Zonisamide Information
Zonisamide () Description
Zonisamide () is an antiseizure drug chemically classified as a sulfonamide and unrelated to other antiseizure agents. The active ingredient is Zonisamide () , 1,2-benzisoxazole-3-methanesulfonamide. The molecular formula is CHNOS with a molecular weight of 212.23. Zonisamide () is a white or almost white crystalline powder, pK = 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 () is supplied for oral administration as capsules containing 25 mg, 50 mg or 100 mg Zonisamide () . Each capsule contains the labeled amount of Zonisamide () plus the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The empty gelatin capsule shells contain D&C Red No. 28, FD&C Blue No. 1, gelatin and titanium dioxide. In addition, the 100 mg empty gelatin capsule contains FD& C Red No. 3.
The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.
Zonisamide () Clinical Pharmacology
The 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. pharmacological studies suggest that Zonisamide () blocks sodium channels and reduces voltage-dependent, transient inward currents (T-type Ca currents), consequently stabilizing neuronal membranes and suppressing neuronal hypersynchronization. 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 studies have demonstrated that Zonisamide () (10 to 30 mcg/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. microdialysis studies demonstrated that Zonisamide () facilitates both dopaminergic and serotonergic neurotransmission.
Zonisamide () is a carbonic anhydrase inhibitor. The contribution of this pharmacological action to the therapeutic effects of Zonisamide () is unknown. However, as a carbonic anhydrase inhibitor, Zonisamide () may cause metabolic acidosis (see ).
Following a 200 mg to 400 mg oral Zonisamide () dose, peak plasma concentrations (range: 2 to 5 mcg/mL) in normal volunteers occur within 2 to 6 hours. In the presence of food, the time to maximum concentration is delayed, occurring at 4 to 6 hours, but food has no effect on the bioavailability of Zonisamide () . Zonisamide () extensively binds to erythrocytes, resulting in an 8-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 mg to 400 mg, but the C and 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 to 7 mcg/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.
Following oral administration of C-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 the C 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 to 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.
The effectiveness of Zonisamide () 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 to 68 years with a mean age of about 35 years. In the two U.S. studies, over 80% of patients were Caucasian; 100% of patients in the European study were Caucasian. Zonisamide () 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 () in one of two dose escalation regimens; either 1) 100 mg/day for 5 weeks, 200 mg/day for one week, 300 mg/day for one week, and then 400 mg/day for 5 weeks; or 2) 100 mg/day for one week, followed by 200 mg/day for 5 weeks, then 300 mg/day for one week, then 400 mg/day for 5 weeks. This design allowed a 100 mg vs. placebo comparison over weeks 1 to 5, and a 200 mg vs. placebo comparison over weeks 2 to 6; the primary comparison was 400 mg (both escalation groups combined) vs. placebo over weeks 8 to 12. The total daily dose was given as twice a day dosing. Statistically significant treatment differences favoring Zonisamide () 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 to 3 month baseline, then were randomly assigned to placebo or Zonisamide () for 3 months. Zonisamide () was introduced by administering 100 mg/day for the first week, 200 mg/day the second week, then 400 mg/day for 2 weeks, after which the dose (Zonisamide () or placebo) could be adjusted as necessary to a maximum dose of 20 mg/kg/day or a maximum plasma level of 40 mcg/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 () for doses of 400 to 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 () at doses between 100 and 400 mg/day. The primary comparison in both trials was for any dose over Weeks 5 to 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 curve for 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.
No differences in efficacy based on age, sex or race, as measured by a change in seizure frequency from baseline, were detected.
Zonisamide () Indications And Usage
Zonisamide () capsules are indicated as adjunctive therapy in the treatment of partial seizures in adults with epilepsy.
Zonisamide () Contraindications
Zonisamide () capsules are contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or Zonisamide () .
Zonisamide () Warnings
Potentially Fatal Reactions to Sulfonamides: Fatalities have occurred, although rarely, as a result of severe reactions to sulfonamides (Zonisamide () is a sulfonamide) including Stevens-Johnson Syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Such reactions may occur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue Zonisamide () immediately. Specific experience with sulfonamide-type adverse reaction to Zonisamide () is described below.
Consideration should be given to discontinuing Zonisamide () in patients who develop an otherwise unexplained rash. If the drug is not discontinued, patients should be observed frequently.
In the U.S. and European randomized controlled trials, 6 of 269 (2.2%) Zonisamide () patients discontinued treatment because of rash compared to none on placebo. Across all trials during the U.S. and European development, rash that led to discontinuation of Zonisamide () was reported in 1.4% of patients (12 events per 1,000 patient-years of exposure). During Japanese development, serious rash or rash that led to study drug discontinuation was reported in 2% of patients (27.8 events per 1,000 patient-years). Rash usually occurred early in treatment, with 85% reported within 16 weeks in the U.S. and European studies and 90% reported within 2 weeks in the Japanese studies. There was no apparent relationship of dose to the occurrence of rash.
