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

Excipients: cellulose microcrystalline 31.4 mg, pregelatinized starch 23.0 mg, silicon dioxide colloid (aerosil) 200 μg, magnesium stearate 0.4 mg, opadrai II (polyvinyl alcohol 1.28 mg, macrogol 0.65 mg, talc 0.47 mg, titanium dioxide 0.23 mg, dye quinoline yellow aluminum lacquer 0.53 mg and dye sunset yellow aluminum lacquer 0.04 mg) 3.2 mg.

One tablet coated with a film coating with a dosage of 100 mg contains:

active substance: Topiramate - 100 mg;

Excipients: cellulose microcrystalline 125.6 mg, pregelatinized starch 92.0 mg, silicon dioxide colloid (aerosil) 800 μg, magnesium stearate 1.6 mg, opadrai II (polyvinyl alcohol 5.12 mg, macrogol 2.58 mg, talc 1.89 mg, titanium dioxide 0.93 mg, dye quinoline yellow aluminum lacquer 2.10 mg and sunset sunset dye yellow aluminum lacquer 0.16 mg) 12.8 mg.

Pharmacotherapeutic group:Antiepileptic agent.

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.11 Topiramate

Pharmacodynamics:

Topiramate is an antiepileptic agent, refers to the class of sulfate-substituted monosaccharides. It blocks sodium channels and suppresses occurrence of repeated potentials of action against the background of prolonged depolarization of the neuron membrane. Increases the activity of gamma-aminobutyric acid (GABA) against certain subtypes of GABA receptors (including GABA receptors), and also modulates the activity of the GABA receptors themselves, inhibits the activation of kainate / AMPK (a-amino-3-hydroxy- 5-methylisoxazole-4-propionic acid) -receptors to glutamate, does not affect the activity of N-methyl-D-aspartate (NMDA) with respect to the NMDA receptor subtype. These effects of topiramate are dose-dependent at a plasma topiramate concentration of 1 to 200 μmol / L, with a minimum activity ranging from 1 to 10 μmol / L.

Besides, topiramate inhibits the activity of certain isoenzymes of carbonic anhydrase (II-IV). By the severity of this pharmacological effect topiramate is significantly inferior to acetazolamide - a known inhibitor of carbonic anhydrase, therefore this action of topiramate is not the main component of its antiepileptic activity.

Pharmacokinetics:

After oral administration topiramate quickly and well absorbed from the gastrointestinal tract. Bioavailability is about 81%. After oral administration of 400 mg of topiramate, the maximum concentration in the plasma (C_m_Oh) 1.5 μg / ml is achieved within 2 hours. Eating does not have a clinically significant effect on the bioavailability of topiramate. The value of C_m_Oh after repeated administration of 100 mg of topiramate twice a day, on average, was 6.76 μg / ml.

The pharmacokinetics of topiramate is linear, the plasma clearance remains constant, and the area under the concentration / time curve (AUC) in the dose range from 100 to 400 mg increases in proportion to the dose.

The connection with blood plasma proteins for topiramate is 13-17% in the plasma concentration range of 0.5-250.0 μg / ml. After a single dose of 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 - about 50% of the values observed in men, which is associated with a higher content of adipose tissue in women. The equilibrium concentration with topiramate in patients with normal renal function is reached after 4-8 days. Penetrates into breast milk and through the placental barrier.

After ingestion, about 20% of the dose is metabolized.Metabolized by hydroxylation, hydrolysis and glucuronation. However, in patients receiving concomitant therapy with antiepileptic drugs (PEP),

which are inducers of microsomal enzymes, the metabolism of topiramate increased to 50%. From blood plasma, urine and feces, six practically inactive metabolites were isolated and identified. With the simultaneous reception of inducers of cytochrome P450 isoenzymes, the level of metabolism of topiramate is up to 50%. The main way to remove unchanged topiramate (about 70%) and its metabolites are the kidneys. After oral administration, the plasma clearance of topiramate was 20-30 ml / min. After repeated ingestion of 50 and 100 mg twice a day, half-life (T_1/2) of topiramate from blood plasma on average is 21 hours. It is removed from the plasma by hemodialysis.

