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

Excipients: calcium hydrogen phosphate dihydrate 65 mg, pregelatinized starch 70.5 mg, magnesium hydroxycarbonate (magnesium carbonate heavy) 30 mg, magnesium stearate 1.5 mg, povidone 8 mg;

Composition of the film shell - Selskoat AQ-02140 6 mg, including: [hypromellose (hydroxypropylmethylcellulose) 3.3 mg, macrogol (polyethylene glycol 400) 0.54 mg, macrogol (polyethylene glycol 6000) 0.84 mg, titanium dioxide 1.278 mg, dye sunset yellow 0.042 mg]. Dosage of 100 mg

1 tablet, film-coated, contains: Active substance: topiramate 100 mg;

Excipients: calcium hydrogen phosphate dihydrate 120 mg, pregelatinized starch 111 mg, magnesium hydroxycarbonate (magnesium carbonate heavy) 50 mg, magnesium stearate 3 mg, povidone 16 mg;

Composition of the film shell - Selskoat AQ-02140 12 mg, including: [hypromellose (hydroxypropylmethylcellulose) 6.6 mg, macrogol (polyethylspglycol 400) 1.080 mg, macrogol (polyethylsingleglycol 6000) 1.68 mg, titanium dioxide 2.556 mg, dye sunset yellow 0.084 mg].

Description:The tablets covered with a film cover of orange color, round, biconcave. On a cross-section of white or almost white color.

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. The exact mechanisms of anticonvulsant and anti-migraine action are not known. Reduces the frequency of occurrence of repeated action potentials, characteristic of a neuron in a state of persistent depolarization, blocking sodium channels. Increases the activity of y-aminobutyric acid (GABA) with respect to certain subtypes of GLMK receptors (including GABA [A] -receptors), and also modulates the activity of the receptors themselves; prevents the activation of kainate sensitivity of the kainate / AMPK subtype (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors to glutamate, does not affect the activity of N-methyl-O-aspartate (NMDA) with respect to the NMDA- receptors. These effects 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.

Inhibits the activity of certain isoenzymes of carbonic anhydrase, however this effect is not the main one in the antiepileptic activity of topiramate.

In animal studies, it has been established that topiramate possesses anticonvulsant activity in tests with maximum electric shock in rats and mice. Effective on models of rodent epilepsy, including tonic convulsions, spontaneous epilepsy of rats, tonic-clonic convulsions caused by excitation of the amygdala or global ischemia.

Pharmacokinetics:

Compared with other anticonvulsant agents, topiramate has a long half-life, linear kinetics, 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 liver enzymes. Topiramate 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 undesirable reactions has not been established.

Suction

Topiramate is absorbed quickly and efficiently. After oral administration of 100 mg of topiramate, the average maximum concentration in plasma (C_max) in healthy volunteers is 1.5 mg / ml and is achieved within 2-3 hours (t_max). After taking 100 mg ¹⁴C-swine topiramate 81% of radioactivity is found in urine. Eating does not have a clinically significant effect on the bioavailability of topiramate.

Distribution

Plasma proteins bind 13-17% of topiramate. 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. The volume of distribution (after a single oral intake of 100-1200 mg) is 0.55-0.8 l / kg, depends on the sex: in women it is approximately 50% of the values observed in men, which is associated with a higher fat content in the body women; this circumstance does not has 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 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_max after repeated ingestion of 100 mg in healthy volunteers is 6.76 μg / ml. The average plasma period of the elimination half-life after repeated administration of 50 and 100 mg of topiramate twice daily is 21h.

With simultaneous application of topiramate in doses of 100-400 mg twice daily with phenytoin or carbamazepine, the concentration of the first in the 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 concentrations Topiramate in the blood is lower than 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 in the combination therapy, is linear, while the clearance of topiramate does not depend on the dose, and the equilibrium concentrations in the plasma increase in proportion to the increase in dose. 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:

Topiramate is used in adults and children older than 3 years with epilepsy (including patients with newly diagnosed epilepsy).

As part of complex therapy:

Toniramate is used in adults and children over 3 years with partial or generalized tonic-clonic seizures, and for treatment of seizures in the background of the Lennox-Gastaut syndrome.

Contraindications:

- Hypersensitivity to the components of the drug.

- Children up to 3 years.

Carefully:

With renal and hepatic insufficiency, nephrourolythiasis (including in the anamnesis and in the family history), hypercalciuria.

Pregnancy and lactation:

Fertility

Studies in animals showed no decrease in fertility after application of topiramate.

The effect on human fertility is not established.

Pregnancy

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

According to the UK Pregnancy Registry and the Registry of Pregnancy, "Antiepileptic drugs in North America" in infants exposed to intrauterine exposure to monotherapy in the first trimester, the risk of developing congenital malformations is increased (for example, facial skull defects such as cleft lip or palate, hypospadias and developmental abnormalities different systems of the body). According to the same registry, when using topiramate as a monotherapy during pregnancy, the incidence of severe congenital malformations was three times higher than that of 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 the results of other studies indicate that.that the risk of developing teratogenic effects in combined treatment 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.

Breastfeeding period

Gopiramate enters the breast milk of animals. The ability to penetrate into 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, while taking into account the importance of the drug for the mother.

Dosing and Administration:

Inside, not liquid, whole, 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 of the concentration of topiramate for the optimization of therapy with drugs is 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

carried out for 2-8 weeks.

Monotherapy

When used as a monotherapy, it is necessary to take into account the possible effect of withdrawal of concomitant anticonvulsant therapy on the frequency of seizures. In cases where there is no need to abruptly cancel concomitant anticonvulsant therapy for safety reasons, it is recommended that the dose of the concomitant drug be reduced by one third every 2 weeks. With the withdrawal of drugs that are inducers of "liver" enzymes, the concentration of topiramate in the blood will increase. In such situations, in the presence of clinical indications, the dose of topiramate can be reduced.Adult patients at the beginning of monotherapy should take 25 mg of topiramate 1 time per day before bedtime for 1 week. Then the dose is increased at intervals of 1-2 weeks by 25 or 50 mg (daily dose divided into two doses). If the patient is intolerant of such a regime of increasing the dose, one can increase the intervals between the dose rises, or increase the dose more smoothly. When choosing a dose, it is necessary to be guided by the clinical effect.

The recommended dose for monotherapy with topiramate in adults is from 100 mg per day to 200 mg per day, divided into 2 doses, and the maximum daily dose is 500 mg. Some patients with refractory forms of epilepsy are tolerated by topiramate monotherapy in doses up to 1 g / day. Children older than 3 years with monotherapy in the first week of treatment - 0.5-1 mg / kg of body weight per day, before bedtime. Then increase the dose at intervals of 1-2 weeks at 0.5-1 mg / kg per day (daily dose divided into two doses). If the child does not tolerate such a regime of increasing the dose, then it is possible to increase the dose more smoothly or to increase the intervals between dose increases. When choosing a dose and the speed of its increase, one must be guided by clinical efficacy.

The recommended dose range for topiramatotherapy alone in children over the age of 3 is 100 mg / day, depending on the clinical efficacy (in children 6-16 years of age it is about 2 mg / kg / day). The maximum daily dose for children with newly diagnosed partial seizures does not exceed 500 mg per day.

Use in combination with other anticonvulsants

In adults, the initial dose is 25-50 mg once a day at night for 1 week. AT further dose can be increased by 25-50 mg in 1-2 weeks before the effective dose is reached. The minimum effective dose is 200 mg per day. Usually the average daily dose is from 200 mg to 400 mg and is taken in two divided doses. Some patients may need an increase in the daily dose to a maximum of 1600 mg. For some, a large effect can be achieved with the drug once a day.

Combined anticonvulsant therapy in children starting 3 years. The recommended total daily dose of topiramate as a supplementary therapy is 5 to 9 mg / kg and is taken in two divided doses. Selection of the dose should start with 25 mg (or less, based on an initial dose of 1 to 3 mg / kg per day), overnight, for 1 week.In the future, the dose can be increased by 1 - 3 mg / kg in 1-2 weeks and take ss in two divided doses. The daily dose to 30 mg / kg is usually well tolerated. In days of hemodialysis topiramate should be used additionally in a dose equal to Vi daily dose, in 2 doses (before and after the procedure). The drug should be discontinued gradually to minimize the possibility of an increase in the frequency of seizures (by 100 mg / week).

Special patient groups

Renal insufficiency: Patients with moderate or severe renal failure are advised to use a half, recommended initial or maintenance doses.

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, visual impairment , 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, behavioral disorders, aggression, apathy, sleep disturbances, suicidal thoughts, attention impairment, 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.

