ZONEGRAN 100mg capsules medication leaflet

Zonegran 100 mg hard capsules

Each hard capsule contains 100 mg of zonisamide.

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

Each hard capsule contains 3 mg hydrogenated vegetable oil (from soyabean)

For the full list of excipients, see section 6.1.

Hard capsule.

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

Zonegran is indicated as:

* monotherapy in the treatment of partial seizures, with or without secondary generalisation, inadults with newly diagnosed epilepsy (see section 5.1);

* adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, inadults, adolescents, and children aged 6 years and above.

Zonegran may be taken as monotherapy or added to existing therapy in adults. The dose should betitrated on the basis of clinical effect. Recommended escalation and maintenance doses are given in

Table 1. Some patients, especially those not taking CYP3A4-inducing agents, may respond to lowerdoses.

When Zonegran treatment is to be discontinued, it should be withdrawn gradually (see section 4.4). Inclinical studies of adult patients, dose reductions of 100 mg at weekly intervals have been used withconcurrent adjustment of other antiepileptic medicine doses (where necessary).

Table 1. Adults - recommended dosage escalation and maintenance regimen

Treatment Titration Phase Usual Maintenance

Regimen Dose

Monotherapy - Week 1 + 2 Week 3 + 4 Week 5 + 6

Newly diagnosed 100 mg/day 200 mg /day 300 mg/day 300 mg per dayadult patients(once a day) (once a day) (once a day) (once a day).

If a higher dose isrequired: increase attwo-weekly intervals inincrements of 100 mgup to a maximum of500 mg.

Adjunctive Week 1 Week 2 Week 3 to 5therapy 50 mg/day 100 mg /day Increase at 300 to 500 mg per day

- with CYP3A4-(in two (in two divided weekly intervalsinducing agents (once a day ordivided doses) doses) in increments of two divided doses).(see section 4.5) 100 mg

- without Week 1 + 2 Week 3 + 4 Week 5 to 10

CYP3A4-inducing 50 mg/day 100 mg/day Increase at 300 to 500 mg per dayagents; or with two-weeklyrenal or hepatic (in two (in two divided (once a day orimpairment divided doses) doses) intervals two divided doses).

in increments of Some patients mayup to 100 mg respond to lower doses.

Zonegran must be added to existing therapy for paediatric patients aged 6 years and above. The doseshould be titrated on the basis of clinical effect. Recommended escalation and maintenance doses aregiven in Table 2. Some patients, especially those not taking CYP3A4-inducing agents, may respond tolower doses.

Physicians should draw the attention of paediatric patients and their parents/carers to the Patient Alert

Box (in the package leaflet) on preventing heatstroke (see section 4.4: Paediatric population).

Table 2. Paediatric population (aged 6 years and above) - recommended dosage escalationand maintenance regimen

Treatment Titration Phase Usual Maintenance Dose

Regimen

Adjunctive Week 1 Weeks 2 to 8 Patients of weight Patients oftherapy 20 to 55 kga weight > 55 kg

- with CYP3A4- 1 mg/kg/day Increase at 6 to 8 mg/kg/day 300 - 500 mg/dayinducing agents weekly intervals(see section 4.5) (once a day) (once a day) (once a day)in increments of1 mg/kg

Week 1 + 2 Weeks ≥ 3

- without 1 mg/kg/day Increase at 6 to 8 mg/kg/day 300 - 500 mg/day

CYP3A4-inducing (once a day) two-weekly (once a day) (once a day)agents intervals inincrements of1 mg/kg

Note:

a. To ensure a therapeutic dose is maintained the weight of a child should be monitored and thedose reviewed as weight changes occur up to a weight of 55kg. The dose regime is6-8 mg/kg/day up to a maximum dose of 500 mg/day.

The safety and efficacy of Zonegran in children aged below 6 years or those below 20 kg have not yetbeen established.

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 and with a body weight less than 20 kg should be treatedwith caution.

