Zonegran

Zonegran

zonisamide

Manufacturer:

Sumitomo Dainippon

Distributor:

Zuellig
/
HI-Eisai

Marketer:

Eisai
Full Prescribing Info
Contents
Zonisamide.
Description
Each film-coated tablet contains 100 mg of zonisamide.
Generic name: Zonisamide (JAN, INN).
Chemical name: 1,2-benzisoxazole-3-methanesulfonamide.
Molecular formula: C8H8N2O3S.
Molecular weight: 212.23.
Melting point: 164-168°C.
Partition coefficient: 1.04 (Chloroform/water solvent. pH 7.04, at room temperature).
Zonisamide is a white to pale yellow crystal or crystalline powder. It is odorless or has a slightly characteristic odor and has a slightly bitter taste. It is freely soluble in acetone, sparingly soluble in methanol, slightly soluble in ethanol, and very slightly soluble in water, ether and chloroform.
Excipients/Inactive Ingredients: It contains microcrystalline cellulose, lactose hydrate, hydroxypropylcelullose, low substituted hydroxypropylcellulose, magnesium stearate, light anhydrous silicic acid, hypromellose, macrogol, titanium oxide and talc.
Action
Pharmacology: Zonisamide, like phenytoin and carbamazepine, selectively prevents tonic extensor convulsions induced by maximal electroshock in mice, rats, rabbits and dogs, and also those induced by pentylenetetrazol in mice.
Zonisamide strongly suppresses cortical focal seizures induced by electrical stimulation of the visual cortex as well as spike and wave discharges induced by cortical application of conjugated estrogen in cats.
Furthermore zonisamide markedly suppresses both spike activities and secondarily generalized seizures induced by cortical application of tungstic acid gel in rats and by cortical freezing in cats.
Zonisamide reduces the duration of after-discharge and increases the threshold current for generalized convulsions in cortical and hippocampal-kindled rats.
Although the exact mechanism of action of zonisamide remains unclear, it is suggested that the drug exerts its anticonvulsant effects by blocking the spread or propagation of seizure discharges and by suppressing epileptogenic focus activity.
Clinical Studies: The results of clinical studies on the sum of 965 cases including double blind comparative study and comparative study are as shown as follows. (See Table 1.)

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Pharmacokinetics: Plasma concentration: (Healthy adults, single administration of 200 mg): See Table 2.

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Plasma protein binding rate: 48.6% (in vitro, human serum, centrifugal ultrafiltration method).
Main metabolites and metabolic pathway: Zonisamide is mainly metabolized in the liver and undergoes glucuronidation etc. after cleavage of isoxazole ring.
Excretion route and excretion rate: Excretion route: Mainly into urine.
Excretion rate: Excretion rate in urine 2 weeks after the administration was 28.9%-47.8% as unchanged compound and 12.4-18.7% as main metabolites which were glucuronides of isoxazole ring cleavage compound. Those were 47.6-60.2% of administered dose. (Healthy adults, 200 mg administration once or twice, and 400 mg administration twice).
Effective blood concentration: Though it depends on severity or individual case of epilepsy, about 20 μg/mL is indicated as a standard in general.
Metabolic enzyme: Subtypes of cytochrome P450: mainly CYP3A.
Pharmacokinetics in patients with renal dysfunction: (Foreign data, single administration of 300 mg). (See Table 3.)