Undesirable reactions are given with the distribution of frequencies and organ systems.The frequency of adverse reactions was classified as follows: very frequent (>1/10), frequent (>1/100. <1/10), infrequent (>1/1000 and <1/100), the rare (>1/10000 and <1/1000) and very rare (<1/10000), the frequency is unknown - according to the available data, the frequency can not be estimated.

Infections: very often - nasopharyngitis *.

From the side of the blood and lymphatic system:

often - anemia;

infrequently - leukopenia, thrombocytopenia, lymphadenopathy, eosinophilia; rarely - neutropenia *.

From the immune system:

often - hypersensitivity;

frequency unknown - angioedema, edema of the conjunctiva *.

From the nervous system:

very often - drowsiness, dizziness, paresthesia;

disorder of coordination, nystagmus, lethargy, memory impairment, impaired concentration, tremor, amnesia, gypsesthesia, perversion of taste sensations, loss of taste sensitivity, disturbed thinking, speech disorders, cognitive disorders, mental disorders, psychomotor disorders, convulsions, sedative effect;

infrequently - aphasia, tonic-clonic seizures by type "grand mal", complex partial seizures, a burning sensation (mainly on the face and in the extremities), cerebellar syndrome, clumsiness, postural dizziness, increased salivation,dysaesthesia, dyskinesia, dyskinesia, dysphasia, "goosebumps", hypogeous, hypokinesia, peripheral neuropathy, parosmia, pre-fainting condition, recurring speech, loss of sensitivity, aura, dystonia, stupor, fainting, in children - psychomotor hyperactivity;

rarely - apraxia, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of reaction to stimuli, in children - disturbance of the circadian rhythm of sleep.

Mental disorders:

very often - depression;

often - delayed thinking, confusion, insomnia, agitation, anxiety, irritability, disorientation, mood disturbance, emotional lability, anger;

infrequently - apathy, erectile dysfunction, sexual dysfunction, impaired sexual arousal, dyspharmia, early waking up in the mornings, euphoria, auditory and visual hallucinations, hypomanic states, decreased libido, panic attacks, paranoia, perseveration of thinking, violation of reading skills, sleep disorders, suicidal thoughts, suicidal attempts, tearfulness;

rare - mania, anorgasmia, a sense of despair *, a decrease in sensations during orgasm, in children - apathy, crying.

From the side of the organ of vision:

often - blurred vision, diplopia, impaired vision; infrequently - blepharospasm, myopia *, photopsia, presbyopia, scotoma, a decrease in visual acuity, increased lacrimation, mydriasis, photophobia, foreign body sensation in the eye *, dry eye *; rarely - ccomodation, glaucoma, amblyopia, eyelid edema *, atrial scotoma, visual agnosia, unilateral blindness, amaurosis fugax, night blindness;

frequency unknown - angle-closure glaucoma *, impaired mobility eye*, maculopathy;

Cabout the sides 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.

Cabout cardiovascular system:

infrequently - a bradycardia, incl. sinus, palpitation, "hot flashes" of blood, hypotension, incl. orthostatic; rarely - the phenomenon of Raynaud.

Cabout the respiratory system:

often - shortness of breath, nasal congestion, epistaxis, cough, in children -

rhinorrhea;

infrequently - dysphonia. shortness of breath during physical exertion, hypersecretion in the paranasal sinuses.

Cabout side of the gastrointestinal tract and hepatobiliary system:

very often - nausea, diarrhea;

often - decreased appetite, anorexia, constipation, pain in the epigastric region, dryness of the oral mucosa, dyspepsia, stomach discomfort, paresthesia in the oral cavity, gastritis, vomiting, abdominal pain;

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, sensitivity in the abdomen, thirst, increased activity of hepatic enzymes;

rarely - hepatitis, hepatic insufficiency.

From the musculoskeletal system and connective tissue:

frequent-myalgia, muscle spasms, muscle cramps, muscle weakness,

arthralgia, musculoskeletal pain in the thorax;

infrequent - stiffness of the muscles, swelling of the joints *, pain in the side, muscular

fatigue;

rarely - discomfort in the extremities *.

