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

Active substanceZonisamideZonisamide

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Zonegran®

capsules inwards

Eysay Europe Limited United Kingdom

Dosage form: & nbspCapsules.

Composition:

Composition per 1 capsule:

Active substance: zonisamide - 25, 50 and 100 mg;

Auxiliary substances (25/50/100 mg): vegetable hydrogenated oil (0.75 / 1.50 / 3.00 mg), microcrystalline cellulose (49.06 / 98.12 / 196.25 mg), sodium lauryl sulfate (0.19 / 0.38 / 0.75 mg ), capsule shell: gelatin (36,895 / 46,575 / 74,239 mg), titanium dioxide (E171) (1,105 / 1,353 / 1,613 mg), iron dye oxide black (E172) (- / 0,072 / -mg), red dye (E129 (- / - / 0,147 mg), dye sunset yellow (E110) (- / - / 0,002 mg), ink 1014. Printerprint SW-9008 *: shellac (36,0- 40,5 / 36,0-40, 5 / 36.0-40.5 μg), propylene glycol (4.5-10.5 / 4.5-10.5 / 4.5-10.5 μg), potassium hydrochloride (0.075-0.150 / 0.075-0.150 / 0,075-0,150 μg), iron dye oxide black (E172) (36.0-42.0 / 36.0-42.0 / 36.0-42 , 0 μg).

* Theoretical quantities, based on the total amount of paint 0.15 mg.

Description:

Capsules by dosage of 25 mg of zonisamide: capsule size 4 with a lid and a white body with a black company logo and the name of the drug with a digital dosage indication "ZONEGRAN 25", containing a white or white with a yellowish hue powder free of visible inclusions.

Capsules with a dosage of 50 mg of zonisamide: capsule size 3 with a gray lid and a white body with a black company logo and the name of the drug with a digital indication of dosage "ZONEGRAN 50" containing white or white with a yellowish tinge powder,free from visible inclusions.

Capsules by dosage of 100 mg of zonisamide: capsule size 1 with a red lid and white body, with a black company logo and the name of the drug with a digital dosage indication "ZONEGRAN 100", containing a white or white with a yellowish tinge powder, free from visible inclusions.

Pharmacotherapeutic group:Antiepileptic agent.

ATX: & nbsp

N.03.A.X.15 Zonisamide

Pharmacodynamics:

Zonisamide is an antiepileptic agent, a benzisoxazole derivative, in vitro slightly inhibits carbonic anhydrase. Chemically, its structure is different from other antiepileptic drugs.

Mechanism of action

The mechanism of action of zonisamide is not fully studied, it probably blocks potential potent sodium and calcium channels, reduces the intensity of synchronized neuronal excitation, inhibits the development of seizures and prevents the further spread of epileptic activity. Zonisamide also reduces convulsive activity of neurons by enhancing the inhibitory effect of gamma-aminobutyric acid (GABA).

Pharmacodynamic effects

Anticonvulsant activity of zonisamide has been studied in various models of epilepsy, in groups with induced or congenital seizures, while zonisamide proved to be an antiepileptic remedy of a wide spectrum of action. Zonisamide prevents the development of maximum electroconvulsive attacks, limits the development of convulsions, including the spread of the focus of excitation from the cortex to the subcortical structures, and also inhibits the activity of the epileptogenic focus. Unlike phenytoin and carbamazepine, zonisamide has a selective effect on attacks occurring in the cerebral cortex.

Clinical efficacy and safety

Monotherapy of partial seizures with secondary generalization or without

The efficacy of zonisamide in monotherapy in patients with newly diagnosed partial epileptic seizures with or without secondary generalization, with generalized tonic-clonic seizures without distinct foci, was shown in a double-blind, parallel-group study involving 583 adult patients to establish no less efficacy of therapy Zonegran® preparation before long-acting carbamazepine therapy,lasted up to 24 months depending on the response to treatment. The dose was raised to the target value of 600 mg of carbamazepine or 300 mg of zonisamide. When patients had seizures, they increased to the next dose, i.e. 800 mg of carbamazepine or 400 mg of zonisamide. If the seizures persisted, the dose was increased to a maximum of 1200 mg for carbamazepine and up to 500 mg for zonisamide. Patients who did not have seizures for 26 weeks, while taking the target dose, continued to receive the same dose for another 26 weeks.

Additional therapy of partial seizures with secondary generalization or without in adults

The efficacy of additional zonisamide therapy was shown in 4 double-blind, placebo-controlled studies lasting up to 24 weeks. These studies showed a decrease in the median incidence of partial epileptic seizures when zonisamide was administered at daily doses of 300-500 mg once or twice daily.

Additional therapy of partial seizures with secondary generalization or without in adolescents and children from the age of 6

In children (aged 6 years and older), the efficacy of zonisamide was demonstrated in a double-blind, placebo-controlled study,duration of 24 weeks with the participation of 207 patients. With a 12-week application of the target dose, the frequency of seizures decreased by 50% or more in 50% of patients who received zonisamide, and in 31% of patients receiving placebo.