Pharmacokinetics in special clinical cases. Renal and plasma clearance of topiramate with mild renal insufficiency (creatinine clearance more than 70 ml / min) is not changed. At an average degree of renal failure (KK 30-69 ml / min), the renal and plasma clearance of topiramate is reduced by 42%and with a severe degree of renal failure (CC less than 30 ml / min), renal and plasma clearance of topiramate is reduced by 54% or more.

With moderate and severe hepatic insufficiency, the plasma clearance of topiramate is reduced by 20-30%.

In elderly patients without renal and hepatic insufficiency, the clearance of topiramate is not changed.

The pharmacokinetics of topiramate in children, as in adults, is linear in nature with a dose-independent clearance; the equilibrium concentration of topiramate in the blood plasma increases in proportion to the increase in dose. In children, the clearance of topiramate is elevated, and T_1/2 is reduced, so at the same dose, based on 1 kg of body weight, the concentration of topiramate in blood plasma in children will be lower than in adults. In children, as in adults, antiepileptic drugs that induce microsomal liver enzymes cause a decrease in the concentration of topiramate in the blood plasma and increase the degree of its metabolism.

Indications:In monotherapy in adults and children from the age of 6 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 secondary generalization or without or generalized tonic-clonic seizures,and also for the treatment of convulsions caused by the Lennox-Gastaut syndrome. Preventing migraine attacks in adults after a thorough evaluation of all possible alternatives. Topiramate It is not intended for the treatment of acute migraine attacks.

Contraindications:

Hypersensitivity to topiramate or any other component of the drug; Children under 6 years of age with monotherapy, up to 3 years in combination therapy for epilepsy;

Children under 18 years of age when used to prevent migraine.

Preventing migraine in pregnant women or women of childbearing age who do not use effective contraception.

Carefully:Renal failure, hepatic insufficiency, hypercalciuria, nephrourolythiasis (including in the anamnesis or in a family anamnesis).

Pregnancy and lactation:

Special controlled studies in which topiramate was used to treat pregnant women, was not conducted. There is evidence of a possible association between the use of topiramate during pregnancy and congenital malformations (eg, craniofacial defects ("cleft lip" / "wolf mouth"), hypospadias, deficiency in fetal and newborn weight.These developmental defects were recorded both with monotherapy with topiramate and with its simultaneous application with other antiepileptic drugs (PEP). Pregnancy registration data and results of studies of monotherapy with topiramate testify to an increase in the probability of giving birth to children with a body weight deficit (less than 2500 g). The relationship of these cases with the administration of topiramate has not been established. Data from other studies indicate that the risk of developing teratogenic effects in combination with other antiepileptic drugs may be higher than with monotherapy.

The use of topiramate in pregnancy is contraindicated. At the time of treatment, the drug requires the use of effective methods of contraception. A limited number of observations of patients suggests that topiramate is excreted in breast milk, therefore, during the application of the drug, breastfeeding should be discontinued.

Women who have childbearing potential are encouraged to use effective contraceptive methods and consider alternative treatments. If topiramate is used during pregnancy, or if the patient becomes pregnant during the period of taking this drug, the doctor should warn her about the potential risk to the fetus.

Dosing and Administration:

Inside, regardless of food intake. Tablets should not be divided.

For optimal control of seizures, it is recommended to begin treatment with low doses with subsequent increase to an effective dose. When used as a monotherapy, it is necessary to take into account the possible effect of withdrawal of concomitant antiepileptic drugs (PEP) on the frequency of seizures. In cases where there is no need to abruptly cancel PEP, their dose is recommended to be reduced gradually, reducing doses by 1/3 every 2 weeks. With the withdrawal of drugs that are inducers of microsomal liver enzymes, the concentration of topiramate in the blood plasma will increase, which should be taken into account in the therapy.

