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

Active substance:
Topiramate	15 mg	25 mg	50 mg
Excipients: [Sugar spheres	63.3 mg	105.5 mg	211.0 mg
{Sucrose (sugar)	39.56-57.92 mg	65.94-96.53 mg	131.87-193.06 mg
Corn starch}	23.74-5.38 mg	39.56-8.97 mg	79.13 to 17.94 mg
Povidone K17 (polyvinylpyrrolidone)	2.8 mg	4.7 mg	9.4 mg
Cellulose acetate]	2.9 mg	4.8 mg	9.6 mg
Weight of the contents of the capsule:	84 mg	140 mg	280 mg
Hard gelatin capsules For capsules the case is transparent, colorless [Gelatin]	up to 100%
White colored lid [Titanium dioxide E 171	2,0%	_	_
Gelatin]	up to 100%	-	-
For capsules transparent, colorless [Gelatin]		up to 100%
For white capsules [Titanium dioxide E 171			2,0%
Gelatin]	-	-	up to 100%
Weight of filled capsules:	145.0 mg	216.0 mg	376.0 mg

Description:

Hard gelatin capsules №2: transparent, colorless, white lid (for dosage 15 mg), № 1 transparent, colorless (for dosage of 25 mg); No. 0: white (for a dosage of 50 mg).

The contents of capsules are small granules 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 belongs to the class of sulfamate-substituted monosaccharides. The precise mechanism by which topiramate has anticonvulsant and anti-migraine effects, is not known. Based on the results of electrophysiological and biochemical studies on the culture of neurons, three properties have been identified that can contribute to the anticonvulsant activity of topiramate.

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials that occur against the background of a prolonged depolarization of the neuron membrane. Topiramate increases the activity of y-aminobutyric acid (GABA) against GABA_Areceptors and increases the ability of GABA to increase the current of chloride ions into neurons, thus topiramate potentiates the activity of this inhibitory neurotransmitter.

This effect is not blocked by flumazenil, a benzodiazepine receptor antagonist. Topiramate does not increase the duration of the channels in the open state, which distinguishes it from barbiturates, which modulate GABA activity_Areceptors.

Since the anticonvulsant effect of topiramate differs significantly from that of benzodiazepines, it is able to modulate the actions of GABA subtypes_Areceptors that are not sensitive to benzodiazepines. Topiramate prevents activation of kainate with the kainate / AMPK subtype (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) - glutamate receptors, does not affect activity N-methyl-O-aspartate (NMDA) with respect to the subtype NMDAglutamate receptors. These effects of topiramate depend on its plasma concentration in the range of 1-200 μmol / l, with a minimum activity within 1-10 μmol / l.

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 carbonic anhydrase, therefore this activity of topiramate is not considered to be the main component of its anticonvulsant 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 in rats, tonic-clonic convulsions caused by 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.

Absenses

Two small studies with one group in children 4-11 years old (CAPSS-326 and TORAMAT- Abs-001). One included 5 children, and the second - 12, until it was prematurely completed due to lack of therapeutic effect. Doses in the study of TORAMAT- Abs-001 were approximately 12 mg / kg and the maximum of two 9 mg / kg / day or 400 mg / day in the study CAPSS-326. The studies served as sufficient evidence of the efficacy or safety of topiramate in children.

Pharmacokinetics:

Compared with other anticonvulsants, topiramate has a long half-life, linear kinetics, preferential renal clearance, low association with plasma proteins and the absence of clinically significant active 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 or undesirable reactions has 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_mOh) in healthy volunteers is 1.5 mg / ml and is achieved within 2-3 hours (T_mOh).

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 the body of 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 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 total plasma clearance of topiramate in humans is approximately 20-30 ml / min.

Topiramate has a low interindividual variability 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, the plasma clearance remains constant, and the area under the "concentration-time" curveAUC) increases in proportion to the dose. Time to reach equilibrium concentration in patients with normal renal function is 4-8 days. Average C_mOhafter 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 the plasma increased in proportion to the dose.

In patients with impaired renal function moderate and severe (creatinine clearance <70 ml / min), the plasma and renal clearance of topiramate is reduced. 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 correcting the dose, one should take into account: the duration of hemodialysis, 2) the clearance of the hemodialysis system used, and 3) the effective renal clearance of topiramate in the patient on dialysis.

