Zonegran

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Zonegran 25 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 25 mg of zonisamide.

Excipient with known effect:
Each hard capsule contains 0.75 mg hydrogenated vegetable oil (from soyabean)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Zonegran is indicated as: 
 monotherapy in the treatment of partial seizures, with or without secondary generalisation, in 

adults with newly diagnosed epilepsy (see section 5.1);
 adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in 

adults, adolescents, and children aged 6 years and above.

4.2 Posology and method of administration

Posology - Adults

Dosage escalation and maintenance
Zonegran may be taken as monotherapy or added to existing therapy in adults. The dose should be 
titrated 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 lower 
doses.

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When Zonegran treatment is to be discontinued, it should be withdrawn gradually (see section 4.4).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



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Table 1. Adults – recommended dosage escalation and maintenance regimen

Treatment 
Regimen

Titration Phase Usual Maintenance 
Dose

Monotherapy -
Newly diagnosed 
adult patients

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

300 mg per day

(once a day). 

If a higher dose is 
required: increase at 
two-weekly intervals in 
increments of 100 mg 
up to a maximum of 
500 mg.

100 mg/day 

(once a day)

200 mg /day

(once a day)

300 mg / day

(once a day)

Adjunctive 
therapy
- with CYP3A4-
inducing agents

(see section 4.5)

Week 1 Week 2 Week 3 to 5

300 to 500 mg per day 

(once a day or 
two divided doses).

50 mg/day 

(in two 
divided doses) 

100 mg /day

(in two divided 
doses)

Increase at 
weekly intervals 

in increments of 
100 mg

- without 
CYP3A4-inducing 
agents; or with 
renal or hepatic 
impairment

Week 1 + 2 Week 3 + 4 Week 5 to 10

300 to 500 mg per day 

(once a day or 
two divided doses). 

Some patients may 
respond to lower doses.

50 mg/day 

(in two 
divided doses)

100 mg / day 

(in two divided 
doses)

Increase at 
two-weekly 
intervals

in increments of 
up to 100 mg

General dosing recommendations for Zonegran in special patient populations

Paediatric population (aged 6 years and above)

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



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

Treatment 
Regimen

Titration Phase Usual Maintenance Dose

Adjunctive 
therapy
- with CYP3A4-
inducing agents 
(see section 4.5)

Week 1 Weeks 2 to 8 Patients of weight 
20 to 55 kga

Patients of 
weight > 55 kg

1 mg/kg/day

(once a day)

Increase at 
weekly intervals 
in increments of 
1 mg/kg

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

- without 
CYP3A4-inducing 
agents

Week 1 + 2 Weeks ≥ 3

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

1 mg/kg/day

(once a day)

Increase at 
two-weekly 
intervals in 
increments of 
1 mg/kg

Note:  
a. To ensure a therapeutic dose is maintained the weight of a child should be monitored and the 

dose reviewed as weight changes occur up to a weight of 55kg. The dose regime is 
6-8 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 yet 
been 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 treated 
with caution.

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

Withdrawal
When Zonegran treatment is to be discontinued, it should be withdrawn gradually (see section 4.4). In
clinical studies of paediatric patients, down-titration was completed by dose reductions at weekly 
intervals 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-titration 
schedule

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.



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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). 

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.

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).

4.3 Contraindications

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

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

4.4 Special warnings and precautions for use

Unexplained rash

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

Withdrawal seizures

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 antiepileptic medicines once seizure 
control with Zonegran has been achieved in the add-on situation, in order to reach monotherapy with 



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Zonegran. Therefore, withdrawal of concomitant anti-epileptic medicinal products must be undertaken 
with caution.

Sulphonamide reactions

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.

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 behaviour

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

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 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 



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Zonegran in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-
induced metabolic acidosis occurs early in treatment although cases can occur at any time during 
treatment. The amounts by which bicarbonate is decreased are usually small – moderate (average 
decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can 
experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal 
disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or 
medicinal products) may be additive to the bicarbonate lowering effects of zonisamide. 

The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger 
patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in 
patients taking zonisamide who have underlying conditions which might increase the risk of acidosis, 
in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients 
with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, 
consideration should be given to reducing the dose or discontinuing Zonegran (by gradual 
discontinuation or reduction of a therapeutic dose) as osteopenia may develop.
If the decision is made to continue patients on Zonegran in the face of persistent acidosis, alkali 
treatment should be considered.

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

Heat stroke

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric
patients (see section 4.4 Paediatric population for full warning). Caution should be used in adults when 
Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders; 
these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity (see 
also section 4.4 Paediatric population).

Pancreatitis

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.

Rhabdomyolysis

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 childbearing potential

Women of childbearing potential must use effective contraception during treatment with Zonegran and 
for one month after discontinuation (see section 4.6). Zonegran 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 Zonegran 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 Zonegran
and to consider other therapeutic options. Physicians treating patients with Zonegran should ensure
that patients are fully informed about the need to use appropriate effective contraception, and should 



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use clinical judgement when assessing whether oral contraceptives (OCs), or the doses of the OC 
components, are adequate based on the individual patient’s clinical situation.