Monotherapy

Adults:

Adults at the beginning of monotherapy - 25 mg 1 time per day at night for 1 week. Then the dose is increased at intervals of 1-2 weeks by 25-50 mg / day (the daily dose is divided into 2 divided doses). If this mode of treatment is intolerant, the dose is increased by a smaller amount or at large intervals. The dose is selected depending on the effectiveness and tolerability of the therapy.The recommended initial target dose is 100-200 mg / day, the maximum daily dose should not exceed 500 mg with monotherapy. Dosing recommendations apply to all adults, including elderly patients who are not suffering from kidney disease.

Children older than 6 years with monotherapy in the first week of treatment - 0.5-1 mg / kg of body weight before bedtime. Then the dose is increased at intervals of 1-2 weeks by 0.5-1 mg / kg per day (the daily dose is divided into two doses). If this mode of therapy is intolerant, the dose is increased more smoothly or at large intervals between dose increases. The magnitude of the dose and the rate of its increase are determined by the clinical efficacy and tolerability of therapy. The recommended dose range for topiramate monotherapy in children is 100 mg / day and depends on the clinical efficacy (in children 6-16 years of age it is about 2 mg / kg / day).

As part of combination therapy

Adults:

When administered as part of combination therapy with other anticonvulsant drugs in adults, the initial dose is 25-50 mg once a day for 1 night. The dose is then increased by 25-50 mg every week until the effective dose is reached.The minimum effective dose is 200 mg / day, the average daily dose is 200-400 mg, the frequency of reception is 2 times a day. Doses over 1600 mg per day have not been studied. The criterion for choosing the dose is the clinical effect and tolerability, in some patients this effect can be achieved with the drug once a day. Dosing recommendations apply to all adults, including elderly patients who are not suffering from kidney disease.

Children:

When prescribed as part of combined anticonvulsant therapy in children over 3 years of age, the recommended total daily dose is 5-9 mg / kg for 2 divided doses. Selection of the dose begins with 25 mg / day (at the rate of 1-3 mg / kg / day) at night for 1 week. In the future, the dose can be increased by 1-3 mg / kg for 1-2 weeks and taken in 2 divided doses. The criterion for correct dose selection is a stable clinical effect and good tolerability. The daily dose to 30 mg / kg is usually well tolerated.

Migraine Prevention

The recommended total daily dose is 100 mg in 2 divided doses. Begin treatment with a dose of 25 mg or less before going to bed for 1 week. Then the dose is increased by 25 mg / day at intervals of 1 week. If this regime is intolerant, the dose is increased by a smaller amount or at longer intervals.The dose is selected depending on the clinical effect. In some patients, a positive result is achieved with a daily dose of 50 mg / day. When applying a daily dose of more than 100 mg / day of an additional effect in the prevention of migraine is not observed.

Patients with renal insufficiency. For moderate patients (CC less than 70 ml / min) and severe (QC less than 30 ml / min) degree of renal insufficiency, the recommended initial dose should be reduced by 2 times, and it should be increased by a smaller amount or after long intervals. The dose is selected depending on the clinical effect. It should be borne in mind that reaching an equilibrium concentration will require more time and will be from 10 to 15 days after each increase in the dose of the drug Topiramate.

Patients in need of hemodialysis. Because the topiramate can be removed by hemodialysis, then on its days the daily dose of the drug should be increased by 50%. The additional dose is divided into 2 parts and is administered before and after hemodialysis. The additional dose may differ depending on the characteristics of the dialysis and the equipment used. The dose is selected depending on the clinical effect.

In patients with hepatic insufficiency a drug Topiramate should be taken with caution under the supervision of a doctor because of reduced clearance of topiramate.

In elderly patients correction of the dose is not required.