It is not always possible to precisely achieve the calculated dose with the commercially availablecapsule strengths of Zonegran. In these cases it is therefore recommended that the Zonegran total doseshould be rounded up or down to the nearest available dose that can be achieved with commerciallyavailable capsule strengths of Zonegran (25 mg, 50 mg and 100 mg).

When Zonegran treatment is to be discontinued, it should be withdrawn gradually (see section 4.4). Inclinical studies of paediatric patients, down-titration was completed by dose reductions at weeklyintervals in increments of about 2 mg/kg (i.e. in accordance with the schedule in Table 3).

Table 3. Paediatric population (aged 6 years and above) - recommended down-titrationschedule

Weight Decrease at weekly intervals in increments of:

20 - 28 kg 25 to 50 mg/day*29 - 41 kg 50 to 75 mg/day*42 - 55 kg 100 mg/day*>55 kg 100 mg/day*

Note:

* All doses are once daily.

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

Zonegran (see section 4.8).

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

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

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

Zonegran hard capsules are for oral use.

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

Hypersensitivity to the active substance, to any of the excipients listed in section 6.1 or tosulphonamides.

Zonegran contains Hydrogenated vegetable oil (from soyabean). Patients must not take this medicinalproduct if they are allergic to peanut or soya.

Serious rashes occur in association with Zonegran therapy, including cases of Stevens-Johnsonsyndrome.

Consideration must be given to discontinuing Zonegran in patients who develop an otherwiseunexplained 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 agentsthat may independently induce skin rashes.

In accordance with current clinical practice, discontinuation of Zonegran in patients with epilepsymust 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 seizurecontrol 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 undertakenwith caution.

Zonegran is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune basedadverse reactions that are associated with medicinal products containing a sulphonamide group includerash, allergic reaction and major haematological disturbances, including aplastic anaemia, which veryrarely can be fatal.

Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia andleucocytosis have been reported. There is inadequate information to assess the relationship, if any,between dose and duration of treatment and these events.

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has beenreported in adult and paediatric patients receiving zonisamide. Symptoms include acute onset ofdecreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, anteriorchamber shallowing, and ocular hyperaemia (redness) and increased intraocular pressure. Thissyndrome may be associated with supraciliary effusion resulting in anterior displacement of the lensand iris, with secondary angle closure glaucoma. Symptoms may occur within hours to weeks ofinitiating therapy. Treatment includes discontinuation of zonisamide, as rapidly as possible in thejudgment of the treating physician, and appropriate measures to reduce intraocular pressure. Elevatedintraocular pressure of any aetiology, if left untreated, can lead to serious sequelae includingpermanent vision loss. Caution should be used when treating patients with history of eye disorderswith zonisamide.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents inseveral indications. A meta-analysis of randomised placebo-controlled trials of anti-epilepticmedicinal products has also shown a small increased risk of suicidal ideation and behaviour. Themechanism of this risk is not known and the available data do not exclude the possibility of anincreased risk for Zonegran.

Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriatetreatment should be considered. Patients (and caregivers of patients) should be advised to seek medicaladvice should signs of suicidal ideation or behaviour emerge.

Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk forrenal 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 stoneformation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors canreliably predict stone formation during zonisamide treatment. In addition, patients taking othermedications associated with nephrolithiasis may be at increased risk. Increasing fluid intake and urineoutput 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 thenormal reference range in the absence of chronic respiratory alkalosis) is associated with Zonegrantreatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect ofzonisamide 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 duringtreatment. The amounts by which bicarbonate is decreased are usually small - moderate (averagedecrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients canexperience more severe decreases. Conditions or therapies that predispose to acidosis (such as renaldisease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, ormedicinal 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 youngerpatients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out inpatients 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 patientswith symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists,consideration should be given to reducing the dose or discontinuing Zonegran (by gradualdiscontinuation 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, alkalitreatment should be considered.

Metabolic acidosis has the potential to lead to hyperammonaemia, which has been reported with orwithout encephalopathy during zonisamide treatment. The risk for hyperammonaemia may beincreased 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. Inpatients who develop unexplained lethargy or changes in mental status during treatment withzonisamide, it is recommended to consider hyperammonaemic encephalopathy and to measureammonia levels.

