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

Composition of hard gelatin capsule: gelatin 80,6-83,5 mg, water 12,5-15,4 mg, sorbitan laurate 0,0397 mg, sodium lauryl sulfate 0,0397 mg, titanium dioxide (E171) 0.99 mg, ink Opacode Black S-l -17822/23 black (ink composition: shellac glaze solution in ethanol, iron oxide black, n-butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide) 5-10 μg.

Description:

Capsules 50 mg: Hard gelatin capsules No. 0, consisting of a white body and a transparent colorless lid. On the cap of the capsule there is an inscription in black ink "ТОР". On the capsule case there is an inscription in black ink "50 mg".

The contents of capsules are 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 is an antiepileptic drug, referred to the class of sulfamate-substituted monosaccharides.

Topiramate blocks sodium channels and suppresses the occurrence of repeated action potentials against a background of prolonged depolarization of the neuron membrane. Topiramate increases the activity of γ-aminobutyric acid (GABA) with respect to certain subtypes of GABA receptors (including GABA_Areceptors), and also modulates the activity of GABA itself_Areceptor inhibits the activation of kainate sensitivity of the kainate / AMPK subtype (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors to glutamate, does not affect activity N-methyl-D-aspartate (NMDA) with respect to the subtype NMDAreceptors. These effects of topiramate are dose-dependent when the drug concentration in the plasma is from 1 μmol to 200 μmol, with a minimum activity ranging from 1 μmol to 10 μmol.

Besides, topiramate inhibits the activity of some isoenzymes of carbonic anhydrase. By the severity of this pharmacological effect topiramate is significantly inferior to acetazolamide, a known inhibitor of coal anhydrase, therefore this activity of topiramate is not considered to be the main component of its antiepileptic activity.

Pharmacokinetics:

Topiramate is absorbed rapidly and effectively. Its bioavailability is 81%. Eating does not have a clinically significant effect on bioavailability of topiramate. Plasma proteins bind 13-17% of topiramate. After a single dose of 1200 mg, the average volume of distribution is 0.55-0.8 l / kg.

The magnitude of the volume of the distribution depends from the floor: in women it is approximately 50% of the values observed in men, which is associated with a higher content of adipose tissue in women.

After ingestion, about 20% of the dose is metabolized. However, in patients receiving concomitant therapy with antiepileptic drugs that induce enzymes responsible for the metabolism of drugs, the metabolism of topiramate rises to 50%. Of the plasma, urine and human feces, six practically inactive metabolites were isolated and identified.

The main way to remove unchanged topiramate (70%) and its metabolites are kidneys. After oral administration, the plasma clearance of topiramate is 20-30 ml / min. The pharmacokinetics of topiramate is linear, the plasma clearance remains constant, and the area under the "concentration-time" curve (AUC) in the dose range from 100 to 400 mg increases in proportion to the dose. In patients with normal renal function, it may take 4 to 8 days to reach a steady plasma concentration. The maximum concentration (C_m_Oh) after repeated oral administration of 100 mg of the drug twice a day on the average was 6.76 μg / ml. After repeated doses of 50 and 100 mg twice a day, the half-life of the topiramate from the plasma averaged 21 hours.

In patients with impaired renal function moderate and severe plasma and renal clearance of topiramate decreases (creatinine clearance (CC) ≤70 ml / min), as a consequence, an increase in the equilibrium concentration of topiramate in blood plasma is possible compared to patients with normal renal function. In addition, patients with impaired renal function require more time to achieve an equilibrium concentration of topiramate in the blood.

Patients with moderate or severe renal insufficiency recommended the use of half the recommended initial and maintenance dose.

Topiramate is effectively excreted from the plasma by hemodialysis. Long-term hemodialysis can lead to a decrease in the concentration of topiramate in the blood below the amount required to maintain an anticonvulsant activity.To avoid a rapid drop in plasma topiramate concentration during hemodialysis, an additional dose of Topamax® may be required.

When adjusting the dose should be taken into account:

1) duration of hemodialysis,

2) the amount of clearance of the hemodialysis system used,

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

The plasma clearance of topiramate is reduced by an average of 26% in patients with hepatic insufficiency moderate or severe. 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

Pharmacokinetic parameters topiramate in children, as well as in adults receiving this drug as an auxiliary therapy, are linear in nature, and its clearance is dose independent, and the equilibrium concentrations in the plasma increase in proportion to the increase in dose. It should be taken into account, however, the fact that in children the clearance of topiramate is elevated, and the half-life of its half-life is shorter.Therefore, 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, antiepileptic drugs that induce microsomal enzymes of the liver cause a decrease in the concentrations of topiramate in plasma.