CANCELLATION OF THE PREPARATION

Antiepileptic drugs, including topiramate, should be phased out gradually in order to minimize the possibility of an increase in the frequency of seizures, reducing the dose by 50-100 mg at a 1-week interval in the treatment of epilepsy and by 25-50 with Topiramate for the prevention of migraine. The children cancellation within 2-8 weeks. If, for medical reasons, rapid suppression of topiramate is required, it is recommended that appropriate monitoring of the patient's condition be performed. The main way of excretion of topiramate and its metabolites in an unchanged form is excretion by the kidneys. The rate of excretion by the kidneys depends on the function of the kidneys and does not depend on age. In patients with moderate or severe impairment of renal function, it may take 10-15 days to reach equilibrium plasma concentrations, compared to 4-8 days in patients with normal renal function. As with the application of other PEPs, the dose selection scheme Topiramate should focus on therapeutic efficacy (that is, the degree of reduction in the frequency of seizures, the absence of side effects) and should take into account the fact that patients with impaired renal function to establish an equilibrium concentration of topiramate in blood plasma for each dose may need a longer time.

Side effects:

The frequency of side effects is classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely - not less than 0, 01%, including single messages.

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

Children

Unwanted reactions, which follow the results of double-blind clinical trials in >2 times more common in children than in adults: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, impaired behavior, aggression, apathy, falling asleep, suicidal thoughts, attention impairment, drowsiness, disturbance in 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.

Table №1.	Undesirable reactions		topiramate
System-	Often	Often	Infrequently	Rarely	Frequency
	Often	Often	Infrequently		Frequency
organ class					unknown
Infections and	Rinofarin-
infestations	git *
From the side		Anemia	Leukopenia,	Neutropenia *
hematopoietic and			thrombocytopenia,
lymphatic			lymphadenopathy,
systems			eosinophilia
From the side		Hypersensitivity			Angioneuroti-
immune		the			Acute edema *,
systems					edema
					conjunctiva *
From the side		Anorexia,	Metabolic	Hyperchlorination
metabolism and		decline	acidosis,	acidosis
supply		appetite	hypokalemia,
			rise
			appetite,
			polydipsia
From the side	Depression	Slowdown	Suicidal	Mania,
psyche		mental	thoughts,	panicky
		activities,	suicidal	disorder,
		insomnia,	attempts,	feeling
		slurred speech,	hallucinations (in	desperation *,
		anxiety,	including	hypomania
		confusion	auditory and
		consciousness,	visual),
		disorientation,	psychotic
		aggressiveness,	disorders,
		change	apathy,
		mood,	lack of
		agitation.	spontaneous speech,
		swings	sleep disturbance,
		mood,	emotional
		depressive mood, anger, violation of behavior	lability,
			decreased libido,
			nervousness, crying, dysphemia, euphoria. paranoia, perseveration, panic attacks, tearfulness, violation of reading, violation of falling asleep, emotional cold, violation of thinking, lack of libido, apathy, insomnia, distraction, early morning awakening, panic reaction, upbeat mood