In patients with hepatic insufficiency moderate or severe, 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 diseases 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 liver enzymes cause a decrease in equilibrium plasma concentrations.

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 combination therapy in adults and children from 2 years with partial (with or without secondary generalization) or generalized tonic-clonic seizures, as well as for the treatment of seizures 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 other component of the drug.

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

Patients with rare hereditary disorders, such as fructose intolerance, glucose-galactose malabsorption or insufficiency of isomaltase sucrose, should not be taken.

Children under 6 years of age with monotherapy and up to 2 years in combination therapy.

Carefully:

Renal / hepatic failure, nephrourolythiasis, 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 Registry of Pregnancy "Antiepileptic drug of North America", infants exposed to intrauterine exposure to topiramate monotherapy in the first trimester have a higher risk of developing congenital malformations (for example, facial skull defects such as cleft 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. There is evidence of an increase in the relative number of infants who are underdeveloped for their gestational age (NHA,is defined as the birth weight below the 10th percentile with an adjustment for gestational age and stratification by sex), among infants exposed to the infertility of the stomatitis in utero. Long-term consequences of NGAs are not defined. The reason for the decrease in body weight at birth and NGV is not established. 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.

Since many drugs penetrate into breast milk, you must either stop taking topiramate, or stop breastfeeding, and the importance of the drug to the mother (see "Special instructions") should be taken into account.

In studies in animals, no effect of topiromate on fertility was found. The effect of topiramate on fertility in humans is not established.

Epilepsy

Topiramate in pregnancy should be prescribed after complete informationwomen about the known risks of uncontrolled epilepsy for pregnancy and the potential risks of the drug for the fetus.

Prevention of migraine

Topiramate is contraindicated during pregnancy or in women of childbearing age who do not use reliable methods of contraception (see the sections "Contraindications" and "Interaction with other medicinal products").

Dosing and Administration:

General recommendations

It is recommended to start treatment with a low dose and gradually increase it 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.

The medicinal preparation Topiromax® is presented in capsules. Capsules are intended for patients who can not swallow a pill, for example, children and the elderly.

Capsules of topiramate may be swallowed whole or taken by carefully opening the capsule and pouring all its contents onto a small portion (teaspoon) of soft food. The mixture of the drug should be immediately swallowed without chewing. Storage for future reception is not allowed.

Monitoring the concentration of topiramate to optimize drug therapy is not required.In rare cases, the simultaneous use of topiramate and phenytoin may require a dose adjustment of the latter. Adding or abolishing phenytoin or carbamazepine with combined therapy with topiramate may require a dose adjustment of the latter.

Topiramate can be taken regardless of food intake.

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 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.

Monotherapy for epilepsy

General Provisions

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

When choosing a dose and its correction should be guided by a clinical response. Treatment should be started with a dose of 25 mg per night 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 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.

The recommended initial dose for monotherapy with topiramate in adults is 100-200 mg / day, divided into 2 doses. The maximum daily dose should not exceed 500 mg in 2 divided doses. Some patients with refractory forms of epilepsy are tolerated by topiramate monotherapy in doses up to 1000 mg per day. The presented recommendations on dosing apply to all adults, including elderly patients without concomitant renal failure.

Children from 6 years old

When choosing a dose and its correction should be guided by a clinical response.In children from 6 years of age in the first week of treatment, the dose of topiramate is 0.5-1 mg / kg of body weight before bedtime. Then the dose is increased with an interval of 1-2 weeks at 0.5-1 mg / kg / day (daily dose divided into 2 divided doses). If the child 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. Depending on the clinical effect, the recommended initial dose for monotherapy with topiramate in children from 6 years is 100 mg / day (corresponding to approximately 2 mg / kg / day for children 6-16 years).

Treatment of epilepsy in combination therapy (partial with secondary generalization or without, or generalized tonic-clonic convulsions, convulsions, caused by the Lennox-Gastaut syndrome)

Adults

Treatment should begin with a dose of 25-50 mg per night for 1 week. It is possible to start taking from lower doses, but this has not been properly studied. Then the dose is increased at intervals of 1-2 weeks by 25 or 50 mg (daily dose divided into two doses). In some patients, anticonvulsant effect can be achieved with taking topiramate 1 time per day.

The minimum effective dose for clinical trials is 200 mg / day. Usually the total daily dose is 200-400 mg in 2 divided doses.The presented recommendations on dosing apply to all adults, including elderly patients without concomitant renal failure (see section "Special instructions").

