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.
|Serious rashes occur in association with Zonegran therapy, including cases of Stevens-Johnson syndrome.|
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 antiepileptic 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 stonesSome patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during zonisamide treatment. 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 adult patients being treated concomitantly with carbonic anhydrase inhibitors such as topiramate or acetazolamide, as there are insufficient data to rule out a pharmacodynamic interaction (see also section 4.4 Paediatric Population and section 4.5).
Heat strokeCases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients (see section 4.4 Paediatric Population for full warning). Caution should be used in adults 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 (see also section 4.4 Paediatric Population)
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 potentialWomen 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 weightZonegran 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. Weight loss is potentially more serious in children (see section 4.4. Paediatric Population).
Paediatric PopulationThe warnings and precautions mentioned above are also applicable to adolescent and paediatric patients. The warnings and precautions mentioned below are more relevant to paediatric and adolescent patients.
Heat stroke and dehydration
Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Heat stroke requiring hospital treatment and leading to death has been reported. Most reports occurred during periods of warm weather. Physicians should discuss with patients and their carers the potential seriousness of heatstroke, situations in which it might arise, as well as action to take in the event of any signs or symptoms. Patients or their carers must be warned to take care to maintain hydration and avoid exposure to excessive temperatures and strenuous physical exercise depending on the condition of the patient. Prescribers should draw the attention of paediatric patients and their parent/carers to the advice in the Packaging Leaflet on preventing heatstroke and overheating in children as provided. In the event of signs or symptoms of dehydration, oligohydrosis, or elevated body temperature, discontinuation of Zonegran should be considered.Zonegran should not be used as co-medication in paediatric patients with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.
|Preventing overheating and dehydration in childrenZonegran can cause children to sweat less and overheat and if the child is not treated this can lead to brain damage and death. Children are most at risk especially in hot weather.
When a child is taking Zonegran:
The child should stay cool especially in hot weather
The child must avoid heavy exercise especially when the weather is hot
The child must drink plenty of cold water
The child must not take any of these medicines:
carbonic anhydrase inhibitors (like topiramate and acetazolamide), and anticholinergic agents (like clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).
IF ANY OF THE FOLLOWING OCCUR, THE CHILD NEEDS URGENT MEDICAL ATTENTION:The skin feels very hot with little or no sweating, or the child becomes confused or has muscle cramps, or the child's heartbeat or breathing become rapid.
• Take the child to a cool, shaded place
• Keep the child's skin cool with water
• Give the child cold water to drink
Body weightWeight loss leading to deterioration of general condition and failure to take anti-epilepsy medication has been related to a fatal outcome (see section 4.8). Zonegran is not recommended for paediatric patients who are underweight (definition in accordance with the WHO age adjusted BMI categories) or have a decreased appetite.The incidence of decreased body weight is consistent across age groups (see section 4.8); however, given the potential seriousness of weight loss in children, weight should be monitored in this population. A dietary supplement or increased food intake should be considered if the patient is failing to gain weight in accordance with growth charts, otherwise Zonegran should be discontinued. There are limited data from clinical studies in patients with a body weight of less than 20 kg. Therefore children aged 6 years and above with a body weight of less than 20 kg should be treated with caution. The long term effect of weight loss in the paediatric population on growth and development is unknown.
Metabolic acidosisThe risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in paediatric and adolescent patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in this population (see section 4.4 - Metabolic acidosis for full warning; see section 4.8 for incidence of low bicarbonate). The long term effect of low bicarbonate levels on growth and development is unknown. Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide (see section 4.5).
Kidney stonesKidney stones have occurred in paediatric patients (see section 4.4 Kidney stones for full warning). Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during zonisamide treatment.Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in those with predisposing risk factors. Renal ultrasound should be performed at the discretion of the physician. In the event kidney stones are detected, Zonegran should be discontinued.
Hepatic dysfunctionIncreased levels of hepatobiliary parameters such as alanine aminotransferase (ALT), aspartate aminotransferease (AST), gamma-glutamyltransferase (GGT) and bilirubin have occurred in paediatric and adolescent patients, without any consistent pattern in the observations of values above the upper limit of normal. Nevertheless, if a hepatic event is suspected, liver function should be evaluated and discontinuation of Zonegran should be considered.
CognitionCognitive impairment in patients affected by epilepsy has been associated with the underlying pathology and/or the administration of anti-epileptic treatment. In a zonisamide placebo-controlled study conducted in paediatric and adolescent patients, the proportion of patients with impaired cognition was numerically greater in the zonisamide group compared with the placebo group. ExcipientsZonegran 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.