From the side	Paresthesia,	Violation	Oppression	Apraxia,
nervous	drowsiness,	attention,	consciousness.	violation of
systems	vertigo	violation of	large	circadian
		memory, amnesia,	convulsive	rhythm of sleep,
		violation of	seizures,	hyperesthesia,
		cognitive	narrowing of fields	hyposmia,
		functions,	view, complex	anosmia,
		violation of	partial	a loss
		mental	seizures,	sense of smell,
		functions,	speech disturbance,	akinesia,
		violation of	psychomotor	lack of
		psychomotor	excitation,	response to
		skills,	fainting,	irritants
		convulsions,	violation of
		violation of	sensitivity,
		coordination	salivation,
		movements,	hypersomnia,
		tremor, lethargy,	aphasia,
		hypoesthesia,	repetition of words,
		nystagmus,	hypokinesia,
		dysgeusia,	dyskinesia.
		violation of	postural
		balance,	dizziness,
		dysarthria,	low quality
		intentional	sleep, feeling
		tremor, sedation	burning, loss
			sensitivity,
			parosmia,
			cerebellar
			syndrome,
			dysesthesia,
			hypogeous,
			stupor,
			clumsiness.
			aura, agesia,
			dysgraphy,
			dysphasia,
			peripheral
			neuropathy,
			pre-obstruction,
			dystonia,
			tingling
From the side of the organ of vision		Visual impairment, diplopia, blurred vision perceptions	Decreased visual acuity, scotoma, myopia , pathological sensations in the eye , dry eyes, photophobia, blepharospasm, lacrimation, photopsy, mydriasis, presbyopia	One-sided blindness, transient blindness, glaucoma, violation of accommodation, violation of binocular view, ciliary scotoma century *, night blindness, amblyopia	Closed-angle glaucoma , maculopathy , violation eye movement *
From the side of hearing and labyrinth		Vertigo, tinnitus, ear pain	Deafness, one-sided hearing loss, sensorineural hearing loss, ear discomfort, hearing loss
From the heart			Bradycardia (including sinus), palpitation
From the side of the vessels			Orthostatic hypotension, decline arterial pressure, "hot flashes", vasomotor violations	Raynaud's syndrome
On the part of the respiratory system, the organs of the thorax and the mediastinum		Shortness of breath, nosebleeds, nasal congestion, rhinorrhea	Dyspnea with exercise, hypersecretion of the paranasal sinuses, dysphonia
From the gastrointestinal tract	Nausea, diarrhea	Vomiting, constipation, epigastric pain, indigestion, abdominal pain, dry mouth, discomfort in the abdomen, paresthesia of the oral mucosa, gastritis, abdominal discomfort	Pancreatitis, flatulence, gastroesophageal reflux, lower abdominal pain, mucosal cavity hypoesthesia, bleeding from the gums, bloating, epigastric discomfort, peritoneal irritation, hypersalivation, cheek pain, bad breath, glossodynia
From the liver and biliary tract				Hepatitis, hepatic impairment
From the side skin and subcutaneous fabrics		Alopecia, rash, pruritus	Anhidrosis, hypoesthesia of the face, hives, erythema, generalized itching, macular rash, skin discoloration, allergic dermatitis, facial edema	Syndrome Stevens- Johnson , erythema multiforme , unpleasant skin odor, periorbital edema *, focal urticaria	Toxic epidermal necrolysis *
From the side muscular- skeletal systems From the side kidney and urinary- pathways		Arthralgia, muscle spasm, myalgia, muscle contracture, muscle weakness, chest pain Nephrolithiasis, pollakiuria, dysuria	Swelling of the joints *, stiffness. osteo- muscular pain in the side, muscle fatigue Uric concrement, urinary incontinence, hematuria, mandatory urge to urinate, renal colic, kidney pain	Discomfort in limbs * The concrement in urethra, renal tuberculous acidosis
From the side sexual bodies and dairy glands			Violation erections, violation of sexual function
Are common violations and violations in place of introduction	Fatigue	Fever, asthenia, proliferation, violation of balance, unpleasant Feel, malaise	Hyperthermia, thirst, influenza-like syndrome, asthenia, cold snap limbs, sensation intoxication, feeling nervousness	Edema of the face, calcification
From the side laboratory- instrumental- of the indicators	Decrease body weight	Increase body weight *	Crystalluria, abnormal leukopenia, rise activity of microsomal liver enzymes	Decrease content bicarbonates in serum
The social circumstances			Violation training

* Identified by the results of spontaneous messages in the postgistribution period. The frequency is calculated from clinical studies.

Overdose:

Signs and symptoms of an overdose: cramps, drowsiness, speech and vision impairment, diplopia, thinking disorders, coordination disorders, dizziness, lethargy, stupor, arterial hypotension, abdominal pain, dizziness, agitation and depression, metabolic acidosis. In most cases, the clinical consequences were not severe, but there were deaths after an overdose using a mixture of several medicines, including topiramate. There is a known case of overdose with topiramate in a dose of up to 110 g, which led to coma for 20-24 hours, and then in 3-4 days a complete recovery.

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 studies in vitro it was shown that Activated carbon adsorbs topiramate.