From the nights and urine of the excretory system:

often - nephrolithiasis, dysuria, pollakiuria:

rarely - concrements in the urine, hematuria, urinary incontinence, frequent urge to

urination, 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, localized urticaria, erythema, generalized itching, macular rash, skin pigmentation disorder, rashes, edema of the face;

infrequent erythema multiform erythema *, periorbital edema *, unpleasant skin odor, Stephen-Johnson syndrome *;

very rarely - generalized edema; frequency unknown - toxic epidermal necrolysis *.

Laboratory indicators:

infrequently - crystalluria, hypokalemia,

rarely - a decrease in the content of hydrocarbonates in the blood,

hyperchloremic acidosis.

Other:

very often - fatigue, weight loss;

often - asthenia, increased body weight *, increased body temperature;

infrequently - metabolic acidosis, cold extremities, influenza-like diseases;

rarely - edema of the face, calcification.

Identified by the results of spontaneous messages in the post-registration period.

The frequency is calculated from clinical studies.

Overdose:

Symptoms: cramps, drowsiness, speech and vision impairment, diplopia, impaired thinking, impaired coordination, lethargy, stupor, lowering of blood pressure, abdominal pain, dizziness, agitation and depression. AT 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.

Treatment: There is no specific antidote, if necessary, symptomatic therapy is performed. It is necessary to immediately induce vomiting and rinse the stomach, increase water intake. In research in vitro it was shown that Activated carbon adsorbs the tonicramate. Hemodialysis is the most affective way of removing topiramate from the body. Patients are advised to adequately increase the amount of fluid consumed.

Interaction:

The effect of topiramate on the concentration of other antiepileptic drugs (PEP)

Simultaneous reception of topiramate with other PEPs (phenytoin, carbamazepine. valproic acid, phenobarbital, primidon) does not affect the values of their equilibrium concentrations in the plasma, except for individual solo, in which the addition of topiramate to phenytoin may cause an increase in the concentration of phenytoin in the plasma. This may be due to the inhibition of a certain isoform of the 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 monitor the concentration of phenytoin in the plasma.

In the study of pharmacokinetics in patients with epilepsy, the addition of terapiramate to lamotrigine did not influence the equilibrium concentration of the latter at doses of topiramate 100-400 mg per day. During the therapy and after lamotrigipa abolition (average dose of 327 mg per day), the equilibrium concentration of topiramate did not change.

Topiramate inhibits isoenzyme CYP2C19, in connection with which it can interact with its substrates (eg, diazepam, imipramine,

oclobemide, proguanil, ompsprazole).

The effect of other antiepileptic drugs on the concentration of topiramate

Fenitoia and carbamazepine reduce the concentration of topiramate in plasma.Addition or abolition of phenytoin or carbamazepia against a background of treatment with topiramate may require a change in the dose of the latter. The dose should be selected, guided by the achievement of the necessary clinical effect. The addition or withdrawal of valproic acid does not cause clinically significant changes in plasma topiramate concentrations and, therefore, does not require a change in the dose of Topiramate. The results of the written interactions are presented below:

Adding a PEP	Concentration of PEP	Concentration topiramate
Phenytoin	Absence of effect (increase in plasma concentration in single cases)	Reduction of plasma concentration by 48%
Carbamazepine	Lack of effect	Reduction 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 medicinal interactions

Digoxin: in the study with simultaneous administration of Topiramate using a single dose of digoxin AUFROM digoxin in the plasma decreased by 12%. When applying or canceling Topiramate to patients receiving digoxin, special attention should be given to routine monitoring of serum digoxin concentration. He it is recommended that Topiramate together with alcohol or other drugs that cause depression of the central nervous system.

Saint John's wort: With the joint administration of topiramate and preparations of St. John's wort, the concentration of topiramate in the blood plasma can decrease, and as a result, the effectiveness of the drug can also shrink. Clinical studies of the interaction of thiiramate and preparations based on St. John's wort have not been performed.

Oral contraceptives: In a study of pharmacokinetic drug interaction in healthy volunteers with oral contraceptives, in which a combined preparation containing norethisterone (1 mg) and ethinyl estradiol (35 μg), topiramate in doses of 50-200 mg / day (in the absence of other drugs) had no statistically significant effect on the mean AUC separate components of oral contraceptives. In another study, when taking topiramate at doses of 200, 400 and 800 mg / day, in addition to valproic acid, patients with epilepsy were noteda statistically significant decrease in ethinyl estradiol (by 18, 21 and 30%, respectively). In both studies topiramate (in a dose of 50-200 mg / day in healthy volunteers and 200-800 mg / day in patients with epilepsy) did not affect the exposure of norethisterone. Despite the dose-dependent decrease in the exposure of ethinylestradiol in doses of 200-800 mg / day (in patients with epilepsy), topiramate in doses of 50-200 mg / day (in healthy patients) did not have a clinically significant effect on its exposure. The clinical significance of the described changes is not known. Patients taking oral contraceptives in combination with topiramate should take into account the risk reducing contraceptive protection and strengthening "breakthrough" bleeding. Patients taking estrogen-containing contraceptives. it is necessary to report any changes in the timing and nature of menstruation. The effectiveness of contraceptives can be reduced even in the absence of "breakthrough" bleeding.