Indications:

Epilepsy

As a means of monotherapy:

in adults and children older than 2 years with epilepsy (including in patients with newly diagnosed epilepsy).

As part of complex therapy:

in adults and children older than 2 years with partial or generalized tonic-clonic seizures, as well as for the treatment of seizures in the background of the syndrome Lennox-Gastaut.

Migraine

Prevention of migraine attacks in adults. The use of Topamax® for the treatment of acute migraine attacks has not been studied.

Contraindications:

Hypersensitivity to any of the components of this drug, children under 2 years.

The use of topiramate for the prevention of migraine attacks is contraindicated during pregnancy, as well as in women with preserved reproductive potential, who do not use reliable methods of contraception.

Carefully:

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

Pregnancy and lactation:

Topiramate showed teratogenic properties in mice, rats and rabbits. In rats topiramate penetrated through the placental barrier.

Special controlled trials in which Topamax® would be used for treatment pregnant women, was not carried out.

Topiramate may cause harm to the fetus when used in pregnant women. Pregnancy records indicate that infants exposed to topiramate in utero during the first trimester of pregnancy have an increased risk of developing congenital malformations (eg, craniofacial defects such as cleft lip or palate, hypospadias and abnormalities in the development of various body systems). These developmental anomalies were documented both with monotherapy with topiramate and with its use within the framework of polytherapy. Data from one of the pregnancy registries showed that with the use of topiramate monotherapy, the incidence of significant congenital malformations increased approximately 3-fold compared to the comparison group that did not take antiepileptic drugs.

In addition, it has been shown that the risk of developing teratogenic effects associated with the use of antiepileptic drugs is higher in the case of combined therapy than in the case of monotherapy.

Compared with the group of patients who do not take antiepileptic drugs, the data on the registration of pregnancies with monotherapy with Topamax® indicate an increase in the probability of giving birth to children with a low body weight (less than 2500 g). One of the pregnancy registries showed an increase in the relative number of infants who are underdeveloped for their gestational age (NGV), defined as the birth weight below the 10th percentile, adjusted for gestational age and stratification by sex) among infants exposed to topiramate 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.

During therapy with topiramate, women with preserved reproductive potential should use reliable methods of contraception. The use of Topamax® in pregnancy in women with uncontrolled epilepsy is justified only if the potential benefit of using the drug for the mother exceeds the possible risk to the fetus.The use of topiramate for the prevention of migraine attacks is contraindicated during pregnancy, as well as in women with preserved reproductive potential, who do not use reliable methods of contraception.

When treating and counseling women with childbearing potential, the attending physician must weigh the relationship between the benefits and risks of treatment and consider alternative treatment options. If Topamax® is used during pregnancy, or if the patient becomes pregnant while taking this drug, it should be warned about the potential risk to the fetus.

A limited number of observations of patients suggests that topiramate is excreted in breast milk in women, so the doctor must decide not to breastfeeding or to stop taking the drug.

When tested in animals, no effect of topiramate on fertility. The effect of topiramate on fertility in humans is not established.

Dosing and Administration:

Inside, regardless of food intake.

To achieve optimal control of epileptic seizures in children and adults, it is recommended to start treatment with low doses of the drug followed by gradual titration to an effective dose.Capsules are intended for patients who have difficulty with swallowing tablets (eg, children and elderly patients).

Topamax® capsules should be gently opened, mix the contents of the capsules with a small amount (about 1 teaspoon) of any soft food. This mixture should be immediately swallowed without chewing. Do not store medicinal product mixed with food until the next dose.

Topamax® capsules can be swallowed whole.

Partial or generalized tonic-clonic seizures, as well as seizures against the background of the Lennox-Gastaut syndrome

Use in combination with other anticonvulsants in adult patients

The minimum effective dose is 200 mg per day. Usually the total daily dose is from 200 mg to 400 mg and is taken in two divided doses. Some patients may need an increase in the daily dose to a maximum of 1600 mg.

It is recommended to start treatment with a low dose, followed by a gradual selection of an effective dose. Selection of the dose begins with 25-50 mg, taking them at night for 1 week. In the future, with a week or two-week intervals, the dose can be increased by 25-50 mg and taken in two divided doses. When choosing a dose, it is necessary to be guided by the clinical effect.In some patients, the effect can be achieved by taking the drug 1 time per day. To achieve the optimal effect of Topamax® treatment, it is not necessary to monitor its concentration in the plasma.

These dose recommendations apply to all adult patients, including the elderly, in the absence of kidney disease (see section "Special instructions").