Children from 2 years old

The recommended total daily dose of topiramate in complex therapy is from 5-9 mg / kg in 2 divided doses. Treatment should begin with 25 mg (or less, based on an initial dose of 1-3 mg / kg / day) overnight for 1 week. Then the dose is increased at intervals of 1-2 weeks at 1-3 mg / kg / day (the daily dose is divided into 2 doses) until the optimal clinical effect is achieved.

Daily doses up to 30 mg / kg / day, which were well tolerated, were studied.

Prevention of migraine

Adults

The recommended total daily dose of topiramate for prevention of migraine attacks is 100 mg in 2 divided doses. Treatment should be started with a dose of 25 mg per night for 1 week. Then the dose is increased with an interval of 1 week at 25 mg per 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.

In some patients, a positive result is achieved with a daily dose of topiramate 50 mg. In clinical studies, patients received various daily doses of topiramate, but not more than 200 mg per day.In some patients, this dose can be effective, but caution should be exercised when it is used because of the increased incidence of adverse reactions.

Children

Due to insufficient data on efficiency and safety topiramate It is not recommended for the treatment or prevention of migraine in children.

Special patient groups

Renal insufficiency

In patients with renal insufficiency (CC <70 ml / min) topiramate should be administered with caution, as its plasma and renal clearance decreases. Patients with concomitant renal dysfunction may need more time to achieve an equilibrium state at each dose selection stage. It is recommended to take half the recommended initial and maintenance dose (see section "Pharmacokinetics").

Because the topiramate is removed from the plasma during hemodialysis, in the days of its administration, an additional dose of topiramate, equal to about half the daily dose, should be taken. The additional dose should be divided into two doses, taken at the beginning and after completion of hemodialysis. The additional dose may vary depending on the characteristics of the equipment for hemodialysis (see the section "Pharmacokinetics").

Liver failure

Patients with hepatic impairment of moderate to severe topiramate Use with caution, as its clearance is reduced.

Elderly

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

Side effects:

Safety of application of topiramate for all indications for use was studied on the clinical database of 4111 patients (3182 took topiramate, 929 - placebo), participated in 20 double-blind clinical trials, 2,847 patients participated in 34 open-label studies. Most adverse reactions were mild or moderate. Undesirable reactions identified in clinical trials and following the results of postgastrial follow-up (marked with "*") are presented in Table 1.

Grouping the frequency of unwanted reactions:

very often: ≥1 / 10

often: ≥ 1/100, <1/10

infrequently: ≥ 1/1000, <1/100

rarely: ≥ 1/10000, <1/1000

the frequency is unknown: according to the available data, the frequency can not be estimated.

The most common adverse reactions (with a frequency of ≥5% compared with the placebo group, observed in at least 1 double-blind controlled study): anorexia,loss of 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.