Zonegran should be used with caution in adult patients being treated concomitantly with carbonicanhydrase inhibitors such as topiramate or acetazolamide, as there are insufficient data to rule out apharmacodynamic interaction (see also section 4.4 Paediatric population and section 4.5).

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatricpatients (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 (seealso section 4.4 Paediatric population).

In patients taking Zonegran who develop the clinical signs and symptoms of pancreatitis, it isrecommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in theabsence of another obvious cause, it is recommended that discontinuation of Zonegran be consideredand appropriate treatment initiated.

In patients taking Zonegran, in whom severe muscle pain and/or weakness develop either in thepresence 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 anotherobvious cause such as trauma or grand mal seizures, it is recommended that Zonegran discontinuationbe considered and appropriate treatment initiated.

Women of childbearing potential must use effective contraception during treatment with Zonegran andfor one month after discontinuation (see section 4.6). Zonegran must not be used in women ofchildbearing potential not using effective contraception unless clearly necessary and only if thepotential benefit is considered to justify the risk to the foetus. Specialist medical advice should begiven to women treated with zonisamide who are of childbearing potential. The woman should befully informed of and understand the possible effects of Zonegran on the foetus and these risks shouldbe discussed with the patient in relation to the benefits before starting treatment. Before the initiationof treatment with Zonegran in a woman of childbearing potential, pregnancy testing should beconsidered. Women planning a pregnancy should meet with their specialists to reassess treatment with

Zonegran and to consider other therapeutic options prior to conception and before contraception isdiscontinued. Women of childbearing potential should be counselled to contact her doctorimmediately if she becomes pregnant or thinks she may be pregnant and is taking Zonegran.

Physicians treating patients with Zonegran should ensure that patients are fully informed about theneed to use appropriate effective contraception, and should use clinical judgement when assessingwhether oral contraceptives (OCs), or the doses of the OC components, are adequate based on theindividual patient’s clinical situation.

Zonegran may cause weight loss. A dietary supplement or increased food intake may be considered ifthe patient is losing weight or is underweight whilst on this medication. If substantial undesirableweight loss occurs, discontinuation of Zonegran should be considered. Weight loss is potentially moreserious in children (see section 4.4. Paediatric population).

The warnings and precautions mentioned above are also applicable to adolescent and paediatricpatients. The warnings and precautions mentioned below are more relevant to paediatric andadolescent patients.

Heat stroke and dehydration

Preventing overheating and dehydration in children

Zonegran can cause children to sweat less and overheat and if the child is not treated this can lead tobrain 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 (likeclomipramine, 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

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatricpatients. Heat stroke requiring hospital treatment was diagnosed in some cases. Heat stroke requiringhospital treatment and leading to death has been reported. Most reports occurred during periods ofwarm weather. Physicians should discuss with patients and their carers the potential seriousness ofheat stroke, situations in which it might arise, as well as action to take in the event of any signs orsymptoms. Patients or their carers must be warned to take care to maintain hydration and avoidexposure to excessive temperatures and strenuous physical exercise depending on the condition of thepatient. Prescribers should draw the attention of paediatric patients and their parent/ carers to theadvice in the Packaging Leaflet on preventing heat stroke and overheating in children as provided. Inthe 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 thatpredispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinalproducts with anticholinergic activity.

Weight loss leading to deterioration of general condition and failure to take anti-epilepsy medicationhas been related to a fatal outcome (see section 4.8). Zonegran is not recommended for paediatricpatients 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 thispopulation. A dietary supplement or increased food intake should be considered if the patient is failingto 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 treatedwith caution. The long term effect of weight loss in the paediatric population on growth anddevelopment is unknown.

The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe inpaediatric and adolescent patients. Appropriate evaluation and monitoring of serum bicarbonate levelsshould be carried out in this population (see section 4.4 - Metabolic acidosis for full warning; seesection 4.8 for incidence of low bicarbonate). The long term effect of low bicarbonate levels ongrowth and development is unknown.

Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydraseinhibitors such as topiramate and acetazolamide (see section 4.5).

Kidney 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 forrenal 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 stoneformation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors canreliably predict stone formation during zonisamide treatment.

Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly inthose with predisposing risk factors. Renal ultrasound should be performed at the discretion of thephysician. In the event kidney stones are detected, Zonegran should be discontinued.

Hepatic dysfunction

Increased levels of hepatobiliary parameters such as alanine aminotransferase (ALT), aspartateaminotransferase (AST), gamma-glutamyltransferase (GGT) and bilirubin have occurred in paediatricand adolescent patients, without any consistent pattern in the observations of values above the upperlimit of normal. Nevertheless, if a hepatic event is suspected, liver function should be evaluated anddiscontinuation of Zonegran should be considered.

Cognition

Cognitive impairment in patients affected by epilepsy has been associated with the underlyingpathology and/ or the administration of anti-epileptic treatment. In a zonisamide placebo-controlledstudy conducted in paediatric and adolescent patients, the proportion of patients with impairedcognition was numerically greater in the zonisamide group compared with the placebo group.

Zonegran 100 mg hard capsules contain a yellow colour called sunset yellow FCF (E110), and a redcolour called allura red AC (E129), which may cause allergic reactions.

Effect of Zonegran on cytochrome P450 enzymes

In vitro studies using human liver microsomes show no or little (<25%) inhibition of cytochrome P450isozymes 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 notexpected to affect the pharmacokinetics of other medicinal products via cytochrome P450-mediatedmechanisms, 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 relevantpharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.

In clinical studies in healthy subjects, steady-state dosing with Zonegran did not affect serumconcentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.

Carbonic anhydrase inhibitors

Zonegran should be used with caution in adult patients treated concomitantly with carbonic anhydraseinhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possiblepharmacodynamic interaction (see section 4.4).

Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydraseinhibitors such as topiramate and acetazolamide (see section 4.4 Paediatric population).

P-gp substrate

An in vitro study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC50 of267 µmol/l and there is the theoretical potential for zonisamide to affect the pharmacokinetics ofsubstances which are P-gp substrates. Caution is advised when starting or stopping zonisamidetreatment or changing the zonisamide dose in patients who are also receiving medicinal productswhich 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 zonisamidepharmacokinetics. The combination of Zonegran with other medicinal products that may lead tourolithiasis may enhance the risk of developing kidney stones; therefore the concomitantadministration of such medicinal products should be avoided.

Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferasesand conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymesmay 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 effectsare unlikely to be of clinical significance when Zonegran is added to existing therapy; however,changes in zonisamide concentrations may occur if concomitant CYP3A4-inducinganti-epileptic or other medicinal products are withdrawn, dose adjusted or introduced, anadjustment of the Zonegran dose may be required. Rifampicin is a potent CYP3A4 inducer. Ifco-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 CYP3A4inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposureparameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine(1200 mg/day) had no clinically relevant effects on the single-dose pharmacokinetics ofzonisamide given to healthy subjects. Therefore, modification of Zonegran dosing should not benecessary when co-administered with known CYP3A4 inhibitors.

Interaction studies have only been performed in adults.

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

Zonegran must not be used in women of childbearing potential not using effective contraceptionunless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus.

Specialist medical advice should be given to women treated with zonisamide who are of childbearingpotential. The woman should be fully informed of and understand the possible effects of Zonegran onthe foetus and these risks should be discussed with the patient in relation to the benefits before startingtreatment. Pregnancy testing in women of childbearing potential should be considered prior toinitiating treatment with zonisamide. Women planning a pregnancy should meet with their specialiststo reassess treatment with zonisamide and to consider other therapeutic options prior to conception andbefore contraception is discontinued.

