Topsaver - instructions for use, doses, side effects, contraindications

Excipients: sugar granules [sucrose, molasses starch] (850-1000 microns) 146.64 mg / 293.28 mg; povidone-K30 11.66 mg / 23.32 mg; ethyl cellulose 3.5 mg / 7.0 mg; triethyl citrate 0.317 mg / 0.63 mg; Macrogol-6000 0.833 mg / 1.67 mg; talc 0.85 mg / 1.70 mg;

gelatin capsule composition (%): titanium dioxide (E171) 3.0 / 2.0; gelatin up to 100 / up to 100; Ink 1 OD 1 (S-1-277002) black **.

** Composition of ink: shellac (59.420%), iron dye oxide black (24.650%), butanol (9.750%), water (3.249%), propylene glycol (1.300%), ethanol (1.080%), isopropanol (0.550%), ammonium hydroxide (0.001% ).

Description:

Dosage of 25 mg: hard gelatin capsules No. 1 with a lid and a white body, with the black ink "7336" on the body and "TEVA"on the lid, containing pellets from almost white to yellowish with a light brownish hue.

Dosage 50 mg: hard gelatin capsules No. 0 with a lid and a white body with an inscription in black ink "50 mg"on the body and"TEVA"on the lid, containing pellets from almost white to yellowish with a light brownish hue.

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.11 Topiramate

Pharmacodynamics:

Topiramate is an antiepileptic agent, refers to the class of sulfate-substituted monosaccharides. It blocks sodium channels and suppresses the occurrence of repeated action potentials against the background of a prolonged depolarization of the neuron membrane. Topiramate increases the activity of gamma-aminobutyric acid (GABA) with respect to some subtypes of GABA receptors (including GABA_Areceptors), and also modulates the activity of GABA itself_A-receptors, prevents the activation of kainate / AMPK (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 with a plasma topiramate concentration of 1-200 μmol / L, with a minimum activity ranging from 1 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 carbonic anhydrase, therefore this action of topiramate is not the main component of its antiepileptic activity.

In animal studies, it has been established that topiramate has anticonvulsant activity in tests with maximum electric shock in rats and mice. Effective in models of rodent epilepsy, including tonic convulsions, spontaneous epilepsy 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 studies of the combination of topiramate with other anticonvulsants, there is no correlation between its concentration and clinical efficacy. There is no information on addiction to topiramate.

Pharmacokinetics:

After oral administration topiramate quickly and well absorbed from the gastrointestinal tract. Bioavailability is about 81%. After oral administration of 400 mg of topiramate, the maximum concentration in the plasma (C_mOh) 1.5 μg / min is achieved within 2 hours. Eating does not have a clinically significant effect on the bioavailability of topiramate.The pharmacokinetics of topiramate is linear in nature with a dose-dependent increase in the concentration of topiramate in plasma at a dose of 200-800 mg / day.

The connection with blood plasma proteins for topiramate is 13-17% in the plasma concentration range of 0.5-250.0 μg / ml. After a single dose of 1200 mg, the average volume of distribution is 0.55-0.8 l / kg. The size of the distribution depends on the sex: in women - about 50% of the values observed in men, which is associated with a higher content of adipose tissue in women.

After ingestion, about 20% of the dose is metabolized. However, in patients receiving concomitant therapy with antiepileptic drugs (PEP), which are inducers of microsomal enzymes, the metabolism of topiramate rises to 50%. From blood plasma, urine and feces, six practically inactive metabolites were isolated and identified.

The main way to remove unchanged topiramate (about 70%) and its metabolites are the kidneys. After oral administration, the plasma clearance of topiramate was 20-30 ml / min. 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 to achieve an equilibrium concentration (C_ss) in plasma may need from 4 to 8 days. The value of C_ma_x after repeated administration of 100 mg of topiramate twice a day, on average, was 6.76 μg / ml. After repeated ingestion of 50 and 100 mg twice a day, the half-life (T_1/2) of topiramate from blood plasma on average is 21 hours.

