polymorphic isoenzyme CYP2C19 systems of cytochrome P450. Therefore, every patient who takes phenytoin and in which clinical signs or symptoms of toxicity develop, it is necessary to the concentration of phenytoin in plasma.

In the study of pharmacokinetics in patients with epilepsy, the addition of topiramate to lamotrigine did not affect the equilibrium concentration (Css) the latter with doses of topiramate 100-400 mg / day. During treatment and after lamotrigine withdrawal (average dose 327 mg / day) Css topiramate did not change.

Topiramate inhibits isoenzyme CYP2C19, in connection with which it can interact with its substrates (eg, diazepam, imipramine, moclobemide, proguanil, omeprazole).

The influence of other PEPs on topiramate

Phenytoin and carbamazepine reduce the concentration of topiramate in plasma. Adding or abolishing phenytoin or carbamazepine against a background of treatment with topiramate may require a change in the dose of the latter. Dose should be selected, focusing on achieving the desired clinical effect. The addition or withdrawal of valproic acid does not cause clinically significant changes in the plasma topiramate concentration and, therefore, does not require a dose change. The results of the described interactions are presented in Table 1.

PEP	Concentration of PEP in plasma	Concentration of topiramate in plasma
Phenytoin	absence of effect (increase in plasma concentration in single cases)	decrease in plasma concentration by 48%
Carbamazepine	lack of effect	decrease in plasma concentration by 40%
Valproic acid	lack of effect	lack of effect
Phenobarbital	lack of effect	not investigated
Primidone	lack of effect	not investigated

Other interactions

The area under the concentration-time curve (AUC) of a single dose of digoxin decreased by 12% with simultaneous administration with topiramate. The clinical significance of this observation is not clear.

There is no evidence of simultaneous application of topiramate and alcohol intake or the use of other drugs that depress the central nervous system (CNS). A combination of topiramate and drugs depressing the central nervous system is not recommended. In a study of the drug interaction of topiramate with oral contraceptives containing norethisterone (1 mg) and ethinyl estradiol (35 μg), the topiarymat at doses of 50-800 mg / day had no significant effect on the effectiveness of norethisterone and in doses of 50-200 mg / day - on the effectiveness of ethinyl estradiol. A significant dose-dependent decrease in the efficacy of ethinylestradiol was observed with doses of topiramate 200-800 mg / day.The clinical significance of the described changes is not clear. Possible decrease in the effectiveness of oral contraceptives and an increased risk of developing breakthrough uterine bleeding should be considered in patients taking topiramate. Patients taking estrogen-containing contraceptives should be warned about the need to inform the doctor about any changes in the timing and nature of menstruation.

In healthy volunteers, there was a decrease AUC lithium by 18% with the simultaneous administration of topiramate at a dose of 200 mg / day. In patients with bipolar affective disorder, the use of topiramate at doses up to 200 mg / day did not affect the pharmacokinetics of lithium, but at higher doses (up to 600 mg / day) AUC lithium was increased by 26%. With the simultaneous use of topiramate and lithium, the concentration of the latter in the blood plasma should be monitored.

With the simultaneous use of risperidone with a single and repeated administration of topiramate to healthy volunteers and patients with bipolar affective disorder, the results were similar. With the simultaneous use of topiramate in doses of 250 mg / day or 400 mg / day AUC risperidone taken in doses of 1-6 mg / day, respectively, decreased by 16% and 33%. In this case, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed insignificantly. The change in the systemic effect of risperidone / 9-hydroxyrisperidone and topiramate was not clinically significant, and this interaction has no significant clinical effect.

The drug interaction of hydrochlorothiazide (25 mg) and topiramate (96 mg) was evaluated in healthy volunteers. The results of the studies showed that in this case the maximum concentration (C_m_Oh) of topiramate is increased by 27% and AUC topiramate - by 29%. The clinical significance of these studies has not been revealed. The pharmacokinetic parameters of hydrochlorothiazide did not undergo significant changes with concomitant therapy with topiramate.

With the simultaneous administration of topiramate and metformin, an increase in C_m_Oh and AUC metformin by 18% and 25%, respectively, whereas the clearance of metformin decreased by 20%. Topiramate did not affect the time to reach C_m_Oh metformin in the blood plasma.The clearance of topiramate when used concomitantly with metformin is reduced. The degree of revealed changes in clearance is not studied. Clinical significance of exposure to met formin on the pharmacokinetics of topiramate is not clear.

