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Generic Name

Drug Description

Presentation

Indications

Adult Dosage

Zonegran must be added to existing therapy and the dose should be titrated on the basis of clinical effect. Doses of 300 mg to 500 mg per day have been shown to be effective, though some patients, especially those not taking CYP3A4-inducing agents, may respond to lower doses.

The recommended initial daily dose is 50 mg in two divided doses. After one week the dose may be increased to 100 mg daily and thereafter the dose may be increased at one weekly intervals, in increments of up to 100 mg.

Use of two weekly intervals should be considered for patients with renal or hepatic impairment and patients not receiving CYP3A4-inducing agents.

Zonegran can be administered once or twice daily after the titration phase.

Patients with renal impairment

Caution must be exercised in treating patients with renal impairment, as there is limited information on use in such patients and a slower titration of Zonegran might be required. Since zonisamide and its metabolites are excreted renally, it should be discontinued in patients who develop acute renal failure or where a clinically significant sustained increase in serum creatinine is observed.

In subjects with renal impairment, renal clearance of single doses of zonisamide was positively correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in subjects with creatinine clearance < 20 ml/min.

Patients with hepatic impairment

Use in patients with hepatic impairment has not been studied. Therefore use in patients with severe hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to moderate hepatic impairment, and a slower titration of Zonegran may be required.

Effect of food

Zonegran may be taken with or without food.

Withdrawal of Zonegran

When Zonegran treatment is to be discontinued, it should be withdrawn gradually. In clinical studies, dose reductions of 100 mg at weekly intervals have been used with concurrent adjustment of other anti-epileptic drug doses.

Child Dosage

The safety and effectiveness in children and adolescents under 18 years have not been established. Therefore use in these patients is not recommended.

Elderly Dosage

Caution should be exercised at initiation of treatment in elderly patients as there is limited information on the use of Zonegran in these patients. Prescribers should also take account of the safety profile of Zonegran.

Contra Indications

Hypersensitivity to zonisamide, to any of the excipients or to sulphonamides.

Special Precautions

Serious rashes occur in association with Zonegran therapy, including cases of StevensJohnson syndrome.

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.

In 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 medications 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 agents must be undertaken with caution.

Zonegran 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.

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. 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 stones have occurred in patients treated with Zonegran. 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.

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.

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. 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.

In 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.

In 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. Physicians treating patients with Zonegran should try to ensure that appropriate contraception is used, and should use clinical judgement when assessing whether OCs, or the doses of the OC components, are adequate based on the individual patient's clinical situation.

Zonegran 100 mg hard capsules contain a yellow colour called sunset yellow FCF (E110), which may cause allergic reactions.

There 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.

Interactions

Effect of Zonegran on cytochrome P450 enzymes.

In vitro studies using human liver microsomes show no or little (<25%) inhibition of cytochrome P450 isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at zonisamide levels approximately two-fold or greater than clinically relevant unbound serum concentrations. Therefore Zonegran is not expected to affect the pharmacokinetics of other medicinal products via cytochrome P450-mediated mechanisms, as demonstrated for carbamazepine, phenytoin, ethinylestradiol and desipramine in vivo.

Potential for Zonegran to affect other medicinal products

Anti-epileptic drugs

In epileptic patients, steadystate dosing with Zonegran resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.

 Oral contraceptives

In clinical studies in healthy subjects, steadystate dosing with Zonegran did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.

Carbonic anhydrase inhibitors

There are insufficient data to rule out possible pharmacodynamic interactions with carbonic anhydrase inhibitors such as topiramate.

P-gp substrate

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).

Potential medicinal product interactions affecting Zonegran

In clinical studies coadministration of lamotrigine had no apparent effect on zonisamide pharmacokinetics.The combination of Zonegran with other medicinal products that may lead to urolithiasis may enhance the risk of developing kidney stones; therefore the concomitant administration of such medicinal products should be avoided.

Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by Nacetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide:

- Enzyme Induction: Exposure to zonisamide is lower in epileptic patients receiving CYP3A4inducing agents such as phenytoin, carbamazepine, and phenobarbitone. These effects are unlikely to be of clinical significance when Zonegran is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4inducing antiepileptic or other medicinal products are withdrawn, dose adjusted or introduced, and an adjustment of the Zonegran dose may be required. Rifampicin is a potent CYP3A4 inducer. If co-administration is necessary, the patient should be closely monitored and the dose of Zonegran and other CYP3A4 substrates adjusted as needed.

- CYP3A4 Inhibition: Based upon clinical data, known specific and non-specific CYP3A4 inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposure parameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1200 mg/day) had no clinically relevant effects on the singledose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of Zonegran dosing should not be necessary when co-administered with known CYP3A4 inhibitors.

Adverse Reactions

Zonegran has been administered to over 1,200 patients in clinical studies, more than 400 of whom received Zonegran for at least 1 year. In addition there has been extensive postmarketing experience with zonisamide in Japan since 1989 and in the USA since 2000.

It should be noted that Zonegran 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.

The most common adverse reactions in controlled adjunctivetherapy studies were somnolence, dizziness and anorexia. Adverse reactions associated with Zonegran obtained from clinical studies and postmarketing surveillance are tabulated below. The frequencies are arranged according to the following scheme:

In addition there have been isolated cases of Sudden Unexplained Death in Epilepsy Patients (SUDEP) receiving Zonegran.

 Additional information on special populations:

Review of post-marketing data suggests that patients aged 65 years or older report a higher frequency than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug Induced Hypersensitivity syndrome (DIHS).

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