Body weight

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. Weight loss is potentially more 
serious in children (see section 4.4. Paediatric population).

Paediatric population

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

Heat stroke and dehydration
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 to 
brain damage and death. Children are most at risk especially in hot weather. 

When a child is taking Zonegran:
• The child should stay cool especially in hot weather 
• The child must avoid heavy exercise especially when the weather is hot 
• The child must drink plenty of cold water  
• The child must not take any of these medicines:
carbonic anhydrase inhibitors (like topiramate and acetazolamide), and anticholinergic agents (like 
clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).  

IF ANY OF THE FOLLOWING OCCUR, THE CHILD NEEDS URGENT MEDICAL 
ATTENTION:
The skin feels very hot with little or no sweating, or the child becomes confused or has muscle cramps, 
or the child’s heartbeat or breathing become rapid. 

 Take the child to a cool, shaded place 
 Keep the child's skin cool with water
 Give the child cold water to drink

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 Zonegran should be considered.

Zonegran should not be used as co-medication in paediatric patients with other medicinal products that 
predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal 
products with anticholinergic activity.



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Body weight
Weight loss leading to deterioration of general condition and failure to take anti-epilepsy medication 
has been related to a fatal outcome (see section 4.8). Zonegran is not recommended for paediatric 
patients who are underweight (definition in accordance with the WHO age adjusted BMI categories)
or have a decreased appetite.

The incidence of decreased body weight is consistent across age groups (see section 4.8); however, 
given the potential seriousness of weight loss in children, weight should be monitored in this 
population. A dietary supplement or increased food intake should be considered if the patient is failing 
to gain weight in accordance with growth charts, otherwise Zonegran should be discontinued. 

There are limited data from clinical studies in patients with a body weight of less than 20 kg. 
Therefore children aged 6 years and above with a body weight of less than 20 kg should be treated 
with caution. The long term effect of weight loss in the paediatric population on growth and 
development is unknown.

Metabolic 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 (see section 4.4 - Metabolic acidosis for full warning; see 
section 4.8 for incidence of low bicarbonate). The long term effect of low bicarbonate levels on 
growth and development is unknown. 

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

Kidney stones
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 for 
renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. 
Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone 
formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can 
reliably predict stone formation during zonisamide treatment.
Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in 
those with predisposing risk factors. Renal ultrasound should be performed at the discretion of the 
physician. In the event kidney stones are detected, Zonegran should be discontinued.

Hepatic 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 Zonegran 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. 

4.5 Interaction with other medicinal products and other forms of interaction

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 



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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 adult patients treated concomitantly with carbonic anhydrase 
inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible 
pharmacodynamic interaction (see section 4.4).

Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydrase 
inhibitors 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 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, 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.  



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Paediatric population
Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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 contraception 
unless 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 childbearing 
potential. Women planning a pregnancy should meet with their specialists to reassess treatment with 
zonisamide and to consider other therapeutic options.

As with all antiepileptic medicines, sudden discontinuation of zonisamide should be avoided as this 
may lead to breakthrough seizures that could have serious consequences for the woman and the 
unborn child. 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.

Pregnancy

There are limited 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.

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 compared
with mothers treated with lamotrigine monotherapy.

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

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.

Fertility

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

4.7 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.



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4.8 Undesirable effects

Summary of the safety profile

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. The most common adverse reactions in a randomised, controlled monotherapy 
trial comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate, 
decreased appetite, and decreased weight. The incidence of markedly abnormally low serum 
bicarbonate (a decrease to less than 17 mEq/l and by more than 5 mEq/l) was 3.8%. The incidence of 
marked decreases in weight of 20% or more was 0.7%.

Tabulated list of adverse reactions

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: 

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

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

System Organ 
Class
(MedDRA 
terminology)

Very 
Common

Common Uncommon Very Rare

Infections and 
infestation

Pneumonia
Urinary tract 
infection

Blood and 
lymphatic 
system disorders

Ecchymosis Agranulocytosis
Aplastic anaemia
Leucocytosis
Leucopoenia
Lymphadenopathy
Pancytopenia,
Thrombocytopenia

Immune system 
disorders

Hypersensitivity Drug-induced 
hypersensitivity syndrome
Drug rash with eosinophilia 
and systemic symptoms

Metabolism and 
nutrition 
disorders

Anorexia Hypokalaemia Metabolic acidosis
Renal tubular acidosis



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System Organ 
Class
(MedDRA 
terminology)

Very 
Common

Common Uncommon Very Rare

Psychiatric 
Disorders

Agitation 
Irritability
Confusional 
state
Depression

Affect lability
Anxiety
Insomnia
Psychotic 
disorder

Anger
Aggression 
Suicidal ideation
Suicide attempt

Hallucination

Nervous system 
disorders

Ataxia
Dizziness
Memory 
impairment
Somnolence

Bradyphrenia
Disturbance in 
attention
Nystagmus
Paraesthesia
Speech disorder
Tremor

Convulsion Amnesia
Coma
Grand mal seizure
Myasthenic syndrome
Neuroleptic malignant 
syndrome
Status epilepticus

Eye disorders Diplopia Angle closure glaucoma
Eye pain
Myopia
Vision blurred
Visual acuity reduced

Respiratory, 
thoracic and 
mediastinal 
disorders

Dyspnoea 
Pneumonia aspiration 
Respiratory disorder
Hypersensitivity-type
Pneumonitis

Gastrointestinal 
disorders

Abdominal pain
Constipation
Diarrhoea
Dyspepsia
Nausea

Vomiting Pancreatitis

Hepatobiliary 
disorders

Cholecystitis
Cholelithiasis

Hepatocellular damage

Skin and 
subcutaneous 
tissue disorders

Rash
Pruritus
Alopecia

Anhidrosis
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis

Musculoskeletal 
and connective 
tissue disorders

Rhabdomyolysis

Renal and 
urinary 
disorders

Nephrolithiasis Calculus urinary Hydronephrosis
Renal failure
Urine abnormality

General 
disorders and 
administration 
site conditions

Fatigue
Influenza-like 
illness
Pyrexia
Oedema 
peripheral

Investigations Decreased 
bicarbonate

Weight 
decreased

Blood creatine 
phosphokinase increased
Blood creatinine increased
Blood urea increased
Liver function tests 
abnormal



14

System Organ 
Class
(MedDRA 
terminology)

Very 
Common

Common Uncommon Very Rare

Injury, 
poisoning and 
procedural 
complications

Heat stroke

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 comparing 
zonisamide with carbamazepine prolonged release
System Organ Class
(MedDRA terminology†)

Very Common Common Uncommon

Infections and 
infestation

Urinary tract infection
Pneumonia

Blood and lymphatic 
disorders

Leukopenia
Thrombocytopenia

Metabolism and 
nutrition disorders

Decreased appetite Hypokalaemia

Psychiatric Disorders Agitation
Depression
Insomnia
Mood swings
Anxiety

Confusional state
Acute psychosis
Aggression
Suicidal ideation
Hallucination

Nervous system 
disorders

Ataxia
Dizziness
Memory impairment
Somnolence
Bradyphrenia
Disturbance in attention 
Paraesthesia

Nystagmus
Speech disorder
Tremor
Convulsion

Eye disorders Diplopia
Respiratory, thoracic 
and mediastinal 
disorders

Respiratory disorder

Gastrointestinal 
disorders

Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting

Abdominal pain

Hepatobiliary disorders Cholecystitis acute
Skin and subcutaneous 
tissue disorders

Rash Pruritus
Ecchymosis

General disorders and 
administration site 
conditions

Fatigue
Pyrexia
Irritability



15

System Organ Class
(MedDRA terminology†)

Very Common Common Uncommon

Investigations Decreased 
bicarbonate

Weight decreased
Blood creatinine 
phosphokinase increased
Alanine aminotransferase 
increased
Aspartate aminotransferase 
increased

Urine analysis 
abnormal

† MedDRA version 13.1

Additional information on special populations:

Elderly
A pooled analysis of safety data on 95 elderly subjects has shown a relatively higher reporting 
frequency 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 frequency 
than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug 
Induced Hypersensitivity syndrome (DIHS).

Paediatric population
The adverse event profile of zonisamide in paediatric patients aged 6 to 17 years in placebo-controlled 
clinical studies was consistent with that of adults. Among 465 subjects in the paediatric safety 
database (including a further 67 subjects from the extension phase of the controlled clinical trial) there 
were 7 deaths (1.5%; 14.6/1000 person-years): 2 cases of status epilepticus, of which one was related 
to severe weight loss (10% within 3 months) in an underweight subject and subsequent failure to take 
medication; 1 case of head injury/haematoma, and 4 deaths in subjects with pre-existing functional 
neurological deficits for various causes (2 cases of pneumonia-induced sepsis/organ failure, 1 SUDEP 
and 1 head injury). A total of 70.4% of paediatric subjects who received ZNS in the controlled study 
or its open label extension had at least one treatment-emergent bicarbonate measurement below 22 
mmol/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 237 
subjects aged 12 to 16 years with a mean duration of exposure of approximately 12 months) has 
shown 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 the 
adult 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 body 
weight of 10% or more was 10.7% (see section 4.4). In some cases of weight decrease there was a 
delay in transition to the next Tanner stage and in bone maturation.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


16

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

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.  

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.

