Zonegran capsules 100 mg 56 pcs
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Active ingredients
Zonisamide
Release form
Capsules
Composition
Active ingredient: Zonisamide (Zonisamide) Concentration of the active substance (mg): 0, 1 g
Pharmacological effect
Zonisamid is an antiepileptic agent derived from benzisoxazole, in vitro slightly inhibits carbonic anhydrase. Chemically, its structure differs from other antiepileptic drugs. Mechanism of action The mechanism of action of zonisamide has not been fully studied, it probably blocks potential-sensitive sodium and calcium channels, reduces the severity of synchronized neural excitation, inhibits the development of seizures and prevents further spread of epileptic activity. Zonisamid also reduces the convulsive activity of neurons by enhancing the inhibitory effect of gamma-aminobutyric acid (GABA). Pharmacodynamic effects The anti-convulsant activity of zonisamide was studied in various models of epilepsy in groups with induced or congenital seizures, while zonisamide showed itself as an anti-epileptic agent of a broad spectrum. Zonisamid prevents the development of maximum electroconvulsive seizures, limits the development of seizures, including the spread of the excitation focus from the cerebral cortex to the subcortical structures, and also inhibits the activity of the epileptogenic focus. Unlike phenytoin and carbamazepine, zonisamide has a selective effect on seizures in the cortex. Clinical efficacy and safetyMonotherapy of partial seizures with secondary generalization or without Efficacy of zonisamide in monotherapy in patients with newly diagnosed partial epileptic seizures with secondary generalization or with generalized tonic-clonic seizures without clear foci was shown in double-blind, with parallel and study groups, with the participation of 583 adult patients to establish no less effective therapy with Zonerag before carbamazepine therapy with prolonged action, which lasted up to 24 months, depending on the response to treatment. The dose was increased to a target value of 600 mg of carbamazepine or 300 mg of zonisamide.If patients had seizures, they were increased to the next dose, i.e. 800 mg of carbamazepine or 400 mg of zonisamide. If the seizures persisted, the dose was increased to a maximum of 1,200 mg for carbamazepine and to 500 mg for zonisamide. Patients who did not have seizures for 26 weeks while receiving the target dose continued to receive the same dose for an additional 26 weeks. Additional therapy for partial seizures with secondary generalization or without it was shown 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 reduction in the median frequency of occurrence of partial epileptic seizures when taking zonisamide in daily doses of 300-500 mg once or twice a day. Additional therapy for partial seizures with secondary generalization or deafness in adolescents and children 6 years old older) efficacy of zonisamide was demonstrated in a double-blind, placebo-controlled, 24-week study involving 207 patients. With a 12-week target dose, there was a 50% or more reduction in the frequency of attacks in 50% of patients receiving zonisamide and in 31% of patients receiving placebo. Specific safety issues that occurred during the study of children included: loss of appetite and weight loss, lower bicarbonate levels, increased risk of urolithiasis, and dehydration. All of 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, a limited amount of data was obtained on the long-term effect of the drug on the growth and development of the child.
Pharmacokinetics
Zonisamid absorption is almost completely absorbed after oral administration, the maximum concentration (Cmax) in plasma is reached within 2-5 hours after administration. The severity of the primary metabolism is insignificant - the absolute bioavailability is estimated at 100%. Bioavailability of zonisamide when administered orally does not depend on the ingestion, although this may slow down the time to reach Cmax in the blood plasma. The AUC (area under the concentration-time curve) and Cmax of zonisamide almost linearly increase after taking a single dose (in the dose range of -800 mg) and after repeated administration (in the dose range of 100-400 mg once a day).An increase in these values when the equilibrium state is reached is somewhat higher than that assumed, based on the dose taken, possibly due to the saturability of zonisamide binding to erythrocytes. The equilibrium state is reached within 13 days. There is a somewhat larger accumulation than expected, compared with a single dose of the drug. Distribution Zonisamide binds to plasma proteins 40-50%, according to the results of in vitro studies, various anticonvulsants (phenytoin, phenobarbital, carbamazepine and sodium valproate) do not have a significant effect on the degree of its binding to plasma proteins. The apparent volume of distribution in adults is 1.1-1.7 l / kg, which indicates a significant distribution of zonisamide in the tissues. The ratio of zonisamide concentrations in erythrocytes and 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 route of metabolism is the cleavage of the benzisoxazole ring to form 2-sulfamoylacetylphenol (SMAP), as well as N- acetylation. The precursor and SMAP can bind with glucuronic acid. Metabolites that are not detected in the blood plasma are deprived of anticonvulsant activity. There is no evidence that zonisamide is able to induce its own metabolism. Zonisamide elimination after reaching Css reaches 0.70 l / h, the final half-life (T1 / 2) is about 60 hours (provided that there is no simultaneous intake of inductors of CYP3A4 isoenzyme activity). T1 / 2 does not depend on the size of the dose taken, nor on the duration of treatment. Fluctuations in the concentration of zonisamide in plasma are insignificant (less than 30%). Metabolites and unchanged zonisamide are excreted mainly through the kidneys. Renal clearance of unchanged zonisamide is relatively low (about 3.5 ml / min); about 15-30% of the dose taken is displayed unchanged. Linearity / non-linearity The concentration of zonisamide increases until an equilibrium state is reached, which usually occurs after about 8 weeks. When comparing the same dose level, patients with higher body mass, as a rule, achieve lower equilibrium serum concentrations, but these differences are insignificant.Age (≥ 12 years) and sex, adjusted by body weight, do not affect the concentrations of zonisamide in patients with epilepsy when the equilibrium concentrations of the drug are reached. The need to reduce the dose when applying any probe, including CYP3A4 isoenzyme inducer is absent. Pharmacodynamic and pharmacokinetic zonisamide ratio reduces the average frequency of attacks for a 28-day period and this decrease is proportional (log-linear relationship) to the average concentration of zonisamide. Use in special patient groups Patients with renal failure. In patients with renal insufficiency, the renal clearance of single doses of zonisamide is directly proportional to creatinine clearance (CK). AUC of zonisamide is increased by 35% in patients with severe renal insufficiency (CC less than 20 ml / min) (see section “Dosage regimen”). Patients with hepatic insufficiency. The pharmacokinetics of zonisamide in patients with hepatic insufficiency has not been well studied. Elderly patients. There are no clinically significant differences in the pharmacokinetics of zonisamide in young (21-40 years) and elderly (65-75 years) patients. Patients of childhood (5-18 years). Limited data show that the pharmacokinetic parameters of zonisamide in a daily dose of 1 mg / kg, 7 mg / kg or 12 mg / kg in children and adolescents are similar to those in adult patients (taking into account the amendment to body weight).
Indications
As an additional drug in adults for the treatment of partial epileptic seizures with or without secondary generalization.
Contraindications
Hypersensitivity to zonisamide and sulfonamides.
Precautionary measures
Do not exceed recommended doses.
Use during pregnancy and lactation
Women with preserved childbearing potential Women with preserved childbearing potential should use reliable methods of contraception during treatment with the Zonegran drug and for 1 month after its discontinuation. Pregnancy There is no sufficient data on the use of the drug Zonegran in pregnant women. Animal studies have shown that zonisamide has potentially reproductive toxicity, the risk of which in humans is unknown. Zonegran should not be used during pregnancy, unless the potential benefits prevail over the possible risk to the fetus. If a woman is planning a pregnancy, the need for anticonvulsant therapy should be analyzed.In case of administration of the drug Zonegran, careful observation is recommended. The risk of congenital malformations in children whose mothers take antiepileptic drugs increases by a factor of 2-3. The following defects are most often detected: splitting of the upper lip, anomalies of the development of the cardiovascular system and defects of the neural tube. Combination therapy with anticonvulsant drugs is accompanied by an increased risk of developing congenital malformations in comparison with monotherapy. There is an unacceptable abolition of anticonvulsant therapy due to the risk of an epileptic seizure, which can lead to serious consequences for both mother and child. Breastfeeding The drug is given with breast milk in concentrations similar to those in plasma, so a decision should be made to discontinue breastfeeding or to discontinue the drug in a nursing mother . Due to the long half-life, breastfeeding can be resumed no earlier than one month after discontinuation of the drug.
Dosage and administration
Is ingested regardless of the meal. The dose is selected based on the therapeutic effect. The effective dose is 300-500 mg / day, although in some cases, in particular, in patients who do not take CYP3A4 inducers, the therapeutic effect may be manifested in smaller doses. The initial dose is 50 mg / day in 2 doses. After 1 week of taking the daily dose can be increased to 100 mg / day. Then the dose can be increased by 100 mg every 7 days, up to a maximum recommended dose of 500 mg / day. Subsequently, during treatment, you can go on to receive 1 time / day. The use of two-week intervals should be considered In patients with hepatic or renal insufficiency, as well as in patients who do not take CYP3A4 inducers, the interval between dose increases can be increased to 2 weeks , reducing the dose by 100 mg per week while taking other anticonvulsants.
Side effects
Determination of the frequency of adverse reactions: very often (more than 1/10), often (more than 1/100 less than 1/10), infrequently (more than 1/1000 less than 1/100), very rarely (less than 1 / 10,000, including individual reports). Infections: not often - pneumonia, urinary tract infections. From the side of the immune system: often - hypersensitivity. From the side of metabolism: very often - anorexia; often - weight loss; infrequently - hypokalemia; very rarely - metabolic acidosis,tubular renal acidosis. On the mental side: very often - arousal, irritability, confusion, depression; often - instability, anxiety, insomnia, psychotic disorder; infrequently - anger, aggression, suicidal thoughts and attempts; very rarely - hallucinations. From the nervous system: very often - ataxia, dizziness, memory impairment, drowsiness; often - bradyphrenia, attention disorders, nystagmus, paresthesia, speech disorder, tremor; infrequently - seizures; very rarely - amnesia, coma, large epileptic seizures, MNS, status epilepticus. From the musculoskeletal system: very rarely - myasthenic syndrome, rhabdomyolysis. From the organ of vision: very often - double vision.From the hematopoietic system: often - ecchymosis; very rarely - agranulocytosis, aplastic anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, thrombocytopenia. On the respiratory system: very rarely - shortness of breath, aspiration pneumonia, respiratory failure. On the part of the digestive system: often - abdominal pain, constipation, dyspepsia, respiratory failure. diarrhea; infrequently - vomiting; very rarely - pancreatitis. From the side of the liver: infrequently - cholecystitis, cholelithiasis; very rarely - hepatocellular damage. From the skin: very rarely - rash, anhidrosis, erythema multiforme, increased incidence of Stevens-Johnson syndrome, pruritus, toxic epidermal necrolysis. From laboratory studies: very often - a decrease in bicarbonate content; very rarely - an increase in CPK; an increase in serum creatinine and urea, an increase in liver enzymes. From the urinary system: often - nephrolithiasis; very rarely - hydronephrosis, renal failure, urine composition disorders. General reactions: infrequently - pyrexia, fatigue, flu-like syndrome; very rarely - heat stroke; in some cases, sudden death in epilepsy (SUDEP).
Overdose
Symptoms: There have been cases of deliberate and unintentional overdose of Zoneran 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, renal dysfunction, hypotension and respiratory depression. A very high plasma concentration of zonisamide (100.1 µg / ml) was observed approximately 31 hours after an overdose of the drug Zonegran and clonazepam. A patient with an overdose of these drugs developed coma and respiratory depression. However, after 5 days he regained consciousness, and he didn’t have any complications. The treatment: there is no specific antidote for the treatment of overdose with the drug. After a presumptive overdose, immediate gastric lavage is indicated against the background of the usual measures aimed at maintaining the airway. Conduct supportive therapy, including regular monitoring of key indicators of the state of the body, and careful observation. Zonisamid has a long T1 / 2, in connection with which the symptoms of its overdose can be persistent. Studies of overdose treatment have not been conducted, however, it is known that hemodialysis reduces the concentration of zonisamide in the blood plasma of patients with renal insufficiency and can be considered as a means of treating overdose.
Interaction with other drugs
Cytochrome P450 system enzymesThe study of the effect of the drug Zonegranin vitro on microsomal oxidation in human hepatocytes showed no significant effect (less than 25%) on the activity of cytochrome P450 isoenzymes of the people in the process of the pi-58–0; blood 2 times or more than therapeutic. It is unlikely that Zonegran will affect the pharmacokinetics of other drugs through the mechanisms associated with cytochrome P450, as demonstrated in vivo for carbamazepine, phenytoin, ethinyl estradiol and desipramine. the drug Zonegran has no effect on the pharmacokinetics of carbamazepine, lamotrigine, phenytoin and valproate sodium. Inhibitors Carboanhydrases: Care should be taken when co-administering the drug Zonegran with carbonic anhydrase inhibitors (for example, topiramate and acetazolamide) because there is insufficient data to exclude pharmacodynamic interaction (seesection "Special instructions"). A zone should not be given to children at the same time as carbonic anhydrase inhibitors, such as topiramate and acetazolamide (see section "Special instructions"). Oral contraceptives The administration of the drug Zonegran and combined oral contraceptives in recommended doses does not affect the concentration in blood serum ethinyl estradiol or norethisterone. P-glycoprotein substrates. In vitro studies show that zonisamide is a weak inhibitor of P-glycoprotein (a multidrug-resistant drug STI (MDR1)) with a concentration of half maximal inhibition (IC50) of 267 μM / L, which is why there is a theoretical possibility of the influence of zonisamide on the pharmacokinetics of drugs that are substrates of P-glycoprotein. It is recommended to start or stop treatment with caution or to change the dose of zonisamide in patients who also take drugs that are P-glycoprotein substrates (for example, digoxin, quinidine). The potential influence of other drugs on the effect of Zonegran is not significant. effects on the pharmacokinetics of zonisamide. With simultaneous administration of the drug Zonegran with drugs that can cause the development of urolithiasis, the risk of nephrourolithiasis increases, and therefore, their simultaneous use should be avoided. Zonisamide is metabolized with the participation of the CYP3A4 isoenzyme, and N-acetyltransferase, as well as through conjugation with glucuronic acid. Consequently, substances that induce or inhibit these enzymes can affect the pharmacokinetics of zonisamide: - Enzyme inducers: the effect of zonisamide is reduced while taking drugs that increase the activity of the CYP3A4 isoenzyme (for example, phenytoin, carbamazepine and phenobarbital). These effects are not clinically significant in cases when the Zonegrain joins the therapy already received, however, clinically significant changes in the concentration of zonisamide are possible with discontinuation, changing the dosage regimen or additional prescription of drugs that induce the CYP3A4 isoenzyme (dose adjustment of the drug Zonegran may be necessary).Rifampicin is a potent inducer of CYP3A4 isoenzyme, if its joint appointment with the drug Zonegran is required, the patient’s condition should be carefully monitored, if necessary, adjusting the dose of Zonegran. The administration of ketoconazole (400 mg / day) or cimetidine (1200 mg / day) did not have a clinically significant effect on the pharmacokinetics of zonisamide taken by healthy volunteers. Changes in the dosing regimen of the drug Zonegran when combined with CYP3A4 isoenzyme inhibitors are not required. Children of the child There were no studies of drug interactions in children.
special instructions
Skin rashes When the drug was administered with the Zonegran, the development of severe skin reactions, including Stevens-Johnson syndrome, was reported. It was recommended that the drug be withdrawn from patients who developed skin rashes and could not be explained by other causes. All patients with a rash on the skin while taking Zonegran should be carefully monitored, especially patients with other anti-epileptic drugs that can cause skin rashes themselves. Cancellation Syndrome Zonegran is discontinued by gradually lowering the dose to avoid epileptic seizures. There is not enough data on the abolition of simultaneously used antiepileptic drugs after achieving seizure control when using the Zonegran drug as part of adjuvant therapy for the transition to the Zonetherapy monotherapy. Therefore, the abolition of concomitant antiepileptic treatment should be carried out with caution. Reactions associated with the presence of the 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 pronounced hematological disorders, includingaplastic anemia, in very rare cases, leading to death. It was reported about the development of cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia of pancytopenia and leukocytosis. Information to assess the possible relationship between these phenomena and the magnitude of the dose of Zonegran taken and the duration of treatment is not enough. Suicidal thinking and behavior The development of suicidal thinking and behavior is possible in patients taking antiepileptic drugs for a number of indications. A meta-analysis of randomized, placebo-controlled studies of antiepileptic drugs also showed an increased risk of suicidal thoughts and behavior. The mechanism of this phenomenon is unknown, available data do not exclude the possibility of an increased risk of suicidal behavior and while taking the drug Zonegran. thoughts and behaviors, and provide appropriate treatment. Patients (and those caring for them) should be advised to seek medical attention if suicidal thoughts and behaviors appear. Nephrolithiasis In some patients, especially with a predisposition to nephrolithiasis, the risk of kidney stones and the onset of such signs and symptoms as renal colic, pain may increase. kidney or side pain. Nephrolithiasis can lead to chronic kidney damage. Risk factors for nephrolithiasis include previous kidney stones, as well as a family history of nephrolithiasis and hypercalciuria. None of these risk factors is a reliable sign that predicts the formation of kidney stones when treated with zonisamide. In addition, the risk may be increased in patients taking other drugs that cause the development of urolithiasis. Increased fluid intake and forced diuresis can reduce the risk of stone formation, including in patients with a predispositionThe development of metabolic acidosis is due to the loss of bicarbonates in the kidneys due to the inhibitory effect of zonisamide on carbonic anhydrase, and possibly at any stage of treatment, although it is more often noted in the early stages of treatment. Similar violations were noted both during the placebo-controlled clinical trials and in the post-marketing period. A decrease in the level of bicarbonates is usually expressed only slightly (the average value is about 3.5 mEq / l with 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, surgical interventions, a diet that promotes the formation of ketone bodies, a number of drugs) can enhance the effect of zonisamide on bicarbonate levels. Risk of occurrence and the severity of metabolic acidosis is increased in young patients. In the event of signs or symptoms of metabolic acidosis, it is recommended to assess the concentration of bicarbonate in serum. If the developed metabolic acidosis does not pass, the possibility of reducing the dose or completely stopping the use of the drug Zonegran (with a gradual reduction of the dose) should be considered, since the development of osteopenia is possible. If it is decided to continue therapy in the presence of persistent acidosis, the use of alkaloids should be considered. Care should be taken when prescribing simultaneously with carbonic anhydrase inhibitors (for example, topiramate and acetazolamide), as there is insufficient data to exclude pharmacodynamic interaction (see the section “Drug Interactions” ). Thermal shock. Cases of decreased 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 cases occurred under conditions of high ambient temperature. Patients and / or their caregivers should be warned about the need to maintain adequate hydration of the body and avoid exposure to elevated temperatures.Care must be taken when prescribing the drug Zonegran at the same time as drugs that promote overheating of the body, including carbonic anhydrase inhibitors and holinoblokatori. In the case of confirmed pancreatitis in the absence of other obvious reasons, it is recommended that Zoneoneg is discontinued and appropriate treatment is given. aldolase. If they are increased, in the absence of other obvious reasons, such as an injury or a large epileptic seizure, it is recommended that the Zonegran drug be withdrawn and appropriate treatment be prescribed. Women with preserved fertility potential after its cancellation (see section “Pregnancy and lactation”). Reducing body weightZonegran can cause weight loss, therefore during the treatment of patients with a reduced body weight or with its decrease, it is necessary to prescribe food additives and enhanced nutrition. With a marked decrease in body weight, the possibility of discontinuation of the drug Zonegran should be considered. The decrease in body weight in children may be more pronounced. Children of childhood The above precautions apply to children and adolescents. Below are the precautions to which particular attention should be paid. 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 in a child, brain damage and death can occur. Children are at high risk, especially in hot weather. If the child is taking the drug Zonegran: - Overheating should be avoided, especially in hot weather. - Exercise should be avoided, especially in hot weather. - Increase water intake. - Do not use the following drugs : carbonic anhydrase inhibitors (such as topiramate and acetazolamide) and anticholinergics (such as clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine, and oxybutynin).