Special safety problems that arose in the conduct of research in children included: impaired appetite and weight loss, lower bicarbonate levels, increased risk of urolithiasis, and dehydration. All these phenomena and especially weight loss can adversely affect the growth and development of the child, and can also lead to a deterioration in overall health. In general, a limited amount of data has been obtained on the long-term effects of the drug on the growth and development of the child.

Pharmacokinetics:

Suction

Zonisamide is almost completely absorbed after oral administration, the maximum concentration (C_max) in plasma is achieved within 2-5 hours after administration. The expression of primary metabolism is insignificant - absolute bioavailability is estimated at 100%. Bioavailability of zonisamide during ingestion does not depend on food intake, although the time of reaching C can be slowed down_max in the blood plasma. The value of AUC (the area under the concentration-time curve) and C_max zonisamide almost linearly increase after taking a single dose (in the dose range of 100-800 mg) and after repeated administration (in the dose range of 100-400 mg once a day). The increase in these values when the equilibrium state was reached was somewhat higher than assumed, based on the accepted dose, possibly in connection with the saturation of the binding of zonisamide with erythrocytes. The equilibrium state is reached within 13 days. There is a somewhat larger accumulation than was expected, compared with a single dose of the drug.

Distribution

Zonisamide binds to plasma proteins by 40-50%, according to the results of studies in vitro, various anticonvulsants (phenytoin, phenobarbital, carbamazepine and sodium valproate) do not significantly affect the degree of its binding to plasma proteins. The apparent volume of distribution in adults is 1.1-1.7 l / kg, indicating a significant distribution of zonisamide in tissues. The ratio of zonisamide concentrations in erythrocytes and plasma is about 15 at low concentrations and about 3 at high concentrations.

Metabolism

Zonisamide metabolized with isoenzyme CYP3A4, main pathway - benzisoxazole ring cleavage to form 2-sulfamoilatsetilfenola (SMAP), and N-acetylation. The starting material and SMAP can bind to glucuronic acid. Metabolites, which are not detected in the blood plasma, are deprived of anticonvulsant activity. The data that zonisamide is able to induce its own metabolism is absent.

Excretion

The zonisamide clearance after achievement of C_ssreaches 0.70 l / h, the final half-life (T_1/2) - about 60 hours (provided there is no simultaneous reception of inducers of the activity of the isoenzyme CYP3A4). T_1/2does not depend on the magnitude of the dose taken, nor on the duration of treatment. Variations in the concentration of zonisamide in plasma are insignificant (<30%). Metabolites and unchanged zonisamide are excreted mainly through the kidneys. The renal clearance of unchanged zonisamide is comparatively low (about 3.5 ml / min); about 15-30% of the accepted dose is excreted unchanged.

Linearity / nonlinearity

The concentration of zonisamide increases until equilibrium is reached, which usually occurs after about 8 weeks.When comparing the same dose level, patients with a higher body weight tend to have lower equilibrium concentrations in the serum, but these differences are insignificant. Age (> 12 years) and gender, corrected for body weight, do not affect zonisamide concentrations in patients with epilepsy when equilibrium concentrations of the drug are reached. The need to reduce the dose when using any PET, including inducers of the isoenzyme CYP3A4, is absent.

Ratio of pharmacodynamics and pharmacokinetics

Zonisamide reduces the average frequency of seizures during the 28-day period and this decrease is proportional (log-linear dependence) of the average concentration of zonisamide.

Use in special patient groups

Patients with renal insufficiency

In patients with renal failure, the renal clearance of single doses of zonisamide is directly proportional to the creatinine clearance (CK). AUC of zonisamide is increased by 35% in patients with severe renal insufficiency (CC <20 ml / min) (see section "Method of administration and dose").

Patients with hepatic insufficiency

The pharmacokinetics of zonisamide in patients with hepatic insufficiency has not been adequately studied.

Elderly patients

There are no clinically significant differences in the pharmacokinetics of zonisamide in young (21-40 years) and elderly (65-75 years) patients.

Patients of childhood (5-18 years)

Limited data indicate that the pharmacokinetic parameters of zonisamide at a daily dose of 1 mg / kg, 7 mg / kg or 12 mg / kg in children and adolescents are similar to those in adult patients (adjusted for body weight).

Indications:

- Monotherapy in adult patients with partial epileptic seizures with secondary generalization or without, with newly diagnosed epilepsy;

- As part of complementary therapy in adults, adolescents and children from the age of 6 with partial epileptic seizures with secondary generalization or without.

Contraindications:

- Hypersensitivity to the active substance, any of the excipients or to sulfonamides.

- Children under 6 years of age (safety and effectiveness of the drug for this category of patients are not established).

- Patients with severe hepatic impairment (use in this category of patients has not been studied).

- Pregnancy and the period of breastfeeding (data on the safety of the drug for this category of patients is not enough (see the section on "Application during pregnancy and during breastfeeding")).

- Simultaneous use in children with carbonic anhydrase inhibitors, such as topiramate and acetazolamide.

Carefully:

- Older patients (available experience is limited).

- Patients with renal insufficiency (due to limited clinical experience, a slower choice of the dose of the drug may be required (see the section "Dosing and Administration")).

- Patients with hepatic insufficiency of mild to moderate severity (due to limited clinical experience, a slower selection of the dose of the drug may be required (see the section "Dosing and Administration")).

