Зонегран®

General characteristics. Structure:

Active ingredient: 25 mg, 50 mg or 100 mg of a zonisamid.

Excipients: the vegetable oil hydrogenated cellulose microcrystallic, sodium lauryl sulfate.

Capsular cover: gelatin, titanium dioxide, dye ferrous oxide black, dye red charming (E129), dye sunset yellow (E110), ink 1014 of Tekprint SW-9008*: shellac, propylene glycol, potassium hydrochloride, dye ferrous oxide black.

* Theoretical quantities, proceeding from total quantity of paint of 0,15 mg.

Pharmacological properties:

Pharmacodynamics. Zonisamid is derivative a benzisoksazola, is the antiepileptic means which is poorly oppressing in vitro karboangidraza. Chemically its structure differs from other antiepileptic means.

Anticonvulsant activity of a zonisamid was checked on various models in some groups with the induced or inborn attacks and зонисамид, apparently, works in these models as antiepileptic broad-spectrum agent. Zonisamid interferes with the maximum electroconvulsive attacks and limits development of spasms, including spread of spasms from a cerebral cortex to subcrustal structures, and also suppresses activity of epileptogenic focus. Unlike Phenytoinum and carbamazepine, зонисамид, however, has selectivity at impact on the attacks arising in a cerebral cortex.

The mechanism of action of a zonisamid is completely not opened, but probably it blocks potentsialochuvstvitelny natrium and calcium channels, lowering, thereby, extent of synchronized neural excitement, blocking development of attacks and preventing further distribution of epileptic activity. Zonisamid also reduces activity of neurons by means of piperidic acid (GAMK).

Pharmacokinetics. Absorption. Zonisamid is almost completely absorbed after oral administration, and the maximum concentration of a zonisamid in plasma is reached within 2-5 hours after reception. Extent of initial metabolism insignificant. Absolute bioavailability is estimated at the level about 100%. Bioavailability at intake does not depend on meal though food can slow down achievement of peak concentration of a zonisamid in serum or a blood plasma.

AUC values (the area under a curve) and the maximum concentration of a zonisamid increase almost linearly after a single dose in the range of doses of 100-800 mg and after repeated doses in the range of 100-400 mg once a day.

The stable state is reached within 13 days. Limit linkng of a zonisamid with erythrocytes can influence achievement of level of a stable state.

Distribution. Zonisamid contacts proteins of plasma for 40-50%, according to results of the researches in vitro, presence of various anti-epileptic drugs (such as, Phenytoinum, Phenobarbitonum, carbamazepine and sodium Valproatum) does not exert impact on linkng with proteins of plasma. The seeming distribution volume at adults about 1,1-1,7 l/kg indicating that it зонисамид is substantially distributed in fabrics. A ratio the erythrocytes/blood plasma make about 15 at low concentration and about 3 at high concentration.

Metabolism. Zonisamid is metabolized mainly by means of recovery splitting of a benzizoksazolovy ring of initial substance by CYP3A4 cytochrome to a form 2 (sulfamoylacetyl) - phenol (SMAP), and also due to N-acetylation.

Initial substance and SMAP can be in addition glyukoronizirovana. Metabolites which are not defined in a blood plasma are deprived of anticonvulsant activity. Data on what зонисамид induces own metabolism are absent.

Removal. Observed removal of a zonisamid in steady state after intake about 0,70 l/h and a final elimination half-life about 60 hours, in the absence of CYP3A4 cytochrome inductors. The elimination half-life does not depend neither on a dose, nor on repeated reception. Fluctuations of concentration of a zonisamid in serum or a blood plasma in the range of a dosage are insignificant (<30%). Metabolites and not changed зонисамид it is removed mainly through kidneys. The renal clearance of not changed zonisamid is rather low (about 3,5 ml/min.); about 15-30% of the accepted dose are removed in not changed look.

Elderly people. There are no clinically significant distinctions in pharmacokinetics of young people (from 21 to 40 years) and elderly (from 65 to 75 years) patients.

Renal failure. At patients with a renal failure (not having the epileptic status) the renal clearance of single doses of a zonisamid positively correlates with clearance of creatinine. The area under curve AUC of a zonisamid in a blood plasma was increased for 35% at patients with clearance of creatinine <20 ml/min.

Liver failure. Researches on patients with a liver failure were not conducted.

Pharmacokinetic researches at patients with a liver failure were not conducted.