Table 1. Undesirable reactions of topiramate

System-Organ Class	Often	Often	Infrequently	Rarely	Frequency unknown
Infections and invasions	Rhinopharyngitis *
From the hematopoietic and lymphatic system		Anemia	Leukopenia, thrombocytopenia, lymphadenopathy eosinophilia	Neutropenia *
From the immune system		Hypersensitivity			Angioedema *
From the side of metabolism and nutrition		Anorexia, fall appetite	Metabolic acidosis, hypokalemia, rise appetite, polydipsia	Hyperchloremic acidosis
From the side of the psyche	Depression	Slowed down thinking, insomnia, slurred speech, anxiety, confusion consciousness, disorientation, aggressiveness, change mood, agitation, emotional lability, depressive mood, anger, violation of behavior	Suicidal thoughts, suicidal attempts, hallucinations (including auditory and visual), psychotic disorders, apathy, labored speech, sleep disorders, emotional lability, decline libido, nervousness, crying, dysphemia, euphoria, paranoia, perseveration thinking, panic attack, tearfulness, violation of reading skills, violation of falling asleep, emotional cold, pathological thinking, lack of libido, lethargy, intrasomal disorder, absent-mindedness, early morning awakening, panic reaction, upbeat mood	Mania, panicky disorder, feeling desperation *, hypomania
From the nervous system	Paresthesia, drowsiness, dizziness	Violation concentration of attention, violation of memory, amnesia, violation of cognitive functions, violation of thinking, violation of psychomotor skills, convulsions, violation of coordination of movements, tremor, retardation, hypoesthesia, nystagmus, dysgeusia, disturbance of balance, dysarthria, intentional tremor, sedation	Oppression consciousness, tonic-clonic seizures of the type "grand mal", narrowing of the fields of vision, complex partial seizures, speech disturbance, psychomotor excitation, fainting, sensory violations, salivation, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness, poor quality of sleep, burning sensation, loss of sensitivity, parosmia, cerebellar syndrome, dysesthesia, hypogeous, stupor, clumsiness, aura, agenesia, dysgraphy, dysphasia, peripheral neuropathy, pre-obstruction, dystonia, sensation of "goosebumps" in the body	Apraxia, violation of circadian rhythm of sleep, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, lack of reactions to stimuli
From the side of the organ of vision		Violation view, diplopia, indistinctness visual perception	Reduction of visual acuity, scotoma, myopia, pathological sensations in the eye , dry eyes, photophobia, blepharospasm, increased lacrimation, photopsy, mydriasis, presbyopia	One-sided blindness, transitory blindness, glaucoma, violation of accommodation, violation of binocular vision, ciliary scotoma, swelling of the eyelids *, night blindness, amblyopia	Closed-angle glaucoma , maculopathy , impaired eye movement , edema of the conjunctiva
From the side of hearing and labyrinth		Vertigo, tinnitus, ear pain	Deafness, one-sided deafness, sensorineural hearing loss, discomfort in the ear, hearing loss
From the heart			Bradycardia (including sinus), sensation palpitation
From the side of the vessels			Orthostatic hypotension, hypotension, "tides"	The Reynaud phenomenon
on the part of the respiratory system, the organs of the thorax and the mediastinum		dyspnea, nasal bleeding, obstruction nose, rhinorrhea, cough	dyspnea with physical activity, hypersecretion paranasal sinuses, dysphonia
from the gastrointestinal tract	nausea, diarrhea	vomiting, constipation, pain in epigastrium, dyspepsia, abdominal pain, dry mouth, discomfort in the abdomen, paresthesia of the oral mucosa, gastritis, abdominal discomfort	pancreatitis, flatulence, gastroesophageal reflux, lower abdominal pain, hypoesthesia of the oral mucosa, bleeding gums, bloating, discomfort in the epigastrium, sensitivity in the abdomen, hypersalivation, pain in the oral cavity, unpleasant smell from the mouth, glossodynia
from the liver and biliary tract				hepatitis, liver failure
from the skin and subcutaneous tissues		alopecia, rash, itching	anhidrosis, hypoesthesia in the face, hives, erythema, generalized itching, macular rash, violation of skin pigmentation, allergic dermatitis, swelling of the face	syndrome Stevens-jonson , polymorphic erythema, unpleasant smell of the skin, periorbital edema *, focal hives	toxic epidermal necrolysis *
from the musculoskeletal system		arthralgia, muscle spasm, myalgia, muscle cramps, muscle weakness, pain in the muscles of the chest	swelling of the joints *, stiffness, osteo-muscle pain in the side, muscle fatigue	discomfort in the extremities *
from the kidneys and urinary tract		nephrolithiasis, pollakiuria, dysuria	exacerbation of urolithiasis (kidney stones), urinary incontinence, incl. at a voltage, hematuria, frequent urge to urinate, renal colic, pain in the kidney	exacerbation of urolithiasis (stones in the urethra), renal tubular acidosis
from the genitals and breast			violation of erections, violation of sexual function
General violations and violations at the site of administration	fatigue	fever, asthenia, irritability, gait disturbance, poor health, anxiety	hyperthermia, thirst, influenza-like syndrome, slowness, asthenia, cold snap limbs, sensation intoxication, sensation anxiety	swelling of the face, calcification
from laboratory-instrumental indicators	weight loss	weight gain *	crystalluria, abnormal test result "tandem-gait", leukopenia, rise activity of "liver" enzymes	decrease in serum bicarbonate levels
social circumstances			impaired ability to learn

* revealed by the results of spontaneous messages in the post-registration period. the frequency is calculated from clinical studies.

dNoand

undesirable reactions, which according to the results of double-blind clinical trials were 2 and more times more common in children than in adults: a decrease in appetite,increased appetite, hyperchloremic acidosis, hypokalemia, impaired behavior, aggression, apathy, sleep disturbance, suicidal thoughts, impaired concentration, inhibition, disturbance of circadian 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, impaired ability to learn.