Pharmacokinetics in special clinical cases

In patients with impaired renal function moderate and severe plasma and renal clearance of topiramate decreases (creatinine clearance <70 ml / min), as a consequence, an increase in the equilibrium concentration of topiramate in blood plasma is possible, but compared with 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 failure are recommended to use half of 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 anticonvulsant activity. To avoid a rapid drop in the concentration of topiramate in the plasma during hemodialysis, an additional dose of Topsaver may be required.

When adjusting the dose should be taken into account:

1) duration of hemodialysis;

2) the clearance value 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 and liver failure, the clearance of topiramate is not changed.

Pharmacokinetics of topiramate in children, as in adults receiving supplementary therapy, is linear in nature with a dose-independent clearance; C_ss Topiramate in blood plasma increases in proportion to the increase in dose. It should be borne in mind that in children the clearance of topiramate is elevated, and T_1/2 is reduced, so at the same dose, based on 1 kg of body weight, the concentration of topiramate in blood plasma in children will be lower than in adults. In children, as in adults, PEP, inducing microsomal enzymes of the liver, cause a decrease in the concentration of topiramate in the blood plasma and increase the degree of its metabolism.

Indications:

Epilepsy

As a means of monotherapy: in adults and children older than 2 years with partial (with secondary generalization or without) or primary generalized tonic-clonic seizures.

As part of complex therapy: in adults and children older than 2 years with partial (with or without secondary generalization) or primary generalized tonic-clonic seizures, as well as for the treatment of seizures associated with the Lennox-Gastaut syndrome.

Migraine

Preventing migraine attacks in adults after a thorough evaluation of all possible alternative treatments.

Topiramate is not intended for the treatment of acute migraine attacks.

Contraindications:

Hypersensitivity to topiramate or any other component of the drug; lactose intolerance, lactase deficiency,glucose-galactose malabsorption; Children under 2 years of age with monotherapy and as part of a combination therapy for epilepsy; children under 18 years of age when used for the prevention of migraine, prevention of migraine in women of childbearing age who do not use adequate contraception.

Carefully:

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

Pregnancy and lactation:

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

Signs of influence on fertility in rats of topiramate in a dose above 100 mg / kg was not observed.

According to the UK Pregnancy Registry and the Register of Pregnancy, "Antiepileptic Drugs in North America" in infants exposed to intrauterine exposure to topiramate monotherapy in the first trimester, the risk of developing congenital malformations (eg, facial skull defects such as cleft of the upper lip or palate, hypospadias and abnormalities development of various body systems). According to the same registry when applying during pregnancy topiramate as monotherapy, the frequency of severe congenital malformations was three times higher than that of peers whose mothers did not take anticonvulsants. In addition, in the treatment group with topiramate compared with the control group, the probability of giving birth to children with a low body weight (<2500 g) is increased. The reason for the decrease in birth weight and underdevelopment for gestational age at birth is not established.

Epilepsy

During pregnancy topiramate should be prescribed only after informing the woman about unknown causes of uncontrolled epilepsy and the potential risks of the drug on the fetus.

Use in the prevention of migraine

Topiramate is contraindicated in women of childbearing age who do not use adequate contraception.

Data from other studies indicate that the risk of developing teratogenic effects in combination with other PEPs may be higher than with monotherapy.

The use of Topsaver during pregnancy is justified only if the potential benefit of using the drug exceeds the possible risk to the fetus.

When treating patients with preserved reproductive potential, it is necessary to carefully weigh the ratio of expected benefit to the possible risk of use and consider the possibility of alternative therapies. When using the drug, adequate contraception should be observed for women with preserved reproductive potential.

A limited number of observations of patients suggests that topiramate is excreted in breast milk, therefore, during the application of Topsaver breast-feeding should be discontinued.

Dosing and Administration:

Inside, regardless of food intake.

The capsule of Topsaver can be swallowed whole, without chewing, squeezed with enough water. When used in patients with difficulty in swallowing, you can carefully open the capsule, mix the contents of the capsule with a small amount (about 1 teaspoon) of any soft food. This mixture should be immediately swallowed without chewing. Do not store mixture of medicine and food until the next dose.