Teenagers (12-18 years). Limited data show that the pharmacokinetics at teenagers with the daily dosage which was established on 1, 7 or 12 mg/kg in the divided doses, matches the pharmacokinetics observed at patients after the amendment on body weight.

Other characteristics. For Zonegrana® dependence "dose-concentration-answer" is definitely not defined. When comparing identical doses at patients with a bigger lump of a body lower equilibrium concentration of drug in blood serum are observed, but this effect is shown quite moderately. Patients with epilepsy have an age (≥12 years) and a floor (after the amendment on body weight) do not exert visible impact on exposure of a zonisamid throughout introduction of doses of drug for achievement of an equilibrium state.

Indications to use:

Зонегран® it is shown as additional medicine at adults at treatment of partial epileptic seizures with secondary generalization or without.

Route of administration and doses:

Inside, washing down with water, during meal or regardless of meal. The dose of drug is selected taking into account medical effect. As shown clinical trials, effective the daily dose of 300-500 mg is though some patients, in particular those which do not accept the drugs inducing CYP3A4 cytochrome can react to smaller doses.

Initial dose are 50 mg divided into two receptions. In one week of reception it is possible to increase a daily dose to 100 mg a day. Then it is possible to increase a dose by 100 mg each 7 days, to the maximum recommended dose of 500 mg a day. In the subsequent during treatment it is possible to pass to a single dose of drug every day.

Use of two-week intervals should be considered for patients with a liver or renal failure, and also the patients who are not accepting the drugs inducing CYP3A4 cytochrome.

Elderly people. It is necessary to be careful at purpose of treatment to elderly people as there is a limited amount of information on use of Zonegrana® for such patients. The health workers prescribing this drug need also to consider a safety profile.

Patients of children's age. Safety and efficiency of Zonegrana® at children and teenagers is not established yet. Data available today are described in the section on a pharmacodynamics, however it is not possible to submit recommendations about dosing at such patients.

Patients with a renal failure. It is necessary to be careful at treatment of patients with a renal failure as there is a limited amount of information on use of Zonegrana® for such patients and the slow titration of Zonegrana® can be necessary.

As зонисамид and its metabolites are removed by kidneys, this drug should be cancelled at patients at whom the acute renal failure developed, or at which clinically significant steady increase in level of creatinine in blood serum is observed.

Patients with a liver failure. Use of drug for patients with a liver failure was not studied. Therefore its use for patients with a heavy liver failure is not recommended. It is necessary to be careful at treatment of patients with a renal failure of easy and moderate severity. At such patients the slow titration of Zonegrana® can be necessary.

Cancellation of Zonegrana®. As shown clinical trials, drug withdrawal is made gradually by reduction of a dosage on 100 mg a week at the concomitant dosed use of other antiepileptic drugs.

Features of use:

Pregnancy and lactation. Researches on animals showed what зонисамид has potential reproductive toxicity. The risk of its emergence at people is unknown.

Зонегран® it is impossible to use during pregnancy unless potential advantages, according to the doctor, prevail over possible risk for a fruit. In case of purpose of Zonegrana® careful observation is recommended.

Women of childbearing age have to apply reliable methods of contraception during treatment of Zonegranom® and one month later after drug withdrawal. There are no sufficient data about use of Zonegrana® for pregnant women. The risk of developing of inborn malformations at children whose mothers accepted antiepileptic medicines, increases by 2-3 times. Such frustration are most often noted: crevice of an upper lip, anomaly of cardiovascular system and defects of a neurotubule. Complex therapy by antiepileptic medicines can be followed by increase in risk of inborn malformations in comparison with monotherapy.

It is not necessary to carry out sharp cancellation of anticonvulsant therapy as it can lead to development of an epileptic seizure that can have serious effects both for mother, and for the child. Drug is emitted in breast milk in concentration similar to that in plasma therefore it is necessary to make the decision on the feeding termination by a breast or on drug withdrawal at nursing mothers. Owing to a long elimination half-life breastfeeding can be resumed not earlier than in a month after drug withdrawal.

At therapy of Zonegranom® heavy skin reactions, including Stephens's syndrome - Johnson were observed.
 
Cancellation of Zonegrana® at patients who had skin rashes which cannot be explained with other reasons is recommended. All patients with the advent of rash during application of Zonegrana® have to be found under fixed observation, especially patients with simultaneous use of other antiepileptic means which are capable to cause skin rashes.

Cancellation of Zonegrana® at patients with epilepsy has to be carried out gradually for avoidance of the attacks connected with drug withdrawal. Cancellation of the accompanying antiepileptic drugs has to be carried out with care.