Combined anticonvulsant therapy in children older than 2 years

The recommended total daily dose of Topamax® as a supplementary therapy is 5 to 9 mg / kg and is taken in two divided doses. Selection of the dose should start with 25 mg (or less, based on an initial dose of 1 to 3 mg / kg per day), taking them at night for 1 week. In the future, with a week or two-week intervals of the dose can be increased by 1 - 3 mg / kg and take it in two divided doses. When selecting a dose, it is necessary be guided by clinical effect. Selection of the dose is started with topamax® capsules in a dosage of 15 mg or 25 mg. The daily dose to 30 mg / kg is usually well tolerated.

Epilepsy (including the first time diagnosed)

Monotherapy: general provisions

If you cancel the attendant anticonvulsant drugs for the purpose of monotherapy with topiramate, it is necessary to take into account the possible influence of this step on the frequency of seizures. In cases where there is no need to abruptly cancel concomitant anticonvulsants for safety reasons, it is recommended that their doses be gradually reduced, reducing the dose concomitant antiepileptic drugs for one third every 2 weeks.

With the withdrawal of drugs that are inducers of microsomal liver enzymes, the concentrations of topiramate in the blood will increase. In such situations, in the presence of clinical indications, the dose of Topamax® can be reduced.

Monotherapy: adults

At the beginning of treatment, the patient should take 25 mg of Topamax® before bedtime for 1 week. Then the dose is increased at intervals of 1-2 weeks by 25 or 50 mg (daily dose divided into two doses). If the patient does not tolerate such a dose-increasing regimen, then the intervals between increase doses, or increase the dose more smoothly. When choosing a dose, it is necessary to be guided by the clinical effect.

The initial dose for monotherapy with topiramate in adults is 100 mg per day, and the maximum daily dose should not exceed 500 mg.Some patients with refractory forms of epilepsy are tolerated by topiramate monotherapy in doses up to 1000 mg per day. These recommendations for dosing apply to all adults, including elderly patients, without kidney disease.

Monotherapy: children

Children over the age of 2 in the first week of treatment should be given topiramate in a dose of 0.5-1 mg / kg of body weight before bedtime. Then the dose is increased at intervals of 1-2 weeks by 0.5-1 mg / kg per day (the daily dose is divided into two doses). If the child does not tolerate such a regime of increasing the dose, then it is possible to increase the dose more smoothly or to increase the intervals between dose increases. The magnitude of the dose and the rate of its increase should be determined by the clinical result. The recommended dose range for monotherapy with topiramate in children over 2 years of age is 100-400 mg / day. Children with newly diagnosed partial seizures can be prescribed up to 500 mg per day.

Migraine

The recommended total daily dose of topiramate for prevention of migraine attacks is 100 mg, taken in 2 divided doses. At the beginning of treatment, the patient should take 25 mg of Topamax® before bedtime 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 dose-increasing regimen, then it is possible to increase the intervals between dose increases, or to increase the dose more smoothly. When choosing a dose, it is necessary to be guided by clinical effect.

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.

Special patient groups

1. Renal insufficiency

Patients with moderate or severe renal failure may need a dose reduction. Recommended use of half of the recommended initial and maintenance dose.

2. Hemodialysis

Because the topiramate is removed from the plasma during hemodialysis, hemodialysis should be administered on the days of hemodialysis an additional dose of Topamax®, equal to about half the daily dose. The additional dose should be divided into two doses, taken at the beginning and after completion of the procedure for hemodialysis.

The additional dose may vary depending on the characteristics equipment used in hemodialysis.

3. Liver failure

Patients with hepatic insufficiency topiramate should be used with caution.

Side effects:

Unwanted reactions are given with a frequency distribution and organ systems. The frequency of unwanted reactions was classified as follows: very often (≥1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and < 1/1000), very rarely (<1/10000, including individual cases) and the frequency is unknown (the frequency can not be estimated from the available data).

The most frequent adverse reactions (whose frequency was more than 5% and exceeded that in the placebo group for at least one of the indications during controlled clinical trials of topiramate) are: anorexia, decreased appetite, delayed thinking, depression, speech disorders, insomnia, disorders coordination of movements, impaired concentration, dizziness, dysarthria, dysgeusia, hypesisusia, inhibition, memory impairment, nystagmus, paresthesia, drowsiness, tremor, diplopia, blurred vision, d aarea, nausea, fatigue, irritability and weight loss.

Infections and invasions: Often: nasopharyngitis.

Violations of the blood and lymphatic system: often: anemia; infrequently: leukopenia, lymphadenopathy, thrombocytopenia, eosinophilia; rarely: neutropenia *.

Immune system disorders: often: hypersensitivity; frequency unknown: allergic edema *, swelling conjunctiva *.