Overdose:

Symptoms

Signs and symptoms of overdose with topiramate: convulsions, drowsiness, speech and vision impairment, diplopia, thinking disorders, coordination disorders, lethargy, stupor, impaired thinking, drowsiness, impaired coordination of movements, lowering blood pressure, abdominal pain, agitation, dizziness and depression. 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 Table 1).section "Special instructions").

Treatment

In case of acute overdose with topiramate, if the patient has recently taken the drug, immediately wash the stomach or induce vomiting. In studies in vitro shown, that Activated carbon adsorbs topiramate. If necessary, symptomatic therapy should be provided and adequate hydration ensured. An effective way to remove topiramate from the body is hemodialysis.

Interaction:

Influence of topiramate on other anticonvulsants (PSS)

Simultaneous application of topiramate with other PSS (phenytoin, carbamazepine, valproic acid, phenobarbital, primidon) does not affect their equilibrium concentration in plasma; In exceptional cases, in some patients, the addition of topiramate to phenytoin may cause an increase in plasma concentration in the plasma. This may be due to the inhibition of a certain isoform of the polymorphic isoenzyme CYP2C19. Therefore, every patient who receives phenytoin, which develops clinical signs or symptoms of toxicity, 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 / day. In addition, during therapy and after lamotrigine withdrawal (average dose 327 mg / 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, moclobemide, proguanil, omeprazole).

The effect of other anticonvulsants on topiramate

Phenytoin and carbamazepine reduce the plasma concentration of topiramate. Adding or abolishing phenytoin or carbamazepine to topiramate therapy may require a change in the dose of the latter. The dose should be selected, focusing on the clinical effect. The addition or withdrawal of valproic acid does not cause clinically significant changes in the plasma concentration of topiramate and, therefore, does not require correction of the dose of the latter. The results of the described interactions are presented below:

The added MSS	Concentration of MSS	Concentration of topiramate
Phenytoin	↔**	↓ (48 %)
Carbamazepine	↔	↓ (40 %)
Valproic acid	↔	↔
Phenobarbital	↔	NO
Primidone		NO

↔ no effect

** - increased concentration in individual patients

↓ decrease in plasma concentration

NO - not investigated

PSS is an anticonvulsant

Other drug interactions

Digoxin

In a single-dose study AUC digoxin in plasma with simultaneous administration of topiramate decreased by 12%. The clinical significance of this finding is unknown. When prescribing or canceling topiramate, patients receiving digoxin, it is necessary to pay special attention to monitoring the plasma concentration of the latter.

The drugs that oppress the central nervous system

In clinical trials, the effects of simultaneous administration of topiramate with alcohol or other agents that depress the central nervous system have not been studied. The simultaneous use of topiramate with alcohol or other agents that depress the central nervous system is not recommended.

St. John's wort perforated

With the simultaneous application of St. John's wort and topiramate, there may be a decrease in plasma concentration and the effectiveness of the latter. Clinical studies aimed at studying such interactions have not been conducted.

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, a statistically significant decrease in ethinyl estradiol (by 18, 21 and 30%, respectively) was noted in patients with epilepsy. 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 of reducing contraceptive protection and enhancing "breakthrough" bleeding.Patients taking estrogen-containing contraceptives should be informed of any changes in the timing and nature of menstruation. The effectiveness of contraceptives can be reduced even in the absence of "breakthrough" bleeding.

Lithium

With the simultaneous use of topiramate at a dose of 200 mg / day and lithium in healthy volunteers, there was a decrease AUC the latter by 18%. In patients with bipolar 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.