To achieve optimal control of epileptic seizures, it is recommended to start therapy with a low dose of the drug with a gradual increasing increase to an effective dose.

To achieve the optimal effect of Topsaver treatment, it is not necessary to monitor its concentration in the plasma. With simultaneous use with phenytoin or carbamazepine in a number of cases, correction of the doses used is necessary.

Antiepileptic drugs, including Topsover, are recommended to be phased out gradually in order to minimize the risk of withdrawal syndrome or the possibility of increasing the number of seizures.

Monotherapy for epilepsy

With the withdrawal of concomitant PEP with the goal of switching to monotherapy with topiramate, it is necessary to take into account the possible effect of this transition on the frequency of seizures. In those cases where there is no need to abruptly abolish associated PEP, it is recommended to reduce their dose gradually, reducing the dose by one third every 2 weeks.

With the cancellation of PEP, which are inducers of microsomal liver enzymes, the concentration of topiramate in the blood plasma can increase. Topsaver can be reduced in the presence of clinical indications.

Adults

The recommended initial dose is 25 mg / day once a day at night. Then the dose is gradually increased with an interval of 1-2 weeks for 25 or 50 mg (daily dose divided into 2 divided doses).With poor tolerability of rapid dose build-up, it is possible to increase the intervals between dose increases, or to increase the dose more smoothly.

The initial daily dose for monotherapy is 100 mg, the maximum daily dose is 500 mg / day in 2 divided doses. Some patients with refractory forms of epilepsy are tolerated by topiramate monotherapy in doses up to 1000 mg per day.

Children over 2 years old

The recommended initial dose is 0.5-1 mg / kg / day before bedtime for 1 week. Then, the dose is increased by 0.5-1 mg / kg / day in 2 divided doses at intervals of 1-2 weeks. If this regime is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose is selected depending on the clinical effect. The recommended range of doses is 100-400 mg / day. Children with newly diagnosed partial seizures can be prescribed up to 500 mg per day.

In the complex therapy of epilepsy (partial (with or without secondary generalization) or primary generalized tonic-clonic seizures, seizures associated with Lennox-Gastaut syndrome).

Adults

The minimum effective dose is 200 mg / day. The average daily dose is 200-400 mg / day in 2 doses, in some patients the clinical effect is achieved with a single dose.Selection of the dose starts with 25-50 mg once a day in the evening for 1 week. Next, you should increase the dose by 25-50 mg at intervals of 1-2 weeks before reaching the effective dose; the frequency of reception is 2 times a day. If this regime is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose is selected depending on the clinical effect. Some patients may need an increase in the daily dose to a maximum of 1600 mg.

Children over 2 years

The recommended daily dose is approximately 5-9 mg / kg / day in 2 divided doses.

Begin treatment with a dose of 25 mg or less (at a rate of 1-3 mg / kg / day) before going to bed for 1 week. Then the dose is increased by 1-3 mg / kg / day in 2 divided doses at intervals of 1-2 weeks. The daily dose of 30 mg / kg / day is usually well tolerated.

Prevention of migraine

The recommended total daily dose is 100 mg in 2 divided doses. Begin treatment with a dose of 25 mg or less at bedtime for 1 week.

Then the dose is increased by 25 mg / day at intervals of 1 week. If this regime is intolerant, the dose is increased by a smaller amount or at longer intervals. The dose is selected depending on the clinical effect. In some patients, a positive result is achieved with a daily dose of 50 mg / day.The use of a daily dose of more than 200 mg / day has not been studied.

Patients with renal insufficiency

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

Patients in need of hemodialysis

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

Patients with hepatic insufficiency Topsover should be taken with caution under the supervision of a doctor because of the reduced clearance of topiramate.

Elderly patients correction of the dose is not required.

Side effects:

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

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: very rarely - nasopharyngitis.

On the part of the blood and lymphatic system: often - anemia; infrequently - leukopenia, thrombocytopenia, lymphadenopathy, thrombocytopenia, eosinophilia; very rarely - neutropenia.