As with all antiepileptic medicines, sudden discontinuation of zonisamide should be avoided as thismay lead to breakthrough seizures that could have serious consequences for the woman and theunborn child. The risk of birth defect is increased by factor 2 to 3 in the offspring of mothers treatedwith an antiepileptic medicinal product. The most frequently reported are cleft lip, cardiovascularmalformations and neural tube defect. Multiple antiepileptic medicinal product therapy may beassociated with a higher risk of congenital malformations than monotherapy.

There are limited data from the use of Zonegran in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). In humans the potential risk of major congenital malformationsand neurodevelopmental disorders is unknown.

Data from a registry study suggest an increase in the proportion of babies born at a low birth weight(LBW), pre-term or small for gestational age (SGA). These increases are from about 5% to 8% for

LBW, from about 8% to 10% for pre-term birth and from about 7% to 12% for SGA, all comparedwith mothers treated with lamotrigine monotherapy.

Zonegran must not be used during pregnancy unless clearly necessary and only if the potential benefitis considered to justify the risk to the foetus. If Zonegran is prescribed during pregnancy, patientsshould be fully informed of the potential harm to the foetus and use of the minimal effective dose isadvised along with careful monitoring.

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 notbe resumed until one month after Zonegran therapy is completed.

There are no clinical data available on the effects of zonisamide on human fertility. Studies in animalshave shown changes in fertility parameters (see section 5.3).

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 earlyin treatment or after a dose increase, patients must be advised to exercise caution during activitiesrequiring 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 whomreceived Zonegran for at least 1 year. In addition there has been extensive post-marketing experiencewith 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 asulphonamide group include rash, allergic reaction and major haematological disturbances includingaplastic 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. The most common adverse reactions in a randomised, controlled monotherapytrial comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate,decreased appetite, and decreased weight. The incidence of markedly abnormally low serumbicarbonate (a decrease to less than 17 mEq/l and by more than 5 mEq/l) was 3.8%. The incidence ofmarked decreases in weight of 20% or more was 0.7%.

Adverse reactions associated with Zonegran obtained from clinical studies and post-marketingsurveillance are tabulated below. The frequencies are arranged according to the following scheme:

very common ≥ 1/10common ≥ 1/100 to < 1/10uncommon ≥ 1/1,000 to < 1/100rare ≥ 1/10,000 to < 1/1,000very rare < 1/10,000not known cannot be estimated from the available data

Table 4. Adverse reactions associated with Zonegran obtained from adjunctive use clinicalstudies and post-marketing surveillance

System Organ Very Common Uncommon Very Rare

Class Common(MedDRAterminology)

Infections and Pneumoniainfestation Urinary tractinfection

Blood and Ecchymosis Agranulocytosislymphatic Aplastic anaemiasystem disorders Leucocytosis

Leucopoenia

Lymphadenopathy

Pancytopenia,

Immune system Hypersensitivity Drug-induceddisorders hypersensitivity syndrome

Drug rash with eosinophiliaand systemic symptoms

Metabolism and Anorexia Hypokalaemia Metabolic acidosisnutrition Renal tubular acidosisdisorders

Psychiatric Agitation Affect lability Anger Hallucination

Disorders Irritability Anxiety Aggression

Confusional Insomnia Suicidal ideationstate Psychotic Suicide attempt

Depression disorder

System Organ Very Common Uncommon Very Rare

Class Common(MedDRAterminology)

Nervous system Ataxia Bradyphrenia Convulsion Amnesiadisorders Dizziness Disturbance in Coma

Memory attention Grand mal seizureimpairment Nystagmus Myasthenic syndrome

Somnolence Paraesthesia Neuroleptic malignant

Speech disorder syndrome

Tremor Status epilepticus

Eye disorders Diplopia Angle closure glaucoma

Eye pain

Myopia

Vision blurred

Visual acuity reduced

Respiratory, Dyspnoeathoracic and Pneumonia aspirationmediastinal Respiratory disorderdisorders Hypersensitivity-type