Clinical efficacy and safety

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 newly 
diagnosed partial seizures with or without secondary generalised tonic-clonic seizures. Subjects were 
randomised to carbamazepine and zonisamide received treatment for a duration of up to 24 months 
depending on response. Subjects were titrated to the initial target dose of 600 mg carbamazepine or 
300 mg of zonisamide. Subjects who experienced a seizure were titrated to the next target dose i.e. 800 
mg carbamazepine or 400 mg of zonisamide. Subjects who experienced a further seizure were titrated 
to the maximal target dose of 1200 mg carbamazepine or 500 mg zonisamide. Subjects who were 
seizure-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 Carbamazepine
n (ITT population) 281 300



17

Six months seizure freedom Diff CI
95%

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 
baseline period

71.7% 75.7% -4.0% -11.7% ; 3.7%

> 4 seizures during 3 month 
baseline period

52.9% 68.9% -15.9% -37.5% ; 5.6%

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 
baseline period

57.4% 64.7% -7.2% -15.7% ; 1.3%

> 4 seizures during 3 month 
baseline period

44.1% 48.9% -4.8% -26.9% ; 17.4%

Seizure Sub-type (6 month 
seizure 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 in 
adults

In adults, 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.

Paediatric population

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

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

Specific safety issues that were encountered in the paediatric studies were: decreased appetite and 
weight loss, decreased bicarbonate levels, increased risk of kidney stones and dehydration. All these 
effects 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 and 
development are limited.

5.2 Pharmacokinetic properties



18

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 Cmax 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 antiepileptic 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.

Linearity/non-linearity

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 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. There is no need for dose adjustment with any of the 
AEDs including CYP3A4 inducers.

Pharmacokinetic/pharmacodynamic relationship

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 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.).



19

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.

5.3 Preclinical safety data

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.

In a repeated-dose oral toxicity study in juvenile rats, at exposure levels similar to those observed in 
paediatric patients at the maximum recommended dose, decreases in body weight and changes in renal 
histopathology and clinical pathology parameters and behavioural changes were observed. Changes in 
renal histopathology and clinical pathology parameters were considered to be related to carbonic 
anhydrase inhibition by zonisamide. The effects at this dose level were reversible during the recovery 
period. At a higher dose level (2-3-fold systemic exposure compared to therapeutic exposure) renal 
histopathological effects were more severe and only partially reversible. Most adverse effects 
observed in the juvenile rats were similar to those seen in the repeated-dose toxicity studies of 
zonisamide in adult rats, but renal tubular hyaline droplets and transitional hyperplasia were observed 
in 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 decreased 
body 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 levels 
equivalent to the maximum therapeutic dose in humans; irregular oestrus cycles and a decreased 
number of live foetuses were observed at exposure levels three times higher.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents
Microcrystalline cellulose 
Hydrogenated vegetable oil (from soyabean)
Sodium laurilsulfate

Capsule shells
Gelatin 
Titanium dioxide (E171) 
Shellac 
Propylene glycol 
Potassium hydroxide 



20

Black iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

PVC/PVDC/aluminium blisters, packs of 14, 28, 56 and 84 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal 

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

7. MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/307/001
EU/1/04/307/005
EU/1/04/307/002
EU/1/04/307/013

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10/03/2005
Date of latest renewal: 21/12/2009

10. DATE OF REVISION OF THE TEXT

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



21

1. NAME OF THE MEDICINAL PRODUCT

Zonegran 50 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 50 mg of zonisamide.

Excipient with known effect:
Each hard capsule contains 1.5 mg hydrogenated vegetable oil (from soyabean)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Zonegran is indicated as: 
 monotherapy in the treatment of partial seizures, with or without secondary generalisation, in 

adults with newly diagnosed epilepsy (see section 5.1);
 adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in 

adults, adolescents, and children aged 6 years and above.

4.2 Posology and method of administration

Posology - Adults 

Dosage escalation and maintenance
Zonegran may be taken as monotherapy or added to existing therapy in adults. The dose should be 
titrated 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 lower 
doses.

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



22

Table 1. Adults – recommended dosage escalation and maintenance regimen

Treatment 
Regimen

Titration Phase Usual Maintenance 
Dose

Monotherapy -
Newly diagnosed 
adult patients

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

300 mg per day

(once a day). 

If a higher dose is 
required: increase at 
two-weekly intervals in 
increments of 100 mg 
up to a maximum of 
500 mg.

100 mg/day 

(once a day)

200 mg /day

(once a day)

300 mg / day

(once a day)

Adjunctive 
therapy
- with CYP3A4-
inducing agents

(see section 4.5)

Week 1 Week 2 Week 3 to 5

300 to 500 mg per day 

(once a day or 
two divided doses).

50 mg/day 

(in two 
divided doses) 

100 mg /day

(in two divided 
doses)

Increase at 
weekly intervals 

in increments of 
100 mg

- without 
CYP3A4-inducing 
agents; or with 
renal or hepatic 
impairment

Week 1 + 2 Week 3 + 4 Week 5 to 10

300 to 500 mg per day 

(once a day or 
two divided doses). 

Some patients may 
respond to lower doses.