From the immune system: often - hypersensitivity; frequency unknown - allergic edema, edema of the conjunctiva.

From the side of the psyche: very often - depression; often - bradyphrenia, insomnia, expressive speech, anxiety, confusion, disorientation, aggressiveness, mood swings, agitation, mood swings, depressed mood, anger, pathological behavior; infrequently - suicidal thoughts, suicide attempts, hallucinations, psychotic disorders, hallucinations auditory, hallucinations visual, apathy, agitation, lack of spontaneous speech, sleep disorder, emotional lability, anxiety, crying, dysphhemia, euphoric mood, paranoia, perseverations, panic attacks, tearfulness , reading disorder, falling asleep, flattened affect, pathological thinking, decreased libido, lethargy, intrasomnic disorder, distraction, early morning awakening, panic reactions, high spirits; rarely - mania, a sense of desperation (mainly in children), hypomania.

From the nervous system: very often - drowsiness, dizziness, paresthesia; often - impaired attention, memory impairment, amnesia,cognitive impairment, impaired mental activity, psychomotor disorders, convulsions, impaired coordination of movement, tremor, lethargy, hypoesthesia, nystagmus, taste distortion, imbalance, dysarthria, ingentional tremor, sedation; infrequently - oppression of consciousness, tonic-clonic seizures by type grand mal, loss of the visual field, complex partial seizures, speech disorder, psychomotor hyperactivity, fainting, sensory disorders, salivation, increased drowsiness, aphasia, repetitive speech, hypokinesia, dyskinesia, postural dizziness, aura, akinesia, loss of sensitivity, stupor, peripheral neuropathy, dysgraphia , dysphasia, parosmia, a burning sensation (predominantly on the face and limbs), cerebellar syndrome (caused by the defeat of the cerebellum or its connections, is caused by a violation of muscle tone, strength, balance coordination, and synergy of movements, gait and stenosis disorder are often caused by damage to the cerebellum worm, symptoms from the limbs (ataxia, adiadochokinesis, miscarriage, dysmetry, atony, etc.) - defeat of the cerebral hemisphere of the same name), awkward movements, dysesthesia,agevzia, hypogeousia, goose bumps, pre-stupor, inability to learn; rarely - apraxia, hyperesthesia, disturbance of circadian rhythms of sleep (in children), hyposmia, anosmia, essential tremor, akinesia, lack of response to stimuli.

From the side of the organ of vision: often - blurred vision, diplopia, impaired vision, nystagmus; infrequent - visual acuity reduction, scotoma, myopia, dry eyes, unpleasant sensations in the eyes, photophobia, blepharospasm, increased lacrimation, photopsy, mydriasis, senile hyperopia; rarely - one-sided blindness, transient blindness, glaucoma, accommodation disorder, ciliary scotoma, impaired spatial perception, eyelid edema, night blindness, amblyopia; frequency unknown - angle-closure glaucoma, maculopathy, frustration of eyeballs.

From the side of the hearing organ and labyrinthine disorders: often - vertigo, noise in the ears, pain in the ears; infrequently - deafness, one-sided deafness, sensorineural hearing loss, discomfort in the ears, hearing loss.

From the heart: infrequently - bradycardia, sinus bradycardia, palpitation.

From the side of the vessels: infrequently - arterial hypotension, orthostatic hypotension, "tides" of blood; rarely - Raynaud's syndrome.

From the respiratory system: often shortness of breath, nosebleeds, nasal congestion, rhinorrhea; infrequently - dyspnea with exercise, dysphonia, hypersecretion in the sinuses of the nose; frequency is unknown - cough.

Co the sides of the digestive system: very often - nausea, diarrhea; often - vomiting, constipation, pain in the upper abdomen, indigestion, dryness of the oral mucosa, abdominal pain, stomach discomfort, paresthesia of the oral mucosa, gastritis, abdominal discomfort; infrequently - pancreatitis, flatulence, gastroesophageal reflex disease, lower abdominal pain, hypoesthesia of the oral cavity mucosa, bleeding gums, bloating, epigastric discomfort, abdominal pain, hypersalivation, oral pain, breath odor, glossodynia.