Зонегран® contains sulphonamide group. Rash, allergic reaction and considerable hematologic disturbances, including aplastic anemia which seldom or never can lead to death belong to serious side reactions from immune system, the medicines connected with reception which contain sulphonamide group.

It was reported about cases of an agranulocytosis, thrombocytopenia, a leukopenia, aplastic anemia, a pancytopenia and a leukocytosis. There is not enough information for assessment of possible interrelation of these phenomena with the accepted dose and duration of treatment.

The suicide orientation of thinking and suicide behavior are recorded at the patients accepting antiepileptic drugs on a number of indications. Meta-analysis of randomized placebos - controlled tests of antiepileptic drugs also showed some increased risk of emergence of suicide thoughts and behavior. By this analysis it is revealed that the frequency of cases of a sutsidalnost (i.e. suicide thoughts or behavior) at the patients accepting зонисамид made 0,4% in comparison with 0,2% at the patients accepting placebo. The mechanism of this risk is unknown, and the available data do not exclude a possibility of the increased risk for the drug Zonegran®. Therefore at observation of patients it is necessary to trace signs of suicide thoughts and behavior, and also it is necessary to study need of the corresponding treatment. Patients (and to the persons who are looking after them) should recommend to ask for medical assistance at emergence of suicide thoughts and behavior.

Cases educations of stones in kidneys at the patients receiving treatment of Zonegranom® are had. Increase in consumption of liquids and removal of urine helps to reduce risk of formation of stones, in particular at patients with the contributing risk factors.

The hyperchloremia, не-анионный connect an interval and a metabolic acidosis (i.e. the lowered level of bicarbonate of serum is lower than area of normal values in the absence of a chronic gas alkalosis) with treatment by the drug Zonegran®.

This metabolic acidosis is caused by loss of bicarbonates in kidneys owing to an inhibiting effect of a zonisamid on a karboangidraza. Such electrolytic imbalance was noted at use of the drug Zonegran® in placebo - controlled clinical tests, and also during the post-marketing period. Generally the metabolic acidosis caused zonisamidy is shown at an early stage of treatment though cases of acidosis are possible at any stage of treatment. Lowering of the level of bicarbonates usually insignificant or moderate (average decrease makes about 3,5 ¼Ø¬ó/l at a daily dose in 300 mg at adults); in rare instances at patients more considerable decrease can be noted.

Conditions or methods of treatment which contribute to acidosis (e.g. diseases of kidneys, heavy disorders of airways, an epileptic state, diarrhea, surgeries, a ketogenic diet, or medicines) can have the additive effect to the decrease in level of bicarbonates caused by action of a zonisamid. In case of signs or symptoms of a possible metabolic acidosis it is recommended to measure bicarbonate level in serum. If the shown metabolic acidosis does not pass, it is necessary to consider the possibility of a dose decline or complete cessation of reception of Zonegrana® (at a gradual dose decline). If the decision to continue treatment of patients of Zonegranom® in the presence of persistent acidosis is made, it is necessary to consider the possibility of use of alkaline neutralization.

Cases of the lowered sweating and the increased body temperature are recorded generally at patients of children's age. In some cases the diagnosis of heatstroke demanding hospitalization is made. The majority of cases occur at warm weather. The sick or looking after them persons have to be warned about need to support hydration and to avoid influence of the increased temperatures. It is necessary to be careful at purpose of Zonegrana® along with other drugs which can lead patients to the indispositions connected with heat; here inhibitors of coal anhydrase and medicines with holinoblokiruyushchy action enter.

At emergence at patients of symptoms of pancreatitis monitoring of level of pancreatic lipases and amylase, cancellation of Zonegrana® and symptomatic therapy is necessary.

If the patients accepting Zonegran® had severe muscular pains and/or weakness at fever or without it, it is recommended to estimate markers of muscular damage. At the increased level, for lack of other obvious reasons, the termination of reception of Zonegrana® and the beginning of the corresponding treatment has to be considered.

Women of childbearing age have to use reliable methods of contraception during therapy zonisamidy and within one month after drug withdrawal.

Зонегран® can cause loss of weight therefore during treatment purpose of nutritional supplements and suralimentation is necessary if the patient has the lowered weight or loses weight. If there is too big loss of weight, it is necessary to consider the possibility of drug withdrawal of Zonegran®.

At conduct of clinical trials the limited number of data for patients with body weight less than 40 kg is obtained. Thus, it is necessary to approach with care treatment of such patients.