Disorders from the metabolism and nutrition: often: anorexia, depression appetite; infrequently: metabolic acidosis, hypokalemia, increased appetite, polydipsia; rarely: hyperchloremic acidosis; hyperammonemia, hyperammonemicemic encephalopathy.

Mental disorders: Often: depression; often: delayed thinking, insomnia, violations of free speech, anxiety, confusion, disorientation, aggressive reactions, mood disorders, agitation, emotional lability, depressed mood, anger, behavioral disorder; infrequently: suicidal thoughts, attempts suicide, hallucinations, psychotic disorders, auditory hallucinations, visual hallucinations, apathy, difficulty speech, sleep disorders, affective lability, decreased libido, excited state, crying, dyspharmia, euphoric mood, paranoia, perseveration of thinking, panic attacks, tearfulness, violation of reading skills, falling asleep, flattening emotions, pathological thinking, loss of libido, lethargy, intrasomnic disorder, absent-mindedness, early waking up in the morning, panic reactions, upbeat mood; rarely: mania, panic disorder, feeling of hopelessness *, hypomania.

Disorders from the central nervous system: very often: paresthesia, drowsiness, dizziness; often: impaired concentration, memory impairment, amnesia, cognitive disorders, impaired thinking, psychomotor disorders, convulsions, impaired coordination of movements, tremor, retardation, hypesthesia, nystagmus, dysgeusia, impaired balance, dysarthria, intentional tremor, sedation; infrequently: oppressed consciousness, tonic-clonic seizures by type "grand mal", visual disturbances, complex partial seizures, speech disorders, psychomotor hyperactivity, fainting, sensory disorders, drooling, hypersomnia, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness, poor sleep quality, burning sensation, loss of sensitivity, parosmia, cerebral syndrome, dysesthesia, hypogeousia, stupor, awkwardness, aura, agevzia, dysgraphia, dysphasia, peripheral neuropathy, pre-fainting condition, dystonia, sensation of "goose bumps" in the body; rarely: apraxia, disturbance of the circadian rhythm of sleep, hyperesthesia, hyposmia, anosmia, essential tremor, akinesia, the absence of reactions to stimuli.

Disturbances on the part of the organ of sight: often: blurred vision, diplopia, visual impairment; infrequently: decreased visual acuity, scotoma, myopia *, strange sensations in the eyes *, dry eyes, photophobia, blepharospasm, increased lacrimation, photopsy, mydriasis, presbyopia; rarely: one-sided blindness, transient blindness, glaucoma, disruption of accommodation, disturbance of visual spatial perception, ciliary scotoma, eyelid edema *, night blindness, amblyopia; frequency unknown: angle-closure glaucoma *, maculopathy *, impaired mobility of the eye *.

Hearing and balance disorders: often: vertigo, ringing in the ears, pain in the ear; infrequently: deafness, unilateral deafness, neurosensory deafness, discomfort in the ear, hearing loss.

Disorders from the cardiovascular system: infrequently: bradycardia, sinus bradycardia, palpitation.

Disorders from the vascular systems: infrequently: hypotension, orthostatic hypotension, hot flushes, hot flashes; rarely: the phenomenon of Raynaud.

Disturbances from respiratory system, thoracic and mediastinal organs: often: dyspnea, nasal bleeding, nasal congestion, rhinorrhea, cough *; infrequently: dyspnoea with physical exertion, hypersecretion in the paranasal sinuses, dysphonia.

Disorders from the gastrointestinal tract: very often: nausea, diarrhea; often: vomiting, constipation, pain in the epigastric region, dyspepsia, abdominal pain, dry mouth, discomfort in the stomach, impaired sensation in the oral cavity, gastritis, abdominal discomfort; infrequently: pancreatitis, flatulence, gastroesophageal reflux, pain in the lower abdomen, decrease sensitivity in the oral cavity, bleeding gums, bloating, discomfort in the epigastric region, sensitivity in the abdomen, hypersalivation, pain in the mouth, bad breath, glossodynia.

Disorders from the hepatobiliary system: rarely: hepatitis, hepatic failure.

Disturbances from the skin and subcutaneous tissues: often: alopecia, rash, itching; infrequently: anhydrase, impaired sensitivity in the face, urticaria, erythema, generalized pruritus, macular rash, impaired skin pigmentation, allergic dermatitis, swelling of the face; infrequently: Stevens-Johnson syndrome *, polymorphic erythema *, skin odor change, paraorbital edema *, localized urticaria; frequency unknown: toxic epidermal necrolysis *.