Hemodialysis is the most effective 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 steady concentrations in the plasma, except for individual patients in whom 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 specific polymorphic isoform of the enzyme of the cytochrome P450 system (CYP2Cmeph). 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 topiramate to lamotrigine did not affect the equilibrium concentration of the latter at doses of topiramate 100-400 mg per day. During treatment and after lamotrigine withdrawal (average dose of topiramate 327 mg / day), the equilibrium concentration of topiramate did not change.

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 joint 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 initiation of joint administration of valproic acid and topiramate, and with an increase in the dose of topiramate.

The results of interaction with antiepileptic drugs are presented in Table 2.

Table number 2. Interaction of topiramate and other PEPs

PEP	Concentration of PEP in blood plasma	Concentration of topiramate in blood plasma
Phenytoin	↔/(noextinction concentration in isolated cases)	↓ (48%)
Carbamazepine	↔	↓(40%)
Valproic acid	↔	↔
Phenobarbital	↔	NO
Primidone	↔	NO
Lamotrigine	↔ (with a dose of topiramate up to 400 mg / day)	↓(13%)

↔ - a change in plasma concentration of less than 10%;

↑ - increased concentration in individual patients;

↓ - decrease in the concentration in the blood plasma;

NO - not investigated.

Other drug interactions

Digoxin: in a study using a single dose of digoxin, the area under the concentration / time curve (AUC) digoxin in plasma with simultaneous administration of topiramate decreased by 12%. The clinical significance of this observation is not clear. When prescribing or canceling topiramate, patients receiving digoxin, special attention should be paid to monitoring the serum digoxin concentration.

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

St. John's worts perforated: with the joint administration of topiramate and preparations of St. John's wort, the concentration of topiramate in the blood plasma may decrease, and as a consequence, the effectiveness of the drug may also decrease. Clinical studies of drug interaction Topiramate and preparations based on St. John's wort have not been perforated.

Oral contraceptives: in the study of drug interaction with oral contraceptives in which a combined preparation containing norethisterone (1 mg) and ethinyl estradiol (35 μg), topiramate in doses of 50-800 mg per day did not render a significant line on the effectiveness of norethisterone and in doses of 50-200 mg per day on the effectiveness of ethinylestradiol. A significant dose-dependent decrease in the efficacy of ethinylestradiol was observed with doses of topiramate 200-800 mg per day. The clinical significance of the described changes is not clear. The risk of reducing the effectiveness of contraceptives and strengthening breakthrough bleeding should be considered in patients taking oral contraceptives in combination with topiramate. Patients taking estrogen-containing contraceptives should inform the attending physician about any changes in the timing and nature of menstruation. The effectiveness of contraceptives can be reduced even in the absence of breakthrough bleeding.

Lithium: in healthy volunteers there was a decrease AUC lithium by 18% with the simultaneous administration of topiramate at a dose of 200 mg per day. In patients with manic-depressive psychosis, the use of topiramate at doses up to 200 mg per day did not affect the pharmacokinetics of lithium, but at higher doses (up to 600 mg per 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.

Risperidone: studies of drug interactions performed with a single and repeated administration of topiramate to healthy volunteers and a manic-depressive psychosis patient yielded the same results. With simultaneous application of topiramate in doses of 250 or 400 mg per day AUC risperidone, taken in doses of 1-6 mg per day, decreased by 16% and 33%, respectively. 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 systemic effects of risperidone / 9-hydroxyrisperidone and topiramate was not clinically significant, and this interaction is unlikely to be of clinical significance.

Hydrochlorothiazide: drug interaction was evaluated in healthy volunteers with separate and co-administered hydrochlorothiazide (25 mg) and topiramate (96 mg). The results of the studies showed that with the simultaneous administration of topiramate and hydrochlorothiazide, the maximum concentration of topiramate increased by 27% and the area under the curve of the concentration of topiramate increased by 29%. The clinical significance of these studies has not been revealed.The administration of hydrochlorothiazide to patients receiving topiramate, may require adjustment of the dose of topiramate. The pharmacokinetic parameters of hydrochlorothiazide did not undergo significant changes with concomitant therapy with topiramate.