Lithium preparations: With the simultaneous use of topiramate at a dose of 200 mg / day and lithium in healthy volunteers, there was a decrease AUC the last 18%. In patients with bipolar disorder, the use of topiramate in doses up to 200 mg / day did not affect the pharmacokinetics of lithium, however, higher doses (up to 600 mg / day) AUC lithium increased by 26%. With the simultaneous use of topiramate and lithium drugs should monitor the concentration of lithium in blood plasma.

Risperidone: Studies of drug interactions performed with a single and repeated administration of topiramate by healthy volunteers and patients with bipolar disorder gave the same results. With the simultaneous use of topiramate in doses: 100, 250 and 00 mg / day AUC risperidone, taken in doses of 1-6 mg per day, decreased by 16% and 33%, respectively. However, the differences in the overall AUC between treatment with a single risperidone and risperidone in combination with topiramate or statistically insignificant. The pharmacokinetics of the general antipsychotic (rasperidone and 9-gendroksirisperidopa) changed insignificantly, the pharmacokinetics of 9-hydroxyrisperidone did not change. There were no significant changes in the systemic effect of risperidone / 9-hydroxyrispsridone and topiramate. When adding topiramate to risperidop (1-6 mg / day), undesirable reactions were recorded more often than with treatment with topiramate (250-400 mg / day): 90% and 54%, respectively.The most frequent adverse reactions with the addition of topiramate to risperidone were: drowsiness (27% and 12%), paresthesia (22% and 0%), and nausea (18% and 9%).

Hydrochlorothiazide: Drug interaction was evaluated in healthy volunteers with separate and simultaneous application of hydrochlorothiazide (25 mg every 24 hours) and topiramate (96 mg every 12 hours). The results of the studies showed that with the simultaneous administration of topiramate and hydrochlorothiazide, an increase in the maximum concentration of topiramate by 27% and AUC of topiramate by 29%. The clinical significance of the results of these studies is not established. The use of hydrochlorothiazide in patients taking topiramate, may require correction of the dose of topiramate. According to the results of laboratory studies, it was found that a decrease in the plasma content of potassium with simultaneous application of topiramate and hydrochlorothiazide is higher than with monotherapy alone.

Metformin: With the simultaneous administration of topiramate and metformin, an increase in the maximum concentration and AUC metformin by 18% and by 25%, respectively, whereas the clearance of metformin with simultaneous application with topiramate was reduced by 20%. Topiramate did not affect the time to reach the maximum concentration of metformin in the blood plasma.The clearance of topiramate when combined with metformin is reduced. The degree of revealed changes in clearance is not studied. The clinical significance of the effects of metformin on the pharmacokinetics of topiramate is not clear. In the case of the addition or withdrawal of topiramate in patients receiving metformin, special attention should be given to a careful study of the condition of patients with diabetes mellitus.

Pioglitazone: Drug interaction was evaluated in healthy volunteers with separate and simultaneous application of pioglitazone and topiramate. There was a decrease in the equilibrium AUC_t pioglitazone to 1 5%, without changing the equilibrium Cmax. These changes were not statistically significant. Also for the active hydroxy metabolite of pioglitazone, a decrease in Cmax and AUC by 13% and 16%, respectively, and for a beer ketometabolite, a decrease in Cmax and AUC na 60%. The clinical significance of the results of these studies is not established. When combined with topiramate and pioglitazone, patients should pay special attention to a careful study of the condition of patients with diabetes mellitus.

