25 mg: Zonegran 25 mg hard capsules

50 mg: Zonegran 50 mg hard capsules

100 mg: Zonegran 100 mg hard capsules

25 mg: Each hard capsule contains 25 mg of zonisamide.

50 mg: Each hard capsule contains 50 mg of zonisamide.

100 mg: Each hard capsule contains 100 mg of zonisamide.

100mg: Excipients: 0.002 mg of sunset yellow FCF (E110) and 0.147 mg of allura red AC (E129).

For a full list of excipients, see section 6.1.

Hard capsule.

25 mg: A white opaque body and a white opaque cap printed with a logo and “ZONEGRAN 25” in black.

50 mg: A white opaque body and a grey opaque cap printed with a logo and “ZONEGRAN 50” in black.

100 mg: A white opaque body and a red opaque cap printed with a logo and “ZONEGRAN 100” in black

Zonegran is indicated as adjunctive therapy in the treatment of adult patients with partial seizures, with or without secondary generalisation.

Adults

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 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 (see section 4.5).

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

Elderly

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 (see section 4.8).

Paediatric population

The safety and efficacy of Zonegran in children and adolescents have not yet been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

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.

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 medicine doses.

Method of administration

Zonegran hard capsules are for oral use.

Effect of food

Zonegran may be taken with or without food (see section 5.2).

Hypersensitivity to the active substance, to any of the excipients or to sulphonamides.

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 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.

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 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 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.

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 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).

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 (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.

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.

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 medicinal products

In epileptic patients, steady-state 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, steady-state dosing with Zonegran did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.

Carbonic anhydrase inhibitors

Zonegran should be used with caution in patients treated concomitantly with carbonic anhydrase inhibitors such as topiramate, as there are insufficient data to rule out a possible pharmacodynamic interaction (see section 4.4).

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 substances 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 medicinal products which are P-gp substrates (e.g. digoxin, quinidine).

Potential medicinal product interactions affecting Zonegran

In clinical studies co-administration 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 N-acetyl-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 CYP3A4-inducing 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 CYP3A4-inducing anti-epileptic 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 single-dose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of Zonegran dosing should not be necessary when co-administered with known CYP3A4 inhibitors.

Women of childbearing potential

Women of childbearing potential must use adequate contraception during treatment with Zonegran, and for one month after discontinuation.

Pregnancy

There are no adequate data from the use of Zonegran in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Zonegran must not be used during pregnancy unless clearly necessary, in the opinion of the physician, and only if the potential benefit is considered to justify the risk to the foetus. The need for anti-epileptic treatment should be reviewed in patients planning to become pregnant. If Zonegran is prescribed, careful monitoring is recommended.

Specialist advice should be given to women who are likely to become pregnant in order to consider the optimal treatment during pregnancy. Women of childbearing potential should be given specialist advice regarding possible effects of Zonegran on the foetus and the risk should be discussed with the patient in relation to the benefits before starting treatment. The risk of birth defect is increased by factor 2 to 3 in the offspring of mothers treated with an antiepileptic medicinal product. The most frequently reported are cleft lip, cardiovascular malformations and neural tube defect. Multiple antiepileptic medicinal product therapy may be associated with a higher risk of congenital malformations than monotherapy.

No sudden discontinuation of anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both mother and child.

Breast-feeding

Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zonegran therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not be resumed until one month after Zonegran therapy is completed.

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.

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 post-marketing 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 (see section 4.4).

The most common adverse reactions in controlled adjunctive-therapy studies were somnolence, dizziness and anorexia. Adverse reactions associated with Zonegran obtained from clinical studies and post-marketing 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).

There have been cases of accidental and intentional overdose in adult and paediatric patients. In some cases, the overdoses were asymptomatic, particularly where emesis or lavage was prompt. In other cases, the overdose was followed by symptoms such as somnolence, nausea, gastritis, nystagmus, myoclonus, coma, bradycardia, reduced renal function, hypotension and respiratory depression. A very high plasma concentration of 100.1 μg/ml zonisamide was recorded approximately 31 hours after a patient took an overdose of Zonegran and clonazepam; the patient became comatose and had respiratory depression, but recovered consciousness five days later and had no sequelae.

Treatment

No specific antidotes for Zonegran overdose are available. Following a suspected recent overdose, emptying the stomach by gastric lavage or by induction of emesis may be indicated with the usual precautions to protect the airway. General supportive care is indicated, including frequent monitoring of vital signs and close observation. Zonisamide has a long elimination half-life so its effects may be persistent. Although not formally studied for the treatment of overdose, haemodialysis reduced plasma concentrations of zonisamide in a patient with reduced renal function, and may be considered as treatment of overdose if clinically indicated.

Pharmacotherapeutic group: Antiepileptics, other antiepileptics, ATC code: N03AX15

Zonisamide is a benzisoxazole derivative. It is an anti-epileptic medicine with weak carbonic anhydrase activity in-vitro. It is chemically unrelated to other anti-epileptic agents.

Clinical efficacy

Efficacy has been demonstrated with Zonegran in 4 double-blind, placebo-controlled studies of periods of up to 24 weeks with either once or twice daily dosing. These studies show that the median reduction in partial seizure frequency is related to Zonegran dose with sustained efficacy at doses of 300-500 mg per day.