Influence on ability to manage motor transport and to work with mechanisms. Зонегран® can cause drowsiness, difficulties of concentration of attention, especially at the beginning of therapy or at increase in a dose therefore patients are recommended to be careful when performing the actions demanding concentration of attention, for example, during the driving or work with mechanisms.

Side effects:

The side reactions connected with reception of Zonegrana®, received as a result of clinical trials and post-marketing observations are given in the underwritten table. Frequency of emergence was defined as: the most frequent (≥ 1/10), frequent (≥ 1/100 <1/10), infrequent (≥ 1/1,000 <1/100) and very rare (<1/10,000, including separate reports).

Systems of bodies	the most frequent	frequent	infrequent	very rare
Infections and invasions			Pneumonia Infections of an urinogenital path
Defeats of immune system		Hypersensitivity
Disturbances of metabolism and food	Anorexia		Hypopotassemia	Metabolic acidosis Tubular renal acidosis
Psychiatric frustration	Excitement, Irritability, Confusion of consciousness, Depression	Instability, alarm, sleeplessness, psychotic frustration	Anger, aggression, suicide thoughts and attempts	Hallucinations
Frustration of a nervous system	Ataxy Dizziness Decrease in memory Drowsiness	Bradyphrenia, disorders of attention, nystagmus, paresthesia, disturbance of the speech, tremor	Spasms	Amnesia Coma Big epileptic seizures Myasthenic syndrome Malignant antipsychotic syndrome, epileptic status
Visual disturbances	Doubling in eyes
Disturbances of blood and lymphatic system		Ecchymoma		Agranulocytosis Aplastic anemia Leukocytosis Leukopenia Lymphadenopathy Panhemocytopenia Thrombocytopenia
Respiratory, thoracic and mediastinal disturbances				Asthma Aspiration pneumonia Breath disturbance
Gastrointestinal frustration		Abdominal pains Konstipation Dyspepsia Nausea Diarrhea	Vomiting	Pancreatitis
Gepatobiliarny frustration			Cholecystitis Cholelithiasis	Hepatocellular damages
Skin frustration and frustration of hypodermic fabrics		Rash		Anhidrosis Multiformny erythema Increase in frequency of emergence of a syndrome of Stephens-Johnson Itch Toxic epidermal necrolysis
Frustration of musculoskeletal and connecting fabric and bones				Rabdomioliz
Deviations in results of inspections	The lowered bicarbonate	Weight reduction		The increased kreatinfosfokinaza level The increased creatinine level The increased urea level in blood Abnormal growth of liver enzymes
Disturbances of urinogenital system		Nephrolithiasis	Nephrolithiasis	Hydronephrosis Renal failure Disturbances of composition of urine
Febriculas		Pyrexia Exhaustion Diseases, similar to flu
Injuries, poisonings and complications of procedures				Heatstroke

Also it was reported about separate cases of sudden unexpected death at epilepsy (SUDEP) of the patients accepting Zonegran®.

Interaction with other medicines:

Tsitokhromny P450 enzymes. Researches in vitro with use of a microsome of a liver of the person show absence or practical absence (<25%) suppression by isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 of P450 cytochrome at the maintenance of a zonisamid not less than twice, than clinically relevant concentration of untied serum. Therefore, it is not supposed that Zonegran® will influence pharmacokinetics of other drugs via the mechanisms connected with P450 cytochrome, as shown for carbamazepine, a fenotoin, ethinylestradiol and in vivo desipramine.

Other antiepileptic medicines. At patients with epilepsy long reception of Zonegrana® did not exert impact on pharmacokinetics of carbamazepine, a lamotridzhin, Phenytoinum, sodium Valproatum.

Karboangidraza inhibitors. It is necessary to be careful at treatment of Zonegranom® of the patients accepting inhibitors of a karboangidraza such as топирамат, owing to lack of data for an exception of possible pharmakodinamichesky interaction.

Oral contraceptives. Reception of Zonegrana® in the set mode does not exert impact on concentration in blood serum of ethinylestradiol or Norethisteronum in the combined oral contraceptives.

P-gp substrate. Studying in vitro shows what зонисамид is weak P-gp (MDR1) inhibitor with IC50 - 267 µmol/l and that there is a theoretical possibility of influence of a zonisamid on pharmacokinetics of medicinal products which are P-gp substrates. It is recommended to begin or stop with care treatment zonisamidy or to change a dose of a zonisamid to patients who also accept the drugs which are P-gp substrates (for example, digoxin, quinidine).