50 mg/day 

(in two 
divided doses)

100 mg / day 

(in two divided 
doses)

Increase at 
two-weekly 
intervals

in increments of 
up to 100 mg

General dosing recommendations for Zonegran in special patient populations

Paediatric population (aged 6 years and above)

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



23

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

Treatment 
Regimen

Titration Phase Usual Maintenance Dose

Adjunctive 
therapy
- with CYP3A4-
inducing agents 
(see section 4.5)

Week 1 Weeks 2 to 8 Patients of weight 
20 to 55 kga

Patients of 
weight > 55 kg

1 mg/kg/day

(once a day)

Increase at 
weekly intervals 
in increments of 
1 mg/kg

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

- without 
CYP3A4-inducing 
agents

Week 1 + 2 Weeks ≥ 3

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

1 mg/kg/day

(once a day)

Increase at 
two-weekly 
intervals in 
increments of 
1 mg/kg

Note:  
a. To ensure a therapeutic dose is maintained the weight of a child should be monitored and the 

dose reviewed as weight changes occur up to a weight of 55kg. The dose regime is 
6-8 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 yet 
been 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 treated 
with caution.

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

Withdrawal
When Zonegran treatment is to be discontinued, it should be withdrawn gradually (see section 4.4). In
clinical studies of paediatric patients, down-titration was completed by dose reductions at weekly 
intervals 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-titration
schedule

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.



24

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). 

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.

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).

4.3 Contraindications

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

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

4.4 Special warnings and precautions for use

Unexplained rash

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

Withdrawal seizures

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 antiepileptic medicines once seizure 
control with Zonegran has been achieved in the add-on situation, in order to reach monotherapy with 



25

Zonegran. Therefore, withdrawal of concomitant anti-epileptic medicinal products must be undertaken 
with caution.

Sulphonamide reactions

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.

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 behaviour

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

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 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 



26

Zonegran in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-
induced metabolic acidosis occurs early in treatment although cases can occur at any time during 
treatment. The amounts by which bicarbonate is decreased are usually small – moderate (average 
decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can 
experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal 
disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or 
medicinal products) may be additive to the bicarbonate lowering effects of zonisamide. 

The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger 
patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in 
patients taking zonisamide who have underlying conditions which might increase the risk of acidosis, 
in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients 
with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, 
consideration should be given to reducing the dose or discontinuing Zonegran (by gradual 
discontinuation or reduction of a therapeutic dose) as osteopenia may develop.
If the decision is made to continue patients on Zonegran in the face of persistent acidosis, alkali 
treatment should be considered.

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

Heat stroke

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric
patients (see section 4.4 Paediatric population for full warning). Caution should be used in adults when 
Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders; 
these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity (see 
also section 4.4 Paediatric population).

Pancreatitis

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.

Rhabdomyolysis

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 childbearing potential

Women of childbearing potential must use effective contraception during treatment with Zonegran and 
for one month after discontinuation (see section 4.6). Zonegran 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 Zonegran 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 Zonegran
and to consider other therapeutic options. Physicians treating patients with Zonegran should ensure 
that patients are fully informed about the need to use appropriate effective contraception, and should 



27

use clinical judgement when assessing whether oral contraceptives (OCs), or the doses of the OC 
components, are adequate based on the individual patient’s clinical situation.

Body weight

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. Weight loss is potentially more 
serious in children (see section 4.4. Paediatric population).

Paediatric population

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

Heat stroke and dehydration
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 to 
brain damage and death. Children are most at risk especially in hot weather. 

When a child is taking Zonegran:
• The child should stay cool especially in hot weather 
• The child must avoid heavy exercise especially when the weather is hot 
• The child must drink plenty of cold water  
• The child must not take any of these medicines:
carbonic anhydrase inhibitors (like topiramate and acetazolamide), and anticholinergic agents (like 
clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).  

IF ANY OF THE FOLLOWING OCCUR, THE CHILD NEEDS URGENT MEDICAL 
ATTENTION:
The skin feels very hot with little or no sweating, or the child becomes confused or has muscle cramps, 
or the child’s heartbeat or breathing become rapid.  

 Take the child to a cool, shaded place 
 Keep the child's skin cool with water
 Give the child cold water to drink

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 Zonegran should be considered.

Zonegran should not be used as co-medication in paediatric patients with other medicinal products that 
predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal 
products with anticholinergic activity.



28

Body weight
Weight loss leading to deterioration of general condition and failure to take anti-epilepsy medication 
has been related to a fatal outcome (see section 4.8). Zonegran is not recommended for paediatric 
patients who are underweight (definition in accordance with the WHO age adjusted BMI categories)
or have a decreased appetite.

The incidence of decreased body weight is consistent across age groups (see section 4.8); however, 
given the potential seriousness of weight loss in children, weight should be monitored in this
population. A dietary supplement or increased food intake should be considered if the patient is failing 
to gain weight in accordance with growth charts, otherwise Zonegran should be discontinued.

There are limited data from clinical studies in patients with a body weight of less than 20 kg. 
Therefore children aged 6 years and above with a body weight of less than 20 kg should be treated 
with caution. The long term effect of weight loss in the paediatric population on growth and 
development is unknown.

Metabolic 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 (see section 4.4 - Metabolic acidosis for full warning; see 
section 4.8 for incidence of low bicarbonate). The long term effect of low bicarbonate levels on 
growth and development is unknown. 