- Simultaneous use in adults with carbonic anhydrase inhibitors, such as topiramate and acetazolamide (insufficient data to exclude pharmacodynamic interaction).

- Simultaneous use in adults with pyrogenic medicines, including carbonic anhydrase inhibitors and drugs with anticholinergic action.

- The initiation of treatment, its cancellation or change in the dose of zonisamide with simultaneous use with P-glycoprotein substrates (for example, digoxin, quinidine)

- Patients weighing less than 20 kg (clinical experience is limited).

Pregnancy and lactation:

Women with preserved childbearing potential

Women with preserved reproductive potential should apply reliable contraceptive methods during treatment with Zonegran® and for 1 month after its withdrawal.

Pregnancy

There is insufficient data on the use of Zonegran® in pregnant women. Studies in animals have shown that zonisamide potentially has reproductive toxicity, the risk of which is unknown in humans.

Zonegran® should not be used during pregnancy, except in cases where the potential benefits, according to the doctor, prevail over the possible risk to the fetus. If a woman is planning a pregnancy, the need for anticonvulsant therapy should be analyzed. When Zonegran® is prescribed, careful monitoring is recommended. The risk of congenital malformations in children whose mothers take antiepileptic drugs increases by 2-3 times. Most often, the following defects are detected: cleavage of the upper lip, anomalies in the development of the cardiovascular system, and neural tube defects.

Combination therapy with anticonvulsant drugs is accompanied by an increased risk of developing congenital malformations in comparison with monotherapy.

It is unacceptable to abruptly cancel anticonvulsant therapy because of the risk of developing an epileptic attack, which can lead to serious consequences for both the mother and the child.

Breast-feeding

The drug is excreted in breast milk in concentrations similar to those in plasma, so you should decide whether to stop breastfeeding or to cancel the drug in nursing mothers. Due to the long half-life, breastfeeding can be resumed no earlier than one month after discontinuation of the drug.

Dosing and Administration:

Inside, washing down with water, regardless of food intake.

Adult patients

Zonegran® can be given to adults in the form of monotherapy, and as an adjunct to already prescribed treatment. The dose of the drug is selected taking into account the clinical effect. The recommended mode of dose increase and the amount of maintenance doses are given in Table 1. Some patients, in particular those who do not take CYP3A4 isoenzyme inducing drugs,may respond to smaller doses.

Table 1. Recommended regimen for increasing the dose and the amount of maintenance doses in adults

Treatment Scheme	Dose selection			Maintenance dose
Monotherapy Adults with newly diagnosed epilepsy	Week 1-2	Week 3-4	Week 5-6	300 mg per day (single administration). If higher doses are required: an increase of 100 mg at a two-week interval to a maximum recommended dose of 500 mg
Monotherapy Adults with newly diagnosed epilepsy	100 mg per day (single administration)	200 mg per day (single administration)	300 mg per day (single dose)
Additional therapy: - Patients taking drugs that induce the isoenzyme CYP3A4	Week 1	Week 2	Week 3-5	from 300 to 500 mg per day (once or in 2 divided doses)
	50 mg per day (in 2 divided doses)	100 mg per day (in 2 divided doses)	an increase of 100 mg at weekly intervals	from 300 to 500 mg per day (once or in 2 divided doses)
- Patients who do not take drugs that induce the isoenzyme CYP3A4 or patients with renal or hepatic insufficiency	A week	A week	A week	from 300 to 500 mg per day (once or in 2 divided doses). Some patients may respond to lower doses.
	1-2	3-4	5-10
	50 mg per day (in 2 admission)	100 mg per day (in 2 admission)	Increase by no more than 100 mg with two-week intervals

Cancel

Zonegran® is canceled gradually by reducing the dose by 100 mg per week while simultaneously adjusting the dose of other co-administered antiepileptic drugs (if necessary).

Teens and children from 6 years old

Zonegran® can be given to children from the age of 6 as an adjunct to already prescribed treatment. The dose of the drug is selected taking into account the clinical effect.

The recommended dose-increasing regimen and the amount of maintenance doses are given in Table 2. Some patients, in particular those who do not take CYP3A4 isoenzyme-inducing drugs, can respond to lower doses. Pay attention to children and their parents or caretakers for special instructions for the patient on measures to prevent heat stroke (see section "Special instructions").

Table 2. Recommended mode of dose increase and the value of maintenance doses in children from 6 years of age

Treatment Scheme	Dose selection		Maintenance dose
Additional therapy: - Patients taking drugs that induce the isoenzyme CYP3A4	Week 1	Week 2-8	Patients with a body weight of 20 to 55 kg *	Patients weighing more than 55 kg
	1 mg / kg per day (once)	an increase of 1 mg / kg at weekly intervals	from 6 to 8 mg / kg per day (once)	from 300 to 500 mg per day (once)
- Patients who do not take drugs that induce the isoenzyme CYP3A4	Week 1-2	Week 3 and onwards	from 6 to 8 mg / kg per day (once)	from 300 to 500 mg per day (once)
	1 mg / kg per day (once)	an increase of 1 mg / kg at two-week intervals

* To ensure maintenance of a maintenance dose, it is necessary to monitor the weight of the child's body and change the dose as the body weight changes to 55 kg. The dosage regimen is 6-8 mg / kg per day up to a maximum daily dose of 500 mg.