With the simultaneous use of pioglitazone and topiramate, a decrease AUC pioglitazone by 15%, without change in C_m_Oh pioglitazone. These changes were not statistically significant. Also for the active hydroxy metabolite of pioglitazone, a decrease in C_m_Oh and AUC by 13% and 16%, respectively, and for active ketometabolite, a decrease in C_m_Oh and AUC by 60%. The clinical significance of these data is not clear.

When using glibenclamide (5 mg / day) alone or simultaneously with topiramate (150 mg / day) in patients with type 2 diabetes mellitus AUC Glibenclamide decreased by 25%. Also, the systemic exposure of 4-trans-hydroxyglybeneclamide and 3-cis-hydroxy-glybene-clamamide was reduced by 13% and 15%, respectively. Glibenclamide did not affect the pharmacokinetics of topiramate in the equilibrium state.

The simultaneous use of topiramate with other drugs predisposing to nephrolithiasis may increase the risk of kidney stones.

The simultaneous use of topiramate and valproic acid in patients who tolerate each drug individually, is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and symptoms disappear after the withdrawal of one of the drugs. This adverse event is not due to pharmacokinetic interaction. The relationship between hyperammonemia and the use of topiramate in the form of monotherapy or in combination with other drugs has not been established. In addition, with the simultaneous administration of topiramate and valproic acid, hypothermia may occur (unintentional drop in body temperature below 35 ° C) in combination with hyperammonemia or independently. This phenomenon can occur both after the beginning of joint intake of valproic acid and topiramate, and with an increase in the daily dose of topiramate.

Additional studies of drug interactions are presented in Table 2.

Table 2. Results of additional studies of the interaction between topiramate and various drugs (LP).

LP	Concentration of LP *	Concentration of topiramate *
Amitriptyline	increase in C_m_Ohand AUC metabolite of nortriptyline by 20%	not investigated
Dihydroergotamine (inside and c / k)	<->	<->
Haloperidol	enlargement AUC metabolite on 31%	not investigated
Propranolol	increase in Cmax 4-OH propranolol by 17% (topiramate 50 mg)	an increase in Cmax by 9% and 16%, an increase in AUC by 9% and 17% (propranolol 40 mg and 80 mg every 12 hours, respectively)
Sumatriptan (inside and c / k)	<->	not investigated
Pisotifen	<->	<->
Diltiazem	AUC reduction of diltiazem by 25% and deacetylldithiasem by 18% and <-> for N-demethylidithiasem	increase in AUC by 20%
Venlafaxine		<->
Flunarizine	AUC increase by 16% (50 mg every 12 hours) **	<->

<-> - no changes C_max and AUC (<15% of the original data);

** with repeated administration of flunarizine (monotherapy), there was an increase AUC by 14%, which may be due to the accumulation of the drug in the process of reaching the equilibrium state.

Special instructions:

If it is necessary to quickly cancel therapy for patients, appropriate control should be established (see the section "Dosing and Administration").

As with other anticonvulsant medications, the frequency of seizures may increase at the beginning of the application of the topiram, or convulsions of a new type may occur. These phenomena can be caused by an overdose,a decrease in the concentration of concomitant medications used, progression of the disease, or a paradoxical reaction.

In therapy with topiramate, sufficient hydration should be provided, which may reduce the risk of developing nephrolithiasis (see below). Sufficient hydration before and during physical exertion or exposure to high temperatures can reduce the risk of unwanted reactions due to thermal effects (see section "Side effect").

Mood / depression

When treating topiramate, there is an increased incidence of mood disorders and depression.

Suicidal thoughts and attempts

With the use of anticonvulsants, the risk of suicidal thoughts and suicidal behavior increases in patients taking these drugs for any of the indications. A meta-analysis of randomized placebo-controlled trials of anticonvulsants showed an increased risk of suicidal ideation and suicidal behavior. The mechanism of this risk is unknown, the available data do not exclude the possibility of an increased risk in the application of topiramate.In double-blind clinical trials, the incidence of suicidal-related events (suicidal thoughts, suicide attempts, suicide) was 0.5% in patients taking topiramate (46 people out of 8652), which is almost 3 times higher than the frequency observed with a placebo (0.2%, 8 people out of 4045).

Therefore, it is necessary to monitor the status of patients in order to identify signs of suicidal tendencies and prescribe appropriate treatment. It is necessary to recommend patients (and if necessary, carers of patients) immediately seek medical help in case of signs of suicidal tendencies or suicidal behavior.