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 administration of topiramate in increasing doses: 100, 250 and 400 mg / day AUC risperidone taken in doses of 1-6 mg per day, decreased by 16 and 33%, respectively (with doses of topiramate 250 and 400 mg / day). However, the differences in the overall AUC between treatment with a single risperidone and risperidone in combination with topiramate were statistically insignificant. The pharmacokinetics of the total antipsychotic fraction (risperidone and 9-hydroxyrisperidone) changed insignificantly, the pharmacokinetics of 9-hydroxyrisperidone did not change. There were no significant changes in the systemic effect of risperidone / 9-hydroxyrisperidone and topiramate. When adding topiramate to risperidone therapy (1-6 mg / day), unwanted reactions were recorded more often than with treatment with topiramate (250 ^ 100 mg / day): 90 and 54%, respectively. The most frequent undesirable 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 C_mOh topiramate by 27% and its AUC on 29%. The clinical significance of the results of these studies is not established.The administration of hydrochlorothiazide to patients receiving topiramate, may require a correction of the dose of the latter. With concomitant therapy with topiramate, the equilibrium pharmacokinetic parameters of hydrochlorothiazide did not undergo significant changes. 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

Drug interaction was assessed in healthy volunteers who received metformin or a combination of metformin and topiramate. The results of the studies showed that with the simultaneous administration of topiramate and metformin, an increase in C_mOh and AUC_0-12h the latter by 18 and by 25%, respectively, whereas the clearance of metformin decreases by 20%. Topiramate does not affect T_mOh metformin. The clinical significance of the change in the pharmacokinetics of metformin under the influence of topiramate is not known. With simultaneous administration with metformin, the total plasma clearance of topiramate decreases. The significance of this phenomenon is not known.The clinical significance of the effect of metformin on the pharmacokinetics of topiramate has not been studied.

When adding or removing topiramate, patients receiving metformin, you should carefully monitor their condition in order to properly control diabetes.

Pioglitazone

Drug interaction was evaluated in healthy volunteers with separate and simultaneous use of pioglitazone and topiramate. There was a decrease in the equilibrium AUC_t pioglitazone by 15%, without changing the equilibrium C_mOh. These changes were not statistically significant. The active hydroxy metabolite of pioglitazone also showed a decrease in equilibrium C_mOh and AUC_t by 13 and 16%, respectively, and for active ketometabolite, the decrease in equilibrium C_mOh and AUC_t was 60%. The clinical significance of this data is not established. With the simultaneous use of topiramate and pioglitazone, you should carefully monitor their condition for proper control of diabetes mellitus.

Glibenclamide

A study was made of the pharmacokinetic drug interaction of glibenclamide (5 mg / day) in an equilibrium state, applied alone or simultaneously with topiramate (150 mg / day) in patients with type 2 diabetes mellitus. When topiramate is used AUC₂₄_hGlibenclamide decreased by 25%. Systemic exposure of 4-trans-hydroxyglybeneclamide (Ml) and 3-cis-hydroxyglybeneclamide (M2) also decreased (by 13 and 15%, respectively). Glibenclamide did not affect the pharmacokinetics of topiramate in the equilibrium state.

When prescribing topiramate for patients receiving glibenclamide (or the administration of glibenclamide to patients receiving topiramate), you should carefully monitor their condition for proper control of diabetes.

Other forms of interaction

Medications predisposing to the development of nephrolithiasis

With the simultaneous use of topiramate with drugs that predispose to the development of nephrolithiasis, may increase the risk of urolithiasis. In the treatment of topiramate, the use of drugs predisposing to the development of nephrolithiasis should be avoided, since they can cause physiological changes that contribute to the formation of urinary stones.

Valproic acid

The combined use of topiramate and valproic acid in patients who tolerate each drug individually,accompanied by hyperammonemia with encephalopathy or without it. In most cases, symptoms and symptoms disappear after the withdrawal of one of the drugs. This undesirable phenomenon is not due to 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 onset of simultaneous administration of valproic acid and topiramate, and with an increase in the daily dose of the latter.

Additional studies of drug interactions

In order to evaluate the potential drug interactions between topiramate and other drugs, a number of clinical studies have been carried out. Below are the changes in C_mOh and AUC due to such interactions. In the second column (the concentration of the drug to be added), the direction of the change in the concentration of the drug indicated in the first column is described, while it is applied to the topiramate.The third column (the concentration of topiramate) describes the direction of the change in the concentration of topiramate under the influence of the added drug.

