Precautions

Important Precautions Precaution on Special Populations Precaution Concerning Dosage & Administration (N/A) Precaution Concerning Use

Important Precautions

(1) 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.

(2) It is recommended that hepatic and renal function tests and blood examinations should be performed regularly during the administration.

(3) 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.

(4) For more appropriate adjustment of the dosage, it is desirable to measure the blood concentration of this drug.

(5) 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.

(6) 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 Zonisamide. 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.

(7) 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.

(8) 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 decision is made to continue patients on Zonisamide in the face of persistent acidosis, alkali treatment should be considered.

9) 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.

(10) 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.

(11) Serious rashes have occurred in association with Zonisamide therapy, including cases of Stevens-Johnson syndrome.

(12) Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported.

(13) 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.

(14)  Abnormality of serum immunoglobulin such as IgA and IgG may occur.


Precautions on Special Populations

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.

USE IN THE 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.

PEDIATRIC USE

There is limited controlled clinical trial data on the safety and effectiveness in children and adolescents.


Precaution Concerning Use

When dispensing the drug: For drugs that are dispensed in a press-through package (PTP), instruct the patient to remove the drug 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.]