Nephrolithiasis

In some patients, especially those with predisposition to urolithiasis, the risk of calculus formation in the kidneys and the appearance of associated symptoms such as renal colic, kidney or side pain may increase. Risk factors for the development of urolithiasis are: nephrolithiasis in the anamnesis (including in the family), hypercalciuria. None of these factors is an accurate predictor of nephrolithiasis when taking topiramate.In addition, the concomitant therapy with drugs that contribute to the development of nephrolithiasis is a risk factor.

Impaired renal function

In patients with renal insufficiency (CC <70 ml / min) topiramate should be administered with caution, as its plasma and renal clearance decreases. Recommendations for dosing in patients with renal insufficiency are presented in the section "Method of administration and dose".

Impaired liver function

In patients with impaired hepatic function topiramate It should be used with caution because of the possible decrease in its clearance.

Myopia and secondary closed angle glaucoma

With the use of topiramate, a syndrome including acute myopia with concomitant secondary closed angle glaucoma is described. Symptoms include acute reduction

visual acuity and / or pain in the eye. Ophthalmic examination can detect myopia, flattening of the anterior chamber of the eye, hyperemia (reddening) of the eyeball, increased intraocular pressure. There may be mydriasis. This syndrome can be accompanied by the secretion of fluid, leading to a shift in the lens and iris forward with the development of a secondaryangle-closure glaucoma. Symptoms usually appear during the first month of application of topiramate. Unlike primary open angle glaucoma, which is rare in patients under 40 years of age, secondary occlusive glaucoma is observed with topiramate in both adults and children. In the event of a syndrome involving myopia associated with occlusive glaucoma, treatment includes stopping the use of topiramate as soon as the attending physician deems it possible and appropriate measures to reduce intraocular pressure. Usually these measures, as a rule, 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 prescribing topiramate for patients with eye diseases in the history, it is necessary to evaluate the ratio of the expected benefit to the possible risk of use.

Acidosis

With the use of topiramate, hyperchloremic, not associated with an anion deficiency, metabolic acidosis (decrease in the content of hydrocarbonates in plasma in the absence of respiratory alkalosis) may occur.Such a decrease in the concentration of serum hydro- carbonates is a consequence of the inhibition of renal carbonic anhydrase by topiramate. The degree of decrease in concentration is usually mild or moderate (mean value is 4 mmol / L when used in adult patients at a dose above 100 mg / day or more and about 6 mg / day / kg of body weight when used in children). In rare cases, the patients had a decrease in the concentration of hydrocarbonates below 10 mmol / l. Some diseases or treatments that predispose to acidosis (eg, kidney disease, severe respiratory disease, epileptic status, diarrhea, surgery, fat-rich foods, certain medications) may serve as additional factors that enhance the hydrocarbonate-lowering effect of topiramate.

Chronic metabolic acidosis increases the risk of formation of urinary calculi and a way to lead to osteopenia.

In children, chronic metabolic acidosis can lead to slower growth. The effect of topiramate on complications associated with the bone system in children and adults has not been systematically studied.

In connection with the foregoing, in the treatment with topiramate, it is recommended to carry out the necessary studies, including determination of the concentration of hydrocarbonates in the serum. When there is metabolic acidosis and its persistence, it is recommended to reduce the dose or gradually stop taking topiramate.

Topiramate should be used with caution in patients with metabolic acidosis or risk factors for its development.

Enhanced nutrition

In the treatment of topiramate in some patients weight can decrease. In patients receiving topiramate, it is recommended to control body weight. If a patient's body weight decreases with topiramate treatment, consideration should be given to the advisability of enhanced nutrition.

Laboratory indicators

In 0.4% of patients who took topiramate hypokalemia was observed, defined as a decrease in serum potassium concentration below 3.5 mmol / l.

Effect on the ability to drive transp. cf. and fur:Topiramate has a weak or moderate influence on the ability to drive vehicles and work with machinery. Topiramate acts on the central nervous system and can cause drowsiness, dizziness and other symptoms. It can also cause visual disturbances. These unwanted reactions can pose a potential threat to patients when driving vehicles and working with machinery, especially during the period of individual sensitivity to the drug. During the treatment period, care must be taken when driving vehicles and working with mechanisms.

Form release / dosage:

The tablets covered with a film cover, on 25 and 100 mg.

Packaging:

For 7 or 10 tablets in a contour mesh package.

For 1,2, 3, 4, 5 or 6 contour squares with instructions for use in a cardboard pack.

Storage conditions:In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002685

Date of registration:29.10.2014

The owner of the registration certificate:BIOKOM, CJSC BIOKOM, CJSC Russia

Manufacturer: & nbsp

BIOKOM, CJSC Russia

Information update date: & nbsp13.09.2015

Illustrated instructions

Instructions

Topiramate (Topiramate)