Consideration must be given to discontinuing Zonegran in patients who develop an otherwise unexplained rash. All patients who develop a rash while taking Zonegran must be closely supervised, with additional levels of caution applied to those patients receiving concomitant antiepileptic agents that may independently induce skin rashes.
Withdrawal seizuresIn accordance with current clinical practice, discontinuation of Zonegran in patients with epilepsy must be accomplished by gradual dose reduction, to reduce the possibility of seizures on withdrawal. There are insufficient data for the withdrawal of concomitant anti-epileptic medicines once seizure control with Zonegran has been achieved in the add-on situation, in order to reach monotherapy with Zonegran. Therefore withdrawal of concomitant anti-epileptic medicinal products must be undertaken with caution.
Sulphonamide reactionsZonegran is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based adverse reactions that are associated with medicinal products containing a sulphonamide group include rash, allergic reaction and major haematological disturbances including aplastic anaemia, which very rarely can be fatal.Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and leucocytosis have been reported. There is inadequate information to assess the relationship, if any, between dose and duration of treatment and these events.
Suicide ideation and behaviourSuicidal 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 medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Zonegran. Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Kidney stonesKidney stones have occurred in patients treated with zonisamide. Zonegran should be used with caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family history of nephrolithiasis and hypercalcuria. 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.
Metabolic acidosisHyperchloraemic, 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 Zonegran 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 Zonegran 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. The amounts by which bicarbonate is decreased are usually small moderate (average decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or medicinal products) may be additive to the bicarbonate lowering effects of zonisamide. The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in patients taking zonisamide who have underlying conditions which might increase the risk of acidosis, in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Zonegran (by gradual discontinuation or reduction of a therapeutic dose) as osteopenia may develop. If the decision is made to continue patients on Zonegran in the face of persistent acidosis, alkali treatment should be considered.Zonegran should be used with caution in patients being treated concomitantly with carbonic anhydrase inhibitors such as topiramate, as there are insufficient data to rule out a pharmacodynamic interaction (see section 4.5).
Heat strokeCases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Most reports occurred during periods of warm weather. Patients or their carers must be warned to take care to maintain hydration and avoid exposure to excessive temperatures. Caution should be used when Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.
PancreatitisIn patients taking Zonegran 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 Zonegran be considered and appropriate treatment initiated.
RhabdomyolysisIn patients taking Zonegran, 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 Zonegran discontinuation be considered and appropriate treatment initiated.Women of child-bearing potential must use adequate contraception during treatment with Zonegran and for one month after discontinuation (see section 4.6). Physicians treating patients with Zonegran should try to ensure that appropriate contraception is used, and should use clinical judgement when assessing whether oral contraceptives (OCs), or the doses of the OC components, are adequate based on the individual patient's clinical situation.
Body-weightThere is limited data from clinical studies in patients with a body weight of less than 40 kg. Therefore these patients should be treated with caution.Zonegran may cause weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight or is underweight whilst on this medication. If substantial undesirable weight loss occurs, discontinuation of Zonegran should be considered.
Zonegran 100 mg hard capsules contain a yellow colour called sunset yellow FCF (E110), and a red colour called allura red AC (E129), which may cause allergic reactions.
|Serious rashes occur in association with Zonegran therapy, including cases of Stevens-Johnson syndrome.