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

Excipients: microcrystalline cellulose 24.15 / 96.60 mg, lactose monohydrate 21.15 / 84.60 mg, pregelatinized starch 5.50 / 22.00 mg, carmellose sodium 4.00 / 16.00 mg, magnesium stearate 0.20 / 0.80 mg;

composition of the shell:

tablets 25 mg: opedray white 2.78 mg [titanium dioxide 0.87 mg, hypromellose-3cp 0.83 mg,

hypromellose-bsR 0.83 mg, macrogol-400 0.22 mg, polysorbate-80 0.03 mg];

tablets 100 mg: opadraj yellow 11,11 mg [titanium dioxide 2,19 mg, hypromellose-3aR 3.67

mg, hypromellose-bsR 3.67 mg, macrogol-400 0.89 mg, polysorbate-80 0.11 mg, dye iron oxide yellow 0.58 mg].

Description:

Tablets with a dosage of 25 mg.

Round, biconvex tablets covered with a film shell of white color, engraved "22" on one side and engraved "E" on the other side, stamping.

Tablets with a dosage of 100 mg.

Round, biconvex tablets, covered with a film coating of dark yellow

color, with engraving "23" on one side and engraving "E" on the other side, applied by embossing.

Pharmacotherapeutic group:Antiepileptic agent.

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.11 Topiramate

Pharmacodynamics:

Topiramate is an antiepileptic drug belonging to the class of sulfamate-substituted monosaccharides. The exact mechanisms of anticonvulsant and anti-migraine action are not known. 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 against a background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of γ-aminobutyric acid (GABA) against GABA_A- receptors 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 receptor activity.

The anticonvulsant effect of topiramate differs significantly from that of benzodiazepines: topiramate can modulate the action of subtypes of GABA receptors that are not sensitive to benzodiazepines. Topiramate (prevents the 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, spontaneous epilepsy of rats, tonic-clonic convulsions caused by the excitation of the amygdala or global ischemia. Topiramate is ineffective in clonic convulsions caused by a GABA receptor antagonist - pentylenetetrazole.

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

Pharmacokinetics:

Compared with other anticonvulsant agents, topiramate has a long half-life, linear kinetics, preferential renal clearance, low association with plasma proteins and the absence of clinically significant metabolites. Topiramate is not characterized by a powerful inducing effect on microsomal enzymes of the liver, it can be taken regardless of food intake, monitoring of the concentration of topiramate is not required. According to the results of clinical studies, the relationship between the plasma concentration of topiramate and its efficacy and 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_m_Oh) In healthy volunteers is 1.5 mg / ml and is achieved within 2-3 hours (t_max).

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

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

Metabolism

After ingestion, healthy volunteers metabolize about 20% of the dose. However, in patients taking concomitant therapy with anticonvulsants - inducers of microsomal liver enzymes, the metabolism of topiramate is increased to 50%.From the plasma, urine and human feces, six metabolites were formed and identified by hydroxylation, hydrolysis and glucuronation. The amount of each metabolite does not exceed 3% of the total radioactivity detected after administration ¹⁴C-topiramate. Two metabolites with the greatest structural similarity to topiramate have practically no anticonvulsant activity. Excretion

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

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

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

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

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

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

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

Pharmacokinetics of topiramate in children under 12 years old

The pharmacokinetics of topiramate in children, as well as in adults,taking it in the combination therapy, is linear, while the clearance of topiramate does not depend on the dose, and the equilibrium concentrations in the plasma increase in proportion to the increase in dose. However, in children the clearance of topiramate is increased, and the half-life is shorter. In this regard, at the same dose, based on 1 kg of body weight, the concentrations of topiramate in plasma in children may be lower than in adults. In children, as in adults, anticonvulsant drugs inducing microsomal enzymes of the liver cause a decrease in the concentrations of topiramate in plasma.

Indications: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, as well as 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 other component of the drug. Preventing migraine attacks during pregnancy or in women of childbearing age who do not use reliable methods of contraception.

Deficiency of lactase, intolerance to galactose, glucose-galactose malabsorption.

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

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

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

Dosing and Administration:

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.

Medicinal preparation Topiramate is a film-coated tablet.It is not recommended to break the integrity of the tablet.

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 abolition of the topiram 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 divided 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 as part of complex therapy (partial with secondary generalization or without or generalized tonic-clonic convulsions, seizures caused by 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 3 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 (daily dose divided into 2 doses) to

achieve the optimal clinical effect.