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

Kidney stones
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 for 
renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. 
Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone 
formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can 
reliably predict stone formation during zonisamide treatment.
Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in 
those with predisposing risk factors. Renal ultrasound should be performed at the discretion of the 
physician. In the event kidney stones are detected, Zonegran should be discontinued.

Hepatic 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 Zonegran 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.   

4.5 Interaction with other medicinal products and other forms of interaction

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 



29

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 adult patients treated concomitantly with carbonic anhydrase 
inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible 
pharmacodynamic interaction (see section 4.4).

Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydrase 
inhibitors 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 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, 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.  

Paediatric population
Interaction studies have only been performed in adults.



30

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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 contraception 
unless 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 childbearing 
potential. Women planning a pregnancy should meet with their specialists to reassess treatment with 
zonisamide and to consider other therapeutic options.

As with all antiepileptic medicines, sudden discontinuation of zonisamide should be avoided as this 
may lead to breakthrough seizures that could have serious consequences for the woman and the 
unborn child. 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.

Pregnancy

There are limited 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.

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 compared 
with mothers treated with lamotrigine monotherapy.

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

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.

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

4.7 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.



31

4.8 Undesirable effects

Summary of the safety profile

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. The most common adverse reactions in a randomised, controlled monotherapy 
trial comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate, 
decreased appetite, and decreased weight. The incidence of markedly abnormally low serum 
bicarbonate (a decrease to less than 17 mEq/l and by more than 5 mEq/l) was 3.8%. The incidence of 
marked decreases in weight of 20% or more was 0.7%.

Tabulated list of adverse reactions

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: 

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

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

System Organ 
Class
(MedDRA 
terminology)

Very 
Common

Common Uncommon Very Rare

Infections and 
infestation

Pneumonia
Urinary tract 
infection

Blood and 
lymphatic 
system disorders

Ecchymosis Agranulocytosis
Aplastic anaemia
Leucocytosis
Leucopoenia
Lymphadenopathy
Pancytopenia,
Thrombocytopenia

Immune system 
disorders

Hypersensitivity Drug-induced 
hypersensitivity syndrome
Drug rash with eosinophilia 
and systemic symptoms

Metabolism and 
nutrition 
disorders

Anorexia Hypokalaemia Metabolic acidosis
Renal tubular acidosis



32

System Organ 
Class
(MedDRA 
terminology)

Very 
Common

Common Uncommon Very Rare

Psychiatric 
Disorders

Agitation 
Irritability
Confusional 
state
Depression

Affect lability
Anxiety
Insomnia
Psychotic 
disorder

Anger
Aggression 
Suicidal ideation
Suicide attempt

Hallucination

Nervous system 
disorders

Ataxia
Dizziness
Memory 
impairment
Somnolence

Bradyphrenia
Disturbance in 
attention
Nystagmus
Paraesthesia
Speech disorder
Tremor

Convulsion Amnesia
Coma
Grand mal seizure
Myasthenic syndrome
Neuroleptic malignant
syndrome
Status epilepticus

Eye disorders Diplopia Angle closure glaucoma
Eye pain
Myopia
Vision blurred
Visual acuity reduced

Respiratory, 
thoracic and 
mediastinal 
disorders

Dyspnoea 
Pneumonia aspiration 
Respiratory disorder
Hypersensitivity-type 
Pneumonitis

Gastrointestinal 
disorders

Abdominal pain
Constipation
Diarrhoea
Dyspepsia
Nausea

Vomiting Pancreatitis

Hepatobiliary 
disorders

Cholecystitis
Cholelithiasis

Hepatocellular damage

Skin and 
subcutaneous 
tissue disorders

Rash
Pruritus
Alopecia

Anhidrosis
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis

Musculoskeletal 
and connective 
tissue disorders

Rhabdomyolysis

Renal and 
urinary 
disorders

Nephrolithiasis Calculus urinary Hydronephrosis
Renal failure
Urine abnormality

General 
disorders and 
administration 
site conditions

Fatigue
Influenza-like 
illness
Pyrexia
Oedema 
peripheral

Investigations Decreased 
bicarbonate

Weight 
decreased

Blood creatine 
phosphokinase increased
Blood creatinine increased
Blood urea increased
Liver function tests 
abnormal



33

System Organ 
Class
(MedDRA 
terminology)

Very 
Common

Common Uncommon Very Rare

Injury, 
poisoning and 
procedural 
complications

Heat stroke

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 comparing 
zonisamide with carbamazepine prolonged release

System Organ Class
(MedDRA terminology†)

Very Common Common Uncommon

Infections and 
infestation

Urinary tract infection
Pneumonia

Blood and lymphatic 
disorders

Leukopenia
Thrombocytopenia

Metabolism and 
nutrition disorders

Decreased appetite Hypokalaemia

Psychiatric Disorders Agitation
Depression
Insomnia
Mood swings
Anxiety

Confusional state
Acute psychosis
Aggression
Suicidal ideation
Hallucination

Nervous system 
disorders

Ataxia
Dizziness
Memory impairment
Somnolence
Bradyphrenia
Disturbance in attention 
Paraesthesia

