Zonegran, 25mg capsules, 14pcs

Composition

Active ingredient:

zonisamide 25 mg;

Auxiliary substances:

hydrogenated vegetable oil;

MCC;

sodium lauryl

sulfate Pharmacological action

Zonegran is an antiepileptic drug.

Pharmacodynamics

Zonisamide is an antiepileptic agent derived from benzisoxazole, in vitro weakly inhibits carbonic anhydrase. Its chemical structure is different from other antiepileptic drugs.

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 neural arousal, inhibits the development of seizures, and prevents the further spread of epileptic activity. Zonisamide also reduces the convulsive activity of neurons by enhancing the inhibitory effect of GABA.

Pharmacodynamic effects

The anticonvulsant activity of zonisamide was studied in various models of epilepsy, in groups with induced or congenital seizures, and zonisamide proved 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 cerebral cortex to subcortical structures, and also suppresses the activity of the epileptogenic focus. Unlike phenytoin and carbamazepine, zonisamide has a selective effect on seizures that occur in the cerebral cortex.

Clinical efficacy

Monotherapy of partial seizures with or without secondary generalization. The efficacy of zonisamide as monotherapy in patients with newly diagnosed partial epileptic seizures with or without secondary generalization, with generalized tonic-clonic seizures without clear focality, was shown in a double-blind, parallel-group study involving 583 adult patients to establish no less effective therapy with Zonegran® before prolonged-acting carbamazepine therapy, which lasted up to 24 months, depending on the response to treatment. The dose was increased to the target value of 600 mg carbamazepine or 300 mg zonisamide. If patients had seizures, they were 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 did not have seizures for 26 weeks while taking the target dose continued to receive the same dose for another 26 weeks.

Complementary therapy of partial seizures with or without secondary generalization in adults. The effectiveness of additional zonisamide therapy was shown in 4 double-blind placebo-controlled trials lasting up to 24 weeks. These studies showed a decrease in the median frequency of partial epileptic seizures when taking zonisamide in daily doses of 300-500 mg 1 or 2 times a day.

Additional therapy of partial seizures with or without secondary generalization in adolescents and children from 6 years of age. In children (aged 6 years and older), the efficacy of zonisamide was demonstrated in a double-blind, placebo-controlled study lasting 24 weeks with 207 patients. With a 12-week target dose, a 50% or more reduction in seizure frequency was observed in 50% of patients treated with zonisamide and 31% of patients treated with placebo.

Specific safety concerns that have been encountered in children’s studies have included: decreased appetite and weight loss, reduced 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, there is limited data on the long-term effect of the drug on the growth and development of the child.

Pharmacokinetics

Suction

Zonisamide is almost completely absorbed after oral use, and plasma cmax is reached within 2-5 hours after use. The severity of primary metabolism is insignificant — absolute bioavailability is estimated at 100%. The oral bioavailability of zonisamide is independent of food intake, although the time to reach_cmax in blood plasma may slow down.

The AUC and cmax of_zonisamide increase almost linearly after taking a single dose (in the dose range of 100-800 mg) and after repeated use (in the dose range of 100-400 mg once a day). The increase in these values upon reaching the equilibrium state was slightly higher than expected, based on the dose taken, possibly due to the saturation of zonisamide binding to red blood cells. The equilibrium state is reached within 13 days. There is a slightly greater accumulation than expected, compared to a single dose of the drug.

Distribution

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

Metabolism

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

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

Deduction

The clearance of zonisamide after reaching C_ss reaches 0.70 l/h, the final T_1/2-about 60 hours (provided that there is no simultaneous use of inducers of the activity of the CYP3A4 isoenzyme). T_1/2 does not depend on the amount of the dose taken, nor on the duration of treatment. Fluctuations in the plasma concentration of zonisamide are insignificant (

Linearity/non-linearity

The zonisamide concentration increases until equilibrium is reached, which usually occurs after about 8 weeks. When comparing the same dose level, patients with higher body weight tend to achieve lower_serum csss, but these differences are insignificant. Age (≥12 years) and sex, adjusted for body weight, do not affect zonisamide concentrations in patients with epilepsy when reaching the C_ss of the drug. There is no need to reduce the dose when using any antiepileptic drugs (AEDs), including inducers of the CYP3A4 isoenzyme.

Correlation of Pharmacodynamics and pharmacokinetics

Zonisamide reduces the average seizure frequency over a 28-day period and this decrease is proportional (log-linear relationship) to the average zonisamide concentration.

Use in special patient groups

Patients with renal insufficiency. In patients with renal insufficiency, the renal clearance of single doses of zonisamide is directly proportional to Cl creatinine. Zonisamide AUC was increased by 35% in patients with severe renal insufficiency (creatinine clearance

Patients with hepatic insufficiency. The pharmacokinetics of zonisamide in patients with hepatic insufficiency are poorly understood.

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

Children’s patients (5-18 years old). Limited data indicate 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; as part of additional therapy in adults, adolescents, and children from 6 years of age with partial epileptic seizures with or without secondary generalization.

Contraindications

• hypersensitivity to the Active ingredient, to any of the excipients or to sulfonamides;
• patients with severe hepatic insufficiency (data on safety and efficacy for these patients is insufficient);
• pregnancy and breastfeeding (data security product for this category of patients is not sufficient (see “pregnancy and breastfeeding”);
• children up to age 6 years (data on safety and efficacy for this category of patients is not enough).
• concomitant use in children with carbonic anhydrase inhibitors such as topiramate and acetazolamide.

With caution

• elderly patients (caution should be exercised when prescribing the drug due to limited available experience;
• patients with renal insufficiency (due to limited clinical experience, a slower dose selection of the drug may be required-see “Method of use and doses”);
• patients with a high risk of nephrolithiasis (see “Special instructions”);
• patients with hepatic insufficiency of mild and moderate severity (due to limited clinical experience, may require a slower titration of the drug — see “Method of use and dose”);
• the simultaneous use in adults with carbonic anhydrase inhibitors such as topiramate and acetazolamide (insufficient data to exclude pharmacodynamic interaction);
• the simultaneous use in adults with pyrogenic Drugs, including carbonic anhydrase inhibitors and drugs with anticholinergic effects;
• initiation of treatment, its cancellation or dose change of zonisamide when used simultaneously with P-glycoprotein substrates (for example, digoxin, quinidine);
• patients with body weight

Side effects

Infectious and parasitic diseases: urogenital infections, pneumonia;

From the blood and lymphatic system: leukopenia, thrombocytopenia;

Metabolic and nutritional disorders: decreased appetite, hypokalemia;

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

From the nervous system: ataxia, dizziness, memory loss, drowsiness, bradyphrenia, attention disorders, paresthesia, nystagmus, speech disorders, tremor, convulsions;

From the side of the organ of vision: diplopia;

Respiratory, thoracic and mediastinal disorders: respiratory disorders;

From the gastrointestinal tract: constipation, diarrhea, dyspepsia, nausea, vomiting, abdominal pain;

From the liver and biliary tract: acute cholecystitis;

Skin and subcutaneous tissue disorders: rash, pruritus, ecchymosis;

General disorders and disorders at the injection site: increased fatigue, fever, irritability;

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

How to take, course of use and dosage

Inside, washed down with water, during a meal or regardless of the meal. The dose of the drug is selected taking into account the therapeutic effect. Clinical studies have shown that a daily dose of 300-500 mg is effective, although some patients, in particular those who do not take cytochrome CYP3A4-inducing drugs, may respond to lower doses.

The initial 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, to the maximum recommended dose of 500 mg per day. In the future, during treatment, you can switch to a single dose of the drug every day.

The use of two-week intervals should be considered for patients with hepatic or renal insufficiency, as well as patients who are not taking cytochrome CYP3A4-inducing drugs.

Overdose

Symptoms: There have been cases of intentional and unintentional overdose with Zonegran® in adults and children. In some cases, overdose was asymptomatic, especially with immediate gastric lavage. In other cases, overdose was accompanied by the following symptoms: drowsiness, nausea, gastritis symptoms, nystagmus, myoclonus, coma, bradycardia, impaired renal function, hypotension and respiratory depression. A very high plasma concentration of zonisamide (100.1 mcg / ml) was observed approximately 31 hours after overdose with Zonegran® and clonazepam. A patient with an overdose of these drugs developed coma and respiratory depression. However, after 5 days, he regained consciousness and did not have any complications.

Treatment: There is no specific antidote for the treatment of overdose with Zonegran®. After a suspected overdose, immediate gastric lavage is indicated against the background of conventional measures aimed at maintaining airway patency. Maintenance therapy is carried out, including regular monitoring of the main indicators of the body’s condition, and careful monitoring. Zonisamide has a long T_1/2, and therefore the symptoms of its overdose may be persistent. No studies have been conducted on the treatment of overdose, however, it is known that hemodialysis reduces the concentration of zonisamide in blood plasma in patients with renal insufficiency and can be considered as a treatment for overdose.

Special instructions

Skin rashes

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

Discontinuation of Zonegran® is recommended in patients who have developed skin rashes that cannot be explained by other causes. All patients who develop skin rashes while taking Zonegran® should be closely monitored, especially patients who are co-administered with other antiepileptic drugs that may themselves cause skin rashes.

Withdrawal syndrome

Discontinuation of Zonegran® is performed by gradually reducing the dose to avoid the occurrence of epileptic seizures. There are insufficient data on the withdrawal of concomitant antiepileptic drugs after achieving seizure control when using Zonegran® as part of adjunctive therapy to switch to monotherapy with Zonegran®. Therefore, discontinuation of concomitant antiepileptic treatment should be carried out with caution.

Reactions associated with the presence of a sulfonamide group

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

Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia, and leukocytosis have been reported. There is insufficient information to assess the possible relationship of these events with the dose of Zonegran and the duration of treatment.

Suicidal thinking and behavior

The development of suicidal thinking and behavior is possible in patients who have taken 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, and the available data do not exclude the possibility of an increased risk of suicidal behavior while taking Zonegran®.

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

Nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of kidney stones and signs and symptoms such as renal colic, kidney pain, or side pain.

Nephrolithiasis can lead to chronic kidney damage. Risk factors for nephrolithiasis include previous kidney stone formation, as well as a family history of nephrolithiasis and hypercalciuria. None of these risk factors is a reliable indicator for predicting the formation of kidney stones during treatment with zonisamide. In addition, the risk may be increased in patients taking other drugs that provoke the development of urolithiasis. Increased fluid intake and forced diuresis can help reduce the risk of stone formation, including in patients with a predisposition to it.

Metabolic acidosis

The formation of hyperchloremic metabolic acidosis without an anion gap (a decrease in the level of bicarbonates in the absence of chronic gas alkalosis) is associated with therapy with Zonegran®. The development of metabolic acidosis is caused by the loss of bicarbonates in the kidneys due to the inhibitory effect of zonisamide on carbonic anhydrase, and is possible at any stage of treatment, although it is more often noted in the early stages of treatment. Similar disorders were observed both in placebo-controlled clinical trials and in the post-marketing period. The decrease in bicarbonate levels is usually insignificant (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 treatments that predispose to the development of acidosis (for example, kidney disease, severe respiratory disorders, status epilepticus, diarrhea, ongoing surgery, a diet that promotes the formation of ketone bodies, a number of medications) may increase the effect of zonisamide on bicarbonate levels.

The risk and severity of metabolic acidosis increases in young patients. In case of signs or symptoms of metabolic acidosis, it is recommended to evaluate the content of bicarbonates in the serum. If the developed metabolic acidosis persists, you should consider reducing the dose or completely stopping taking Zonegran® (with a gradual dose reduction), since osteopenia may develop.If a decision is made to continue therapy in the presence of persistent acidosis, the possibility of using alkaloids should be considered.

Caution should be exercised when prescribing concomitantly with carbonic anhydrase inhibitors (for example, topiramate and acetazolamide), as there is insufficient data to exclude a pharmacodynamic interaction (see “Interaction”).

Heat stroke

Cases of reduced sweating and increased body temperature were recorded mainly in patients under 18 years of age. In some cases, heat stroke occurred, requiring inpatient treatment. Most of the cases occurred under high ambient temperatures. Patients and / or their caregivers should be warned to maintain adequate hydration and avoid exposure to elevated temperatures. Caution should be exercised when prescribing Zonegran® concomitantly with drugs that promote overheating of the body, including carbonic anhydrase inhibitors and holinoblockers.

Pancreatitis

If patients develop signs of pancreatitis while taking Zonegran®, it is necessary to monitor the level of pancreatic lipases and amylase. In the case of confirmed pancreatitis in the absence of other obvious causes, it is recommended to cancel Zonegran® and prescribe appropriate treatment.

Rhabdomyolysis

If patients taking Zonegran® develop severe muscle pain and/or weakness, especially accompanied by fever, an assessment of the content of markers of muscle damage, including the level of CPK and aldolase, is required. If they increase, in the absence of other obvious causes, such as trauma or a major epileptic seizure, it is recommended to cancel Zonegran® and prescribe appropriate treatment.

Women with preserved childbearing potential

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

Weight loss

Zonegran® can cause weight loss, so during the treatment of patients with low body weight or when it decreases, it is necessary to prescribe dietary supplements and enhanced nutrition. Discontinuation of Zonegran should be considered if there is a marked decrease in body weight. Weight loss in children may be more pronounced.

Children’s patients

The above precautions apply to children and adolescents. The following are the precautions that you should pay special attention to.

Heat stroke and dehydration

Prevention of overheating and dehydration in children. Zonegran® can cause decreased sweating and lead to overheating, and if the child is not properly treated, brain damage and death can occur. Children are at high risk, especially in hot weather.

If the child is taking Zonegran®: avoid overheating, especially in hot weather; avoid significant physical activity, especially in hot weather; increase water intake; do not use the following medications: carbonic anhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergic medications (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).

If you experience any of the following symptoms, you should immediately seek medical attention: a feeling of intense heat from the skin with little or no sweating, or if the child experiences confusion, muscle spasms, or if the child’s heartbeat or breathing increases. It is necessary to place the child in a cool shaded place; moisten the child’s skin with water to cool it; give the child a drink of cool water.

Decreased sweating and increased body temperature have been reported, mainly in children. In some cases, heat stroke occurred, requiring hospitalization. In some cases, fatal heatstroke has been reported. In most cases, the phenomenon occurred in warm weather. The patient and their caregivers should be warned about the possible severity of heat stroke, the situations where it may occur, and the measures that should be taken if any signs or symptoms occur. Patients or their caregivers should be warned to consume sufficient fluids and avoid excessive physical activity, depending on the patient’s condition. If signs and symptoms of dehydration, oligohydrosis, or fever occur, discontinuation of Zonegran should be considered.

Zonegran® should not be used in children who are simultaneously receiving other drugs, the use of which in patients is predisposed to the appearance of disorders associated with exposure to excessive heat; this includes carbonic anhydrase inhibitors and drugs with anticholinergic effects.

Weight loss

Cases of weight loss were described, which led to deterioration of the general condition and discontinuation of the antiepileptic drug, leading to a fatal outcome. The use of Zonegran® is not recommended in children with low body weight or in children with poor appetite.

The frequency of weight loss is similar in different age groups, however, given the possible severity of weight loss in children, it is necessary to monitor body weight in this group of patients. If the patient’s weight gain is delayed, based on the physical development maps, it is recommended to review the diet or increase the amount of food taken, otherwise the use of Zonegran®should be discontinued.

In clinical studies, limited data were obtained in patients with a body weight of less than 20 kg. In this regard, care should be taken 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 zonisamide-related acidosis in children and adolescents may be higher and more severe. In this group of patients, appropriate monitoring and control of serum bicarbonate levels should be performed. The long-term effect of low bicarbonate levels on growth and development is unknown.

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

Nephrolithiasis

Kidney stones have been reported in children. Some patients, especially those with a predisposition to nephrolithiasis, may have an increased risk of kidney stones and associated signs and symptoms, such as renal colic, kidney pain, or side pain. 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 indicator for predicting the formation of kidney stones during treatment with zonisamide.

Increased fluid intake and forced diuresis may reduce the risk of kidney stones, especially in individuals with risk factors. Ultrasound examination of the kidneys may be performed at the discretion of the doctor. If kidney stones are detected, Zonegran®should be discontinued.

Impaired liver function

In children and adolescents, an increase in liver and biliary tract function indicators, such as ALT, AST, GGT, and bilirubin, was observed, but no obvious patterns were found for values exceeding the ULN.

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

Cognitive functions

Cognitive impairment in patients with epilepsy is associated with the underlying disease and / or with the use of AEDs.

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 to the placebo group.

Auxiliary substances

The composition of Zonegran® dosage of 100 mg includes the dyes “Sunny Sunset yellow” (E%%129), which can cause allergic reactions.

Influence on the ability to drive vehicles and work with mechanisms. Special studies of the effect of the drug on the ability to drive vehicles and work with mechanisms have not been conducted. Zonegran® can cause (especially at the beginning of therapy or with increasing doses) drowsiness and difficulty concentrating, and therefore, during treatment, caution should be exercised when engaging in activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Capsules

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25 °C

Shelf life

3 years

Active ingredient

Zonisamide

Conditions of release from pharmacies

By prescription

Dosage form

Capsules