From the side of the liver: rarely - hepatitis, hepatic insufficiency.

From the skin and subcutaneous tissues: often - alopecia, facial skin hypoesthesia; infrequently - anhydrase, vitiligo, macular rash, skin discoloration, allergic dermatitis; rarely Stevens-Johnson syndrome (mainly in children), periorbital edema, facial edema, erythema, oligohydrosis (mainly in children), redness of the skin,unpleasant skin odor, acne, skin pigmentation disorder; frequency unknown - toxic epidermal necrolysis.

Co the side of the musculoskeletal system and connective tissue: often - arthralgia, muscle spasm, myalgia, including in the chest, muscle cramps, muscle weakness; infrequently - swelling of the joints, stiffness in the muscles, muscle fatigue, pain in the side; rarely - discomfort in the limbs.

From the side of metabolism and nutrition: often - anorexia, decreased appetite; infrequently - metabolic acidosis, hypokalemia, increased appetite, polydipsia; rarely - hypochloraemic acidosis.

Co hand kidney and urinary system: often - nephrolithiasis, dysuria, pollakiuria; infrequent - urolithiasis, urinary incontinence and urinary incontinence, hematuria, frequent urge to urinate, renal colic, pain in the kidney; rarely - concrements of the ureter, renal tubular acidosis.

From the side of the reproductive system: infrequently - erectile dysfunction, sexual dysfunction.

Other: very often fatigue; often - fever, asthenia, irritability, gait disturbance,pathology of sensation (characterized by the following symptoms change in sensitivity (hyperstasy, hypesthesia, anesthesia), senestopathy, agnosia, psychosensory disorders, illusions, hallucinations), malaise; infrequently - hyperthermia, thirst, flu-like syndrome, inertness, cold extremities, a feeling of intoxication, a sense of anxiety; rarely - edema of the face, calcification.

Laboratory and instrumental data: very often - weight loss; often - weight gain; infrequently - kristalluriya, anomalous result of the test "tandem gait," a decrease in the number of white blood cells, increased activity of "liver" transaminases; rarely - a decrease in the concentration of bicarbonates in the blood plasma.

Special Groups:

Children:

Below is a list of unwanted reactions that, 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 thoughts , impaired concentration, inhibition, disturbance of the circadian rhythm of sleep, poor quality of sleep.increased lacrimation, sinus bradycardia, poor health, gait disturbances.

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

Overdose:

Symptoms: convulsions, disorders of consciousness up to coma, drowsiness, headache, speech disorder, accommodation disorder, diplopia, thinking disorders, speech and vision impairment, lethargy, movement coordination disorder, stupor, marked decrease in blood pressure, abdominal pain, agitation, dizziness, depression . Possible development of metabolic acidosis. In most cases, the clinical consequences were not severe, but there were deaths after an overdose of combinations of NEPs that included topiramate. There is a known case of overdose of topiramate in a dose of up to 110 g, which led to coma for 20-24 hours, and then a full recovery in 3-4 days.

Treatment: cause vomiting, rinse the stomach, increase the amount of fluid consumed, symptomatic therapy. In studies in vitro shown, that Activated carbon adsorbs topiramate. Hemodialysis is effective. Patients are advised to adequately increase the amount of fluid consumed.

Interaction:

Influence of topiramate on other PEPs

Simultaneous application of topiramate with other PEPs (phenytoin, carbamazepine, valproic acid, phenobarbital, primidon) has no significant effect on their concentration in the blood plasma, except for individual patients in whom the addition of topiramate to phenytoin may cause an increase in the concentration of phenytoin in the blood plasma. This may be due to the fact that topiramate inhibits a specific polymorphic isoenzyme CYP2C19 of the cytochrome 1450 system. Therefore, in every patient who takes phenytoin and in which clinical signs or symptoms of toxicity develop, it is necessary to control the concentration of phenytoin in the blood plasma.

