Expiration date: 09/2025

pharmachologic effect

Zonegran - antiepileptic

pharmacodynamics

Zonisamide is an antiepileptic agent, a benzisoxazole derivative, in vitroslabo inhibits carbonic anhydrase. Its structure is chemically different from other antiepileptic drugs.

Mechanism of action

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

Pharmacodynamic effects

Anticonvulsant activity of zonisamide has been studied in various models of epilepsy, in groups with induced or innate seizures, with zonisamide showed himself as a broad spectrum antiepileptic action. Zonisamide prevents the development of maximal electroconvulsive seizures, limits the development of seizures, including the distribution center of excitation from the cerebral cortex to the subcortical structures and suppresses epileptogenic focus activity. Unlike phenytoin and carbamazepine, zonisamide has a selective effect on seizures occurring in the cerebral cortex.

Clinical efficacy

Monotherapy with partial seizures with secondary generalization or bez.Effektivnost zonisamide as monotherapy in patients with newly diagnosed partial epileptic seizures with secondary generalization or without, with generalized tonic-clonic seizures without a clear foci has been shown in a double-blind, parallel-group study, with involving 583 adult patients to establish the noninferiority Zonegran® drug therapy before treatment with carbamazepine prolonged action, which lasted up to 24 months, depending on the response to treatment. Performed to increase the target value of the dose of 600 mg or 300 mg carbamazepine zonisamide. In the presence of seizures in patients was carried out to increase to the next dose, ie, Carbamazepine 800 mg or 400 mg zonisamide. If the seizures persisted, the dose was increased to a maximum of 1200 mg of carbamazepine and 500 mg of zonisamide. Patients whose seizures were absent for 26 weeks in patients receiving the target dose, continue to receive the same dose for a further 26 weeks.

Additional treatment of partial seizures with secondary generalization and without adults. The effectiveness of adjunctive therapy zonisamide was demonstrated in 4 double-blind placebo-controlled studies, which lasted up to 24 weeks. These studies showed a decrease in the median frequency of partial seizures when receiving zonisamide at daily doses of 300-500 mg of 1 or 2 times per day.

Additional treatment of partial seizures with secondary generalization and without adolescents and children from 6 years. In children (aged 6 years and older) the effectiveness of zonisamide was demonstrated in a double-blind, placebo-controlled study lasting 24 weeks with the participation of 207 patients. In a 12-week application of the target dose was observed decrease in the frequency of attacks by 50% and more than 50% of patients treated with zonisamide, and 31% of patients receiving placebo.

Special security concerns that arose during the studies in children include: appetite loss and weight loss, reduction of bicarbonates, increasing the risk of kidney stone disease and dehydration. All these phenomena, and especially weight loss can adversely affect the growth and development of the child, and may also lead to poor general health. In general, received a limited amount of data on the long-term effect of the drug on the growth and development of the child.

Pharmacokinetics

Suction

Zonisamide almost completely absorbed after oral administration, Cmax in plasma attained within 2-5 hours after ingestion. Intensity of primary metabolism is insignificant - the absolute bioavailability is estimated at 100%. Zonisamide bioavailability when administered independent of food intake, although it may slow down the time to achieve a plasma Cmax.

Value AUC and Cmax zonisamide increases almost linearly after a single dose (in the dose range of 100-800 mg), and after multiple doses (at the dose range of 100-400 mg 1 time per day). Increasing these values ??when a slight excess of the equilibrium state is assumed on the basis of the dose, possibly in connection with zonisamide saturability binding to erythrocytes. The equilibrium state is achieved within 13 days. Accumulation occurs somewhat greater than 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 extent of its binding to plasma proteins. Apparent Vd in adults is 1.1-1.7 l / kg, indicating a significant tissue distribution zonisamide. Zonisamide ratio of concentrations in blood plasma and red blood cells is about 15 at low concentrations and about 3 - at high concentrations.

Metabolism

With zonisamide metabolized isoenzyme CYP3A4, main pathway - benzizoksazolnogo ring cleavage to form 2-sulfamoilatsetilfenola (SMAP), and N-acetylation.

The starting material and the SMAP can communicate with glucuronic acid. Metabolites that are not detected in plasma, devoid of anticonvulsant activity. Data that zonisamide is able to induce its own metabolism absent.

breeding

Clearance after zonisamide achieve Css reaches 0.70 l / h, the final T1 / 2 - about 60 hours (assuming no simultaneous reception isoenzyme activity inducers CYP3A4). T1 / 2 is not dependent on the magnitude of the received dose or duration of treatment. Fluctuations in plasma concentrations of zonisamide insignificant (

Linearity / non-linearity

zonisamide concentration increases until it reaches an equilibrium state, which typically occurs in about 8 weeks. When comparing the same dose level, patients with higher body weight of patients, usually lower Css achieved in serum, but these differences are insignificant. Age (?12 years) and gender, corrected for body weight, do not influence the concentration of zonisamide in epileptic patients when the drug Css. The need for dose reduction in the application of any anti-epileptic drugs (AEDs), including: isoenzyme inducers of CYP3A4, is absent.

The ratio of pharmacodynamics and pharmacokinetics

Zonisamide reduces the average frequency of seizures per 28-day period and this decrease is proportional to (log-linear relationship), the average concentration of zonisamide.

Use in special patient groups

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

Patients with liver failure. The pharmacokinetics of zonisamide in patients with hepatic insufficiency has been poorly studied.

Elderly patients. No clinically significant differences in the pharmacokinetics of zonisamide in young (21-40 years) and older (65-75 years) patients.

Child patients (5-18 years). Limited data indicate that the pharmacokinetic parameters of zonisamide in 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).

testimony

Monotherapy in patients with partial epileptic seizures with secondary generalization or without, with newly diagnosed epilepsy, as part of an adjunctive therapy in adults, adolescents and children from 6 years of age with partial epileptic seizures with secondary generalization or not.

Contraindications

• hypersensitivity to the active substance, any of the excipients or sulfonamides,
  
• Patients with severe hepatic insufficiency (safety and efficacy data for this category of patients is not enough)
  
• Pregnancy and breast-feeding (for the preparation of safety data for this category of patients is not enough (see. "Pregnancy and lactation")
  
• Children under 6 years of age (safety and efficacy data for this category of patients is not enough).
  
• simultaneous use in children with carbonic anhydrase inhibitors such as topiramate and acetazolamide.
  

Carefully

• Elderly patients (caution must be exercised when administering the drug because of the limited experience available,
  
• patients with renal failure (due to limited clinical experience, may require a slower titration of the drug - see "Dosage and Administration".)
  
• Patients at high risk of nephrolithiasis (see. "Special Instructions")
  
• Patients with hepatic light and moderate deficiency (due to limited clinical experience, may require a slower titration of the drug - see "Dosage and Administration".)
  
• simultaneous use in adults with carbonic anhydrase inhibitors such as topiramate and acetazolamide (insufficient data to exclude the pharmacodynamic interaction)
  
• simultaneous use in adults with pyrogenic drugs, including carbonic anhydrase inhibitors and drugs with anticholinergic activity,
  
• the beginning of the treatment, its cancellation or modification of zonisamide dose while the use of P-glycoprotein substrates (eg digoxin, quinidine)
  
• patients with a body weight
  

special instructions

skin rashes

When therapy with Zonegran® reported on the development of severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.

Recommended Zonegran® cancellation of the drug in patients who were skin rashes and that can not be explained by other causes. All patients with the appearance of skin rash while taking Zonegran® drug should be closely monitored, especially patients with simultaneous appointment of other antiepileptic drugs, which themselves can cause skin rashes.

withdrawal

Abolition Zonegran® drug produced by gradually reducing the dose to avoid occurrence of epileptic seizures. Insufficient data on the abolition of simultaneously used antiepileptic drugs after achieving seizure control with the use of the drug within Zonegran® adjunctive therapy to go to monotherapy Zonegran®. Therefore, the abolition of concomitant antiepileptic treatment should be done with caution.