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

Topiramate is not recommended for the treatment or prevention of migraine in children (insufficient data on efficacy and safety).

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 of 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 hemodialysis equipment (see Fig.section "Pharmacokinetics").

Liver failure

Patients with hepatic impairment of moderate to severe topiramate should be

Apply with caution, as its clearance is reduced.

Elderly

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

Side effects:

The safety of the application of the topiarmate for all indications to the use was studied by clinical database of 4111 patients (3182 received topiramate, 929 - placebo), who participated in 20 double-blind clinical trials, 2847 patients participated in 34 open-label studies. Most adverse reactions were mild or moderate. Undesirable reactions identified in clinical studies and results of post-registration monitoring (marked with "*") are presented in Table 1. Grouping of the frequency of undesired reactions:

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> 5% in comparison with the placebo group, it was observed for at least 1 double-blind controlled trial): anorexia, decreased appetite, slowing of mental activity, depression, slurred speech, insomnia,impaired coordination of movements, attention disturbance, dizziness, dysarthria, taste disorders, hypoesthesia, lethargy, memory loss, nystagmus, paresthesia, drowsiness, tremor, diplopia, visual impairment, diarrhea, nausea, fatigue, irritability, weight loss.

Children

Unwanted reactions, which were> 2 times more frequent in children than in adults, as a result of double-blind clinical trials: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, impaired behavior, aggression, apathy, sleep disturbance, suicidal ideation, impaired attention, drowsiness, violation of the daily rhythm of sleep, poor sleep quality, increased lacrimation, sinus bradycardia, general unsatisfactory condition, gait disturbance.

Undesirable reactions that arise in clinical studies exclusively in children: eosinophilia, psychomotor agitation, vertigo, vomiting, hyperthermia, fever, learning disability.

Table 1. Undesirable reactions of topiramate

System-

Frequency

Organic

grade

Often

Infrequently

Rarely

unknown

Infections and invasions

Rhinopharyngitis *

From the hematopoietic and lymphatic system

Anemia

Leukopenia, thrombocytopenia,

lymphadenopathy,

eosinophilia

Neutropenia *

From the side

immune

systems

Hypersensitivity

Angioedema edema, edema

conjunctiva *

From the side of metabolism and nutrition

Anorexia,

decline

appetite

Metabolic acidosis, hypokalemia, increased appetite, polydipsia

Hyperchloro-

mantic

acidosis

From the side of the psyche

Depression

Slowdown

mental

activities,

insomnia,

indistinct

speech,

anxiety, confusion, disorientation,

aggression,

mood changes, agitation,

mood swings, depressed mood, anger, impaired behavior

Suicidal thoughts,

suicidal

attempts,

hallucinations

(including

auditory and

visual),

psychotic

disorders,

apathy,

lack of

spontaneous

speech, sleep disturbance, emotional lability,

decline

libido,

nervousness,

crying, dysphemia,

euphoria,

paranoia,

perseveration,

panic

attack,

tearfulness,

violation of

reading,

violation of

falling asleep,

emotional

cold,

violation of

thinking,

lack of

libido, apathy,

insomnia,

distraction,

early

the morning

awakening,

panic

reaction,

upbeat

mood

Mania,

panicky

disorder

, feeling

desperation *,

hypomania

From the side

nervous

systems

Paresthesia, drowsiness, vertigo

Violation of attention, memory impairment, amnesia, violation of cognitive functions, violation of mental functions, violation of psychomotor skills, convulsions, violation of coordination of movements, tremor, lethargy, hypesthesia, nystagmus, dysgeusia, imbalance, dysarthria, intentional tremor, dissection

Inhibition of consciousness, large convulsive seizures,

narrowing of fields

view,

complex

partial

seizures,

violation of

speech,

psychomotor agitation, fainting, impaired sensation,

salivation, hypersomnia, aphasia, repetition

words,

hypokinesia, dyskinesia, postural dizziness, poor quality of sleep, feeling

burning, loss of sensation, parosmia, cerebellar syndrome, dysesthesia, hypogeousia, stupor, clumsiness,

aura, agesia,

dysgraphy,

dysphasia,

peripheral

neuropathy,

pre-obstruction,

dystonia,

tingling

Apraxia, disturbance of the circadian rhythm of sleep, hyperesthesia, hyposmia, anosmia, loss of smell, akinesia, lack of response to stimuli