Pneumonitis

Gastrointestinal Abdominal pain Vomiting Pancreatitisdisorders Constipation

Dyspepsia

Nausea

Hepatobiliary Cholecystitis Hepatocellular damagedisorders Cholelithiasis

Skin and Rash Anhidrosissubcutaneous Pruritus Erythema multiformetissue disorders Alopecia Stevens-Johnson syndrome

Toxic epidermal necrolysis

Musculoskeletal Rhabdomyolysisand connectivetissue disorders

Renal and Nephrolithiasis Calculus urinary Hydronephrosisurinary Renal failuredisorders Urine abnormality

General Fatiguedisorders and Influenza-likeadministration illnesssite conditions Pyrexia

Oedemaperipheral

Investigations Decreased Weight Blood creatinebicarbonate decreased phosphokinase increased

Blood creatinine increased

Blood urea increased

Liver function testsabnormal

Injury, Heat strokepoisoning andproceduralcomplications

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

Table 5. Adverse reactions in a randomised, controlled monotherapy trial comparingzonisamide with carbamazepine prolonged release

System Organ Class Very Common Common Uncommon(MedDRA terminology†)

Infections and Urinary tract infectioninfestation Pneumonia

Blood and lymphatic Leukopeniadisorders Thrombocytopenia

Metabolism and Decreased appetite Hypokalaemianutrition disorders

Psychiatric Disorders Agitation Confusional state

Depression Acute psychosis

Insomnia Aggression

Mood swings Suicidal ideation

Anxiety Hallucination

Nervous system Ataxia Nystagmusdisorders Dizziness Speech disorder

Memory impairment Tremor

Somnolence Convulsion

Bradyphrenia

Disturbance in attention

Paraesthesia

Eye disorders Diplopia

Respiratory, thoracic Respiratory disorderand mediastinaldisorders

Gastrointestinal Constipation Abdominal paindisorders Diarrhoea

Dyspepsia

Nausea

Hepatobiliary disorders Cholecystitis acute

Skin and subcutaneous Rash Pruritustissue disorders Ecchymosis

General disorders and Fatigueadministration site Pyrexiaconditions Irritability

Investigations Decreased Weight decreased Urine analysisbicarbonate Blood creatinine abnormalphosphokinase increased

Alanine aminotransferaseincreased

Aspartate aminotransferaseincreased† MedDRA version 13.1

Additional information on special populations:

A pooled analysis of safety data on 95 elderly subjects has shown a relatively higher reportingfrequency of oedema peripheral and pruritus compared to the adult population.

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

Induced Hypersensitivity syndrome (DIHS).

The adverse event profile of zonisamide in paediatric patients aged 6 to 17 years in placebo-controlledclinical studies was consistent with that of adults. Among 465 subjects in the paediatric safetydatabase (including a further 67 subjects from the extension phase of the controlled clinical trial) therewere 7 deaths (1.5%; 14.6/1000 person-years): 2 cases of status epilepticus, of which one was relatedto severe weight loss (10% within 3 months) in an underweight subject and subsequent failure to takemedication; 1 case of head injury/haematoma, and 4 deaths in subjects with pre-existing functionalneurological deficits for various causes (2 cases of pneumonia-induced sepsis/organ failure, 1 SUDEPand 1 head injury). A total of 70.4% of paediatric subjects who received ZNS in the controlled studyor its open label extension had at least one treatment-emergent bicarbonate measurement below 22mmol/L. The duration of low bicarbonate measurements was also long (median 188 days).