The potential interaction of medicines influencing Zonegran®. At simultaneous use of Zonegrana® with other medicines which can lead to an urolithiasis perhaps increase in risk of development of stones in kidneys therefore simultaneous use of such medicines should be avoided.

Zonisamid is partially metabolized by CYP3A4, and also N-acetyls-transferases and merge to glucuronic acid, therefore, substances which induce or inhibit these enzymes, can exert impact on pharmacokinetics of a zonisamid:

Induction of enzymes: concentration of a zonisamid in blood is less at the patients with epilepsy accepting the drugs inducing CYP3A4 cytochrome such as Phenytoinum, carbamazepine and Phenobarbitonum. These influences can hardly have the clinical importance in cases when treatment of Zonegranom® is added to already existing therapy; nevertheless, changes in concentration of a zonisamid are possible at the cancellation, change of a dosage or purpose of additional drugs of antiepileptic action or other medicines displaying CYP3A4 and, in that case, dose adjustment of Zonegrana® can be required. Rifampicin is the powerful inductor CYP3A4. If the combined introduction of drugs is required, it is necessary to watch carefully a condition of the patient, if necessary adjusting a dose of Zonegrana® and other CYP3A4 of substrates.

CYP3A4 inhibition: on the basis of clinical data, the known specific and nonspecific CYP3A4 inhibitors, apparently, do not exert clinically significant impact on parameters of pharmacokinetics of a zonisamid. Dosing in the set mode of a ketokonazol (400 mg/day) or Cimetidinum (1200 mg/day) did not make clinically significant impact on pharmacokinetics of the zonisamid accepted by healthy people. Therefore, at reception along with drugs of which the inhibition of CYP3A4 is characteristic changes of doses of a zonisamid are not required.

Contraindications:

Hypersensitivity to components of drug or sulfonamides.

It is not recommended:
• At children's age up to 18 years;
• At a heavy liver failure;
• At an acute renal failure or at clinically designated steady increase in creatinine in blood serum;
• At pregnancy;
• In the period of a lactation.

With care. Patients of advanced age - limited data on clinical trials. It is necessary to be careful at the beginning of use of drug.

Patients of children's and teenage age - limited data on clinical trials.

Patients with a renal failure - it is necessary to be careful at treatment of patients with a renal failure, owing to limited data on clinical trials. Drug dose adjustment can be required. It is necessary to stop administration of drug to patients at whom the acute renal failure develops or at which clinically designated continuous increase in creatinine in blood serum is observed.

Patients with a liver failure - it is not studied. It is not recommended to accept drug to patients with a heavy liver failure, to take drug at a slight and moderately severe liver failure with caution. Drug dose adjustment can be required. Patients with high risk of a nephrolithiasis, including the previous formation of stones, genetic predisposition to a nephrolithiasis or a giperkaltsinuriya, or at reception of other drugs exerting impact on a nephrolithiasis.

The patients having factors which can increase risk or effects of a metabolic acidosis.

The patients who are in risk group of heatstroke owing to warm weather, early age or at combined use with other medical supplies which promote thermal frustration, including karboangidraza inhibitors (for example топирамат) and medicines with anticholinergic action.

Patients with body weight have less than 40 kg - limited data on clinical trials.

Overdose:

Symptoms: drowsiness, nausea, gastritis, nystagmus, myoclonus, coma, bradycardia, renal failure, hypotension and respiratory depression.

Very high concentration of a zonisamid in a blood plasma (100,1 mkg/ml) was noted approximately in 31 hour after a case of overdose of Zonegranom® and clonazepam. At the patient with overdose by these drugs the coma and respiratory depression developed. However in 5 days he recovered consciousness, and he noted no complications.

Treatment: there is no specific drug for treatment of overdose of Zonegrana®. After alleged overdose of Zonegrana® the immediate gastric lavage by emptying or calling of vomiting with usual precautionary measures for protection of respiratory tracts can be shown. The general supporting treatment, including regular control of the main indicators of a condition of an organism, and careful observation is shown.

Zonisamid has a long elimination half-life therefore its influence can have resistant character. Though formal researches for treatment of overdose were not conducted, the hemodialysis reduced concentration of a zonisamid in a blood plasma at patients with the lowered renal function, and can be considered as treatment of symptoms of overdose in case of clinical indications.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 3 years. Not to use drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

14 capsules in the blister (PVC/PVDH/aluminium). On 1, 2 or 4 blisters together with the application instruction place in a cardboard pack.