The safety and efficacy of Zonegran® in children younger than 6 years of age or in children weighing less than 20 kg have not been established.

In clinical studies, limited data were obtained in patients with a body weight of less than 20 kg. In this regard, in children aged 6 years and older with a body weight of less than 20 kg in treatment should be careful.

Cancel

Zonegran® is canceled gradually by reducing the dose by 2 mg / kg per week (according to the recommendations in Table 3).

Table 3. Recommended dose reduction scheme for children from 6 years of age

Body mass	*Dose reduction with weekly intervals at :**
20 - 28 kg	from 25 to 50 mg per day
29 - 41 kg	from 50 to 75 mg per day
42 - 55 kg	100 mg per day
More than 55 kg	100 mg per day

* with a single admission.

Use in elderly patients

Care should be taken when prescribing the drug because of limited experience. It is necessary to take into account the safety profile of the drug (see section "Side effect").

Use in patients with renal insufficiency

Caution should be exercised in treating patients with renal insufficiency due to limited clinical experience - a slower dose selection may be required. As zonisamide and its metabolites are excreted by the kidneys, it should be discarded in patients who developed acute renal failure, or clinically significant hypercreatininaemia is observed.

Use in patients with hepatic impairment

The use of the drug in patients with hepatic insufficiency has not been studied. Use in patients with severe hepatic insufficiency is not recommended.Care should be taken when treating patients with mild to moderate hepatic insufficiency - a slower dose selection may be required.

Side effects:

The experience with Zonegran® includes clinical trials for more than 1200 patients, 400 of whom received Zonegran® for at least 1 year, and extensive post-marketing use (in Japan since 1989, in the US since 2000).

Zonisamide contains a sulfonamide group. Serious adverse reactions from the immune system associated with taking drugs that contain a sulfonamide group include the appearance of skin rashes and other allergic reactions, as well as the development of severe hematologic disorders, including aplastic anemia, in very rare cases leading to lethal outcome (see section "Special instructions"). The most frequent adverse reactions in controlled studies of complex therapy were drowsiness, dizziness, and anorexia. The most frequent adverse reactions in a randomized controlled trial of monozoa zonisamide compared with sustained release carbamazepine in the group of patients who received zonisamide, decreased bicarbonate levels, loss of appetite and weight loss. The frequency of significant reduction in serum bicarbonate levels (reduction to less than 17 mEq / L and more than 5 mEq / L) was 3.8%. The frequency of a significant decrease in body weight by 20% or more was 0.7%.

Frequency of occurrence was defined as: very often (> 1/10), often (> 1/100 <1/10), infrequently (> 1/1000 <1/100) and very rarely (<1/10000).

Table 4. Adverse reactions, revealed during clinical trials of complex therapy and post-marketing observations

Systems of organs	Often	Often	Infrequently	Rarely
Infectious and parasitic diseases			Pneumonia Urogenital infections
Violations of the blood and lymphatic system		Ecchymosis		Agranulocytosis Aplastic anemia Leukocytosis Leukopenia Lymphadenopathy Pancytopenia Thrombocytopenia
Immune system disorders		Hypersensitivity reactions		Syndrome of hypersensitivity to the drug Drug rash with eosinophilia and systemic symptoms
Disorders of metabolism and nutrition	Anorexia		Hypocapaemia	Metabolic Acidosis Tubular Renal Acidosis
Disorders of the psyche	Excitation Irritability Confusion consciousnesses Depression	Affective lability Anxiety Insomnia Psychotic disorders	Anger Aggressiveness Suicidal thoughts Suicidal attempts	Hallucinations
Disturbances from the nervous system	Ataxia Dizziness Decreased memory Drowsiness	Bradyphrenia Violation attention Nystagmus Paresthesia Violation of speech Tremor	Convulsions	Amnesia Coma Large epileptic seizures Myasthenic syndrome Malignant neuroleptic syndrome, Epileptic status
Disturbances on the part of the organ of sight	Diplopia
Disturbances from the respiratory system, chest and mediastinal organs				Dyspnea Aspiration pneumonia Respiratory depression Hypersensitive pneumonitis
Disorders from the gastrointestinal tract		Abdominal pain Constipation Diarrhea Dyspepsia Nausea	Vomiting	Pancreatitis
Disturbances from the liver and bile ducts			Cholecystitis Holelithiasis	Hepatocellular injury
Disturbances from the skin and subcutaneous tissues		Rash Itchy Alopecia		Anhidrosis Erythema multiforme Stevens-Johnson syndrome Toxic epidermal necrolysis
Disturbances from musculoskeletal and connective tissue				Rhabdomyolysis
Disorders from the kidneys and urinary tract		Nephrolithiasis	Urolithiasis	Hydronephrosis Renal failure Impairment of urine composition
General disorders and disorders at the site of administration		Increased fatigue Flu-like conditions Increase in body temperature Peripheral edema
Laboratory and instrumental data	Reduction in the level of bicarbonates	Weight loss		Increase in the level of creatine phosphokinase Increase in the level of creatinine Increase in the level of urea Violation of biochemical parameters of liver function
Trauma, intoxication and complications of manipulation				Heatstroke

Single cases of sudden unexplained death of patients with epilepsy who took Zonegran® (SUDEP) are described.