From the side

body

view

Violation

view,

diplopia,

indistinctness

visual

perceptions

Decrease

visual acuity,

scotoma,

myopia*,

pathological

sensations in

eye *, dryness

eye,

photophobia,

blepharospasm,

lacrimation,

photopsy,

mydriasis,

presbyopia

One-sided

blindness,

transitory

blindness,

glaucoma,

violation of

accommodation

, violation of

binocular

vision,

ciliary

scotoma

century *, night

blindness, amblyopia

Closed-
linear
glaucoma*,
maculopathy
*, violation
of movement
eye*

From the side

hearing and

labyrinth

Vertigo, noise

in the ears, pain

in the ear

Deafness,

one-sided

hearing loss, sensorineural hearing loss, discomfort in the ear, hearing loss

From the side

hearts

Bradycardia (in

including

sinus)

sensation palpitation

From the side

respiratory

system,

bodies

thoracic

cells and

the mediastinum

Dyspnea,

nasal

Bleeding,

obstruction

nose, rhinorrhea

Shortness of breath with

load,

hypersecretion

paranasal

sinuses,

dysphagia

From the side

gastro-

intestinal

tract

Nausea,

diarrhea

Vomiting, constipation,

pain in

epigastrium,

dyspepsia,

pain in

belly,

dryness in

mouth,

discomfort in

belly,

paresthesia

mucous

shells

oral cavity,

gastritis,

discomfort in

abdomen

Pancreatitis,

flatulence,

gastroesophageal-

alleys

reflux, pain

in the lower abdomen,

hypoesthesia

mucous

shells

oral cavity,

bleeding

from the gums,

bloating,

discomfort in

epigastrium,

irritation

peritoneum,

Hypersalivation,

pain in cheek,

unpleasant

smell from the mouth,

glossodynia

From the side

liver and

bile-

other ways

Hepatitis,

hepatic

inadequate

the

From the side

skin and

subcutaneous

fabrics

Alopecia,

rash, itching

Anhidrosis,

hypoesthesia

person,

hives,

erythema,

generalized

itching,

macular

rash,

change

color,

allergic

dermatitis, edema

faces

Syndrome

Stevens-

Johnson *,

polyforms

naya

erythema*,

unpleasant

smell of the skin,

periorbite-

swelling *,

focal

hives

Toxic

epidermal-

the

necrolysis *

From the side

muscular-

skeletal

systems

Arthralgia,

muscular

spasm,

myalgia,

contracture

muscles,

muscular

weakness,

pain in

muscles

breasts

Swelling of the joints *,

stiffness,

osteo-

muscle pain

in the side,

muscular

fatigue

Discomfort

limbs *

Discomfort

limbs *

pathways

Nephrolithiasis,

pollakiuria,

dysuria

Uric

concrement,

Incontinence urine, hematuria, mandatory urge to urinate, renal colic, kidney pain

Concrete

in the urethra,

Renal tubular acidosis

From the side

sexual

bodies and

dairy

glands

Violation

erections,

violation of

sexual

function

Are common

violations and

violations in

place

introduction of

Fatigue

Fever,

asthenia,

proliferator-

tion,

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

instrument

lately

indicators

Decrease

body weight

Increase

body weight *

Crystalluria,

pathological leukopenia,

rise

activity

"hepatic" enzymes

Decrease

bicarbonate content

serum

The social

circumstantial

the

Violation

training

* Identified by the results of spontaneous messages in the postgistribution period.

The frequency is calculated from clinical studies.

Overdose:

Symptoms

Signs and symptoms of overdose with topiramate: seizures, drowsiness, speech and vision impairment, diplopia, thinking disorders, coordination of movements, lethargy, stupor, 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 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 MSS (phenytoin, carbamazepine, valproic acid, phenobarbital, primidon) does not affect their equilibrium concentration in the 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. 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. Adding or removing 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 in patients with epilepsy, there was a statistically significant decrease in ethinyl estradiol (by 18, 21 and 30%, respectively). In both studies topiramate (in a dose of 50-200 mg / day in healthy volunteers and 200-800 mg / day in patients with epilepsy) did not affect the exposure of norethisterone. Despite the dose-dependent decrease in the exposure of ethinylestradiol in doses of 200-800 mg / day (in patients with epilepsy), topiramate in doses of 50-200 mg / day (in healthy patients) did not have a clinically significant effect on its exposure. The clinical significance of the described changes is not known. Patients taking oral contraceptives in combination with topiramate should take into account the risk 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) did not change significantly, the pharmacokinetics of 9-hydroxyrisperidone did not change. Significant changes in the systemic effect of risperidone / 9-hydroxyrisperidone and topiramate occurred.When adding topiramate to risperidone therapy (1-6 mg / day), unwanted reactions were recorded more often than with treatment with topiramate (250-400 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). The results of the studies showed that with the simultaneous administration of topiramate and hydrochlorothiazide, an increase in C_m_Oh 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 that of montorapia. 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_m_Oh and AUC0-12 h of the latter by 18 and by 25%, respectively, whereas the clearance of metformin decreases by 20%. Topiramate does not affect t_max 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. In the case of the addition or withdrawal of topiramate in patients receiving metformin, you should carefully monitor their condition for proper control of 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_m_Oh. These changes were not statistically significant. The active hydroxy metabolite of pioglitazone also showed a decrease in equilibrium C_m_Oh and AUC_t by 13 and 16%, respectively, and for active ketometabolite, the decrease in equilibrium C_m_Oh 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 AUC244 glibenclamide was reduced by 25%. Systemic exposure of 4-trans-hydroxyglyben clamid (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 is accompanied by hyperammonemia with or without encephalopathy. 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

A number of clinical studies have been carried out to evaluate potential drug interactions between topiramate and other drugs. Below are the changes in C_m_Oh 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

Added drug a drug		Concentration of added medicinal product*		Concentration of topiramate*
Amitriptyline		increase in C_m_Oh and AUC metabolite (nortriptyline) by 20%		not investigated
Dihydroergotarmine (oral and subcutaneous)		↔		↔
Haloperidol		enlargement AUC metabolite by 31%		not investigated
Propranolol		increase in C_m_Oh 4-hydroxypropranolol by 17% (topiramate 50 mg)		increase in C_m_Oh 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		enlargement AUC at 20	%
	diltiazem by 25% and deacetylldithiasem by 18% and N-detylldithiazema
Venlafaxine	↔		↔
Flunarizine	enlargement AUC by 16% (50 mg every 12 hours)^ь

expressed in% of C_mOhand AUC with monotherapy↔ - no change in C_mOh and AUC (<15% of the original data) ^b With repeated administration of a single flunarizine, an increase AUC by 14%, which may be due to the accumulation of the drug in the process of reaching the equilibrium state.

Special instructions:

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

As with other 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.

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. Meta-analysis of randomized placebo-controlled trials of anticonvulsantsshowed 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 phenomena associated with suicide (suicidal ideation, suicide attempts, suicide) was 0.5% in patients treated with 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

Some patients, especially with a predisposition to kidney stones, may increase the risk of formation of stones in kidneys and onset of symptoms associated with it, such as renal colic, a pain in the kidney or the side.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.

Violation of the function of the nights

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

Impaired liver function

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

Myopia and secondary closed-angle glaucoma

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

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 acidosis (eg, kidney disease, severe respiratory disease, epileptic status, diarrhea, surgery, fat-rich foods, certain medications) may serve as additional factors that enhance the hydrocarbonate-lowering effect of topiramate.

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

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

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

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

Enhanced nutrition

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

Laboratory indicators

In 0.4% of patients who took topiramate hypokalaemia was observed,

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:

Tablets, film-coated, 25 mg, 100 mg.

Packaging:

For 60 tablets in a bottle of HDPE white color, sealed with a screwed polypropylene lid and sealed with aluminum foil. Each bottle contains a bag of silica gel.

One bottle together with the instruction for use is placed in a cardboard box. For 10 tablets in a blister of PVC / Al. For 3 blisters together with instructions for use in a pack of cardboard.

Storage conditions:In a dry, the 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 expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002165

Date of registration:31.07.2013

Date of cancellation:2018-07-31

The owner of the registration certificate:Aurobindo Pharma Co., Ltd.Aurobindo Pharma Co., Ltd. India

Manufacturer: & nbsp

AUROBINDO PHARMA, Ltd. India

Representation: & nbspAurobindo Pharma, ZAOAurobindo Pharma, ZAO

Information update date: & nbsp05.10.2015

Illustrated instructions

Instructions

Topiramate (Topiramate)