In a study of pharmacokinetics in patients with epilepsy, the addition of topiramate to lamotrigine did not affect Css the latter with doses of topiramate 100-400 mg / day. During treatment and after lamotrigine withdrawal (average dose 327 mg / day) Css topiramate did not change.

Topiramate inhibits isoenzyme СУР2С19. in connection with which it can interact with its substrates (eg, diazepam, imipramine, moclobemide, proguanil, omeprazole).

The effect of other PEP on the concentration of topiramate

Phenytoin and carbamazepine reduce the concentration of topiramate in blood plasma. Adding or abolishing phenytoin or carbamazepine against a background of treatment with topiramate may require a change in the dose of the latter. Dose should be selected, focusing on achieving the desired clinical effect. Add or cancel valproic acid does not cause clinically significant changes in the concentration of topiramate in the blood plasma and does not require a dose change. The results of these interactions are presented in Table 1.

Table №1. Interaction of topiramate and other PEPs

PEP	Concentration of PEP in blood plasma	Concentration of topiramate in blood plasma
Phenytoin	↔/ ↑ (25%)	↓ (48%)
Carbamazepine	↔	↓(40%)
Valproic acid	↔	↔
Phenobarbital	↔	NO
Primidone	↔	NO
Lamotrigine	↔ (with a dose of topiramate up to 400 mg / day)	↓(13%)

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

↑ - increased concentration in individual patients;

↓ - decrease in the concentration in the blood plasma;

NO - not investigated.

Other interactions

AUC single dose digoxin decreased by 12% with simultaneous application with topiramate. The clinical significance of this observation is not clear. With the simultaneous use or withdrawal of topiramate in patients taking digoxin, it is necessary to carefully monitor the concentration of digoxin in the blood serum.

There is no data on simultaneous application of topiramate and admission alcohol or application other drugs that depress the central nervous system (CNS). It is not recommended combination of topiramate and drugs, depressing the central nervous system, or alcohol.

In the study of the drug interaction of topiramate with oral contraceptive (PC), containing norethisterone (1 mg) and ethinyl estradiol (35 μg), topiramate in doses of 50-800 mg per day did not have a significant effect on the effectiveness of norethisterone and in doses of 50-200 mg per day - the effectiveness of ethinylestradiol. A significant dose-dependent decrease in the efficacy of ethinylestradiol was observed in doses of topiramate 200-800 mg per day. The clinical significance of the described changes is not clear.

Possible reduction in the contraceptive effect of the PC and an increased risk of developing acyclic uterine bleeding should be considered in patients taking topiramate. Patients taking estrogen-containing PCs should be warned about the need to inform the doctor about any changes in the timing and nature of menstruation. The effectiveness of PC can be reduced even in the absence of acyclic bleeding.

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 bipolar affective disorder, the use of topiramate at doses up to 200 mg per day did not affect the pharmacokinetics of lithium, but at higher doses (up to 600 mg per day) AUC and C_mOhlithium increased by 26% and 27%, respectively. With the simultaneous use of topiramate and lithium, the concentration of the latter in the blood plasma should be monitored.

With simultaneous application risperidone with a single and repeated administration of topiramate to healthy volunteers and patients with bipolar affective disorder gave the same results. With the simultaneous use of topiramate in doses of 250 or 400 mg / day AUC risperidone, taken in doses of 1-6 mg / day, decreases by 16 and 33%, respectively. In this case, the pharmacokinetics of 9-hydroxyrisperidone did not change, and the total pharmacokinetics of the active substances (risperidone and 9-hydroxyrisperidone) changed insignificantly.The change in the systemic effect of risperidone / 9-hydroxyrisperidone and topiramate was not clinically significant, and this interaction has no significant clinical effect.

Drug Interactions hydrochlorothiazide (25 mg) and topiramate (96 mg) was evaluated in healthy volunteers. The results of the studies showed that in this case the maximum concentration (C_mOh) of topiramate is increased by 27% and AUC topiramate - by 29%. The clinical significance of these studies has not been revealed. With the simultaneous use of hydrochlorothiazide and topiramate, you may need to adjust the dose of topiramate. The pharmacokinetic parameters of hydrochlorothiazide did not undergo significant changes with concomitant therapy with topiramate.