Table 5. Adverse Reactions Identified in a Randomized Controlled Study of Zonisamide-Based Monotherapy in Comparison with Extended Release Carbamazepine

Systems of organs	Often	Often	Infrequently
Infectious and parasitic diseases			Urogenital infections Pneumonia
Violations of the blood and lymphatic system			Leukopenia Thrombocytopenia
Disorders of metabolism and nutrition		Decreased appetite	Hypokalemia
Disorders of the psyche		Excitement Depression Insomnia Emotional lability Anxiety	Confusion of consciousness Acute psychosis Aggressiveness Suicidal thoughts Hallucinations
Disturbances from the nervous system		Ataxia Dizziness Deterioration of memory Drowsiness Bradifrenia Disturbance of attention Paresthesia	Nystagmus Violation of speech Tremor Cramps
Disturbances on the part of the organ of sight		Diplopia
Disturbances from the respiratory system, chest and mediastinal organs			Disturbance of breathing
Disorders from the gastrointestinal tract		Constipation Diarrhea Dyspepsia Nausea Vomiting	Abdominal pain
Disturbances from the liver and bile ducts			Acute cholecystitis
Disturbances from the skin and subcutaneous tissues		Rash	Itching Ecchymosis
General disorders and disorders at the site of administration		Increased fatigue Raising body temperature Irritability
Laboratory and instrumental data	Reduction in the level of bicarbonates	Weight reduction Increase in the level of creatine phosphokinase Increase in the level of alanine aminotransferase Increase in the level of aspartate aminotransferase	Impaired urine test

Additional safety information in specific patent groups

Elderly patients

A summary analysis of safety data in 95 elderly patients showed a relatively higher incidence of peripheral edema and itching compared with younger patients. A review of post-marketing data on the tolerability of therapy with Zonegran® in elderly patients (over 65 years) suggests that Stevens-Johnson syndrome and drug hypersensitivity reactions are more common in this category of patients than in the general population.

Patients of childhood

The safety profile of zonisamide in children participating in placebo-controlled clinical trials (aged 6 to 17 years) corresponds to the safety profile of the drug in adults. Of the 465 patients included in the child safety database (including 67 patients who continued to participate in the open phase of the continued controlled clinical trial), 7 children died (1.5%, 14.6 / 1000 patient-years) : in 2 cases as a result of epileptic status,of which one was associated with a significant reduction in body weight (by 10% for 3 months) in a patient with a low body weight, followed by withdrawal of the drug; in 1 case, as a result of a traumatic brain injury / hematoma and in 4 cases, deaths occurred in patients with previous functional neurologic deficit of different genesis (2 cases of sepsis associated with pneumonia / multiple organ failure, 1 case of SUDEP and 1 case of craniocerebral trauma) . A total of 70.4% of patients who in a controlled study or in an open phase of the continuation of this study were receiving zonisamide, during the therapy at least once the level of bicarbonates was less than 22 mmol / l. A low level of bicarbonate persisted for a long period of time (median 188 days).

In a consolidated analysis of safety data from 420 children (183 aged 6 to 11 years and 237 aged 12 to 16 years, whose median duration of treatment was approximately 12 months), relatively more frequent reports of the occurrence of pneumonia, dehydration,decrease in sweating, impairment of biochemical parameters of liver function, otitis media, pharyngitis, sinusitis and upper respiratory tract infections, cough, nosebleeds and rhinitis, abdominal pain, vomiting, rash and eczema, as well as fever compared to adult patients younger than 12 years). With a lower frequency, there were reports of amnesia, increased levels of creatinine, lymphadenopathy, and thrombocytopenia. The incidence of weight loss by 10% or more was 10.7% (see section "Special instructions"). In some cases of weight loss, there was a delay in the transition to the next stage of Tanner and maturation of bone tissue.

Announcement of unwanted reactions

It is extremely important to notify of undesirable reactions that occurred during the post-marketing use of the drug. This will control the ratio of the benefits and risks of the drug. Please inform medical workers of any undesired reactions.

Overdose:

Symptoms

There have been cases of intentional and unintentional overdose of Zonegran® in adults and children.In some cases, the overdose was asymptomatic, especially with immediate gastric lavage. In other cases, the overdose was accompanied by the following symptoms: drowsiness, nausea, symptoms of gastritis, nystagmus, myoclonus, coma, bradycardia, impaired renal function, arterial hypotension and respiratory depression. A very high concentration of zonisamide in blood plasma (100.1 μg / ml) was noted approximately 31 hours after an overdose of Zonegran® and clonazepam. A patient with an overdose of these drugs developed coma and respiratory depression. However, after 5 days he regained consciousness, and he had no complications.