Nystagmus
Speech disorder
Tremor
Convulsion

Eye disorders Diplopia
Respiratory, thoracic 
and mediastinal 
disorders

Respiratory disorder

Gastrointestinal 
disorders

Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting

Abdominal pain

Hepatobiliary disorders Cholecystitis acute
Skin and subcutaneous 
tissue disorders

Rash Pruritus
Ecchymosis

General disorders and 
administration site 
conditions

Fatigue
Pyrexia
Irritability



34

System Organ Class
(MedDRA terminology†)

Very Common Common Uncommon

Investigations Decreased 
bicarbonate

Weight decreased
Blood creatinine 
phosphokinase increased
Alanine aminotransferase 
increased
Aspartate aminotransferase 
increased

Urine analysis 
abnormal

† MedDRA version 13.1

Additional information on special populations:

Elderly
A pooled analysis of safety data on 95 elderly subjects has shown a relatively higher reporting 
frequency 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 frequency 
than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug 
Induced Hypersensitivity syndrome (DIHS).

Paediatric population
The adverse event profile of zonisamide in paediatric patients aged 6 to 17 years in placebo-controlled 
clinical studies was consistent with that of adults. Among 465 subjects in the paediatric safety 
database (including a further 67 subjects from the extension phase of the controlled clinical trial) there 
were 7 deaths (1.5%; 14.6/1000 person-years): 2 cases of status epilepticus, of which one was related 
to severe weight loss (10% within 3 months) in an underweight subject and subsequent failure to take 
medication; 1 case of head injury/haematoma, and 4 deaths in subjects with pre-existing functional 
neurological deficits for various causes (2 cases of pneumonia-induced sepsis/organ failure, 1 SUDEP 
and 1 head injury). A total of 70.4% of paediatric subjects who received ZNS in the controlled study 
or its open label extension had at least one treatment-emergent bicarbonate measurement below 22 
mmol/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 237 
subjects aged 12 to 16 years with a mean duration of exposure of approximately 12 months) has 
shown 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 the 
adult 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 body 
weight of 10% or more was 10.7% (see section 4.4). In some cases of weight decrease there was a 
delay in transition to the next Tanner stage and in bone maturation.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


35

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

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.  

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.

Clinical efficacy and safety

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 newly 
diagnosed partial seizures with or without secondary generalised tonic-clonic seizures. Subjects were 
randomised to carbamazepine and zonisamide received treatment for a duration of up to 24 months 
depending on response. Subjects were titrated to the initial target dose of 600 mg carbamazepine or 
300 mg of zonisamide. Subjects who experienced a seizure were titrated to the next target dose i.e. 800 
mg carbamazepine or 400 mg of zonisamide. Subjects who experienced a further seizure were titrated 
to the maximal target dose of 1200 mg carbamazepine or 500 mg zonisamide. Subjects who were 
seizure-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 Carbamazepine
n (ITT population) 281 300



36

Six months seizure freedom Diff CI
95%

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 
baseline period

71.7% 75.7% -4.0% -11.7% ; 3.7%

> 4 seizures during 3 month 
baseline period

52.9% 68.9% -15.9% -37.5% ; 5.6%

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 
baseline period

57.4% 64.7% -7.2% -15.7% ; 1.3%

> 4 seizures during 3 month 
baseline period

44.1% 48.9% -4.8% -26.9% ; 17.4%

Seizure Sub-type (6 month 
seizure 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 in 
adults

In adults, 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.

Paediatric population

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

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

Specific safety issues that were encountered in the paediatric studies were: decreased appetite and 
weight loss, decreased bicarbonate levels, increased risk of kidney stones and dehydration. All these 
effects 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 and 
development are limited.

5.2 Pharmacokinetic properties



37

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 Cmax 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 antiepileptic 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.

Linearity/non-linearity

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 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. There is no need for dose adjustment with any of the 
AEDs including CYP3A4 inducers.

Pharmacokinetic/pharmacodynamic relationship

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

Special patient groups



38

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.

5.3 Preclinical safety data

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.

In a repeated-dose oral toxicity study in juvenile rats, at exposure levels similar to those observed in 
paediatric patients at the maximum recommended dose, decreases in body weight and changes in renal 
histopathology and clinical pathology parameters and behavioural changes were observed. Changes in 
renal histopathology and clinical pathology parameters were considered to be related to carbonic 
anhydrase inhibition by zonisamide. The effects at this dose level were reversible during the recovery 
period. At a higher dose level (2-3-fold systemic exposure compared to therapeutic exposure) renal 
histopathological effects were more severe and only partially reversible. Most adverse effects 
observed in the juvenile rats were similar to those seen in the repeated-dose toxicity studies of 
zonisamide in adult rats, but renal tubular hyaline droplets and transitional hyperplasia were observed 
in 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 decreased 
body 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 levels 
equivalent to the maximum therapeutic dose in humans; irregular oestrus cycles and a decreased 
number of live foetuses were observed at exposure levels three times higher.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents
Microcrystalline cellulose 
Hydrogenated vegetable oil (from soyabean)
Sodium laurilsulfate



39

Capsule shells
Gelatin 
Titanium dioxide (E171) 
Shellac 
Propylene glycol 
Potassium hydroxide 
Black iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

PVC/PVDC/aluminium blisters, packs of 14, 28, 56 and 84 hard capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal 

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

7. MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/307/010
EU/1/04/307/009
EU/1/04/307/003
EU/1/04/307/012

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10/03/2005
Date of latest renewal: 21/12/2009



40

10. DATE OF REVISION OF THE TEXT

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



41

1. NAME OF THE MEDICINAL PRODUCT

Zonegran 100 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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).