With simultaneous application of topiramate and metformin there was an increase in C_mOh and AUC metformin at 18 and 25%, respectively, whereas the clearance of metformin decreased by 20%. Topiramate did not affect the time to reach C_max metformin in the blood plasma. The clearance of topiramate with simultaneous application with metformin decreased. The degree of revealed changes in clearance is not studied. The clinical significance of the effects of metformin on the pharmacokinetics of topiramate is not clear. In the case of application or withdrawal of topiramate in patients receiving metformin, should carefully monitor the course of diabetes.

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

When applying glibenclamide (5 mg per day) in isolation or simultaneously with topiramate (150 mg per day) in patients with type 2 diabetes mellitus AUC Glibenclamide decreased by 25%. Also, the systemic exposure of 4-trans-hydroxyglybeneclamide and 3-cis-hydroxyglybene clamamide was reduced by 13% and 15%, respectively. Glibenclamide did not affect the pharmacokinetics of topiramate in the equilibrium state. With simultaneous use of glibenclamide and topiramate, the patient's condition should be carefully monitored.

Simultaneous application of topiramate with other drugs predisposing to nephrolithiasis, may increase the risk of kidney stones.

Simultaneous application of topiramate and valproic acid in patients who tolerate each drug well, it is accompanied by hyperammonemia with or without encephalopathy. In most cases, symptoms and symptoms disappear after the withdrawal of one of the drugs. This adverse event is not caused by pharmacokinetic interaction. The relationship between hyperammonemia and the use of topiramate alone or in combination with other drugs has not been established.

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

Additional studies of drug interactions are presented in the table №2.

Table number 2. The results of additional studies on the interaction between topiramate and various drugs(LP)

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

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

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

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

NO - not investigated.

Special instructions:

Topsaver, like other PEPs, should be gradually phased out to minimize the possibility of an increased frequency of seizures, reducing the dose by 50-100 mg at a 1-week interval for the treatment of epilepsy and 25-50 for migraine prophylaxis. Children are canceled gradually within 2-8 weeks.If, according to medical indications, a quick cancellation of Topsaver is required, it is recommended that appropriate monitoring of the patient's condition be performed.

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.

The main way of excretion of topiramate and its metabolites in an unchanged form is excretion by the kidneys. The rate of excretion by the kidneys depends on the function of the kidneys and does not depend on age. Patients with moderate or severe renal dysfunction to achieve equilibrium plasma concentrations may need 10-15 days compared to 4-8 days in patients with normal renal function.

As with other AEDs dose drug selection circuit Topsaver it should be focused on the therapeutic efficacy (i.e. the degree of reduction of seizure frequency, lack of side effects), and should take into account,that in patients with impaired renal function to establish an equilibrium concentration of topiramate in the blood plasma for each dose may take a longer time.

With topiramate therapy, it is possible to develop oligodidrosis (decreased sweating) and anhydrase. 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. When treatment with Topsaver increases the risk of kidney stones and the appearance of appropriate clinical symptoms, such as renal colic, especially in patients predisposed to nephrolithiasis and hypercalciuria. None of these risk factors reliably leads to the formation of concrements during therapy with topiramate, but with simultaneous application with other medications,predisposing to the development of nephrolithiasis (acetazolamide, triamterene, ascorbic acid in a dose of more than 2 g / day), the risk of developing nephrolithiasis rises. Topsaver should be avoided against the background of increased formation of ketone bodies in the body due to an increased risk of developing nephrolithiasis.