With simultaneous application of topiramate and metformin there was an increase in C_m_Ohand AUC metformin at 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 with simultaneous application with metformin decreased. 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 case of addition or withdrawal of Topiramate in patients receiving metformin carefully monitor the course of diabetes.

With simultaneous application pioglitazone and topiramate was found to decrease AUC pioglitazone by 15%, without change in C_m_Ohpioglitazone. These changes were not statistically significant. Also for the active hydroxy metabolite of pioglitazone, a decrease in C_m_Oh and AUC at 13 and 16%, respectively, and for the active ketometabolite, a decrease in C_m_Oh and AUC by 60%. The clinical significance of these data is not clear. In the case of co-administration of Topiramate and pioglitazone, the course of diabetes mellitus should be closely monitored.

When applying glibenclamide (5 mg per day) in isolation or simultaneously with topiramate (150 mg per day) in patients with type 2 diabetes mellitus AUC Glibenclamide decreased by 25%. The systemic exposure of 4-trans-hydroxyglybene clamid and 3-cis-hydroxyglybene clamamide was also reduced by 13 and 15%, respectively. Glibenclamide did not affect the pharmacokinetics of topiramate in the equilibrium state. When appointing patients with glibenclamide and topiramate simultaneously, it is necessary to take into account possible pharmacokinetic interaction and carefully monitor the condition of patients to assess the course of diabetes mellitus.

Other drugs: should avoid the simultaneous use of topiramate with drugs that predispose to nephrolithiasis, because of the increased risk of kidney stones.

Additional studies of drug interactions are presented in Table 3.

Table number 3. The results of additional studies on the interaction between topiramate and various medicines (LP).

Medicinal preparation (LP)	Concentration of LP in blood plasma^a	Concentration of topiramate in blood plasma^a
Amitriptyline	increase in C_m_Oh and AUC metabolite of nortriptyline by 20%	NO
Dihydroergotamine (inside and subcutaneous injection (SC))	↔	↔
Haloperidol	enlargement AUC metabolite by 31%	NO
Propranolol	increase in C _m_Oh for 4-OH propranolol by 17% (topiramate 50 mg)	increase in C_m_Oh by 9%, an increase AUC by 16% (propranolol 40 and 80 mg every 12 hours)
Sumatriptan (inside and c / k)	↔	NO
Pisotifen	↔	↔
Diltiazem	decrease AUC diltiazem by 25% and deacetylldithiasem by 18%, and for N-detylldithiazema	enlargement AUC by 20%
Venlafaxine	↔
Flunarizine	enlargement AUC by 16% (50 mg every 12 hours)^b	↔

^a - expressed in% of the values of C _m_Ohin blood plasma and AUC with monotherapy;

↔ - no change in C _m_Oh in blood plasma and AUC (up to 15% of the initial data);

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

NO - not investigated.

Special instructions:Antiepileptic drugs, including topiramate, should be abolished gradually to minimize the possibility of an increase in the frequency of seizures. If by medical indications need a rapid abolition of topiramate, then it is necessary to carry out appropriate monitoring of the patient's condition.

As with any disease, the dose selection scheme should focus on the clinical effect and take into account the fact that patients with impaired renal function to establish a stable concentration of topiramate in plasma for each dose may need a longer time (10 to 15 days, in contrast to 4-8 days in patients with normal renal function). The rate of excretion through the kidneys depends on the function of the kidneys and does not depend on age. In therapy with topiramate, an adequate increase in the amount of fluid consumed is very important, which can reduce the risk of developing nephrolithiasis, as well as side effects that may occur under the influence of physical exertion or high temperatures. Mood disturbance / depression and suicidal attempts.

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

During clinical trials in patients with epilepsy with topiramate, cases associated with an increase in suicidal activity (suicidal ideation, suicide attempts and completed suicide) were observed with the use of topiramate: the incidence was 0.5% in patients receiving 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, and patient care staff should be informed about the need to consult a doctor if they have signs of suicidal tendencies and suicidal behavior.

Patients with any personality disorder need special control,

especially at the beginning of treatment with topiramate.