Disturbances from musculoskeletal system and connective tissue: often: arthralgia, muscle spasms, myalgia, muscle cramps, muscle weakness, musculoskeletal pain in the chest; infrequently: swelling of the joints *, stiffness of the muscles, pain in the side, fatigue in the muscles; rarely: discomfort in the extremities *.

Disorders from the kidneys and urinary tract: often: nephrolithiasis, pollakiuria, dysuria; infrequent: exacerbation of urolithiasis (kidney stones), urinary incontinence with tension, hematuria, urinary incontinence, frequent urge to urinate, renal colic, pain in the kidney; rarely: exacerbation urolithiasis (stones in the urethra) renal tubular acidosis *.

Violations of the genitals and mammary gland: infrequently: erectile dysfunction, sexual dysfunction.

General disorders and disorders, caused by the way of application: very often: fatigue; often: increased body temperature, asthenia, irritability, gait disturbance, poor health, anxiety; infrequently: hyperthermia, thirst, flu-like syndrome *, sluggishness, coldness of the limbs, a feeling of intoxication, a feeling of anxiety; rarely: swelling of the face, calcification.

Change in laboratory indicators: very often: weight loss; often: weight gain *; infrequently: crystalluria, abnormal test result "tandem walk", leukopenia, increased activity of hepatic enzymes in serum, rarely: decrease the content of hydrocarbonates in the blood.

Violations of social functioning: infrequently: impaired ability to training.

* - an undesirable reaction was registered in the post-marketing period from spontaneous messages. The frequency is calculated on the basis of data from clinical studies.

Special groups:

Children:

Below is a list of unwanted reactions,which in controlled clinical trials were registered in children 2 and more times more often than in adults: decreased appetite, increased appetite, hyperchloremic acidosis, hypokalemia, behavioral disorders, aggressive reactions, apathy, falling asleep, suicidal ideation, impaired concentration, inhibition , disturbance of the circadian rhythm of sleep, poor sleep quality, increased lacrimation, sinus bradycardia, poor health, gait disturbance.

Below is a list of unwanted reactions that, during controlled clinical trials, were recorded only in children: eosinophilia, psychomotor hyperactivity, vertigo, vomiting, hyperthermia, pyrexia, impaired ability to learn.

Overdose:

Signs and symptoms of Topamax® overdose: seizures, drowsiness, speech and vision impairments, diplopia, thinking disorders, movement coordination disorders, lethargy, stupor, hypotension, abdominal pain, dizziness, agitation and depression. In most cases, the clinical consequences were not severe, but there were deaths after an overdose using a mixture of several medicines, including topiramate. Overdose of topiramate can cause severe metabolic acidosis (see section "Special instructions"). A case of an overdose is known when the patient took a dose of topiramate from 96 to 110 g, which entailed someone who continued for 20-24 hours. After 3-4 days the patient's condition returned to normal.

Treatment

In case of acute overdose of Topamax®, if the patient has taken food shortly before, immediately wash the stomach or induce vomiting. In studies in vitro it was shown that Activated carbon adsorbs topiramate. If necessary, symptomatic therapy should be given. An effective way to remove topiramate from the body is hemodialysis. Patients are advised to adequately increase the amount of fluid consumed.

Interaction:

Influence of Topamax® on the concentration of other antiepileptic drugs (PEP)

Simultaneous administration of Topamax® with other PEP (phenytoin, carbamazepine, valproic acid, phenobarbital, primidon) does not affect the values of their equilibrium concentrations in the plasma, with the exception of individual patients in whom the addition of Topamax ® to phenytoin may cause an increase in the plasma phenytoin concentration.This may be due to the inhibition of the specific polymorphic isoform of the cytochrome P450 enzyme (CYP2C19 isoenzyme). Therefore, every patient who takes phenytoin and in which clinical signs or symptoms of toxicity develop, it is necessary to monitor the concentration of phenytoin in the plasma.

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

The impact of others antiepileptic drugs for the concentration of Topamax®

Phenytoin and carbamazepine reduce the concentration of Topamax ® in plasma. Adding or abolishing phenytoin or carbamazepine while on Topamax® treatment may require a change in the dose of the latter. Dose should be selected, focusing on achieving the desired clinical effect.

The addition or removal of valproic acid does not cause clinically significant changes in the concentration of Topamax® in plasma and, therefore,does not require a change in the dose of Topamax®.

The results of these interactions are summarized in the following table:

Added PEP	Concentration of PEP	Concentration Topamax®
Phenytoin	↔**	↓ (48%)
Carbamazepine	↔	↓ (40%)
Valproic acid	↔	↔
Phenobarbital	↔	NO
Primidone	↔	NO

↔ = No effect

** = Increased concentration in single patients

↓ = Decreased plasma concentration

N = Not investigated

PEP = antiepileptic drug

Other drug interactions

Digoxin: a study using single dose AUC area under the curve ( "concentration-time") in plasma digoxin while receiving Topamaks® preparation was reduced by 12%. The clinical significance of this observation is not clear. When Topamax® is prescribed or withdrawn, host digoxin, special attention should be paid to monitoring the concentration of digoxin in the serum.