When Topsover is used, the syndrome, which is an acute myopia, associated with secondary closed-angle glaucoma, may develop. The syndrome is accompanied by a sharp attack of visual acuity and / or eye pain. In ophthalmological examination, myopia, flattening of the anterior chamber, hyperemia (reddening of the eyes) and increased intraocular pressure are detected, and also mydriasis. The described syndrome can be associated with supraciliary ejaculation, which causes a shift in the lens and iris and the development of secondary closed-angle glaucoma. Typically, symptoms occur after a month of primary therapy. Unlike primary open-angle glaucoma, which was rarely detected in patients under 40 years of age, secondary closed angle glaucoma associated with the use of topiramate was observed in both children and adults.Treatment provides for the withdrawal of Topsaver if the doctor deems it appropriate, and taking appropriate measures to reduce 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, patients with eye diseases in the anamnesis should evaluate the ratio of expected benefit to the possible risk of use.

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

With the use of topiramate, hyperchloremic, not associated with an anion deficiency, metabolic acidosis (eg, a decrease in bicarbonate concentration in the blood plasma below the norm in the absence of respiratory alkalosis) may occur.Such a decrease in the concentration of bicarbonate in the blood plasma is a consequence of the inhibition of renal carbonic anhydrase by topiramate. In most cases, the decrease in the concentration of bicarbonate in the blood plasma occurs at the beginning of Topsaver, although this effect may occur in any period of treatment with Topsaver. Reducing the concentration of bicarbonate in the blood plasma is usually weak or moderate (mean plasma concentration 4 mmol / L when used in adults at a dose of more than 100 mg / day and in children at a dose of about 6 mg / kg / day). Reducing the concentration of bicarbonate in the blood plasma less than 10 mmol / l was noted in rare cases. Some diseases or methods of treatment that predispose to the development of acidosis (e.g., renal disease, severe respiratory disease, status epilepticus, diarrhea, surgery, increased formation of ketone bodies in the body, taking certain medications) may be additional factors enhancing bicarbonate-reducing effect of topiramate. Chronic metabolic acidosis increases the risk of developing nephrolithiasis.In children, chronic metabolic acidosis can cause osteomalacia and lead to a slowdown in growth.

In the treatment of topiramate, it is recommended to carry out the necessary studies, including determining the concentration of bicarbonates in the blood plasma. In the event of metabolic acidosis and its persistence, it is recommended to reduce the dose of Topsaver or stop taking it.

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

During clinical trials in patients with epilepsy with topiramate almost 3 times more often than in the placebo group, there were cases associated with an increase in suicidal activity (suicidal ideation, suicide attempts and completed suicide): the incidence was 0.5% in patients receiving topiramate (46 of 8652 patients) and 0.2% in patients receiving placebo. The mechanism of this risk is unknown. When Topsover is used, patients should be examined for suicidal thoughts and suicidal behavior.If suicidal activity is detected in patients, consideration should be given to the possibility of appropriate treatment. Patients, their relatives, and patient care staff should be informed about the need to consult a doctor if they have signs of suicidal tendencies and suicidal behavior. Patients with any personality disorders need special control, especially at the beginning of Topsaver treatment.

With prolonged use of Topsover, weight loss is possible, especially in children during intensive growth. With a persistent reduction in body weight, the patient should be advised to take an additional meal. If this measure is ineffective, consider changing the dosage regimen.

In 0.4% of patients who took topiramate, observed hypokalemia, defined as a decrease in serum potassium levels below 3.5 mmol / l.

The use of Topsaver for acute migraine attacks has not been studied.

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

During the treatment with Topsaver, the patient should refrain from driving and doing potentially dangerous activities,requiring increased concentration of attention and speed of psychomotor reactions, due to the fact that acting on CNS, Topsaver can cause drowsiness, dizziness, blurred vision and other adverse symptoms.

Form release / dosage:Capsules, 25 mg and 50 mg.

Packaging:

For 60 capsules in vials of HDPE with lids made of PP.

1 bottle with instructions for use in a cardboard pack.

Storage conditions:

Store at a temperature of no higher than 25 ° C, in a place protected from light and moisture. The bottle should be tightly closed.

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-003264

Date of registration:21.10.2015

Expiration Date:21.10.2020

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Industries, Ltd. Israel

Representation: & nbspTeva Teva Israel

Information update date: & nbsp02.01.2017

Illustrated instructions

Instructions

Topsaver (Topsaver)