Glibenclamide: a study was made of the drug interaction to study the pharmacokinetics of glibenclamide (5 mg per day) in an equilibrium state, applied alone or simultaneously with topiramate (150 mg per day) in patients with type 2 diabetes mellitus. When topiramate is used AUC Glibenclamide decreased by 25%. Also, the systemic effect of active metabolites was reduced. Glibenclamide not elated on the pharmacokinetics of topiramate in the equilibrium state. When topiramate is used in patients receiving glibenclamide (or the use of glibenclamide in patients receiving topiramate), you should carefully monitor the patient's condition for assessing the course of diabetes.

Valproic Acid: The combined 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 caused by pharmacokinetic interaction. The relationship between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established.

With the simultaneous administration of topiramate and valproic acid, hypothermia can occur (unintentional decrease in body temperature below 35 ° C) in combination with hyperammonemia or independently. This phenomenon can occur both after the simultaneous administration of valproic acid and toiramate, and with an increase in the daily dose of the latter.

Other drugs: should avoid the use of drugs that predispose to the development of nephrolithiasis, because they can cause physiological changes that promote the formation of kidney stones.

DAdditional studies of drug interactions are presented in the table:

LP	Concentration of LP *	Concentration of thiuramate *
Amitriptyline	Increase in C_max and AUC metabolite of nortriptyline by 20%	Not investigated
Tsihydroergotamine (inside and c / k)	↔	↔
Haloperidol	Increase AUC metabolite by 31%	Not investigated
Propranolol	Increase in C_max4-0Н propranolol by 17% (topiramate 50 mg)	Increase in C_max by 9% and 16%, an increase AUC by 9% and 17% (propranolol 40 mg and 80 mg every 12 hours, respectively)
Sumatriptan (inside and c / k)	↔	Not investigated
Pisotifen	↔	↔
Diltiazem	Decrease AUC diltiazem by 25% and deacetylldithiasem by 18% and ↔for N- dimethyldithiasema	Increase AUC by 20%
Venlafaxine	↔	↔
Flunarizine	Increase AUC by 16% (50 mg every 12 hours) **	↔

[1] * is expressed as% of the values of C_shah and AUC with monotherapy;

** 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.

↔ no change in C_maxand AUC (<15% of the original data).

Special instructions:

Topiramate should be withdrawn gradually to minimize the possibility of an increase in the frequency of seizures, and if medical indications require the rapid cancellation of topiramate, then it is required to establish observations on patients. In clinical trials, doses were reduced by 50-100 mg at weekly intervals for adults with epilepsy. Children in clinical trials topiramate gradually canceled within 2-8 weeks.

As with other anticonvulsants, at the beginning of topiramate use, the frequency of seizures may increase, or convulsions of a new type may occur. These phenomena can be caused by an overdose, a decrease in the concentration of concurrently used drugs, the 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"). As with any disease, the dose selection scheme should be guided on clinical effect (i.e., degree of seizure control, absence adverse reactions) and take into account the fact that in patients with impaired kidney function to establish a stable concentration in the plasma for each dose may need a longer time.

It is not recommended to take topiramate together with alcohol or other drugs that cause depression of the central nervous system.

Oligohydrosis

Oligohydrosis (reduced sweating), which occurs with topiramate, may lead to hospitalization. The situation is characterized by a decrease in sweating and an increase in body temperature, in some cases this is observed with an increase in ambient temperature.Most of these cases relate to the use of the drug in children, monitoring is necessary in children receiving treatment with the drug, especially in hot weather.

It also requires care in prescribing topiramate in conjunction with other medications, predisposing to increase in body temperature: other carbonic anhydrase inhibitors, drugs with anticholinergic activity.

Mood disturbance / depression and suicidal attempts

When Topiramate is used, there is an increase in the incidence of mood disorders (including increased aggressiveness), psychotic reactions and depression.

ATo clinical studies in patients with epilepsy, topiramate when used more frequently than in the placebo group were observed events associated with increased activity suicide (suicidal ideation, suicidal attempts, and completed suicide): 0.5% frequency in patients treated topiramate (46 of 8652 patients) and 0.2% in patients receiving placebo. The mechanism of this risk is unknown. When using topiramate, patients should be examined for suicidal thoughts and suicidal behavior.If suicidal activity is detected in patients, consideration should be given to the possibility of appropriate treatment. Patients, their relatives, caregivers should be informed about the need to see a doctor if they show signs of suicidal tendencies and suicidal behavior, patients with any personality disorders need special control, especially at the beginning of treatment with topiramate.

Nephrolithiasis.