Treatment

There is no specific antidote for overdose treatment with Zonegran®. After an alleged overdose, immediate gastric lavage is shown against the background of normal measures aimed at maintaining airway patency. Provide supportive therapy, including regular monitoring of the basic indicators of the state of the body, and careful observation. Zonisamide has a long T1, and therefore the symptoms of his overdose can be persistent.Studies of treatment of overdose have not been conducted, however, it is known that hemodialysis reduces the concentration of zonisamide in blood plasma in patients with renal insufficiency and can be considered as an overdose treatment tool.

Interaction:

Enzymes of the cytochrome P450 system

The study of the effect of Zonegran® in vitro on microsomal oxidation in human hepatocytes showed no significant effect (<25%) on the activity of cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 at concentrations of zonisamide in blood plasma 2 times or more than therapeutic . It is unlikely that Zonegran® will affect the pharmacokinetics of other drugs through mechanisms associated with cytochrome P450, this is demonstrated in vivo for carbamazepine, phenytoin, ethinyl estradiol and desipramine.

Potentially possible effects of Zonegran® on other drugs

Other antiepileptic drugs

In patients with epilepsy, prolonged use of Zonegran® does not affect the pharmacokinetics of carbamazepine, lamotrigine, phenytoin, and sodium valproate.

Inhibitors of carbonic anhydrase

Caution should be exercised when co-administering the drug Zonegran® with carbonic anhydrase inhibitors (eg, topiramate and acetazolamide) because insufficient data to exclude the pharmacodynamic interaction (see. Section "Special instructions"), Zonegran® should not be given to children at the same time with inhibitors carbonic anhydrase, such as topiramate and acetazolamide (see section "Special instructions").

Oral contraceptives

The drug Zonegran® and combined oral contraceptives at recommended doses has no effect on the concentration in the blood serum of ethinylestradiol or norethisterone.

Substrates of P-glycoprotein

Research results in vitro show that zonisamide is a weak inhibitor of P-glycoprotein (MDR1) with a half-maximal inhibition concentration (IC₅₀) - 267 pmol / l, whereby there is a theoretical possibility of influence on the pharmacokinetics of zonisamide drugs that are substrates of P-glycoprotein. Recommended with caution to start or stop the treatment or change the dose of zonisamide in patients who are also taking drugs that are substrates of P-glycoprotein (eg, digoxin, quinidine).

Potentially possible effects of other drugs on Zonegran®

With simultaneous use with lamotrigine, no significant effect on the pharmacokinetics of zonisamide was found. With simultaneous prescription of Zonegran® with medicines that can cause the development of urolithiasis, the risk of developing nephrourolythiasis increases, and therefore, their simultaneous use should be avoided.

Zonisamide is metabolized with the participation of the isoenzyme CYP3A4, and N-acetyl-transferases, and also through conjugation with glucuronic acid. Consequently, substances that induce or inhibit these enzymes can influence the pharmacokinetics of zonisamide:

Inductors of enzymes: the effect of zonisamide is reduced with the simultaneous administration of drugs that increase the activity of the isoenzyme CYP3A4 (for example, phenytoin, carbamazepine and phenobarbital). These effects are not clinically significant in cases where Zonegran® joins the treatment already received, however, clinically significant changes in zonisamide concentrations are possible with cancellation,a change in the dosage regimen or the addition of medications indicating the isoenzyme CYP3A4 (a dosage adjustment of Zonegran® may be required). Rifampicin is a powerful inducer of the CYP3A4 isoenzyme, if its co-administration with Zonegran® is required, the patient's condition should be monitored carefully, adjusting the dose of Zonegran® if necessary.
Inhibitors of enzymes: the clinical data did not show a significant effect of CYP3A4 isoenzyme inhibitors on the pharmacokinetic parameters of zonisamide. The administration of ketoconazole (400 mg / day) or cimetidine (1200 mg / day) had no clinically significant effect on the pharmacokinetics of zonisamide taken by healthy volunteers. Changes in the dosage regimen of Zonegran® during combined administration with CYP3A4 isoenzyme inhibitors are not required. Patients of children's age Studies of drug interactions in children have not been conducted.

Special instructions:

Skin rashes

When therapy with Zonegran® was reported on the development of severe skin reactions, including Stevens-Johnson syndrome.

It is recommended to cancel Zonegran® in patients who have skin rashes and can not be explained by other causes. All patients with the appearance of skin rashes during the use of Zonegran® should be closely monitored, especially patients with concomitant administration of other antiepileptic drugs that are themselves capable of causing skin rashes.

The withdrawal syndrome

The discontinuation of Zonegran® is effected by gradually reducing the dose to avoid the occurrence of epileptic seizures. There is insufficient data on the abolition of concomitant antiepileptic drugs after control of seizures with the use of Zonegran® in the framework of ancillary therapy for the transition to monotherapy with Zonegran®. Therefore, the abolition of concomitant antiepileptic treatment should be conducted with caution.

Reactions associated with the presence of the sulfonamide group

Zonegran® contains a sulfonamide group. To serious adverse reactions from the immune system associated with taking medications that contain a sulfonamide group,include the appearance of skin rashes and other allergic reactions, as well as the development of severe hematologic disorders, including aplastic anemia, in very rare cases leading to death.

The development of cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia of pancytopenia, and leukocytosis was reported. Information for assessing the possible relationship of these phenomena with the magnitude of the dose of Zonegran® taken and the duration of treatment is not enough.

