Zonegran – antiepileptic.
Zonisamide is antiepileptics benzisoxazole derivative, in vitroslabo inhibits carbonic anhydrase. Its structure chemically different from other antiepileptic drugs.
Mechanism of action
zonisamide mechanism of action is not fully understood it is likely to block the voltage-sodium and calcium channels, reduces the severity synchronized neuronal excitation, inhibits the development of seizures, and prevents further spread of seizure activity. Zonisamide also reduces the seizure activity of neurons by enhancing inhibitory effect of GABA.
The pharmacodynamic effects
The anticonvulsant activity of zonisamide was examined in various models of epilepsy, in the groups with congenital or induced seizures, thus zonisamide proved as broad spectrum antiepileptic action. Zonisamide prevents the development of maximal electroshock seizures, limits the development of seizures, including the spread of excitation from focal cerebral cortex to subcortical structures and suppresses epileptogenic focus activity. Unlike phenytoin and carbamazepine, zonisamide has a selective effect on seizures occurring in the cerebral cortex.
Monotherapy partial seizures with secondary generalization or bez.Effektivnost zonisamide in monotherapy in patients with newly diagnosed partial epileptic seizures with or without secondary generalization, with generalized tonic-clonic seizures without clear foci has been shown in a double-blind, parallel study groups with involving 583 adult patients to establish the noninferiority of therapy with carbamazepine therapy before Zonegran® prolongirova nnogo action lasted up to 24 months depending on the response to treatment. Carried increase the dose to the target value of 600 mg carbamazepine or 300 mg zonisamide. In the presence of seizures in patients was carried out to increase the next dose, i.e. 800 mg of carbamazepine or 400 mg zonisamide. If seizures were maintained, the dose was increased to a maximum of 1200 mg for carbamazepine and up to 500 mg zonisamide. Patients whose seizures were absent for 26 weeks in patients receiving the target dose, continue to receive the same dose for another 26 weeks.
Adjunctive therapy of partial seizures with secondary or without generalization in adults. Efficacy zonisamide adjunctive therapy has been shown in 4 double-blind, placebo-controlled trials, 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.
Adjunctive therapy of partial seizures with or without secondary generalization in adolescents and children 6 years of age. 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 12-week application target dose reduction of seizure frequency was observed in 50% or more in 50% of patients treated with zonisamide, and 31% of patients receiving placebo.
Special security concerns that arose during the studies in children include: deterioration of appetite and weight loss, decreased bicarbonate levels, 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 a deterioration of 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.
Zonisamide almost completely absorbed after oral administration, Cmax in plasma attained within 2-5 hours after ingestion. Intensity of primary metabolism is negligible – an absolute bioavailability is estimated at 100%. Zonisamide bioavailability when taken orally is not dependent on food intake, while at the same time can slow down time in the blood plasma Cmax achievements.
The magnitude of AUC and Cmax zonisamide substantially linearly increased after a single dose (in the dose range of 100-800 mg) and, after multiple administration (in a dosage range of 100-400 mg 1 time per day). Increasing these values upon reaching equilibrium slightly higher than assumed, based on 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.
Zonisamide binds to the plasma protein at 40-50%, according to the results of studies in vitro, various anticonvulsants (phenytoin, phenobarbital, carbamazepine and valproate sodium) did not significantly affect the degree 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 erythrocytes and blood plasma is about 15 at low concentrations and about 3 – at high concentrations.
Zonisamide metabolized with isoenzyme CYP3A4, main pathway – benzisoxazole 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 the blood plasma, devoid of anticonvulsant activity. Evidence that zonisamide is able to induce its own metabolism absent.
Clearance after zonisamide achieve Css reaches 0.70 l / h, the final T1 / 2 – about 60 hours (assuming no simultaneous reception inductors activity isoenzyme CYP3A4). T1 / 2 is not dependent on the magnitude of the received dose or duration of treatment. Fluctuations in the plasma concentration of zonisamide negligible (< 30%). The metabolites and unchanged zonisamide are derived primarily through the kidneys. Renal clearance of unchanged zonisamide is relatively low (about 3.5 ml / min); about 15-30% of the dose is excreted unchanged.
Linearity / non-linearity
zonisamide concentration increases to reach an equilibrium state, which typically occurs after about 8 weeks. When comparing the same dose level, patients with higher weight patients, as a rule, achieved lower serum Css, but these differences are minor. Age (≥12 years) and gender, corrected for body weight, no effect on zonisamide concentrations in patients with epilepsy when the Css drug. The need to reduce the dose of the application of any antiepileptic drugs (AEDs) including isoenzyme inducers of CYP3A4, offline.
The ratio of pharmacodynamics and pharmacokinetics
Zonisamide reduces the mean frequency of attacks per 28-day period and this reduction is proportional to (log-linear relationship) the average concentration zonisamide.
Use in special patient groups
Patients with renal insufficiency. 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 failure (Cl creatinine < 20 ml / min) (see “Dosing and dose.”).
Patients with hepatic insufficiency. The pharmacokinetics of zonisamide in patients with hepatic insufficiency has been insufficiently studied.
Elderly patients. No clinically relevant differences in the pharmacokinetics of zonisamide in young (21-40 years) and elderly (65-75 years) patients.
Child patients (5-18 years). 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).
MANUFACTURING Eisai Limited, UK
The active ingredient is:
zonisamide 100 mg;
hydrogenated vegetable oil;
sodium lauryl sulfate
Monotherapy in patients with partial epileptic seizures with or without secondary generalization, with newly diagnosed epilepsy;
as part of an adjunctive therapy in adults, adolescents and children from 6 years with partial epileptic seizures with or without secondary generalization.
- hypersensitivity to the active substance, any of the excipients or to sulfonamides;
- Patients with severe hepatic insufficiency (safety and efficacy data for this category of patients is not enough);
- Pregnancy and breastfeeding (safety data preparation for this category of patients is not enough (see “Pregnancy and breastfeeding»);.
- Children under 6 years of age (safety and efficacy data for this category of patients is not enough).
- the simultaneous use in children with carbonic anhydrase inhibitors such as topiramate and acetazolamide.
- elderly patients (caution must be exercised when administering the drug due to the limited experience available;
- patients with renal failure (due to the limited clinical experience may require a slower titration formulation – see “Dosing and dose».);
- Patients with a high risk of nephrolithiasis (see “Special instructions».);
- patients with hepatic insufficiency mild and moderate severity (due to the limited clinical experience may require a slower titration formulation – see “Dosing and dose».);
- simultaneous use in adults with carbonic anhydrase inhibitors such as acetazolamide and topiramate (insufficient data to exclude pharmacodynamic interaction);
- simultaneous use in adults with pyrogenic drugs, including carbonic anhydrase inhibitors and drugs with an anticholinergic action;
- initiation of treatment, its abolition or modification of zonisamide dose while the use of substrates of P-glycoprotein (e.g., digoxin, quinidine);
- Patients weighing < 20 kg (clinical experience is limited)
Infectious and parasitic diseases: urogenital infections, pneumonia;
From the blood and lymphatic system: leukopenia, thrombocytopenia;
Metabolism and nutrition: loss of appetite, hypokalaemia;
Mental disorders: agitation, depression, insomnia, emotional lability, anxiety, confusion, acute psychosis, aggression, suicidal thoughts, hallucinations;
From the nervous system: ataxia, dizziness, memory loss, drowsiness, bradifreniya, attention disturbances, paresthesia, nystagmus, speech disorder, tremor, convulsions;
On the part of the organ of vision: diplopia;
The respiratory system, thorax and mediastinum: respiratory failure;
On the part of the digestive tract: constipation, diarrhea, dyspepsia, nausea, vomiting, abdominal pain;
Of the liver and biliary tract: acute cholecystitis;
Skin and subcutaneous tissue disorders: rash, pruritus, ecchymosis;
General disorders and at the injection site: fatigue, fever, irritability;
Laboratory and instrumental data: reduction of bicarbonates, weight loss, increased CPK, increased ALT, increased AST, impaired urine analysis.
How to accept, acceptance rate and dosage
Inside, with water, during a meal, or, regardless of the meal. 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 of 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. Subsequently, during the treatment, you can go to 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.
In a dry place, protected from light at a temperature not higher than 25 ° C
When therapy with Zonegran® informed about the development of severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.
Zonegran® recommended abolition of the drug in patients who develop skin rashes and which 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 concurrent administration of other antiepileptic drugs, which themselves can cause skin rashes.
Abolition of the drug Zonegran® produced by gradually reducing the dose to avoid occurrence of epileptic seizures. Insufficient data on cancellation simultaneously used antiepileptic drugs after achieving seizure control with the use of the drug within Zonegran® adjunctive therapy to access Zonegran® monotherapy. So the abolition of concomitant antiepileptic treatment should be done with caution.
Responses associated with the presence of the sulfonamide group
Zonegran® contains a sulfonamide group. Serious adverse reactions of immune system related to reception of preparations that contain a sulfonamide group include the appearance of skin rash and other allergic reactions and 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 for evaluating the possible correlation with the magnitude of these phenomena Zonegran® received doses of drug and duration of treatment is insufficient.
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, available evidence does not exclude the possibility of an increased risk of suicidal behavior and formation in patients receiving Zonegran® preparation.
Need to monitor patients for the emergence of suicidal ideation and behaviors and appropriate treatment provided. Patients (and their carers parties) should be advised to seek medical help at occurrence of suicidal thoughts and behavior.
Some patients, especially those with a predisposition to nephrolithiasis, may increase the risk of stone formation in the kidneys and the appearance of such 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 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. Increasing fluid intake and diuresis helps reduce the risk of stone formation, including and in patients with a predisposition to it.
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 caused by the loss of bicarbonate in the kidneys as a result of the inhibitory effect of zonisamide on carbonic anhydrase, and may at any stage of treatment, although increasingly concentrated on the early stages of treatment. Such violations occurred both during the placebo-controlled clinical studies and in post-marketing period. Reducing bicarbonates typically expressed only slightly (mean value of about 3.5 mEq / L at a daily dose of 300 mg in adults); in rare cases, a significant decrease can be observed in patients. Conditions or treatments that predispose to the development of acidosis (e.g., renal disease, severe respiratory disorders, status epilepticus, diarrhea held surgical intervention, diet, promotes the formation of ketone bodies, a number of drugs) can strengthen zonisamide influence the level of bicarbonate.
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 fledged metabolic acidosis fails, consider a dose reduction or complete cessation of drug Zonegran® (s tapering), as possible development of osteopenia. If you decide to continue treatment in the presence of persistent acidosis, should consider the possibility of alkaloids.
Care should be taken when assigning simultaneously with carbonic anhydrase inhibitors (e.g. acetazolamide and topiramate) as insufficient data to exclude pharmacodynamic interaction (see. “Interaction”).
Cases reduce sweating and increase in body temperature recorded mainly in patients under 18 years. In some cases there is heat stroke, which required hospital treatment. Most cases occur in 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 must be taken when assigning Zonegran® drug simultaneously with drugs that promote overheating organism, including carbonic anhydrase inhibitors and holinoblokatory.
With the development of symptoms of pancreatitis in patients taking the drug for Zonegran®neobhodim monitoring the level of pancreatic lipases and amylases. In the case of pancreatitis confirmed the absence of other obvious reasons, it is recommended Zonegran® removal of the drug and appropriate treatment.
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 is recommended removal of the drug Zonegran® and 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”).
Zonegran® may cause reduction of body weight, so during the treatment of patients with a reduced body weight or decrease its necessary purpose food additives and enhanced nutrition. In marked decrease in body weight should consider repealing Zonegran® drug. Decrease in body weight in children may be more pronounced.
The above precautions are applicable to children and adolescents. The following are the precautions that need your attention.
Heat stroke and dehydration
Prevention of overheating and dehydration in children. Zonegran® may cause perspiration reduction and lead to overheating, and in the absence of appropriate assistance the child may occur brain damage and death. Children are at high risk, especially in hot weather.
If the child takes medication Zonegran®: avoid overheating, especially in hot weather; avoid significant physical exertion, especially in hot weather; should increase the intake of water; should not be applied following drugs: carbonic anhydrase inhibitors (such as acetazolamide and topiramate) and anticholinergics (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).
If you experience 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 in the event of a child’s mental confusion, muscle cramps or heart palpitations or breathing in a child. You must place the child in a cool, shady 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, especially in children. In some cases, there is 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 caregivers for them the possibility of serious heat stroke, situations where it might be, 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; here include carbonic anhydrase inhibitors and drugs with an anticholinergic action.
We describe the case of weight loss, which led to a deterioration of 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 frequency is the same in different age groups, however, given the potential severity of reducing 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 growth chart, it is advisable to review the diet and increase the amount of food intake, otherwise it is necessary to stop the use of the drug Zonegran®.
In clinical studies, the limited data obtained in patients weighing less than 20 kg. In this regard, the treatment of children aged 6 years and older with a body weight less than 20 kg should be careful. Effect of long-term preservation of low birth weight on growth and development in children are unknown.
The risk of acidosis associated with the use of zonisamide in children and adolescents may be higher and be more severe. In this group of patients is necessary to carry out appropriate monitoring and control of the levels of bicarbonate in serum. Long-term impact of low levels of bicarbonate on growth and development is unknown.
Zonegran® The drug should not be used in children in conjunction with other carbonic anhydrase inhibitors such as topiramate and acetazolamide.
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 kidneys and appearance-related signs and symptoms such as renal colic, renal pain or flank pain. Urolithiasis 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.
Increased fluid intake and 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 any explicit laws for values greater than 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 impairment in patients with epilepsy 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 higher in the group to quantify zonisamide compared with the placebo group.
The preparation of 100 mg dose Zonegran® dyes include “sunset yellow” (E110), and “red amazing” (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 psychomotor speed reactions.
Symptoms: have been cases of intentional and unintentional 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 ug / mL) was observed approximately 31 hours after drug overdose 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 observed any complications.
Treatment: specific antidote for the treatment of drug overdose Zonegran® does not exist. After overdose shown presumed immediate gastric lavage on a background of conventional measures to maintain airway patency. A supportive therapy, including regular monitoring of vital signs, and closely monitored. Zonisamide has a long T1 / 2, and therefore the symptoms of overdose can be persistent. Studies overdose treatment has been conducted, however it is known that hemodialysis reduces the concentration of zonisamide in plasma in patients with renal failure and can be considered as a means of treating overdose.