Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3104
| Predicate | Object |
|---|---|
| rdf:type | |
| rdfs:label |
Zonisamide (Capsule)
|
| dailymed-instance:descripti... |
Zonisamide capsules are antiseizure drugs chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is zonisamide, 1,2-benzisoxazole-3-methanesulfonamide. The empirical formula is CHNOS with a molecular weight of 212.23. Zonisamide is a white powder, pKa = 10.2, and is moderately soluble in water (0.80 mg/mL) and 0.1 N HCl (0.50 mg/mL). The chemical structure is: Zonisamide capsules are supplied for oral administration as capsules containing 25 mg, 50 mg or 100 mg zonisamide. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, FD&C Yellow #6, gelatin, hydrogenated vegetable oil, microcrystalline cellulose and titanium dioxide. FD&C Yellow #10 and FD&C Blue #1 are present in the 25 mg and 50 mg strengths only.
|
| dailymed-instance:clinicalP... |
Mechanism of ActionThe precise mechanism(s) by which zonisamide exerts its antiseizure effect is unknown. Zonisamide demonstrated anticonvulsant activity in several experimental models. In animals, zonisamide was effective against tonic extension seizures induced by maximal electroshock but ineffective against clonic seizures induced by subcutaneous pentylenetetrazol. Zonisamide raised the threshold for generalized seizures in the kindled rat model and reduced the duration of cortical focal seizures induced by electrical stimulation of the visual cortex in cats. Furthermore, zonisamide suppressed both interictal spikes and the secondarily generalized seizures produced by cortical application of tungstic acid gel in rats or by cortical freezing in cats. The relevance of these models to human epilepsy is unknown. Zonisamide may produce these effects through action at sodium and calcium channels. In vitro pharmacological studies suggest that zonisamide blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Cacurrents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. In vitro binding studies have demonstrated that zonisamide binds to the GABA/benzodiazepine receptor ionophore complex in an allosteric fashion which does not produce changes in chloride flux. Other in vitro studies have demonstrated that zonisamide (10���30��g/mL) suppresses synaptically-driven electrical activity without affecting postsynaptic GABA or glutamate responses (cultured mouse spinal cord neurons) or neuronal or glial uptake of [H]-GABA (rat hippocampal slices). Thus, zonisamide does not appear to potentiate the synaptic activity of GABA. In vivo microdialysis studies demonstrated that zonisamide facilitates both dopaminergic and serotonergic neurotransmission. Zonisamide also has weak carbonic anhydrase inhibiting activity, but this pharmacologic effect is not thought to be a major contributing factor in the antiseizure activity of zonisamide. PharmacokineticsFollowing a 200���400 mg oral zonisamide dose, peak plasma concentrations (range: 2���5��g/mL) in normal volunteers occur within 2���6 hours. In the presence of food, the time to maximum concentration is delayed, occurring at 4���6 hours, but food has no effect on the bioavailability of zonisamide. Zonisamide extensively binds to erythrocytes, resulting in an eight-fold higher concentration of zonisamide in red blood cells (RBC) than in plasma. The pharmacokinetics of zonisamide are dose proportional in the range of 200���400 mg, but the Cand AUC increase disproportionately at 800 mg, perhaps due to saturable binding of zonisamide to RBC. Once a stable dose is reached, steady state is achieved within 14 days. The elimination half-life of zonisamide in plasma is about 63 hours. The elimination half-life of zonisamide in RBC is approximately 105 hours. The apparent volume of distribution (V/F) of zonisamide is about 1.45 L/kg following a 400 mg oral dose. Zonisamide, at concentrations of 1.0���7.0��g/mL, is approximately 40% bound to human plasma proteins. Protein binding of zonisamide is unaffected in the presence of therapeutic concentrations of phenytoin, phenobarbital or carbamazepine. Metabolism and ExcretionFollowing oral administration ofC-zonisamide to healthy volunteers, only zonisamide was detected in plasma. Zonisamide is excreted primarily in urine as parent drug and as the glucuronide of a metabolite. Following multiple dosing, 62% of theC dose was recovered in the urine, with 3% in the feces by day 10. Zonisamide undergoes acetylation to form N-acetyl zonisamide and reduction to form the open ring metabolite, 2���sulfamoylacetyl phenol (SMAP). Of the excreted dose, 35% was recovered as zonisamide, 15% as N-acetyl zonisamide, and 50% as the glucuronide of SMAP. Reduction of zonisamide to SMAP is mediated by cytochrome P450 isozyme 3A4 (CYP3A4). Zonisamide does not induce its own metabolism. Plasma clearance of zonisamide is approximately 0.30���0.35 mL/min/kg in patients not receiving enzyme-inducing antiepilepsy drugs (AEDs). The clearance of zonisamide is increased to 0.5 mL/min/kg in patients concurrently on enzyme-inducing AEDs. Renal clearance is about 3.5 mL/min. The clearance of an oral dose of zonisamide from RBC is 2 mL/min.<br/>Special Populations: Renal Insufficiency: Single 300 mg zonisamide doses were administered to three groups of volunteers. Group 1 was a healthy group with a creatinine clearance ranging from 70���152 mL/min. Group 2 and Group 3 had creatinine clearances ranging from 14.5���59 mL/min and 10���20 mL/min, respectively. Zonisamide renal clearance decreased with decreasing renal function (3.42, 2.50, 2.23 mL/min, respectively). Marked renal impairment (creatinine clearance<20 mL/min) was associated with an increase in zonisamide AUC of 35% . Renal clearance is about 3.5 mL/min. The clearance of an oral dose of zonisamide from RBC is 2 mL/min. Hepatic Disease: The pharmacokinetics of zonisamide in patients with impaired liver function have not been studied . Age: The pharmacokinetics of a 300 mg single dose of zonisamide was similar in young (mean age 28 years) and elderly subjects (mean age 69 years). Gender and Race: Information on the effect of gender and race on the pharmacokinetics of zonisamide is not available. Interactions of Zonisamide with Other Antiepilepsy Drugs (AEDs): Concurrent medication with drugs that either induce or inhibit CYP3A4 may alter serum concentrations of zonisamide. Concomitant administration of phenytoin and carbamazepine increases zonisamide plasma clearance from 0.30-0.35 mL/min/kg to 0.35���0.5 mL/min/kg. The half-life of zonisamide is decreased to 27 hours by phenytoin, to 38 hours by phenobarbital and carbamazepine, and to 46 hours by valproate. Plasma protein binding of phenytoin and carbamazepine was not affected by zonisamide administration . Clinical StudiesThe effectiveness of zonisamide capsules as adjunctive therapy (added to other antiepilepsy drugs) has been established in three multicenter, placebo-controlled, double blind, 3-month clinical trials (two domestic, one European) in 499 patients with refractory partial onset seizures with or without secondary generalization. Each patient had a history of at least four partial onset seizures per month in spite of receiving one or two antiepilepsy drugs at therapeutic concentrations. The 499 patients (209 women, 290 men) ranged in age from 13���68 years with a mean age of about 35 years. In the two US studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Zonisamide capsules or placebo was added to the existing therapy. The primary measure of effectiveness was median percent reduction from baseline in partial seizure frequency. The secondary measure was proportion of patients achieving a 50% or greater seizure reduction from baseline (responders). The results described below are for all partial seizures in the intent-to-treat populations. In the first study (n = 203), all patients had a 1-month baseline observation period, then received placebo or zonisamide capsules in one of two dose escalation regimens; either 1) 100 mg/day for five weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for five weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for five weeks, then 300 mg/day for one week, then 400 mg/day for five weeks. This design allowed a 100 mg vs. placebo comparison over weeks 1���5, and a 200 mg vs. placebo comparison over weeks 2���6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8���12. The total daily dose was given as twice a day dosing. Statistically significant treatment differences favoring zonisamide capsules were seen for doses of 100, 200, and 400 mg/day. In the second (n = 152) and third (n = 138) studies, patients had a 2���3 month baseline, then were randomly assigned to placebo or zonisamide capsules for three months. Zonisamide capsules were introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for two weeks, after which the dose (zonisamide capsules or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40��g/mL. In the second study, the total daily dose was given as twice a day dosing; in the third study, it was given as a single daily dose. The average final maintenance doses received in the studies were 530 and 430 mg/day in the second and third studies, respectively. Both studies demonstrated statistically significant differences favoring zonisamide capsules for doses of 400���600 mg/day, and there was no apparent difference between once daily and twice daily dosing (in different studies). Analysis of the data (first 4 weeks) during titration demonstrated statistically significant differences favoring zonisamide capsules at doses between 100 and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5���12. Figure 1 presents the proportion of patients (X-axis) whose percentage reduction from baseline in the all partial seizure rate was at least as great as that indicated on the Y-axis in the second and third placebo-controlled trials. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in seizure rate), while a negative value indicates a worsening from baseline (i.e., an increase in seizure rate). Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curvefor placebo. The proportion of patients achieving any particular level of reduction in seizure rate was consistently higher for the zonisamide groups compared to the placebo groups. For example, Figure 1 indicates that approximately 27% of patients treated with zonisamide experienced a 75% or greater reduction, compared to approximately 12% in the placebo groups. Figure 1 Proportion of Patients Achieving Differing Levels of SeizureReduction in Zonisamide and Placebo Groups in Studies 2 and 3 No differences in efficacy based on age, sex or race, as measured by a change in seizure frequency from baseline, were detected.
|
| dailymed-instance:activeIng... | |
| dailymed-instance:supply |
Zonisamide capsules 25 mg are dark green, opaque, hard gelatin capsules imprint with cor over 177 body and cap. They are supplied as follows: Bottles of 100 (NDC 64720-177-10)Bottles of 1000 (NDC 64720-177-11) Zonisamide capsules 50 mg are dark green cap with white body, opaque, hard gelatin capsules imprint with cor over 178 body and cap. They are supplied as follows: Bottles of 100 (NDC 64720-178-10)Bottles of 1000 (NDC 64720-178-11) Zonisamide capsules 100 mg are orange cap with white body, opaque, hard gelatin capsules imprint with cor over 179 body and cap. They are supplied as follows: Bottles of 100 (NDC 64720-179-10)Bottles of 500 (NDC 64720-179-50)Bottles of 1000 (NDC 64720-179-11) Store at 20��- 25��C (68��- 77��F); excursions permitted to 15��- 30��C (59��- 86��F) [see USP Controlled Room Temperature]. Dispense in a light-resistant, tight container as defined in the USP. Keep this and all drugs out of the reach of children
|
| dailymed-instance:genericDr... | |
| dailymed-instance:activeMoi... | |
| dailymed-instance:inactiveI... | |
| dailymed-instance:possibleD... | |
| dailymed-instance:precautio... |
GeneralSomnolence is commonly reported, especially at higher doses of zonisamide . Zonisamide is metabolized by the liver and eliminated by the kidneys; caution should therefore be exercised when administering zonisamide capsules to patients with hepatic and renal dysfunction . Kidney StonesAmong 991 patients treated during the development of zonisamide capsules, 40 patients (4.0%) with epilepsy receiving zonisamide capsules developed clinically possible or confirmed kidney stones (e.g. clinical symptomatology, sonography, etc.), a rate of 34 per 1000 patient-years of exposure (40 patients with 1168 years of exposure). Of these, 12 were symptomatic, and 28 were described as possible kidney stones based on sonographic detection. In nine patients, the diagnosis was confirmed by a passage of a stone or by a definitive sonographic finding. The rate of occurrence of kidney stones was 28.7 per 1000 patient-years of exposure in the first six months, 62.6 per 1000 patient-years of exposure between 6 and 12 months, and 24.3 per 1000 patient-years of exposure after 12 months of use. There are no normative sonographic data available for either the general population or patients with epilepsy. The clinical significance of the sonographic finding is unknown. The analyzed stones were composed of calcium or urate salts. In general, increasing fluid intake and urine output can help reduce the risk of stone formation, particularly in those with predisposing risk factors. It is unknown, however, whether these measures will reduce the risk of stone formation in patients treated with zonisamide capsules. Effect on Renal FunctionIn several clinical studies, zonisamide was associated with a statistically significant 8% mean increase from baseline of serum creatinine and blood urea nitrogen (BUN) compared to essentially no change in the placebo patients. The increase appeared to persist over time but was not progressive; this has been interpreted as an effect on glomerular filtration rate (GFR). There were no episodes of unexplained acute renal failure in clinical development in the US, Europe, or Japan. The decrease in GFR appeared within the first 4 weeks of treatment. In a 30-day study, the GFR returned to baseline within 2���3 weeks of drug discontinuation. There is no information about reversibility, after drug discontinuation, of the effects on GFR after long-term use. Zonisamide capsules should be discontinued in patients who develop acute renal failure or a clinically significant sustained increase in the creatinine/BUN concentration. Zonisamide capsules should not be used in patients with renal failure (estimated GFR<50 mL/min) as there has been insufficient experience concerning drug dosing and toxicity. Sudden Unexplained Death in EpilepsyDuring the development of zonisamide capsules, nine sudden unexplained deaths occurred among 991 patients with epilepsy receiving zonisamide capsules for whom accurate exposure data are available. This represents an incidence of 7.7 deaths per 1000 patient years. Although this rate exceeds that expected in a healthy population, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with refractory epilepsy not receiving zonisamide capsules (ranging from 0.5 per 1000 patient-years for the general population of patients with epilepsy, to 2���5 per 1000 patient-years for patients with refractory epilepsy; higher incidences range from 9���15 per 1000 patient-years among surgical candidates and surgical failures). Some of the deaths could represent seizure-related deaths in which the seizure was not observed. Status EpilepticusEstimates of the incidence of treatment emergent status epilepticus in zonisamide-treated patients are difficult because a standard definition was not employed. Nonetheless, in controlled trials, 1.1% of patients treated with zonisamide capsules had an event labeled as status epilepticus compared to none of the patients treated with placebo. Among patients treated with zonisamide capsules across all epilepsy studies (controlled and uncontrolled), 1.0% of patients had an event reported as status epilepticus. Information for PatientsPatients should be advised as follows: Laboratory TestsIn several clinical studies, zonisamide was associated with a mean increase in the concentration of serum creatinine and blood urea nitrogen (BUN) of approximately 8% over the baseline measurement. Consideration should be given to monitoring renal function periodically . Zonisamide was associated with an increase in serum alkaline phosphatase. In the randomized, controlled trials, a mean increase of approximately 7% over baseline was associated with zonisamide compared to a 3% mean increase in placebo-treated patients. These changes were not statistically significant. The clinical relevance of these changes is unknown.<br/>Drug Interactions: Effects of zonisamide capsules on the pharmacokinetics of other antiepilepsy drugs (AEDs): Zonisamide had no appreciable effect on the steady state plasma concentrations of phenytoin, carbamazepine, or valproate during clinical trials. Zonisamide did not inhibit mixed-function liver oxidase enzymes (cytochrome P450), as measured in human liver microsomal preparations, in vitro. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. Effects of other drugs on zonisamide capsules pharmacokinetics: Drugs that induce liver enzymes increase the metabolism and clearance of zonisamide and decrease its half-life. The half-life of zonisamide following a 400 mg dose in patients concurrently on enzyme-inducing AEDs such as phenytoin, carbamazepine, or phenobarbital was between 27���38 hours; the half-life of zonisamide in patients concurrently on the non-enzyme inducing AED, valproate, was 46 hours. Concurrent medication with drugs that either induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Interaction with cimetidine: Zonisamide single dose pharmacokinetic parameters were not affected by cimetidine (300 mg four times a day for 12 days). Carcinogenesis, Mutagenesis, and Impairment of FertilityNo evidence of carcinogenicity was found in mice or rats following dietary administration of zonisamide for two years at doses of up to 80 mg/kg/day. In mice, this dose is approximately equivalent to the maximum recommended human dose (MRHD) of 400 mg/day on a mg/mbasis. In rats, this dose is 1���2 times the MRHD on a mg/mbasis. Zonisamide increased mutation frequency in Chinese hamster lung cells in the absence of metabolic activation. Zonisamide was not mutagenic or clastogenic in the Ames test, mouse lymphoma assay, sister chromatid exchange test, and human lymphocyte cytogenetics assay in vitro, and the rat bone marrow cytogenetics assay in vivo. Rats treated with zonisamide (20, 60, or 200 mg/kg) before mating and during the initial gestation phase showed signs of reproductive toxicity (decreased corpora lutea, implantations, and live fetuses) at all doses. The low dose in this study is approximately 0.5 times the maximum recommended human dose (MRHD) on a mg/mbasis. The effect of zonisamide on human fertility is unknown.<br/>Pregnancy: Pregnancy Category C : Zonisamide was teratogenic in mice, rats, and dogs and embryolethal in monkeys when administered during the period of organogenesis. Fetal abnormalities or embryo-fetal deaths occurred in these species at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans, indicating that use of this drug in pregnancy entails a significant risk to the fetus. A variety of external, visceral, and skeletal malformations was produced inanimals by prenatal exposure to zonisamide. Cardiovascular defects were prominent in both rats and dogs. Following administration of zonisamide (10, 30, or 60 mg/kg/day) to pregnant dogs during organogenesis, increased incidences of fetal cardiovascular malformations (ventricular septal defects, cardiomegaly, various valvular and arterial anomalies) were found at doses of 30 mg/kg/day or greater. The low effect dose for malformations produced peak maternal plasma zonisamide levels (25��g/mL) about 0.5 times the highest plasma levels measured in patients receiving the maximum recommended human dose (MRHD) of 400 mg/day. In dogs, cardiovascular malformations were found in approximately 50% of all fetuses exposed to the high dose, which was associated with maternal plasma levels (44��g/mL) approximately equal to the highest levels measured in humans receiving the MRHD. Incidences of skeletal malformations were also increased at the high dose, and fetal growth retardation and increased frequencies of skeletal variations were seen at all doses in this study. The low dose produced maternal plasma levels (12��g/mL) about 0.25 times the highest human levels. In cynomolgus monkeys, administration of zonisamide (10 or 20 mg/kg/day) to pregnant animals during organogenesis resulted in embryo-fetal deaths at both doses. The possibility that these deaths were due to malformations cannot be ruled out. The lowest embryolethal dose in monkeys was associated with peak maternal plasma zonisamide levels (5��g/mL) approximately 0.1 times the highest levels measured in patients at the MRHD. In a mouse embryo-fetal development study, treatment of pregnant animals with zonisamide (125, 250, or 500 mg/kg/day) during the period of organogenesis resulted in increased incidences of fetal malformations (skeletal and/or craniofacial defects) at all doses tested. The low dose in this study is approximately 1.5 times the MRHD on a mg/m2 basis. In rats, increased frequencies of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, decreased skeletal ossification) were observed among the offspring of dams treated with zonisamide (20, 60, or 200 mg/kg/day) throughout organogenesis at all doses. The low effect dose is approximately 0.5 times the MRHD on a mg/mbasis. Perinatal death was increased among the offspring of rats treated with zonisamide (10, 30, or 60 mg/kg/day) from the latter part of gestation up to weaning at the high dose, or approximately 1.4 times the MRHD on a mg/mbasis. The no effect level of 30 mg/kg/day is approximately 0.7 times the MRHD on a mg/mbasis. There are no adequate and well-controlled studies in pregnant women. Zonisamide capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labour and DeliveryThe effect of zonisamide capsules on labor and delivery in humans is not known. Use in Nursing MothersIt is not known whether zonisamide is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from zonisamide, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account the importance of the drug to the mother. Zonisamide capsules should be used in nursing mothers only if the benefits outweigh the risks. Pediatric UseThe safety and effectiveness of zonisamide capsules in children under age 16 have not been established. Cases of oligohidrosis and hyperpyrexia have been reported . Geriatric UseSingle dose pharmacokinetic parameters are similar in elderly and young healthy volunteers . Clinical studies of zonisamide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
|
| dailymed-instance:overdosag... |
Human ExperienceExperience with zonisamide capsules daily doses over 800 mg/day is limited. During zonisamide capsules clinical development, three patients ingested unknown amounts of zonisamide capsules as suicide attempts, and all three were hospitalized with CNS symptoms. One patient became comatose and developed bradycardia, hypotension, and respiratory depression; the zonisamide plasma level was 100.1��g/mL measured 31 hours post-ingestion. Zonisamide plasma levels fell with a half-life of 57 hours, and the patient became alert five days later. ManagementNo specific antidotes for zonisamide capsules overdosage are available. Following a suspected recent overdose, emesis should be induced or gastric lavage performed with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation. Zonisamide has a long half-life . Due to the low protein binding of zonisamide (40%), renal dialysis may not be effective. The effectiveness of renal dialysis as a treatment of overdose has not been formally studied. A poison control center should be contacted for information on the management of zonisamide overdosage.
|
| dailymed-instance:genericMe... |
Zonisamide
|
| dailymed-instance:fullName |
Zonisamide (Capsule)
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Zonisamide
|