A pooled analysis of safety data on 420 paediatric subjects (183 subjects aged 6 to 11 years, and 237subjects aged 12 to 16 years with a mean duration of exposure of approximately 12 months) hasshown a relatively higher reporting frequency of pneumonia, dehydration, decreased sweating,abnormal liver function tests, otitis media, pharyngitis, sinusitis and upper respiratory tract infection,cough, epistaxis and rhinitis, abdominal pain, vomiting, rash and eczema, and fever compared to theadult population (particularly in subjects aged below 12 years) and, at a low incidence, amnesia,creatinine increased, lymphadenopathy, and thrombocytopenia. The incidence of a decrease in bodyweight of 10% or more was 10.7% (see section 4.4). In some cases of weight decrease there was adelay in transition to the next Tanner stage and in bone maturation.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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 usualprecautions to protect the airway. General supportive care is indicated, including frequent monitoringof vital signs and close observation. Zonisamide has a long elimination half-life so its effects may bepersistent. Although not formally studied for the treatment of overdose, haemodialysis reduced plasmaconcentrations of zonisamide in a patient with reduced renal function, and may be considered astreatment 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 carbonicanhydrase activity in-vitro. It is chemically unrelated to other anti-epileptic agents.

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

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

Monotherapy in partial seizures, with or without secondary generalisation

Efficacy of zonisamide as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine prolonged release (PR) in 583 adult subjects with newlydiagnosed partial seizures with or without secondary generalised tonic-clonic seizures. Subjects wererandomised to carbamazepine and zonisamide received treatment for a duration of up to 24 monthsdepending on response. Subjects were titrated to the initial target dose of 600 mg carbamazepine or300 mg of zonisamide. Subjects who experienced a seizure were titrated to the next target dose i.e. 800mg carbamazepine or 400 mg of zonisamide. Subjects who experienced a further seizure were titratedto the maximal target dose of 1200 mg carbamazepine or 500 mg zonisamide. Subjects who wereseizure-free for 26 weeks at a target dose level continued on this dose for another 26 weeks.

Main outcomes of this study are presented in this table:

Table 6. Efficacy results for Monotherapy Study 310

Zonisamide Carbamazepinen (ITT population) 281 300

Six months seizure freedom Diff CI95%

PP-population* 79.4% 83.7% -4.5% -12.2% ; 3.1%

ITT-population 69.4% 74.7% -6.1% -13.6% ; 1.4%< 4 seizures during 3 month 71.7% 75.7% -4.0% -11.7% ; 3.7%baseline period> 4 seizures during 3 month 52.9% 68.9% -15.9% -37.5% ; 5.6%baseline period

Twelve months seizure freedom

PP-population 67.6% 74.7% -7.9% - 17.2% ; 1.5%

ITT-population 55.9% 62.3% -7.7% - 16.1% ; 0.7%< 4 seizures during 3 month 57.4% 64.7% -7.2% -15.7% ; 1.3%baseline period> 4 seizures during 3 month 44.1% 48.9% -4.8% -26.9% ; 17.4%baseline period

Seizure Sub-type (6 monthseizure freedom-PP population)

All partial 76.4% 86.0% -9.6% -19.2% ; 0.0%

Simple partial 72.3% 75.0% -2.7% -20.0% ; 14.7%

Complex partial 76.9% 93.0% -16.1% -26.3% ; -5.9%

All generalized Tonic-Clonic 78.9% 81.6% -2.8% -11.5% ; 6.0%

Secondary Tonic-Clonic 77.4% 80.0% -2.6% -12.4% ; 7.1%

Generalized Tonic-Clonic 85.7% 92.0% -6.3% -23.1% ; 10.5%

PP = Per Protocol Population; ITT = Intent To Treat Population

*Primary endpoint

Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation inadults

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

Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, inadolescent and paediatric patients (aged 6 years and above)

In paediatric patients (aged 6 years and above), efficacy has been demonstrated with zonisamide in adouble-blind, placebo-controlled study, which included 207 subjects and had a treatment duration ofup to 24 weeks. A 50% or greater reduction from baseline in seizure frequency during the 12-weekstable dose period was seen in 50% of the zonisamide-treated subjects and 31% of the patients onplacebo.

Specific safety issues that were encountered in the paediatric studies were: decreased appetite andweight loss, decreased bicarbonate levels, increased risk of kidney stones and dehydration. All theseeffects and specifically weight loss may have deleterious implications for growth and development,and may lead to general deterioration of health. Altogether, data on effects on long-term growth anddevelopment are limited.