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A difference was found between patients with renal dysfunction and those with normal renal function in renal clearance and excretion rate into urine.
Indications/Uses
ZONISAMIDE (ZONEGRAN) is indicated for the following epilepsy seizure types: Partial seizures: simple partial seizures [focal seizure (including Jacksonian type), autonomic seizure, psychomotor seizure]; complex partial seizures [psychomotor seizure, focal seizure]; secondarily generalized tonic-clonic seizures [tonic-clonic seizures (grand-mal)].
Generalized seizures: tonic-clonic seizures [tonic-clonic seizure (generalized convulsion, grand-mal)]; tonic seizures [generalized convulsion]; atypical absence [petit mal variant].
Combined seizures [combined seizure].
Dosage/Direction for Use
The usual starting dose for adults is 1-2 tablets (100-200 mg of zonisamide) per day, taken orally in one to three divided doses or as prescribed by the physician. The dose may be gradually increased every one to two weeks up to 2-4 tablets (200-400 mg) daily in one to three divided doses. The maximum daily dose should be 600 mg.
The usual starting dose for children above 6 years old is 2-4 mg/kg of zonisamide per day, taken orally in one to three divided doses or as prescribed by the physician. The dose may be gradually increased every one to two weeks up to 4-8 mg/kg daily in one to three divided doses. The maximum daily dose should be 12 mg/kg.
Overdosage
Symptoms: In some cases, overdose were asymptomatic. In other cases, the overdose was followed by symptoms such as somnolence, nausea, gastritis, nystagmus, myoclonus, coma, bradycardia, reduced renal function, hypotension and respiratory depression.
Treatment: No specific antidotes for Zonisamide overdose are available. Emptying the stomach by gastric lavage or by induction of emesis may be indicated with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation. Haemodialysis reduced plasma concentration of zonisamide in patients with reduced renal function, and may be considered as treatment of overdose if clinically indicated.
Contraindications
[ZONISAMIDE (ZONEGRAN) is contraindicated in the following patients]: Patients with a history of hypersensitivity to zonisamide or any of its ingredients or to sulfonamides.
Special Precautions
Careful Administration [ZONISAMIDE (ZONEGRAN) should be administered carefully in the following patients]: Patients with severe hepatic dysfunction or those with its anamnesis. [Blood concentration of this drug may be elevated.]
Clinically Significant Precautions: Since a radical reduction of the dose or an abrupt discontinuance of the administration may cause status epilepticus, while the patients take the drug, the discontinuance should be carefully carried out by reducing the dose gradually for example.
Special attention should be paid to the elderly and debilitated patients.
It is recommended that hepatic and renal function tests and blood examinations should be performed regularly during the administration.
Since drowsiness and decreases in attentiveness, concentration, reflex movement, etc. may occur, the patients should be instructed not to be engaged in potentially dangerous tasks such as operating machinery or driving vehicles during the drug administration.
For more appropriate adjustment of the dosage, it is desirable to measure the blood concentration of this drug.
Since decreased sweating may occur, and body temperature may rise especially in the summer period, careful attention should be paid to the rise of body temperature during treatment with zonisamide, particularly in pediatric patients. If such symptoms are observed, keep the patient hydrated and out of high temperature environment as much as possible, and take appropriate countermeasures such as reduction of the dose or discontinuance of the administration.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. This analysis revealed that the incidence of suicidality (i.e. suicidal ideation or behavior) in patients on zonisamide was 0.4% compared to 0.2% in patients on placebo. 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. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Zonisarnide. Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients and their caregivers should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Kidney stones have occurred in patients treated with Zonisamide. Zonisamide should be used with caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family history of nephrolithiasis and hypercalciuria. Such patients may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. In addition, patients taking other medications associated with nephrolithiasis may be at increased risk. Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in those with predisposing risk factors.
Hyperchloremic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with Zonisamide treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of Zonisamde in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment.
Bicarbonate decrements are usually mild to moderate (average decrease of approximately 3.5 mEq/L at daily doses of 300 mg in adults); rarely patients can experience more severe decrements. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diet, or drugs) may be additive to the bicarbonate lowering effects of zonisamide. If signs or symptoms or possible metabolic acidosis are observed, measurement of serum bicarbonate is recommended. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Zonisamide (using drug tapering). If the decision is made to continue patients on Zonisamide in the face of persistent acidosis, alkali treatment should be considered.
Consideration must be given to discontinuing Zonisamide in patients who develop an otherwise unexplained rash. All patients who develop a rash while taking Zonisamide must be closely supervised, with additional levels of caution applied to those patients receiving concomitant anti-epileptic agents that may independently induce skin rashes.
In patients taking Zonisamide, in whom severe muscle pain and/or weakness develop either in the presence or absence of a fever, it is recommended that markers of muscle damage be assessed, including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another obvious cause such as trauma or grand mal seizures, it is recommended that Zonisamide tapering and/or discontinuation be considered and appropriate treatment initiated.
Serious rashes have occurred in association with Zonisamide therapy, including cases of Stevens-Johnson syndrome.
Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported.
In patients taking Zonisamide who develop the clinical signs and symptoms of pancreatitis, it is recommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the absence of another obvious cause, it is recommended that discontinuation of Zonisamide be considered and appropriate treatment initiated.
Other Precautions: Abnormality of serum immunoglobulin such as IgA and IgG may occur.
Effects on the Ability to Drive or Operate Machinery: Since drowsiness and decreases of attentiveness, concentration, reflex movement, may occur, the patients should be instructed not to be engaged in potentially dangerous tasks eg, operating machinery or driving vehicles during the drug administration.
Use in Children: There is limited controlled clinical trial data on the safety and effectiveness in children and adolescents.
Use in Elderly: Single dose pharmacokinetic parameters are similar in elderly and young healthy volunteers. Caution should be exercised at initiation of treatment in elderly patients as there is limited information on the use of Zonisamide in these patients.
Use In Pregnancy & Lactation
This drug should be administered to pregnant women or women suspected of being pregnant, only if the therapeutic benefits are thought to outweigh any possible risks. [It has been reported that the taking of this drug by women during pregnancy, resulted to teratogenicity such as ventricular septal defect and atrial septal defect. Abortion and malformations such as cleft palate and ventricular septal defect in experimental animals (mice, rats, dogs and monkeys) have been also reported. Respiratory disorders have been also reported in children whose mothers had received this drug during pregnancy.
When this drug is administered to nursing mothers, their lactation should be avoided. [It has been reported that this drug was excreted in breast milk in women.] Breastfeeding must not be resumed until one month after Zonisamide therapy.
Adverse Reactions
Zonisamide has been administered to over 1,200 patients in clinical studies, more than 400 of whom received Zonisamide for at least 1 year. The most common adverse reactions in controlled adjunctive-therapy studies were somnolence, dizziness and anorexia. Adverse reactions associated with Zonisamide obtained from clinical studies and post-marketing surveillance are tabulated as follows*. (See Table 4.)

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Drug Interactions
This drug is mainly metabolized by the drug-metabolizing enzyme CYP3A. [See Pharmacology: Pharmacokinetics under Actions].
Precautions for co-administration [ZONISAMIDE (ZONEGRAN) should be administered with care when co-administered with the following drugs.)] (See Table 5.)

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An in vitro study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC50 of 267 μmol/L and there is the theoretical potential for zonisamide to affect the pharmacokinetics of drugs which are P-gp substrates. Caution is advised when starting or stopping zonisamide treatment or changing the zonisamide dose in patients who are also receiving drugs which are P-gp substrates (e.g. digoxin, quinidine).
Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide.
Caution For Usage
When dispensing the drug: For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove Zonegran from the package prior to use. [It has been reported that if the PTP is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, and perforation may occur resulting in severe complications such as mediastinitis.]
Storage
Store at temperatures not exceeding 30°C.
MIMS Class
ATC Classification
N03AX15 - zonisamide ; Belongs to the class of other antiepileptics.
Presentation/Packing
FC tab 100 mg (white; Face: P132, Reverse: Plain) x 100's.
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