In some patients, in particular, with a predisposition to nephrolithiasis, the risk of kidney stones and the appearance of associated symptoms, such as renal colic, may increase. To reduce this risk, an adequate increase in the amount of fluid consumed is necessary.

The risk factors for developing nephrolithiasis are history of nephrolithiasis (in t.ch. in the family), hypercalciuria, concomitant therapy with drugs that promote the development of nephrolithiasis.

Impaired renal function.

The rate of excretion through the kidneys depends on the function of the kidneys and does not depend on age. In patients with moderate or severe renal dysfunction, stable plasma concentrations may be required from 10 to 15 days, in contrast to 4-8 days in patients with normal renal function.

In patients with renal insufficiency (CC <70 ml / min) topiramate should be administered with caution, as its plasma and renal clearance decreases.

Violation of the function of the liver.

In patients with impaired hepatic function topiramate should be used with caution because of the possible reduction in the clearance of this drug.

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 of visual acuity and / or pain in the eye. With ophthalmic a myopia, a flattening of the anterior chamber eyes, redness (redness) of the eyeball, increased intraocular pressure. There may be mydriasis, this syndrome may be accompanied by fluid secretion, leading to a shift in the lens and iris forward with the development of secondary closed-angle glaucoma. Symptoms usually appear 1 month after the application of topiramate. Unlike primary open-angle glaucoma, which is rarely observed in patients under 40 years of age, secondary closed-angle glaucoma is observed with topiramate in both adults and children.Treatment includes stopping the use of topiramate and appropriate measures aimed at lowering the 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.

Defects of the visual field were observed in patients taking topiramate, regardless of their increased intraocular pressure. In clinical trials, most of these cases were reversible and visual field defects disappeared after the withdrawal of topiramate therapy. If you have visual problems while taking topiramate, you should consider the possibility of discontinuing therapy.

Metabolic acidosis.

When topiramate is used, hyperchloremic, not associated with an anion deficiency, metabolic acidosis (eg, a decrease in bicarbonate concentration in the plasma below the normal level in the absence of respiratory alkalosis) may occur.Such a decrease in serum bicarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carboanhydrase. The reduction in concentration is usually mild or moderate (mean value is 4 mmol / L when administered in adult patients at a dose above 100 mg per day and about 6 mg per day per kg of body weight when used in pediatric practice). In rare cases, patients showed a decrease in the concentration of hydrocarbonates below the level of 10 mmol / l. In rare cases, the patients had a decrease in the concentration of hydrocarbonates below 10 mmol / l. Some of the diseases or treatments that predispose to the development of apidosis (eg, kidney disease, severe respiratory disease, epileptic status, diarrhea, surgical interventions, 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 urinary calculi formation and can 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.

Cognitive impairment

Violation of cognitive functions in epilepsy is multifactorial in nature, and can be caused by the underlying cause of the disease, directly epilepsy or antiepileptic therapy. In adult patients receiving topiramate, there were cases of cognitive impairment requiring dose reduction or discontinuation of therapy. Data on the effect of topiramate on cognitive functions in children is inadequate and its effects need further study.

Enhanced nutrition.

In the treatment of topiramate in some patients, weight may decrease body. In patients receiving topiramate, it is recommended to monitor body weight.

If the patient's weight gain is reduced with topiramate, consider the feasibility of enhanced nutrition.

Topiramate acts on the central nervous system and can cause

drowsiness, dizziness, visual impairment and other symptoms. Therefore, during the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Drug incompatibility: examples are not known.

Form release / dosage:

Tablets coated with a film coat of 25 mg and 100 mg.

Packaging:

By 7, 10, 15 or 30 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

According to 1, 2, 4, 8 contour cell packs of 7 tablets or 1, 3, 6 contiguous cell packs of 10 tablets or 2, 4 contour cell packs of 15 tablets, or 1, 2 circuit packs of 30 tablets each together with the instructions for use are placed in a pack of cardboard.

Storage conditions:In a dry, protected from light place at a temperature of no higher than 25 ° C.Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-000059

Date of registration:01.12.2010

Date of cancellation:2015-12-01

The owner of the registration certificate:CANONFARMA PRODUCTION, CJSC CANONFARMA PRODUCTION, CJSC Russia

Manufacturer: & nbsp

CANONFARMA PRODUCTION, CJSC Russia

Information update date: & nbsp08.10.2015

Illustrated instructions

Instructions

Topiramate (Topiramate)