Reactions related to the presence of the sulfonamide group

Zonegran® contains a sulfonamide group. Serious adverse reactions on the part of 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 pronounced hematological disorders, including aplastic anemia, in rare cases leading to death.

It has been reported about the development of cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, pancytopenia and leucocytosis. Information to assess the possible association of these events with the value received Zonegran® dose of drug and length of treatment is not enough.

Suicidal Thinking and Behavior

Development of suicidal thinking and behavior is possible in patients taking antiepileptic drugs for a variety of indications. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs has also shown an increased risk of suicidal thoughts and behavior.

The mechanism of this phenomenon is unknown, the available data do not exclude the possibility of increased risk of suicidal behavior and in patients receiving the drug Zonegran®.

It is necessary to monitor patients for the emergence of suicidal ideation and behaviors and appropriate treatment provided. Patients (and caregivers parties) should be advised to seek medical help at occurrence of suicidal thoughts and behavior.

nephrolithiasis

Some patients, especially those with a predisposition to nephrolithiasis, may increase the risk of stone formation in the kidney and the appearance of signs and symptoms such as renal colic, renal pain or flank pain.

Nephrolithiasis can lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone formation in the kidney and nephrolithiasis and hypercalciuria in family history. None of these risk factors is not a reliable sign that allows to predict the formation of kidney stones in the treatment of zonisamide. In addition, the risk may be increased in patients taking other drugs that trigger the development of urolithiasis. Increase fluid intake, and forced diuresis helps reduce the risk of stone formation, including and patients with a predisposition to it.

Metabolic acidosis

Formation hyperchloraemic metabolic acidosis without anion gap (decreased bicarbonate levels in the absence of chronic gas alkalosis) is associated with drug therapy Zonegran®. The development of metabolic acidosis is caused by a loss of bicarbonate in the kidneys due to the inhibitory effect of zonisamide on carbonic anhydrase, and may at any stage of treatment, although increasingly concentrated in the early stages of treatment. Similar violations were observed in the course of placebo-controlled clinical studies and post-marketing in the period. Reducing the level of bicarbonate is usually expressed only slightly (mean of approximately 3.5 mEq / l at daily dose of 300 mg in adults), in rare cases, a significant decrease can be observed in patients. Conditions or therapies predisposing to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, performed surgery, diet, promotes the formation of ketone bodies, a number of drugs) may help to strengthen the effect of zonisamide on the level of bicarbonates.

The risk and severity of metabolic acidosis increases in young patients. If signs or symptoms of metabolic acidosis is recommended to evaluate the content of bicarbonate in serum. If you had developed metabolic acidosis persists, consider dose reduction or complete discontinuation Zonegran® (with a gradual reduction of the dose), as possible development of osteopenia. If you decide to continue treatment in the presence of persistent acidosis, should consider the use of alkaloids.

Caution must be exercised in the appointment along with carbonic anhydrase inhibitors (eg topiramate and acetazolamide) because insufficient data to exclude the pharmacodynamic interaction (see. "Interaction").

Heatstroke

Cases reduce sweating and increase in body temperature recorded mainly in patients under 18 years. In some cases there is a heat stroke, which required hospital treatment. Most cases occurred in the conditions of high ambient temperature. Patients and / or caregivers should be alerted about the need to maintain adequate hydration of the body and to avoid exposure to high temperatures. Care should be taken when appointing Zonegran® drug simultaneously with drugs that contribute to overheating of the body, including carbonic anhydrase inhibitors and holinoblokatory.

pancreatitis

With the development of the patients symptoms of pancreatitis in patients receiving the drug Zonegran®neobhodim monitoring the level of pancreatic lipase and amylase. If pancreatitis is confirmed, in the absence of other obvious reasons, we recommend removal of the drug Zonegran® and appropriate treatment.

rhabdomyolysis

With the development in patients taking Zonegran®, severe muscle pain and / or weakness, especially accompanied by a fever, an evaluation of the content of markers of muscle damage, including CPK and aldolase levels. If they increase, in the absence of other obvious causes, such as trauma or grand mal seizure drug is recommended cancellation Zonegran® and appointment of appropriate treatment.

Women with childbearing potential stored

Women with childbearing potential must be saved to use reliable methods of contraception during treatment with Zonegran® and for 1 month after its cancellation (see. "Pregnancy and breastfeeding").

Weight loss

Zonegran® can cause weight loss, so in the treatment of patients with low body weight or reducing it should be the appointment of food additives and enhanced nutrition. In marked decrease in body weight should consider removing Zonegran® drug. Reducing body weight in children may be more pronounced.

Child patients

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

Heat stroke 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 assistance to the child can occur brain damage and death. Children are at high risk, especially in hot weather.

If your child takes medication Zonegran®: to avoid overheating, especially in hot weather, to avoid a significant exercise, especially in hot weather, you should increase your intake of water should not be used the following drugs: carbonic anhydrase inhibitors (such as acetazolamide and topiramate) and anticholinergics (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).

If you have any of the following symptoms, you should immediately seek medical care: the feeling of intense heat from the skin with a slight perspiration, or in his absence, or if there is a child's confusion, muscle cramps or heart palpitations or breathing in a child. It is necessary to place a child in a cool, shaded place, moisten the skin of the child with water to cool it, give the child a drink of cool water.

Reported cases reduce sweating and fever, primarily in children. In some cases there is a heat stroke, requiring hospitalization. In a number of cases reported heatstroke deaths. In most cases, the phenomenon occurred during warm weather. It is necessary to warn the patient and carers for them the possibility of serious heat stroke, situations where it may occur, as well as measures to be taken in the event of any signs or symptoms. Patients or carers for them, it is necessary to warn of the need to use a sufficient amount of fluids and avoiding excessive exercise, depending on the patient's condition. If signs and symptoms of dehydration, oligogidroza or fever, you should consider abolishing Zonegran® drug.

Zonegran® The drug should not be used in children, while receiving other drugs, the application of which occurs in patients predisposed to the appearance of disorders associated with exposure to excessive heat, these include carbonic anhydrase inhibitors and medicinal products with anticholinergic action.

Weight loss

We describe the case of weight loss, which led to a deterioration in the general condition and eliminate the use of antiepileptic drug, leading to death. Application Zonegran® drug is not recommended in children who are underweight or in children with poor appetite.

weight loss is the same frequency in different age groups, however, given the possibility of a serious reduction in body weight in children, in this group of patients is necessary to control body weight. At a delay of weight gain in a patient based on the maps of physical development, it is recommended to review the diet and increase the amount of food intake, otherwise it is necessary to halt the use of the drug Zonegran®.

In clinical studies, obtained limited data in patients weighing less than 20 kg. In this regard, in the treatment of children from 6 years of age or older with a body weight less than 20 kg caution. Effect of prolonged 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 carry more severe in children and adolescents. In this group of patients is necessary to carry out appropriate monitoring and control of serum bicarbonate levels. The long-term impact of low levels of bicarbonate on growth and development is not known.

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

nephrolithiasis

The children reported the appearance of kidney stones. Some patients, especially those with a predisposition to nephrolithiasis, may increase the risk of stone formation in the kidney and the occurrence of associated signs and symptoms, such as renal colic, renal pain or flank pain. Kidney stones can lead to chronic kidney damage. Risk factors include previous urolithiasis formation of kidney stones and a family history of nephrolithiasis and hypercalciuria. None of these risk factors is not a reliable sign that allows to predict the formation of kidney stones in the treatment of zonisamide.

Increase fluid intake, and forced diuresis can reduce the risk of kidney stones, especially in patients with risk factors. At the discretion of the physician may be held ultrasound of the kidneys. In case of kidney stones drug Zonegran®sleduet cancel.

Abnormal liver function

In children and adolescents showed an increase in liver function and bile ducts, such as ALT, AST, GGT and bilirubin, but no explicit laws to values ??exceeding the ULN, has not been established.

However, in cases of suspected occurrence of adverse events of the liver, liver function should assess and decide on the abolition of Zonegran® drug.

Cognitive function

Violation of cognitive functions in patients with epilepsy is associated with the underlying disease and / or with the use of AEDs.

In the placebo-controlled study using zonisamide in children and adolescents, the proportion of patients with impaired cognitive function was quantitatively higher in the zonisamide compared with the placebo group.

Excipients

The preparation Zonegran® dosage of 100 mg of dyes include "sunset yellow" (E110) and "red charming" (E129) which may cause allergic reactions.

Effects on ability to drive and work with mehanizmami.Spetsialnye study of the effect of the drug on the ability to drive vehicles and operate machinery have not been conducted. Zonegran® can cause (especially at the beginning of therapy or when the dose is increased), drowsiness and concentration difficulties, in connection with which, in the period of treatment must be careful during the occupation activities that require high concentration and speed of psychomotor reactions.

Composition

Active ingredient: 25 mg zonisamide,

Inactive ingredients: hydrogenated vegetable oil, MCC, sodium lauryl sulfate

Dosing and Administration

Inside, squeezed water, at mealtimes or independently of food intake. Dose selected on the basis of therapeutic effect. As shown in clinical studies, the effective daily dose is 300-500 mg, although some patients, particularly those who do not take drugs that induce cytochrome CYP3A4, can respond to lower doses.

The starting dose is 50 mg, divided into two steps. After one week, receiving the daily dose can be increased to 100 mg per day. Thereafter, the dosage can be increased by 100 mg every 7 days up to a maximum recommended dose of 500 mg per day. Later during the treatment you can go on a single dose of the drug every day.

Using a two-week intervals should be considered for patients with hepatic or renal insufficiency as well as patients not taking drugs that induce cytochrome CYP3A4.

Side effects

• Infectious and parasitic diseases: urogenital infections, pneumonia,
  
• From the blood and lymphatic system: leukopenia, thrombocytopenia,
  
• Metabolism and nutrition: loss of appetite, hypokalemia,
  
• Mental disorders: agitation, depression, insomnia, emotional instability, anxiety, confusion, acute psychosis, aggression, suicidal thoughts, hallucinations,
  
• From the nervous system: ataxia, dizziness, memory loss, drowsiness, bradifreniya, impaired attention, paraesthesia, nystagmus, speech disorder, tremor, convulsions,
  
• On the part of the organ of vision: diplopia,
  
• The respiratory system, organs, thoracic and mediastinal disorders: respiratory failure,
  
• On the part of the digestive tract: constipation, diarrhea, dyspepsia, nausea, vomiting, abdominal pain,
  
• On the part of the liver and biliary tract: acute cholecystitis,
  
• Skin and subcutaneous tissue disorders: rash, pruritus, ecchymosis,
  
• General disorders and administration site at: fatigue, fever, irritability,
  

Laboratory and instrumental data: reduction of bicarbonates, weight loss, increased CPK, increased ALT, increased AST, violation of a urine test.

Overdose

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

Treatment: the specific antidote for the treatment of drug overdose Zonegran® does not exist. After the alleged overdose shows immediate gastric lavage on a background of conventional measures aimed at maintaining the airway. Supportive therapy, including regular monitoring of vital signs and careful observation. Zonisamide has a long T1 / 2, and therefore the symptoms of overdose can be persistent. Research overdose treatment is not carried out at the same time it is known that hemodialysis reduces concentrations of zonisamide in the blood plasma of patients with renal insufficiency and can be considered as a means of treating overdose.