Pharmacodynamic effects

The anticonvulsant activity of zonisamide has been evaluated in a variety of models, in several species with induced or innate seizures, and zonisamide appears to act as a broad-spectrum anti-epileptic in these models. Zonisamide prevents maximal electroshock seizures and restricts seizure spread, including the propagation of seizures from cortex to sub-cortical structures and suppresses epileptogenic focus activity. Unlike phenytoin and carbamazepine however, zonisamide acts preferentially on seizures originating in the cortex.

Mechanism of action

The mechanism of action of zonisamide is not fully elucidated, but it appears to act on voltage-sensitive sodium and calcium channels, thereby disrupting synchronised neuronal firing, reducing the spread of seizure discharges and disrupting subsequent epileptic activity. Zonisamide also has a modulatory effect on GABA-mediated neuronal inhibition.

Absorption

Zonisamide is almost completely absorbed after oral administration, generally reaching peak serum or plasma concentrations within 2 to 5 hours of dosing. The first-pass metabolism is believed to be negligible. Absolute bioavailability is estimated to be approximately 100%. Oral bioavailability is not affected by food, although peak plasma and serum concentrations may be delayed.

Zonisamide AUC and C_max values increased almost linearly after single dose over the dose range of 100-800 mg and after multiple doses over the dose range of 100-400 mg once daily. The increase at steady state was slightly more than expected on the basis of dose, probably due to the saturable binding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater than expected accumulation occurs relative to single dosing.

Distribution

Zonisamide is 40 - 50 % bound to human plasma proteins, with in vitro studies showing that this is unaffected by the presence of various anti-epileptic medicinal products (i.e., phenytoin, phenobarbitone, carbamazepine, and sodium valproate). The apparent volume of distribution is about 1.1 – 1.7 l/kg in adults indicating that zonisamide is extensively distributed to tissues. Erythrocyte/plasma ratios are about 15 at low concentrations and about 3 at higher concentrations.

Biotransformation

Zonisamide is metabolised primarily through reductive cleavage of the benzisoxazole ring of the parent drug by CYP3A4 to form 2-sulphamoylacetylphenol (SMAP) and also by N-acetylation. Parent drug and SMAP can additionally be glucuronidated. The metabolites, which could not be detected in plasma, are devoid of anticonvulsant activity. There is no evidence that zonisamide induces its own metabolism.

Elimination

Apparent clearance of zonisamide at steady-state after oral administration is about 0.70 l/h and the terminal elimination half-life is about 60 hours in the absence of CYP3A4 inducers. The elimination half-life was independent of dose and not affected by repeat administration. Fluctuation in serum or plasma concentrations over a dosing interval is low (< 30 %). The main route of excretion of zonisamide metabolites and unchanged drug is via the urine. Renal clearance of unchanged zonisamide is relatively low (approximately 3.5 ml/min); about 15 - 30 % of the dose is eliminated unchanged.

Special patient groups

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 (see also section 4.2.).

Patients with an impaired liver function: The pharmacokinetics of zonisamide in patients with impaired liver function have not been adequately studied.

Elderly: No clinically significant differences were observed in the pharmacokinetics between young (aged 21-40 years) and elderly (65-75 years).

Children and Adolescents (5-18 years): Limited data indicate that pharmacokinetics in children and adolescents dosed to steady state at 1, 7 or 12 mg/kg daily, in divided doses, are similar to those observed in adults, after adjustment for bodyweight.

Other characteristics

No clear Zonegran dose-concentration-response relationship has been defined. When comparing the same dose level, subjects of higher total body weight appear to have lower steady-state serum concentrations, but this effect appears to be relatively modest. Age ( 12 years) and gender, after adjustment for body weight effects, have no apparent effect on zonisamide exposure in epileptic patients during steady-state dosing.

Findings not observed in clinical studies, but seen in the dog at exposure levels similar to clinical use, were liver changes (enlargement, dark-brown discolouration, mild hepatocyte enlargement with concentric lamellar bodies in the cytoplasm and cytoplasmic vacuolation) associated with increased metabolism.

Zonisamide was not genotoxic and has no carcinogenic potential.

Zonisamide caused developmental abnormalities in mice, rats, and dogs, and was embryolethal in monkeys, when administered during the period of organogenesis at zonisamide dosage and maternal plasma levels similar to or lower than therapeutic levels in humans.

Capsule contents

Microcrystalline cellulose

Hydrogenated vegetable oil

Sodium laurilsulfate

Capsule shells

Gelatin

Titanium dioxide (E171)

Shellac

Propylene glycol

Potassium hydroxide

Black iron oxide (E172)

Additionally the 100 mg capsule shells contain:

Allura red AC (E129)

Sunset yellow FCF (E110)

Not applicable.

3 years.

Do not store above 30°C.

25 mg: PVC/PVDC/Aluminium foil blisters, packs of 14, 28, 56 and 84 hard capsules.

50 mg: PVC/PVDC/Aluminium foil blisters, packs of 14, 28, 56 and 84 hard capsules.

100 mg: PVC/PVDC/aluminium foil blisters, packs of 28, 56, 84, 98 and 196 hard capsules.

Not all pack sizes may be marketed.

No special requirements.

Eisai Limited

European Knowledge Centre

Mosquito Way

Hatfield

Hertfordshire AL10 9SN

United Kingdom

16^th January 2012

POM - Medicinal product subject to medical prescription

Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu