Zonegran, 50 mg capsules, 28 pcs.

Zonegran is an antiepileptic.

Pharmacodynamics

Zonisamide is an antiepileptic agent, a benzisoxazole derivative, in vivo weakly inhibits carboangidase. Chemically, its structure is different from other antiepileptic drugs.

The mechanism of action

The mechanism of action of zonisamide is not fully understood; it probably blocks potential-sensitive sodium and calcium channels, reduces the severity of synchronized neuronal excitation, inhibits seizure development, and prevents further spread of epileptic activity. Zonisamide also reduces seizure activity of neurons by enhancing the inhibitory effect of GABA.

Pharmacodynamic effects

The anticonvulsant activity of zonisamide has been studied in various epilepsy models, in groups with induced or congenital seizures, with zonisamide proving to be a broad spectrum antiepileptic agent. Zonisamide prevents the development of maximal electroconvulsive seizures, limits the development of seizures, including the spread of the focus of excitation from the cortex to subcortical structures, and suppresses epileptogenic focus activity. Unlike phenytoin and carbamazepine, zonisamide has a selective effect on seizures occurring in the cortex.

Clinical efficacy

Monotherapy of partial seizures with or without secondary generalization.The efficacy of zonisamide in monotherapy in patients with newly diagnosed partial seizures with or without secondary generalization, with generalized tonic-clonic seizures without clear foci, has been demonstrated in a double-blind, parallel-group, 583 adult patient study to establish the equal effectiveness of Zonegran® therapy over sustained-release carbamazepine therapy, which lasted up to 24 months depending on treatment response. The dose was increased up to the target value of 600 mg of carbamazepine or 300 mg of zonisamide. If patients had seizures, the dose was increased to the next dose, i.e., 800 mg of carbamazepine or 400 mg of zonisamide. If seizures persisted, the dose was increased to a maximum of 1200 mg for carbamazepine and 500 mg for zonisamide. Patients who had no attacks at 26 weeks on the target dose continued on the same dose for an additional 26 weeks.

Additional therapy for partial seizures with or without secondary generalization in adults. The efficacy of adjunctive therapy with zonisamide has been shown in 4 double-blind, placebo-controlled studies lasting up to 24 weeks. These studies showed a reduction in the median incidence of partial epileptic seizures when zonisamide was given in daily doses of 300-500 mg once or twice daily.

Additional therapy for partial seizures with or without secondary generalization in adolescents and children from 6 years of age. In children (ages 6 years and older), the efficacy of zonisamide was demonstrated in a double-blind, placebo-controlled, 24-week study involving 207 patients. At the 12-week target dose, there was a 50% or greater reduction in seizure frequency in 50% of patients who received zonisamide and 31% of patients who received placebo.

Particular safety concerns that have arisen in studies in children have included: worsened appetite and weight loss, decreased bicarbonate levels, increased risk of urolithiasis, and dehydration. All of these phenomena and especially weight loss can adversely affect child growth and development and can also lead to poorer overall health. In general, there are limited data on the long-term effects of the drug on child growth and development.

Pharmacokinetics

Intake

Zonisamide is almost completely absorbed after oral administration, Cmax in plasma is reached within 2-5 h after administration. The expression of primary metabolism is insignificant – the absolute bioavailability is estimated at 100%. Bioavailability of zonisamide when administered orally is not dependent on food intake, although the time to reach Cmax in plasma may be delayed.

The AUC and Cmax values of zonisamide increase almost linearly after a single dose (in the dosage range 100-800 mg) and after multiple doses (in the dosage range 100-400 mg once daily). The increase in these values when reaching the equilibrium state was slightly greater than expected based on the dose taken, possibly due to the saturation of zonisamide binding to erythrocytes. The equilibrium state is reached within 13 days. There is slightly more accumulation than expected when compared to a single dose.

Distribution

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

Metabolism

Zonisamide is metabolized with participation of CYP3A4 isoenzyme; the main metabolic pathway is cleavage of the benzisoxazole ring to form 2-sulfamoylacetylphenol (SMAP), and N-acetylation.

The starting substance and SMAP can bind to glucuronic acid. Metabolites that are not detected in plasma lack anticonvulsant activity. There is no evidence that zonisamide can induce its own metabolism.

The clearance of zonisamide after reaching Css reaches 0.70 l/h, the final T1/2 is about 60 h (assuming no simultaneous administration of inducers of CYP3A4 isoenzyme activity). T1/2 does not depend on the dose taken or the duration of treatment. Fluctuations in plasma concentration of zonisamide are insignificant (<30%). Metabolites and unchanged zonisamide are excreted mainly through the kidneys. Renal clearance of unchanged zonisamide is relatively low (about 3.5 ml/min); about 15-30% of the dose taken is excreted unchanged.

Linearity/nonlinearity

The concentration of zonisamide increases until an equilibrium state is reached, which usually occurs after approximately 8 weeks. When comparing the same dose level, patients with higher body weight tend to achieve lower serum Css, but these differences are not significant. Age (≥12 years) and sex, adjusted for body weight, have no effect on zonisamide concentrations in patients with epilepsy when the Css of the drug is reached. There is no need for dose reduction with any antiepileptic drugs (PEDs), including CYP3A4 isoenzyme inducers.

Ratio of pharmacodynamics and pharmacokinetics

Zonisamide decreases mean seizure frequency over a 28-day period, and this decrease is proportional (log-linear relationship) to mean zonisamide concentration.

Performance in special patient groups

Patients with renal impairment. In patients with renal impairment, the renal clearance of single doses of zonisamide is directly proportional to Cl creatinine. The AUC of zonisamide is increased by 35% in patients with severe renal insufficiency (Cl creatinine <20 ml/min) (see “Dosage and administration”).

Patients with hepatic impairment. The pharmacokinetics of zonisamide in patients with hepatic impairment have not been adequately studied.

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

Patients of pediatric age (5-18 years). Limited data show that the pharmacokinetic parameters of zonisamide at a daily dose of 1, 7, or 12 mg/kg in children and adolescents are similar to those in adult patients (adjusted for body weight).

Indications

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

In adjunctive therapy in adults, adolescents and children from 6 years of age with partial epileptic seizures with or without secondary generalization.

Active ingredient

Zonisamide

Composition

Active substance:

Zonisamide 50 mg;

Associates:

vegetable oil hydrogenated;

MCC;

sodium lauryl sulfate

How to take, the dosage

Ingestion with water, with or without meals. The dose of the drug is adjusted to the therapeutic effect. A daily dose of 300-500 mg has been shown to be effective in clinical studies, although some patients, particularly those who do not take CYP3A4 cytochrome inducing drugs, may respond to lower doses.

The starting dose is 50 mg divided into two doses. After one week of use, the daily dose can be increased to 100 mg per day. The dose can then be increased by 100 mg every 7 days, up to a maximum recommended dose of 500 mg per day. Thereafter, you may switch to a single dose every day during treatment.

The use of two-week intervals should be considered for patients with hepatic or renal impairment and for patients not taking CYP3A4 cytochrome inducing drugs.

Special Instructions

Skin rashes

Severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during therapy with Zonegran®.

Stop of Zonegran® is recommended in patients who develop a skin rash that cannot be explained by other causes. All patients who develop a skin rash while taking Zonegran® should be closely monitored, especially those who are concomitantly prescribed other antiepileptic drugs that may themselves cause a skin rash.

The withdrawal syndrome

Zonegran® is withdrawn by gradually reducing the dose to prevent epileptic seizures. There is insufficient data on discontinuation of concomitant antiepileptic drugs after achieving seizure control with Zonegran® as adjunctive therapy to switch to Zonegran® monotherapy. Therefore, withdrawal of concomitant antiepileptic treatment should be done with caution.

Reactions associated with the sulfonamide group

Zonegran® contains a sulfonamide group. Serious immune system related adverse reactions when taking products containing the sulfonamide group include skin rash and other allergic reactions as well as the development of significant hematologic disorders, including aplastic anemia, which in very rare cases can be fatal.

The development of cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia and leukocytosis has been reported. There is insufficient information to evaluate the possible relationship of these events to the dose of Zonegran® and the duration of treatment.

Suicidal ideation and behavior

Suicidal ideation and behavior may develop in patients who are taking antiepileptic medications for a variety of indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs also showed an increased risk of suicidal thoughts and behaviors.

The mechanism of this phenomenon is unknown, and the data do not rule out the possibility of increased risk of suicidal behavior with Zonegran® as well.

Patients should be monitored for suicidal ideation and behavior, and appropriate treatment should be considered. Patients (and their caregivers) should be advised to seek medical attention if suicidal thoughts and behaviors occur.

Nephrolithiasis

In some patients, especially those with a predisposition to nephrolithiasis, there may be an increased risk of kidney stones and signs and symptoms such as renal colic, kidney pain, or pain in the side.

Nephrolithiasis can lead to chronic kidney damage. Risk factors for nephrolithiasis include previous kidney stone formation and a family history of nephrolithiasis and hypercalciuria. None of these risk factors is a reliable predictor of kidney stone formation with treatment with zonisamide. In addition, the risk may be increased in patients taking other drugs that provoke urolithiasis. Increasing fluid intake and increasing diuresis helps decrease the risk of stone formation, including in patients who are predisposed to it.

Metabolic acidosis

The development of hyperchloremic metabolic acidosis without anion gap (decreased bicarbonate levels in the absence of chronic gas alkalosis) is associated with therapy with Zonegran®. The development of metabolic acidosis is caused by loss of bicarbonates in the kidneys due to the inhibitory effect of zonisamide on carboanhydrase, and is possible at any stage of treatment, although it is more often noted in the early stages of treatment. Such abnormalities have been noted both in placebo-controlled clinical trials and in the post-marketing period. Decreases in bicarbonate levels are usually mild (median value is approximately 3.5 mEq/L at a daily dose of 300 mg in adults); in rare cases, patients may experience more significant decreases. Conditions or treatments that predispose to the development of acidosis (e.g., kidney disease, severe respiratory distress, epileptic status, diarrhea, surgical procedures underway, ketone-promoting diet, several medications) may contribute to the effect of zonisamide on bicarbonate levels.

The risk of occurrence and severity of metabolic acidosis is increased in young patients. If signs or symptoms of metabolic acidosis occur, it is recommended that serum bicarbonate levels be evaluated. If metabolic acidosis does not resolve, a dose reduction or complete discontinuation of Zonegran® should be considered (with gradual dose reduction) because osteopenia may occur. If it is decided to continue therapy with persistent acidosis, alkaloids should be considered.

Caution should be exercised when prescribing concomitantly with carboanhydrase inhibitors (e.g., topiramate and acetazolamide) as there is insufficient data to rule out pharmacodynamic interaction (see “Interactions”).

Temperature shock

In cases of decreased sweating and increased body temperature have been reported mainly in patients under 18 years of age. In a number of cases, heat stroke occurred, which required inpatient treatment. Most cases occurred in a high ambient temperature environment. Patients and/or caregivers should be warned to maintain adequate body hydration and avoid exposure to elevated temperatures. Caution should be exercised when prescribing Zonegran® concomitantly with drugs that promote overheating, including carboenhydrase inhibitors and cholinoblockers.

Pancreatitis

If patients show signs of pancreatitis while taking Zonegran® , pancreatic lipase and amylase levels should not be monitored. In case of confirmed pancreatitis in absence of other evident reasons it is recommended to cancel Zonegran® and initiate appropriate treatment.

Rhabdomyolysis

If patients taking Zonegran® develop severe muscle pain and/or weakness, especially if accompanied by fever, evaluation of markers of muscle damage including CPK and aldolase levels is required. If these are elevated, in the absence of other obvious causes such as trauma or a major epileptic seizure, withdrawal of Zonegran® and appropriate treatment is recommended.

Women of preserved childbearing potential

Women of preserved childbearing potential should use reliable contraception during treatment with Zonegran® and for 1 month after withdrawal (see “Use in pregnancy and lactation”).

Weight loss

Zonegran® may cause weight loss, so nutritional supplements and enhanced nutrition should be prescribed during treatment of patients with underweight or weight loss. In severe weight loss, discontinuation of Zonegran® should be considered. Weight loss in children may be more pronounced.

Paediatric patients

The above precautions apply to children and adolescents. The following are precautions to watch out for.

Temperature shock and dehydration

Prevention of overheating and dehydration in children. Zonegran® can cause decreased sweating and lead to overheating, and if left untreated, can cause brain damage and death in a child. Children are at high risk, especially in hot weather.

If the child is taking Zonegran®: overheating should be avoided, especially in hot weather; significant physical activity should be avoided, especially in hot weather; water intake should be increased; the following medications should not be used Carboanhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergic drugs (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin).

If any of the following symptoms occur, seek medical attention immediately: fever in the skin with little or no sweating, or if the child becomes confused, has muscle cramps, or has a rapid heartbeat or breathing. Place the child in a cool, shaded area; moisten the child’s skin with water to cool it; give the child a cool drink of water.

In cases of decreased sweating and increased body temperature, mostly in children, have been reported. In some cases, heat stroke has occurred, requiring hospitalization. In some cases, fatal heat stroke has been reported. In most cases, the phenomenon occurred in warm weather. Patients and caregivers should be warned about the possible severity of heat stroke, the situations in which it may occur, and the steps to take if any signs or symptoms appear. Patients or their caregivers should be advised to drink plenty of fluids and avoid excessive physical activity, depending on the patient’s condition. If signs and symptoms of dehydration, oligohydrosis, or elevated body temperature occur, discontinuation of Zonegran® should be considered.

Zonegran® should not be used in children who are concomitantly receiving other drugs that predispose patients to excessive heat related disorders; this includes carboenhydrase inhibitors and anticholinergic drugs.

Weight loss

There have been reported cases of weight loss resulting in worsening of general well-being and discontinuation of antiepileptic drug use, resulting in death. Zonegran® is not recommended for underweight children or children with poor appetite.

The incidence of weight loss is similar in different age groups, however, considering the possible severity of weight loss in children, weight loss in this group of patients should be monitored. If weight gain in a patient is delayed, based on growth charts, a review of dietary intake or an increase in food intake is recommended; otherwise, Zonegran® should be discontinued.

In clinical studies, limited data have been obtained in patients weighing less than 20 kg. Therefore, caution should be exercised when treating children aged 6 years and older with a body weight of less than 20 kg. The effect of long-term 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 may be higher and more severe in children and adolescents. Appropriate monitoring and control of serum bicarbonate levels should be performed in this group of patients. The long-term effect of low bicarbonate levels on growth and development is unknown.

Zonegran® should not be used concomitantly with other carboanhydrase inhibitors such as topiramate or acetazolamide in children.

Nephrolithiasis

In children, the occurrence of kidney stones has been reported. In some patients, especially those with a predisposition to nephrolithiasis, there may be an increased risk of kidney stones and associated signs and symptoms, such as renal colic, kidney pain, or pain in the side. Urolithiasis can lead to chronic kidney damage. Risk factors for urolithiasis include previous kidney stone formation and a hereditary predisposition to nephrolithiasis and hypercalciuria. None of these risk factors is a reliable predictor of kidney stone formation with treatment with zonisamide.

Augmentation of fluid intake and forced diuresis may reduce the risk of kidney stone formation, especially in those with risk factors. A kidney ultrasound may be performed at the doctor’s discretion. If kidney stones are found, Zonegran® should be discontinued.

Liver dysfunction

In children and adolescents, increased liver and biliary tract function parameters such as ALT, AST, GGT, and bilirubin have been observed, but no clear pattern for values greater than BHN has been found.

However, if liver adverse events are suspected, liver function should be evaluated and Zonegran® should be discontinued.

Cognitive function

Cognitive impairment in patients with epilepsy has been associated with the underlying disease and/or with the use of PEP.

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.

Auxiliary ingredients

The 100 mg dose of Zonegran® contains the dyes Sunset Yellow (E110) and Charming Red (E129), which may cause allergic reactions.

Impact on the ability to drive vehicles and operate machinery.No special studies of the effect of the drug on the ability to drive vehicles and operate machinery have been conducted. Zonegran® may cause (especially at the beginning of therapy or when increasing the dose) somnolence and difficulties in concentration, therefore during the treatment period caution should be exercised when carrying out activities requiring high concentration and quick psychomotor reactions.

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Contraindications

• hypersensitivity to the active substance, any of the excipients or to sulfonamides;
• patients with severe hepatic impairment (data on safety and effectiveness of the drug for this category of patients are insufficient);
• pregnancy and breastfeeding (there is insufficient data on the safety of the drug in this category of patients (see “Administration of Pregnancy and Breastfeeding”). “Pregnancy and lactation);
• children under 6 years of age (data on the safety and efficacy of the drug are insufficient for this patient population).
• Concomitant use in children with carbohydrate inhibitors such as topiramate and acetazolamide.

Cautions

• Elderly patients (caution should be exercised when prescribing due to limited experience;
• Patients with renal impairment (due to limited clinical experience, a slower adjustment of the drug dose may be required – see Dosage Guideline. “
• Patients with high risk of nephrolithiasis (see Special Instructions);
• Patients with mild to moderate hepatic impairment (due to limited clinical experience, slower dosing may be required – see Administration and Dosing. “
• Simultaneous use in adults with carbohydrate inhibitors such as topiramate and acetazolamide (insufficient data to rule out pharmacodynamic interaction);
• Simultaneous use in adults with pyrogenic drugs, including carbohydrate inhibitors and drugs with anticholinergic effects;
• treatment initiation, withdrawal, or change in dose of zonisamide when used concomitantly with P-glycoprotein substrates (e.g., digoxin, quinidine);
• patients with body weight <20 kg (clinical experience limited).

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Side effects

Infectious and parasitic diseases: urogenital infections, pneumonia;

Blood and lymphatic system disorders: Leukopenia, thrombocytopenia;

Metabolic and nutritional disorders: decreased appetite, hypokalemia;

Mental disorders: agitation, depression, insomnia, emotional lability, anxiety, confusion, acute psychosis, aggressiveness, suicidal thoughts, hallucinations;

Nervous system disorders: Ataxia, dizziness, decreased memory, somnolence, bradyphrenia, attention deficit disorder, paresthesias, nystagmus, speech impairment, tremor, seizures;

Visual organ: Diplopia;

Respiratory system, chest and mediastinum: respiratory impairment;

Gastrointestinal disorders: constipation, diarrhea, dyspepsia, nausea, vomiting, abdominal pain;

Liver and biliary tract: acute cholecystitis;

Skin and subcutaneous tissue: rash, itching, ecchymosis;

General disorders and disorders at the site of administration: increased fatigue, increased body temperature, irritability;

Laboratory and instrumental findings: reduced bicarbonate levels, weight loss, increased CPK levels, increased ALT levels, increased AST levels, impaired urinalysis.

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