Suicidal thinking and behavior

The development of suicidal thinking and behavior is possible in patients taking antiepileptic drugs for a number of indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed an increased risk of suicidal thoughts and behavior. The mechanism of this phenomenon is unknown, the available data do not exclude the possibility of an increased risk of suicidal behavior and against Zonegran®. It is necessary to observe patients for the appearance of suicidal thoughts and behavior, and also to provide appropriate treatment.Patients (and caregivers) should be advised to seek medical help when suicidal thoughts and behavior occur.

Nephrolithiasis

In some patients, especially those with a predisposition to nephrolithiasis, there may be an increased risk of kidney stones and the appearance of such signs and symptoms as renal colic, kidney pain, or side pain. Nephrolithiasis can lead to chronic kidney damage. Risk factors for nephrolithiasis include the previous formation of kidney stones, as well as nephrolithiasis and hypercalciuria in a family history. None of these risk factors is a reliable indicator that allows predicting the formation of kidney stones in the treatment of zonisamide. In addition, the risk may be increased in patients taking other drugs that cause the development of urolithiasis. Increased fluid intake and forced diuresis helps reduce the risk of stone formation, including in patients with a predisposition to it.

Metabolic acidosis

Formation of hyperchloroemic metabolic acidosis without anionic rupture (decrease in the level of bicarbonates in the absencechronic gas alkalosis) is associated with therapy with Zonegran®. The development of metabolic acidosis is due to the loss of bicarbonates in the kidneys due to the inhibitory effect of zonisamide on carbonic anhydrase, and possibly at any stage of treatment, although more often seen in the early stages of treatment. Similar violations were noted both during the placebo-controlled clinical trials, and in the postmarketing period. The decrease in the level of bicarbonates is usually less pronounced (the average value is approximately 3.5 mEq / L at a daily dose of 300 mg in adults); In rare cases, patients may experience a more significant decrease. Conditions or treatment methods that predispose to the development of acidosis (eg, kidney disease, severe respiratory disorders, epileptic status, diarrhea, surgical interventions, a diet that promotes the formation of ketone bodies, a number of drugs) can enhance the effect of zonisamide on bicarbonate levels.

The risk of occurrence and severity of metabolic acidosis increases in young patients.In case of signs or symptoms of metabolic acidosis, it is recommended to evaluate the concentration of bicarbonates in the serum. If metabolic acidosis does not develop, consider lowering the dose or completely stopping Zonegran®(with a gradual decrease in the dose), since the development of osteopenia is possible. If you decide to continue therapy with persistent acidosis, consider using alkaloids.

Caution should be exercised in conjunction with carbonic anhydrase inhibitors (for example, topiramate and acetazolamide), since there is insufficient data to exclude pharmacodynamic interaction (see the section "Interaction with other drugs").

Heatstroke

Cases of sweating and body temperature increase were recorded mainly in patients under 18 years old. In a number of cases, there was a heat stroke that required hospital treatment. Most of the cases occurred under conditions of high ambient temperature. Patients and / or caregivers should be warned about the need to maintain adequate hydration and avoid exposure to elevated temperatures.Caution should be exercised when prescribing Zonegran® concomitantly with preparations that promote overheating, including inhibitors of carbonic anhydrase and cholinergic blockers.

Pancreatitis

With the development of signs of pancreatitis in patients with the use of Zonegran®, the level of pancreatic lipases and amylase needs to be monitored. In the case of confirmed pancreatitis, in the absence of other obvious reasons, it is recommended that Zonegran® be discontinued and the appropriate treatment is prescribed.

Rhabdomyolysis

When developing patients taking Zonegran®, severe muscle pain and / or weakness, especially accompanied by fever, an evaluation of the content of muscle damage markers, including the level of creatine phosphokinase and aldolase, is required. If they are increased, in the absence of other obvious causes, such as trauma or a major epileptic attack, it is recommended that Zonegran® be discontinued and that appropriate treatment be prescribed.

Women with preserved childbearing potential

Women with preserved reproductive potential must use reliable methods of contraception during treatment with Zonegran® and for 1 month after it has been discontinued (see.section "Application during pregnancy and during breast-feeding").

Weight loss

Zonegran® can cause a decrease in body weight, so when treating patients with reduced body weight or when it decreases, it is necessary to appoint food supplements and reinforced nutrition. With a marked decrease in body weight, the possibility of discontinuing Zonegran® should be considered. The decrease in body weight in children may be more pronounced.

Patients of childhood

The above precautions apply to children and adolescents. The following are the precautions to be taken into account.

Heat shock and dehydration

Prevention of overheating and dehydration in children Zonegran® can cause a decrease in sweating and lead to overheating, and in the absence of appropriate care, the child may experience brain damage and death. Children are at high risk, especially in hot weather.

If the child is taking Zonegran®:

- Do not overheat, especially in hot weather

- Avoid significant physical exertion, especially in hot weather

- Increase water consumption

- Do not use the following drugs: carbonic anhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergic drugs (such as clomipramine, hydroxysine, diphenhydramine, haloperidol, imipramine and oxybutynin).