Zonisamide is almost completely absorbed after oral administration, generally reaching peak serum orplasma concentrations within 2 to 5 hours of dosing. The first-pass metabolism is believed to benegligible. Absolute bioavailability is estimated to be approximately 100%. Oral bioavailability is notaffected by food, although peak plasma and serum concentrations may be delayed.

Zonisamide AUC and Cmax values increased almost linearly after single dose over the dose range of100-800 mg and after multiple doses over the dose range of 100-400 mg once daily. The increase atsteady state was slightly more than expected on the basis of dose, probably due to the saturablebinding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater thanexpected accumulation occurs relative to single dosing.

Zonisamide is 40 - 50 % bound to human plasma proteins, with in vitro studies showing that this isunaffected by the presence of various antiepileptic medicinal products (i.e., phenytoin,phenobarbitone, carbamazepine, and sodium valproate). The apparent volume of distribution is about1.1 - 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.

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

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

Zonisamide exposure increases with time until steady state is achieved by approximately 8 weeks.

When comparing the same dose level, subjects of higher total body weight appear to have lowersteady-state serum concentrations, but this effect appears to be relatively modest. Age ( 12 years) andgender, after adjustment for body weight effects, have no apparent effect on zonisamide exposure inepileptic patients during steady-state dosing. There is no need for dose adjustment with any of the

AEDs including CYP3A4 inducers.

Zonisamide lowers the 28-day average seizure frequency and the decrease is proportional (log-linear)to zonisamide average concentration.

Special patient groups

In subjects with renal impairment, renal clearance of single doses of zonisamide was positivelycorrelated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% insubjects with creatinine clearance <20 ml/min (see also section 4.2.).

Patients with an impaired liver function: The pharmacokinetics of zonisamide in patients withimpaired 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 andadolescents dosed to steady state at 1, 7 or 12 mg/kg daily, in divided doses, are similar to thoseobserved in adults, after adjustment for bodyweight.

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 withconcentric lamellar bodies in the cytoplasm and cytoplasmic vacuolation) associated with increasedmetabolism.

Zonisamide was not genotoxic and has no carcinogenic potential.

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

In a repeated-dose oral toxicity study in juvenile rats, at exposure levels similar to those observed inpaediatric patients at the maximum recommended dose, decreases in body weight and changes in renalhistopathology and clinical pathology parameters and behavioural changes were observed. Changes inrenal histopathology and clinical pathology parameters were considered to be related to carbonicanhydrase inhibition by zonisamide. The effects at this dose level were reversible during the recoveryperiod. At a higher dose level (2-3-fold systemic exposure compared to therapeutic exposure) renalhistopathological effects were more severe and only partially reversible. Most adverse effectsobserved in the juvenile rats were similar to those seen in the repeated-dose toxicity studies ofzonisamide in adult rats, but renal tubular hyaline droplets and transitional hyperplasia were observedin the juvenile study only. At this higher dose level, juvenile rats showed a decrease in growth,learning, and developmental parameters. These effects were considered likely related to the decreasedbody weight and exaggerated pharmacologic effects of zonisamide at the maximum tolerated dose.

In rats, decreased numbers of corpora lutea and implantation sites were observed at exposure levelsequivalent to the maximum therapeutic dose in humans; irregular oestrus cycles and a decreasednumber of live foetuses were observed at exposure levels three times higher.

Microcrystalline cellulose

Hydrogenated vegetable oil (from soyabean)

Sodium laurilsulfate

Capsule shells

Gelatin

Titanium dioxide (E171)

Allura red AC (E129)

Sunset yellow FCF (E110)

Shellac

Potassium hydroxide

Black iron oxide (E172)

Not applicable.

3 years.

Do not store above 30°C.

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

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amdipharm Limited3 Burlington Road,

Dublin 4,

D04 RD68,

Ireland

EU/1/04/307/006

EU/1/04/307/004

EU/1/04/307/011

EU/1/04/307/007

EU/1/04/307/008

Date of first authorisation: 10/03/2005

Date of latest renewal: 21/12/2009

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu