Zonegran, 25 mg capsules 14 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 shown in a double-blind, parallel-group, 583 adult patients to be as effective as therapy with Zonegran^® before sustained-release carbamazepine therapy, lasting up to 24 months, depending on treatment response. Dose escalation to a target of 600 mg of carbamazepine or 300 mg of zonisamide was carried out. 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

Absorption

. Zonisamide is almost completely absorbed after oral administration, C_max 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 independent of food intake, although the time to reach C_max in plasma may be delayed.

The AUC and C_max values of zonisamide increase almost linearly after a single dose (in the 100-800 mg dose range) and after multiple doses (in the 100-400 mg dose range 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 V_d 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.

Elevation

The clearance of zonisamide after reaching C_ss reaches 0.70 l/h, the final T_1/2 is about 60 h (assuming no simultaneous administration of CYP3A4 isoenzyme activity inducers). T_1/2 does not depend on the amount of dose taken or the duration of treatment. Fluctuations in plasma concentration of zonisamide are insignificant (

Linearity/nonlinearity

The concentration of zonisamide increases until equilibrium 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 C_ss, 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 in achieving C_ss of the drug. 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. AUC of zonisamide is increased by 35% in patients with severe renal impairment (Cl creatinine

Patients with hepatic impairment. The pharmacokinetics of zonisamide in patients with hepatic impairment have not been well 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 daily doses 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 adjunctive therapy in adults, adolescents and children from 6 years of age with partial epileptic seizures with or without secondary generalization.

Active ingredient

Composition

Active substance:

zonisamide 25 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

The development of severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, has been reported during therapy with Zonegran®.

Withdrawal 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

The withdrawal of Zonegran® is done by gradually reducing the dose to avoid the onset of epileptic seizures. There is insufficient data on concomitant antiepileptic drug withdrawal after seizure control is achieved 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 adverse reactions to the immune system associated with use of products containing the sulfonamide group include skin rash and other allergic reactions as well as 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 taking antiepileptic drugs 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®.

Patients should be monitored for suicidal ideation and behavior, and appropriate treatment should be considered. Patients (and their caregivers) should be encouraged to seek medical attention when 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 common 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, consider reducing the dose or stopping Zonegran® (with gradual dose reduction) since 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 hydration of the body and avoid exposure to elevated temperatures. Caution should be exercised when prescribing Zonegran® concomitantly with drugs that promote overheating in the body, including carboenhydrase inhibitors and choline blockers.

Pancreatitis

If patients show signs of pancreatitis while taking Zonegran® , pancreatic lipase and amylase levels should be monitored. If pancreatitis is confirmed in the absence of other obvious causes, withdrawal of Zonegran® is recommended and appropriate treatment should be prescribed.

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; therefore supplements and increased nutrition should be prescribed during treatment of patients with underweight or weight loss. In severe weight loss, the possibility of withdrawal 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

Preventing overheating and dehydration in children. Zonegran® can cause decreased sweating and lead to overheating, and if left untreated, a child may suffer brain damage and death. 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 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.

The drug Zonegran® should not be used in children concomitantly receiving other drugs that predispose patients to heat-related disorders; this includes carboenhydrase inhibitors and drugs with anticholinergic effects.

Weight loss

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

The incidence of weight loss is similar in different age groups, however, given 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, it is recommended to change the patient’s diet or increase the amount of food intake, otherwise the Zonegran® should be stopped.

In clinical studies, limited data have been obtained in patients weighing less than 20 kg. Therefore, caution should be exercised when treating children 6 years of age 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 stopped.

Liver dysfunction

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

However, if liver adverse events are suspected, liver function should be evaluated and the decision to discontinue Zonegran® should be made.

Cognitive function

Cognitive impairment in patients with epilepsy is 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.

Excipients

The 100 mg dosage form 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.

Contraindications

Cautions

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, memory loss, somnolence, bradyphrenia, impaired attention, paresthesias, nystagmus, speech impairment, tremor, seizures;

On the visual organ: Diplopia;

Respiratory system, chest and mediastinal organs: respiratory impairment;

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

Liver and biliary tract disorders: acute cholecystitis;

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

General disorders and disorders at the injection site: increased fatigue, elevated body temperature, irritability;

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

Overdose

Symptoms: There have been cases of intentional and unintentional overdose with Zonegran® in adults and children. In some cases overdose has been 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, arterial hypotension and respiratory depression. Very high plasma concentrations of zonisamide (100.1 µg/ml) were observed approximately 31 hours after overdose with Zonegran® and clonazepam. The patient who overdosed on these drugs developed coma and respiratory depression. However, he regained consciousness 5 days later and no complications were noted.

Treatment: There is no specific antidote for the treatment of overdose with Zonegran®. After suspected overdose immediate gastric lavage is indicated with the usual measures to maintain airway patency. Supportive therapy, including regular monitoring of key body parameters, and close monitoring is carried out. Zonisamide has a long T1/2, due to which the symptoms of its overdose may be persistent. No overdose treatment studies have been conducted; however, hemodialysis is known to reduce plasma concentrations of zonisamide in patients with renal impairment and may be considered as a treatment for overdose.