IF ANY OF THE BELOW-LISTED SYMPTOMS ARE IMMEDIATELY, IMMEDIATELY MAY APPLY FOR MEDICAL CARE: Sensation of severe heat from the skin with little or no sweating, or when the child has confusion, muscle spasms, or with increased palpitation or breathing in the child.

- it is necessary to put the child in a cool shaded place;

- moisten the child's skin with water to cool it;

- give your child a cool drink of water.

Cases of sweating and fever, mainly in children, have been reported. In some cases, there was a heat stroke that required hospitalization. In a number of cases, a thermal shock was reported with a fatal outcome. In most cases, the phenomenon occurred in warm weather. The patient and caregivers should be warned about the possible severity of the heat stroke, the situations in which it may occur, and the measures to be taken if any signs or symptoms appear.Patients or caregivers need to be warned about the need to consume enough fluid and avoid excessive physical exertion, depending on the patient's condition. In case of signs and symptoms of dehydration, oligohydrosis, or fever, consideration should be given to the withdrawal of Zonegran®.

Zonegran® should not be used in children receiving other medicines at the same time, in which patients are prone to the appearance of abnormalities associated with exposure to excessive heat; This includes inhibitors of carbonic anhydrase and drugs with anticholinergic action.

Weight loss

There were cases of weight loss, which led to worsening of the general condition and discontinuation of the antiepileptic drug, leading to death. The use of Zonegran® is not recommended in children with reduced body weight or in children with poor appetite.

The frequency of weight loss is the same in different age groups, however, given the possible seriousness of weight loss in children, this group of patients need to control body weight.If the patient's weight gain is delayed, based on physical development cards, it is recommended to revise the diet or increase the amount of food taken, otherwise Zonegran® should be discontinued.

In clinical studies, limited data were obtained in patients with a body weight of less than 20 kg. Therefore, care should be taken when treating children aged 6 years and over with a body weight of less than 20 kg. The effect of prolonged maintenance of low body weight on growth and development in children is unknown.

Metabolic acidosis

The risk of acidosis associated with the use of zonisamide, in children and adolescents may be higher and more severe. In this group of patients, appropriate monitoring and control of serum bicarbonate levels is necessary. The long-term effect of low levels of bicarbonates on growth and development is unknown.

Zonegran® should not be used in children with other carbonic anhydrase inhibitors, such as topiramate or acetazolamide.

Nephrolithiasis

Children reported on the appearance of kidney stones.In some patients, especially those with a predisposition to nephrolithiasis, there may be an increased risk of kidney stones and related symptoms and symptoms, such as renal colic, kidney pain, or side pain. Urolithiasis can lead to chronic kidney damage. Risk factors for urolithiasis include the previous formation of kidney stones and a hereditary predisposition to nephrolithiasis and hypercalciuria. None of these risk factors is a reliable indicator that allows predicting the formation of kidney stones in the treatment of zonisamide. Increased fluid intake and forced diuresis can reduce the risk of kidney stones, especially in people with risk factors. At the discretion of the doctor, ultrasound can be performed on the kidneys. In the case of kidney stones, Zonegran®should be canceled.

Impaired liver function

In children and adolescents, there was an increase in liver and bile duct function such as alanine aminotransferase (ALT), aspartate aminotransferase (ACT), gamma-glutamyltransferase (GGT) and bilirubin, but no apparent patterns for values exceeding the upper limit of normal were established.Nevertheless, if there is a suspicion of the occurrence of undesirable phenomena on the part of the liver, liver function should be evaluated and the question of withdrawal of Zonegran® medication should be resolved.

Cognitive functions

Cognitive impairment in patients with epilepsy is associated with underlying disease and / or antiepileptic drugs. In a placebo-controlled study using zonisamide in children and adolescents, the proportion of patients with cognitive impairment was quantitatively higher in the zonisamide group compared with the placebo group.

Excipients

The formulation of Zonegran® with a dosage of 100 mg includes dye "sunset yellow" (E110) and "red charming" (E129), which can cause allergic reactions.

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

Special studies of the effect of the drug on the ability to drive vehicles and work with mechanisms have not been carried out. Zonegran® can cause (especially at the beginning of therapy or with increasing doses) drowsiness and difficulty concentrating, and therefore, during the treatment period, care must be taken when engaging in activities,requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Capsules 25 mg, 50 mg, 100 mg.

Packaging:

For 14 capsules in a blister of PVC / PVDC / aluminum foil.

For 1 blister (for a dosage of 25 mg), 2 blisters (for a dosage of 50 mg) or 4 or 7 blisters (for a dosage of 100 mg), together with the instruction for use, is placed in a cardboard box.

The places of opening the cardboard pack are glued with two transparent protective stickers.

Storage conditions:

Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:PL-000739

Date of registration:29.09.2011

The owner of the registration certificate:Eysay Europe LimitedEysay Europe Limited United Kingdom

Manufacturer: & nbsp

EISAI MANUFACTURING, Ltd. United Kingdom

Representation: & nbspEYSIY LLCEYSIY LLCRussia

Information update date: & nbsp25.10.2015

Illustrated instructions

Instructions

Zonegran® (Zonegran)