Medications that depress the central nervous system: within the framework of clinical studies, the effects of simultaneous administration of Topamax® with alcohol or other substances depressing the functions of the central nervous system have not been studied. It is recommended not to take Topamax ® together with alcohol or other drugs that cause depression of the central nervous system.

St. John's wort perforated

With the joint administration of Topamax® and preparations based on St. John's wort (perforated)Hypericum perforatum) the concentration of topiramate in plasma may decrease and, as a consequence, the effectiveness of the drug may also decrease. Clinical studies of the interaction of Topamax® and preparations based on St. John's wort have not been performed.

Oral contraceptives: in the study of drug interaction with oral contraceptives, which used a combined preparation containing norehisterone (1 mg) and ethinyl estradiol (35 μg), Topamax® in doses of 50-800 mg per day did not significantly affect the effectiveness of norethisterone and in doses of 50-200 mg per day - the effectiveness of ethinylestradiol. Essential dose-dependent reduction in efficacy ethinyl estradiol was observed at doses of Topamax ® 200-800 mg per day. The clinical significance of the described changes is not clear. The risk of reducing the effectiveness of contraceptives and strengthening "breakthrough" bleeding should be considered in patients taking oral contraceptives in combination with Topamax ®. Patients, taking estrogen-containing contraceptives, it is necessary to report any changes in the timing and nature of menstruation. The effectiveness of contraceptives can be reduced even in the absence of "breakthrough" bleeding.

Lithium: in healthy volunteers there was a decrease AUC lithium by 18% with the simultaneous administration of topiramate at a dose of 200 mg per day. In patients with manic-depressive psychosis the use of topiramate at doses up to 200 mg per day did not affect the pharmacokinetics of lithium, but at higher doses (up to 600 mg per day) the lithium AUC 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 doses of 250 or 400 mg per day AUC risperidone, taken in doses of 1-6 mg per day, decreased by 16% and 33%, respectively. The pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed slightly.The change in the systemic effect of risperidone / 9-hydroxyrisperidone and topiramate was not clinically significant, and this interaction is unlikely to be of clinical significance.

Hydrochlorothiazide: medicinal the interaction was evaluated in healthy volunteers with separate and combined use of hydrochlorothiazide (25 mg) and topiramate (96 mg). The results of the studies showed that with the simultaneous administration of topiramate and hydrochlorothiazide, an increase in the maximum concentration of topiramate by 27% and the area under the curve AUC of topiramate by 29%. The clinical significance of these studies has not been revealed. The administration of hydrochlorothiazide to patients receiving topiramate, may require correction of the dose of topiramate. Pharmacokinetic parameters hydrochlorothiazide did not undergo significant changes with concomitant therapy with topiramate.

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, the maximum concentration and the area under the curve increase AUC metformin by 18% and by 25%, respectively, whereas the clearance of metformin with simultaneous application with the topiramate decreased by 20%. Topiramate did not affect the time to reach the maximum concentration of metformin in the blood plasma. The clearance of topiramate when used concomitantly with metformin is reduced. The degree of revealed changes in clearance is not studied. The clinical significance of the effects of metformin on the pharmacokinetics of topiramate is not clear. In the case of the addition or withdrawal of Topamax® in patients receiving metformin, should be carefully monitor the patient to assess the course 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 area under the curve AUC pioglitazone by 15%, without changing the maximum concentration of the drug. These changes were not statistically significant. For active gpirotitazone also showed a decrease in the maximum concentration and area under the curve AUC by 13% and by 16% respectively,and for active ketometabolite, a decrease was found in both the maximum concentration and the area under the curve AUC by 60%. The clinical significance of these data is not clear. When patients simultaneously use Topamax® and pioglitazone, patients should carefully monitor their condition to assess the course of diabetes mellitus.

Glibenclamide: A study was made of the drug interaction to study the pharmacokinetics of glibenclamide (5 mg in day) in an equilibrium state, applied alone or simultaneously with topiramate (150 mg per day) in patients with type 2 diabetes mellitus. When topiramate is used AUC Glibenclamide decreased by 25%. The systemic exposure of 4-trans-hydroxy-glibenclamide and 3-cis-hydroxyglybeneclamide was also decreased (by 13% and 15%, respectively). Glibenclamide did not affect the pharmacokinetics of topiramate in the equilibrium state. It is found statistically unreliable decrease AUC pioglitazone by 15% in the absence of a change in C_m_Oh. When prescribing topiramate to patients, receiving glibenclamide (or the appointment of glibenclamide to patients receiving topiramate), should be carefully to monitor the patient's condition for evaluation of the course of diabetes mellitus.