Summary of pharmacokinetic studies of drug interactions

Adding medicinal product	Concentration of the added drug^a	Concentration of topiramate^a
Amitriptyline	increase in C_mOh and AUC metabolite (nortriptyline) by 20%	not investigated
Dihydroergotarmine (oral and subcutaneous)	↔	↔
Haloperidol	enlargement AUC metabolite by 31%	not investigated
Propranolol	increase in C_mOh 4-hydroxypropranolol on 17% (topiramate 50 mg)	increase in C_mOh by 9 and 16%, an increase AUC by 9 and 17%, respectively (for propranol 40 and 80 mg every 12 hours)
Sumatriptan (oral and subcutaneous)	↔	not investigated
Pisotifen	↔	↔
Diltiazem	decrease AUC diltiazem by 25% and deacetylldithiasem by 18% and ↔ N- demethylldithiazema	enlargement AUC by 20%
Venlafaxine	↔	↔
Flunarizine	enlargement AUC by 16% (50 mg every 12 hours)^b	↔

^a expressed in% of C_mOh and AUC with monotherapy

↔ no change in C_mOh and AUC (≤15% of the original data)

^bWith multiple administration of a single flunarizine, there was an increase in AUC by 14%, which may be due to the accumulation of the drug in the process of reaching the equilibrium state.

Special instructions:

Antiepileptic drugs should be withdrawn gradually to minimize the possibility of increasing the frequency of seizures. If it is necessary to quickly cancel therapy for patients, appropriate control should be established (see the section "Dosing and Administration").

As with other anticonvulsants, at the beginning of topiramate use, the incidence of seizures may increase or a new type of cramp 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.

Patients with moderate or severe renal dysfunction to achieve stable plasma concentrations may need 10 to 15 days, in contrast to 4-8 days in patients with normal renal function. As with any disease, the dose selection scheme should focus on the clinical effect (degree of control seizures, lack of side effects) and take into account the fact that patients with impaired renal function to achieve a stable plasma concentration for each dose may need a longertime.

Oligohydrosis

With the application of topiramate, the occurrence of oligohydrosis (decrease in sweating) is described. Reducing sweating and hyperthermia (increased body temperature) can be particularly vulnerable to young children who are in a high ambient temperature. 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" (subsection "Renal failure").

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 in 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 secondary closed-angle 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.

Defects of the field of view

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, disappeared after the abolition of therapy. If visually impaired, consider discontinuing therapy.

Metabolic 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 the development of acidosis (eg, kidney disease, severe respiratory disease,epileptic status, diarrhea, surgical interventions, fat-rich food, 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 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.

Depending on the underlying disease in the treatment with topiramate, it is recommended that a proper assessment of the condition is carried out, including the determination of serum bicarbonate concentration. In the presence of signs or symptoms (eg, Kussmaul breathing, dyspnea, anorexia, nausea, vomiting, excessive fatigue, tachycardia, or arrhythmia), indicating metabolic acidosis, it is recommended to measure the content of bicarbonates in the blood serum. When developing and maintaining metabolic acidosis, you should consider reducing the dose or canceling topiramate (gradually).

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

Cognitive impairment

Cognitive impairment in epilepsy is multifactorial and may be due to a causative disease, epilepsy or antiepileptic therapy. In the literature, cognitive impairment was described in adults receiving topiramate treatment, which required a reduction in dose or discontinuation of therapy. However, studies on the effect on cognitive outcomes in children taking topiramate, are insufficient, and their influence on these parameters requires further study.

Enhanced nutrition

In the treatment of topiramate, some patients may have decreased body weight. 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.

Effect on the ability to drive transp. cf. and fur:

Topiramate has a weak or moderate effect 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 may pose a potential threat to patients when driving vehicles and operating machinery, especially during the period of individual sensitivity to the drug.

Form release / dosage:

Capsules, 15 mg, 25 mg, 50 mg.

Packaging:

For 7 or 10 capsules in a contour mesh box made of a polymer film of gas-impervious and foil of aluminum printed lacquered.

For 28 or 60 capsules in a polymer bottle of high-pressure polyethylene LDPE with a polymeric cover with a control of the first opening, with an insert of silica gel.

Each vial or 4 contour packs of 7 capsules, or 6 contour packs of 10 capsules, together with the instructions for use, are placed in a pack of cardboard.

Storage conditions:

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-003565

Date of registration:13.04.2016

Expiration Date:13.04.2021

The owner of the registration certificate:VEROPHARM SA VEROPHARM SA Russia

Manufacturer: & nbsp

VEROPHARM SA Russia

Representation: & nbspVEROPHARM, AO VEROPHARM, AO Russia

Information update date: & nbsp28.06.2016

Illustrated instructions

Instructions

Topiromax® (Topiromax)