Nephrolithiasis

In patients with a predisposition to nephrolithiasis, the risk of kidney stones is increased,for the prevention of which an adequate increase in the amount of liquid consumed is necessary. Risk factors for developing nephrolithiasis are nephrolithiasis in history (including family history), hypercalciuria, concomitant therapy with drugs that contribute to the development of nephrolithiasis.

Impaired renal function

Care should be taken when prescribing the drug Topiramate patients with renal insufficiency (creatinine clearance <70 ml / min). This is due to the fact that in such patients the clearance of the drug is lowered.

Impaired liver function

In patients with impaired liver function topiramate should be taken cautiously due to the possible decrease 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 visual acuity and / or eye pain. In ophthalmological examination, myopia, flattening of the anterior chamber, hyperemia (reddening of the eyes) and increased intraocular pressure are detected, and also mydriasis.The described syndrome can be associated with supraciliary ejaculation, which causes a shift in the lens and iris and the development of secondary closed-angle glaucoma. Typically, symptoms occur after a month of primary therapy. Unlike primary open-angle glaucoma, which was rarely detected in patients under 40 years of age, secondary closed angle glaucoma associated with the use of topiramate was observed in both children and adults. Treatment provides for drug cancellation Topiramate, if the doctor considers it appropriate, and taking appropriate measures to reduce intraocular pressure. Increased intraocular pressure in the absence of adequate treatment can lead to serious complications, including loss of vision.

Metabolic acidosis

When topiramate is used, hyperchloremic, not associated with an anion deficiency, metabolic acidosis may occur. Such a decrease in serum bicarbonate concentration is a consequence of the inhibitory effect of topiramate on renal carboanhydrase. In most cases, the decrease in the concentration of hydrocarbonates in the blood plasma occurs at the beginning of the administration of topiramate, although this effect can occur in any period of treatment with the drug Topiramate. Reducing the concentration of hydrocarbonates in the blood plasma is usually weak or moderate (mean plasma concentration 4 mmol / L when administered in adults at a dose of more than 100 mg / day and in children at a dose of about 6 mg / kg / day). Reducing the concentration of hydrocarbonates in the blood plasma less than 10 mmol / l was noted in rare cases. Some diseases or methods of treatment that predispose to the development of acidosis (e.g., renal disease, severe respiratory disease, status epilepticus, diarrhea, surgery, increased formation of ketone bodies in the body, taking certain medications) may be additional factors enhancing bicarbonate-reducing effect of topiramate. Chronic metabolic acidosis increases the risk of developing nephrolithiasis. In children, chronic metabolic acidosis can cause osteomalacia and lead to a slowdown in growth. The effect of topiramate on growth and possible complications of the bone system in children has not been systematically studied in children and adults.

In the treatment of topiramate, the necessary studies should be carried out, including the determination of the concentration of hydrocarbonates in the blood serum.When there is metabolic acidosis and its persistence, it is recommended to reduce the dose or stop taking the drug. Enhanced nutrition

If the patient loses weight when taking topiramate, then it is necessary to consider the feasibility of enhanced nutrition.

In the treatment with topiramate, the occurrence of oligohydrosis or anhidrosis is possible. Reducing sweating and hyperthermia can occur in children exposed to high ambient temperatures. In this connection, adequate fluid intake, which can reduce the risk of side effects, including nephrolithiasis, is very important.

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:Film coated tablets 25 mg and 100 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and foil of aluminum printed lacquered or 100 tablets per can of polymer. For 1,2, 3, 4, 5 contour mesh packages or one jar together with the instruction for use is placed in a pack of cardboard.

Storage conditions:Store in a dark 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 expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002577

Date of registration:13.08.2014

Date of cancellation:2019-08-13

The owner of the registration certificate:ALSI Pharma, ZAO ALSI Pharma, ZAO Russia

Manufacturer: & nbsp

ALSI Pharma, ZAO Russia

Information update date: & nbsp30.09.2015

Illustrated instructions

Instructions

Topiramate (Topiramate)