Other drugs: simultaneous Topamax® with drugs predisposing to nephrolithiasis, may increase the risk formation of kidney stones. During treatment with Topamax®, drugs should be avoided, predisposing to nephrolithiasis, Because they can cause physiological changes, promoting nephrolithiasis.

Valproic acid: combined application of topiramate and valproic acids in patients who tolerate each drug well, are accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and signs disappear after the withdrawal of one of the drugs (see Fig. section "Special instructions" and "Side effect"). This adverse reaction is not due to a pharmacokinetic interaction.

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

Additional studies of drug interactions: a number of clinical trials have been conducted to evaluate potential drug interactions between topiramate and other drugs.

The results of these interactions are summarized in the following table:

Drug to be added	Concentration of the added drug^a	Concentration of topiramate^a
Amitriptyline	increase in the maximum concentration and AUC of the metabolite of nortriptyline by 20%	not investigated
Dihydroergotamine (orally and subcutaneously)	↔	↔
Haloperidol	an increase in the AUC metabolite by 31%	not investigated
Propranolol	increase in the maximum concentration for 4-OH propranolol by 17% (topiramate 50 mg)	an increase in the maximum concentration by 9% and 16%, an increase in AUC by 9 and 17%, (for propranolol 40 mg and 80 mg every 12 hours), respectively
Sumatriptan (oral and subcutaneous)	↔	not investigated
Pisotifen	↔	↔
Diltiazem	a decrease in AIL diltiazem by 25% and reduction of deacetylldithiasem by 18%, and ↔ for N-demethylidithiasem	increase in AUC by 20%
Venlafaxine	↔	↔
Flunarizine	AUC increase by 16% (50 mg every 12 hours)^b	↔

^a is expressed in% of the values of the maximum concentration in the blood plasma and AUC in monotherapy

↔ = No changes in the maximum concentration in the blood plasma and AUC (≤ 15% of the initial data)

^b With repeated administration of a single flunarizine, an increase AUC by 14%, which may be due to accumulation of the drug in the process of achieving the equilibrium state.

Special instructions:

Antiepileptic drugs, including Topamax®, should be withdrawn gradually to minimize the possibility of an increase in seizure frequency. To reduce the dose by 25-50 mg, Topamax® capsules are used in a dosage of 15 mg or 25 mg. In clinical studies, doses were reduced by 50-100 mg at weekly intervals for adults with epilepsy and 25-50 mg in adults receiving 100 mg of Topamax® per day for the prevention of migraine. Children in clinical trials of Topamax ® were gradually withdrawn within 2-8 weeks. If, according to medical indications, Rapid cancellation of Topamax® is necessary, it is recommended that appropriate monitoring of the patient's condition be performed.

As in the case of the use of other antiepileptic drugs, in some patients taking topiramate, there is an increase in the frequency of seizures or new types of seizures. This phenomenon may be a consequence of an overdose, a decrease in the concentration of antiepileptic drugs used together, progression of the disease or paradoxical effect.

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

As with any disease, the dose selection scheme should focus on the clinical effect (ie, the degree of control of seizures, the absence of side effects) and take into account the fact that in patients with impaired renal function to establish a stable concentration in the plasma for each dose may be needed for a longer time.

With topiramate therapy, it is possible to develop oligohydrosis (decreased sweating) and anhidrosis.Reducing sweating and hyperthermia (fever) can occur in children exposed to high ambient temperatures. In this regard, with the treatment of topiramate, it is very important to adequately increase the amount of fluid consumed, which can reduce the risk of developing nephrolithiasis, as well as the side effects that can occur under the influence of physical exertion or elevated temperatures.

Mood / depression

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

Suicide attempts

With the use of antiepileptic drugs, including the drug Topamax®, the risk of suicidal thoughts and suicidal behavior increases in patients taking these drugs for any of the indications.

In double-blind clinical trials, the incidence of suicidal-related events (suicidal thoughts, suicide attempts, suicide) was 0.5% in patients who received topiramate (in 46 of 8652 patients), which is approximately 3 times higher compared to patients receiving placebo (0.2%, 8 patients out of 4045).One case of suicide was documented in a double-blind study of bipolar disorder in a patient who received topiramate.

