Zoresan Special Precautions

Unexplained rash: Consideration must be given to discontinuing Zonisamide (Zoresan) in patients who develop an otherwise unexplained rash. All patients who develop a rash while taking Zonisamide (Zoresan) must be closely supervised, with additional levels of caution applied to those patients receiving concomitant antiepileptic agents that may independently induce skin rashes.
Withdrawal seizures: In accordance with current clinical practice, discontinuation of Zonisamide (Zoresan) 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 Zonisamide (Zoresan) has been achieved in the add-on situation, in order to reach monotherapy with Zonisamide (Zoresan). Therefore, withdrawal of concomitant anti-epileptic medicinal products must be undertaken with caution.
Sulphonamide reactions: Zonisamide (Zoresan) 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.
Acute myopia and secondary angle closure glaucoma: A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in adult and paediatric patients receiving zonisamide. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anterior chamber shallowing, and ocular hyperaemia (redness) and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms may occur within hours to weeks of initiating therapy. Treatment includes discontinuation of zonisamide, as rapidly as possible in the judgment of the treating physician, and appropriate measures to reduce intraocular pressure. Elevated intraocular pressure of any aetiology, if left untreated, can lead to serious sequelae including permanent vision loss. Caution should be used when treating patients with history of eye disorders with zonisamide.
Suicide ideation and behavior: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomized 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 Zonisamide (Zoresan).
Therefore, patient's suicidal ideation or should be monitored for signs of suicidal ideation and behaviors and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should sign of behaviour emerge.
Kidney stones: 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. 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 acidosis: Hyperchloraemic, 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 zonisamide 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 Zonisamide (Zoresan) (by gradual discontinuation or reduction of a therapeutic dose) as osteopenia may develop.
If the decision is made to continue patients on Zonisamide (Zoresan) in the face of persistent acidosis, alkali treatment should be considered.
Metabolic acidosis has the potential to lead to hyperammonaemia, which has been reported with or without encephalopathy during zonisamide treatment. The risk for hyperammonaemia may be increased in patients concomitantly taking other medications that can cause hyperammonaemia (e.g. valproate), or who have an underlying urea cycle disorder or reduced hepatic mitochondrial activity. In patients who develop unexplained lethargy or changes in mental status during treatment with zonisamide, it is recommended to consider hyperammonaemic encephalopathy and to measure ammonia levels.
Zonisamide (Zoresan) 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.
Heat stroke: Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients. Caution should be used in adults when Zonisamide (Zoresan) is prescribed with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.
Pancreatitis: In patients taking Zonisamide (Zoresan) 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 (Zoresan) be considered and appropriate treatment initiated.
Rhabdomyolysis: In patients taking Zonisamide (Zoresan), 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 (Zoresan) discontinuation be considered and appropriate treatment initiated.
Body weight: Zonisamide (Zoresan) 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 Zonisamide (Zoresan) should be considered. Weight loss is potentially more serious in children.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, given that some patients may experience drowsiness or difficulty with concentration, particularly early in treatment or after a dose increase, patients must be advised to exercise caution during activities requiring a high degree of alertness, e.g., driving or operating machines.
Women of childbearing potential: Women of childbearing potential must use effective contraception during treatment with Zonisamide (Zoresan) and for one month after discontinuation. Zonisamide (Zoresan) must not be used in women of childbearing potential not using effective contraception unless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus. Specialist advice should be given to women who are of childbearing potential regarding the possible effects of Zonisamide (Zoresan) on the foetus and these risks should be discussed with the patient in relation to the benefits before starting treatment. Women planning a pregnancy should meet with their specialists to reassess treatment with Zonisamide (Zoresan) and to consider other therapeutic options. Physicians treating patients with Zonisamide (Zoresan) should ensure that patients are fully informed about the need to use appropriate effective contraception, 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.
Use in Children: The warnings and precautions mentioned previously are also applicable to adolescent and paediatric patients. The warnings and precautions mentioned as follows are more relevant to paediatric and adolescent patients.
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 heat stroke, 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 heat stroke and overheating in children as provided. In the event of signs or symptoms of dehydration, oligohydrosis, or elevated body temperature, discontinuation of Zonisamide (Zoresan) should be considered.
Zonisamide (Zoresan) 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.
Body weight: Weight loss leading to deterioration of general condition and failure to take anti-epilepsy medication has been related to a fatal outcome. Zonisamide (Zoresan) 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; 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 Zonisamide (Zoresan) 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 acidosis: The 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. The long term effect of low bicarbonate levels on growth and development is unknown.
Zonisamide (Zoresan) should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide.
Kidney stones: Kidney stones have occurred in paediatric patients.
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, Zonisamide (Zoresan) should be discontinued.
Hepatic dysfunction: Increased levels of hepatobiliary parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (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 Zonisamide (Zoresan) should be considered.
Cognition: Cognitive 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.