Oligohidrosis, sometimes resulting in heat stroke and hospitalization, is seen in association with Zonisamide () in pediatric patients.
During the pre-approval development program in Japan, one case of oligohidrosis was reported in 403 pediatric patients, an incidence of 1 case per 285 patient-years of exposure. While there were no cases reported in the U.S. or European development programs, fewer than 100 pediatric patients participated in these trials.
In the first 11 years of marketing in Japan, 38 cases were reported, an estimated reporting rate of about 1 case per 10,000 patient-years of exposure. In the first year of marketing in the U.S., 2 cases were reported, an estimated reporting rate of about 12 cases per 10,000 patient-years of exposure. These rates are underestimates of the true incidence because of under-reporting. There has also been one report of heat stroke in an 18 year old patient in the U.S.
Decreased sweating and an elevation in body temperature above normal characterized these cases. Many cases were reported after exposure to elevated environmental temperatures. Heat stroke, requiring hospitalization, was diagnosed in some cases. There have been no reported deaths.
Pediatric patients appear to be at an increased risk for Zonisamide () -associated oligohidrosis and hyperthermia. Patients, especially pediatric patients, treated with Zonisamide () should be monitored closely for evidence of decreased sweating and increased body temperature, especially in warm or hot weather. Caution should be used when Zonisamide () is prescribed with other drugs that predispose patients to heat-related disorders; these drugs include, but are not limited to, carbonic anhydrase inhibitors and drugs with anticholinergic activity.
The practitioner should be aware that the safety and effectiveness of Zonisamide () in pediatric patients have not been established, and that Zonisamide () is not approved for use in pediatric patients.
Antiepileptic drugs (AEDs), including Zonisamide () , increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.
Table 3 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Zonisamide () or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers (see ).
Zonisamide () causes hyperchloremic, non-anion gap, metabolic acidosis (i.e., decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) (see ). This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of Zonisamide () on carbonic anhydrase.
Generally, Zonisamide () -induced metabolic acidosis occurs early in treatment, but it can develop at any time during treatment. Metabolic acidosis generally appears to be dose dependent and can occur at doses as low as 25 mg daily.
Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, ketogenic diet or specific drugs) may be additive to the bicarbonate lowering effects of Zonisamide () .
Some manifestations of acute or chronic metabolic acidosis include hyperventilation, nonspecific symptoms such as fatigue and anorexia, or more severe sequelae including cardiac arrhythmias or stupor. Chronic, untreated, metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis. Nephrolithiasis has been observed in the clinical development program in 4% of adults treated with Zonisamide () , has also been detected by renal ultrasound in 8% of pediatric treated patients who had at least one ultrasound prospectively collected, and was reported as an adverse event in 3% (4/133) of pediatric patients (see ).
Chronic, untreated metabolic acidosis may result in osteomalacia (referred to as rickets in pediatric patients) and/or osteoporosis with an increased risk for fracture. Of potential relevance, Zonisamide () treatment was associated with reductions in serum phosphorus and increases in serum alkaline phosphatase, changes that may be related to metabolic acidosis and osteomalacia (see ).
Chronic, untreated metabolic acidosis in pediatric patients may reduce growth rates. A reduction in growth rate may eventually decrease the maximal height achieved. The effect of Zonisamide () on growth and bone-related sequelae has not been systematically investigated.
Measurement of baseline and periodic serum bicarbonate during treatment is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Zonisamide () (using dose tapering). If the decision is made to continue patients on Zonisamide () in the face of persistent acidosis, alkali treatment should be considered.
Serum bicarbonate was not measured in the adjunctive-controlled trials of adults with epilepsy. However, serum bicarbonate was studied in three clinical trials for indications which have not been approved: a placebo-controlled trial for migraine prophylaxis in adults, a controlled trial for monotherapy in epilepsy in adults, and an open-label trial for adjunctive treatment of epilepsy in pediatric patients (3 to 16 years). In adults, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses of 100 mg to nearly 4 mEq/L at daily doses of 300 mg. In pediatric patients, mean serum bicarbonate reductions ranged from approximately 2 mEq/L at daily doses from above 100 mg up to 300 mg, to nearly 4 mEq/L at daily doses from above 400 mg up to 600 mg.
In two controlled studies in adults, the incidence of a persistent treatment-emergent decrease in serum bicarbonate to less than 20 mEq/L (observed at two or more consecutive visits or the final visit) was dose related at relatively low Zonisamide () doses. In the monotherapy trial of epilepsy, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 21% for daily Zonisamide () doses of 25 mg or 100 mg, and was 43% at a daily dose of 300 mg. In a placebo-controlled trial for prophylaxis of migraine, the incidence of a persistent treatment-emergent decrease in serum bicarbonate was 7% for placebo, 29% for 150 mg daily, and 34% for 300 mg daily. The incidence of persistent markedly abnormally low serum bicarbonate (decrease to less than 17 mEq/L and more than 5 mEq/L from a pretreatment value of at least 20 mEq/L in these controlled trials was 2% or less.
In the pediatric study, the incidence of persistent, treatment-emergent decreases in serum bicarbonate to levels less than 20 mEq/L was 52% at doses up to 100 mg daily, was 90% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. The incidence of a persistent markedly abnormally low serum bicarbonate value was 4 % at doses up to 100 mg daily, was 18% for a wide range of doses up to 600 mg daily, and generally appeared to increase with higher doses. Some patients experienced moderately severe serum bicarbonate decrements down to a level as low as 10 mEq/L.
The relatively high frequencies of varying severities of metabolic acidosis observed in this study of pediatric patients (compared to the frequency and severity observed in various clinical trial development programs in adults) suggest that pediatric patients may be more likely to develop metabolic acidosis than adults.
Use of Zonisamide () was frequently associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) psychiatric symptoms, including depression and psychosis, 2) psychomotor slowing, difficulty with concentration, and speech or language problems, in particular, word-finding difficulties, and 3) somnolence or fatigue.
In placebo-controlled trials, 2.2% of patients discontinued Zonisamide () or were hospitalized for depression compared to 0.4% of placebo patients. Among all epilepsy patients treated with Zonisamide () , 1.4% were discontinued and 1% were hospitalized because of reported depression or suicide attempts. In placebo-controlled trials, 2.2% of patients discontinued Zonisamide () or were hospitalized due to psychosis or psychosis-related symptoms compared to none of the placebo patients. Among all epilepsy patients treated with Zonisamide () , 0.9% were discontinued and 1.4% were hospitalized because of reported psychosis or related symptoms.
Psychomotor slowing and difficulty with concentration occurred in the first month of treatment and were associated with doses above 300 mg/day. Speech and language problems tended to occur after 6 to 10 weeks of treatment and at doses above 300 mg/day. Although in most cases these events were of mild to moderate severity, they at times led to withdrawal from treatment.
Somnolence and fatigue were frequently reported CNS adverse events during clinical trials with Zonisamide () . Although in most cases these events were of mild to moderate severity, they led to withdrawal from treatment in 0.2% of the patients enrolled in controlled trials. Somnolence and fatigue tended to occur within the first month of treatment. Somnolence and fatigue occurred most frequently at doses of 300 to 500 mg/day.
Zonisamide () Precautions
Among 991 patients treated during the development of Zonisamide () , 40 patients (4%) with epilepsy receiving Zonisamide () developed clinically possible or confirmed kidney stones (e.g., clinical symptomatology, sonography, etc.), a rate of 34 per 1,000 patient-years of exposure (40 patients with 1,168 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 1,000 patient-years of exposure in the first 6 months, 62.6 per 1,000 patient-years of exposure between 6 and 12 months, and 24.3 per 1,000 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. Although the clinical significance of the sonographic findings may not be certain, the development of nephrolithiasis may be related to metabolic acidosis (see ). 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 () .
Although not approved in pediatric patients, sonographic findings consistent with nephrolithiasis were also detected in 8% of a subset of Zonisamide () -treated pediatric patients who had at least one renal ultrasound prospectively performed in a clinical development program investigating open-label treatment. The incidence of kidney stone as an adverse event was 3% (see ).
Patients should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Zonisamide () . Patients should be instructed to take Zonisamide () only as prescribed.
Patients should be advised as follows: (See )
In 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 (see ).
Zonisamide () increases serum chloride and alkaline phosphatase and decreases serum bicarbonate (see ), phosphorus, calcium and albumin.
No evidence of carcinogenicity was found in mice or rats following dietary administration of Zonisamide () for 2 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/m basis. In rats, this dose is 1 to 2 times the MRHD on a mg/m basis.
Zonisamide () was mutagenic in an chromosomal aberration assay in CHL cells. Zonisamide () was not mutagenic or clastogenic in other assays (Ames, mouse lymphoma tk assay, chromosomal aberration in human lymphocytes) or in the rat bone marrow cytogenetics assay.
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/m basis.
Zonisamide () Adverse Reactions
The most commonly observed adverse events related to treatment with Zonisamide () (an incidence at least 4% greater than placebo) in controlled clinical trials and shown in descending order of frequency were somnolence, anorexia, dizziness, ataxia, agitation/irritability, and difficulty with memory and/or concentration.
In controlled clinical trials, 12% of patients receiving Zonisamide () as adjunctive therapy discontinued due to an adverse event compared to 6% receiving placebo. Approximately 21% of the 1,336 patients with epilepsy who received Zonisamide () in clinical studies discontinued treatment because of an adverse event. The adverse events most commonly associated with discontinuation were somnolence, fatigue and/or ataxia (6%), anorexia (3%), difficulty concentrating (2%), difficulty with memory, mental slowing, nausea/vomiting (2%), and weight loss (1%). Many of these adverse events were dose related (see and ).
Zonisamide () Drug Abuse And Dependence
The abuse and dependence potential of Zonisamide () has not been evaluated in human studies (see ). In a series of animal studies, Zonisamide () did not demonstrate abuse liability and dependence potential. Monkeys did not self-administer Zonisamide () in a standard reinforcing paradigm. Rats exposed to Zonisamide () did not exhibit signs of physical dependence of the CNS-depressant type. Rats did not generalize the effects of diazepam to Zonisamide () in a standard discrimination paradigm after training, suggesting that Zonisamide () does not have abuse potential of the benzodiazepine-CNS depressant type.
Zonisamide () Overdosage
No specific antidotes for Zonisamide () 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 (see ). Due to the low protein binding of Zonisamide () (40%), renal dialysis may 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.
Zonisamide () Dosage And Administration
Zonisamide () capsules are recommended as adjunctive therapy for the treatment of partial seizures in adults. Safety and efficacy in pediatric patients below the age of 16 have not been established. Zonisamide () capsules should be administered once or twice daily, using 25 mg, 50 mg or 100 mg capsules. Zonisamide () capsules are given orally and can be taken with or without food. Capsules should be swallowed whole.
The prescriber should be aware that, because of the long half-life of Zonisamide () , up to 2 weeks may be required to achieve steady-state levels upon reaching a stable dose or following dosage adjustment. Although the regimen described below is one that has been shown to be tolerated, the prescriber may wish to prolong the duration of treatment at the lower doses in order to fully assess the effects of Zonisamide () at steady-state, noting that many of the side effects of Zonisamide () are more frequent at doses of 300 mg per day and above. Although there is some evidence of greater response at doses above 100 to 200 mg/day, the increase appears small and formal dose-response studies have not been conducted.
The initial dose of Zonisamide () capsules should be 100 mg daily. After 2 weeks, the dose may be increased to 200 mg/day for at least 2 weeks. It can be increased to 300 mg/day and 400 mg/day, with the dose stable for at least 2 weeks to achieve steady-state at each level. Evidence from controlled trials suggests that Zonisamide () capsule doses of 100 to 600 mg/day are effective, but there is no suggestion of increasing response above 400 mg/day (see ). There is little experience with doses greater than 600 mg/day.
Zonisamide () How Supplied:
Zonisamide () Capsules are available as 100 mg capsules.
The 100 mg capsule is a violet opaque cap/light blue opaque body, hard-shell gelatin capsule filled with white to off-white powder. The capsule is axially printed with over in black ink on both the cap and body. They are available as follows:
NDC 51079-768-20 - Unit dose blister packages of 100 (10 cards of 10 capsules each).
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Protect from moisture and light.
Zonisamide () Medication Guide Zonisamide Capsules
Read this Medication Guide before you start taking Zonisamide () capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
Zonisamide () is a prescription medicine that is used with other medicines to treat partial seizures in adults.
It is not known if Zonisamide () is safe or effective in children under 16 years of age.
Do not take Zonisamide () if you are allergic to medicines that contain sulfa.
Before taking Zonisamide () , tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins or herbal supplements. Zonisamide () and other medicines may affect each other causing side effects.
Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist each time you get a new medicine.
Zonisamide () can cause serious side effects including:
Call your healthcare provider right away if you have any of the symptoms listed above.
Side effects can happen at any time, but are more likely to happen during the first several weeks after starting Zonisamide () .
Tell your healthcare provider about any side effect that bothers you or that does not go away. These are not all of the possible side effects of Zonisamide () . For more information, ask your healthcare provider or pharmacist.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Zonisamide () for a condition for which it was not prescribed. Do not give Zonisamide () to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Zonisamide () . If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Zonisamide () that is written for health professionals.
For more information, call Mylan Pharmaceuticals Inc. toll free at 1-877-446-3679 (1-877-4-INFO-RX).
Active ingredient: Zonisamide ()
Inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The empty gelatin capsule shells contain D&C Red No. 28, FD&C Blue No. 1, gelatin and titanium dioxide. In addition, the 100 mg empty gelatin capsule contains FD& C Red No. 3. The imprinting ink contains the following: black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Manufactured by:Mylan Pharmaceuticals Inc.Morgantown, WV 26505
Distributed by:UDL Laboratories, Inc.Rockford, IL 61103
S-108327/10
Zonisamide ()