Thus, it is necessary to monitor the condition of patients in order to identify signs of suicidal thoughts and prescribe appropriate treatment. It is necessary to recommend to patients (and if necessary, carers of patients) to seek medical help immediately if signs of suicidal thoughts or suicidal behavior appear.

Nephrolithiasis

In some patients, in particular, with a predisposition to nephrolithiasis, the risk of kidney stones and related symptoms such as renal colic, kidney pain, and pain in the side may increase. To reduce this risk, an adequate increase in the amount of fluid consumed is necessary. Risk factors for developing nephrolithiasis are nephrolithiasis in history (including family history), hypercalciuria, concomitant therapy with drugs that contribute to the development of nephrolithiasis.

Impaired renal function

Caution should be exercised in prescribing Topamax® to patients with renal insufficiency (creatinine clearance <70ml / min). This is due to the fact that in such patients the clearance of the drug is lowered.

Impaired liver function

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

Myopia and secondary closed angle glaucoma

When using Topamax®, a syndrome including acute myopia with concomitant secondary closed-angle glaucoma is described. Symptoms include acute visual acuity and / or eye pain. 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 1 month after the start of Topamax®. Unlike primary open angle glaucoma, which is rarely seen 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 Topamax® as soon as the attending physician deems it possible and appropriate measures aimed at lowering the intraocular pressure. Usually these measures 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, and visual field defects disappeared after the withdrawal of topiramate therapy. If you have visual problems while taking topiramate, you should consider the possibility of discontinuing therapy.

Metabolic acidosis

When topiramate is used, hyperchloremic, not associated with an anion deficiency, metabolic acidosis (eg, a decrease in the concentration of hydrocarbonates in the plasma below the normal level in the absence of respiratory alkalosis) may occur. Similar a decrease in the concentration of serum hydrogen bicarbonates is a consequence of the inhibitory effect of topiramate on renal carboanhydrase. In most cases, a decrease in concentration Hydrocarbonates occur at the beginning of the drug, although this effect can occur in any period of treatment with topiramate. The degree of concentration reduction is usually weak or moderate (mean value is 4 mmol / L when used in adult patients at a dose above 100 mg per day and about 6 mg per day per kg of body weight when used in pediatric practice). In rare cases, patients showed a decrease in the concentration of hydrocarbonates below the level of 10 mmol / l.

Some diseases or treatments that predispose to the development of acidosis (eg, kidney disease, severe respiratory disease, epileptic status, diarrhea, surgery, ketogenic diet,taking certain medications) may be additional factors that enhance the hydrocarbonate-reducing effect of topiramate.

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

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. In case of symptoms of metabolic acidosis (for example, deep Kussmaulian breathing, dyspnoea, anorexia, nausea, vomiting, fatigue, tachycardia or arrhythmia), it is recommended to determine the concentration of hydrocarbonates in the serum. When there is metabolic acidosis and its persistence, it is recommended to reduce the dose or stop taking topiramate.

Cognitive impairment

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

Hyperammonemia and encephalopathy

When topiramate was used, development of hyperammonemia with encephalopathy or without it (see the "Side effect" section). The risk of developing hyperammonemia in topiramate is dose-dependent. Hyperammonaemia more often observed while the use of topiramate and valproic acid (see. The section "Other drug interactions"). Clinical symptoms hyperammonemic encephalopathy is often a severe impairment of consciousness and / or cognitive function and lethargy. In most cases, hyperammonemic encephalopathy regresses with withdrawal of therapy. In patients with developed lethargy or changes in the mental status of an unclear genesis receiving topiramate as monotherapy or in combination therapy, it is recommended to take into account the possibility giperammoniemicheskoy encephalopathy and determine the level of ammonia in the blood.

Enhanced nutrition

If the patient loses body weight when treated with Topamax®, consider whether amplified power supply.

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

Topamax® acts on the central nervous system and can cause drowsiness, dizziness, and other symptoms. It can also cause visual impairment. These adverse events can pose a risk to patients managing the car and moving mechanisms, especially during the period until the patient's reaction to the drug is established.

Form release / dosage:Capsules, 50 mg.

Packaging:

For 28 or 60 capsules in a bottle of high-density polyethylene.

The bottle, along with instructions for medical use, is placed in a cardboard box.

Storage conditions:

Store in a dry 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 indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-005288/08

Date of registration:04.07.2008 / 18.05.2012

Expiration Date:Unlimited

The owner of the registration certificate:Johnson & Johnson, LLC Johnson & Johnson, LLC Russia

Manufacturer: & nbsp

BIOKOM, CJSC Russia

CILAG, AG Switzerland

JANSSEN-CILAG, S.p.A. Italy

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp02.01.2017

Illustrated instructions

Instructions

Topamax® (Topamax®)