Excipient with known effect:
Each hard capsule contains 3 mg hydrogenated vegetable oil (from soyabean)

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

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

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Zonegran is indicated as: 
 monotherapy in the treatment of partial seizures, with or without secondary generalisation, in 

adults with newly diagnosed epilepsy (see section 5.1);
 adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation, in 

adults, adolescents, and children aged 6 years and above.

4.2 Posology and method of administration

Posology - Adults 

Dosage escalation and maintenance
Zonegran may be taken as monotherapy or added to existing therapy in adults. The dose should be 
titrated 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 lower 
doses.

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



42

Table 1. Adults – recommended dosage escalation and maintenance regimen

Treatment 
Regimen

Titration Phase Usual Maintenance 
Dose

Monotherapy -
Newly diagnosed 
adult patients

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

300 mg per day

(once a day). 

If a higher dose is 
required: increase at 
two-weekly intervals in 
increments of 100 mg 
up to a maximum of 
500 mg.

100 mg/day 

(once a day)

200 mg /day

(once a day)

300 mg / day

(once a day)

Adjunctive 
therapy
- with CYP3A4-
inducing agents

(see section 4.5)

Week 1 Week 2 Week 3 to 5

300 to 500 mg per day 

(once a day or 
two divided doses).

50 mg/day 

(in two 
divided doses) 

100 mg /day

(in two divided 
doses)

Increase at 
weekly intervals 

in increments of 
100 mg

- without 
CYP3A4-inducing 
agents; or with 
renal or hepatic 
impairment

Week 1 + 2 Week 3 + 4 Week 5 to 10

300 to 500 mg per day 

(once a day or 
two divided doses). 

Some patients may 
respond to lower doses.

50 mg/day 

(in two 
divided doses)

100 mg / day 

(in two divided 
doses)

Increase at 
two-weekly 
intervals

in increments of 
up to 100 mg



43

General dosing recommendations for Zonegran in special patient populations

Paediatric population (aged 6 years and above)

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

Treatment 
Regimen

Titration Phase Usual Maintenance Dose

Adjunctive 
therapy
- with CYP3A4-
inducing agents 
(see section 4.5)

Week 1 Weeks 2 to 8 Patients of weight 
20 to 55 kga

Patients of 
weight > 55 kg

1 mg/kg/day

(once a day)

Increase at 
weekly intervals
in increments of 
1 mg/kg

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

- without 
CYP3A4-inducing 
agents

Week 1 + 2 Weeks ≥ 3

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

1 mg/kg/day

(once a day)

Increase at 
two-weekly 
intervals in 
increments of 
1 mg/kg

Note:  
a. To ensure a therapeutic dose is maintained the weight of a child should be monitored and the 

dose reviewed as weight changes occur up to a weight of 55kg. The dose regime is 
6-8 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 yet 
been 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 treated 
with caution.

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

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



44

Table 3. Paediatric population (aged 6 years and above) – recommended down-titration 
schedule

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.

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). 

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.

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).

4.3 Contraindications

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

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



45

4.4 Special warnings and precautions for use

Unexplained rash

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

Withdrawal seizures

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 antiepileptic medicines once seizure 
control with Zonegran has been achieved in the add-on situation, in order to reach monotherapy with 
Zonegran. Therefore, withdrawal of concomitant anti-epileptic medicinal products must be undertaken 
with caution.

Sulphonamide reactions

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.

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 behaviour

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.  



46

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

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 Zonegran 
treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of 
zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of 
Zonegran in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-
induced metabolic acidosis occurs early in treatment although cases can occur at any time during 
treatment. The amounts by which bicarbonate is decreased are usually small – moderate (average 
decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can 
experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal 
disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or 
medicinal products) may be additive to the bicarbonate lowering effects of zonisamide. 

The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger 
patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in 
patients taking zonisamide who have underlying conditions which might increase the risk of acidosis, 
in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients 
with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, 
consideration should be given to reducing the dose or discontinuing Zonegran (by gradual 
discontinuation or reduction of a therapeutic dose) as osteopenia may develop.
If the decision is made to continue patients on Zonegran in the face of persistent acidosis, alkali 
treatment should be considered.

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

Heat stroke

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric
patients (see section 4.4 Paediatric population for full warning). Caution should be used in adults when 
Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders; 
these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity (see 
also section 4.4 Paediatric population).

Pancreatitis

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.



47

Rhabdomyolysis

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 childbearing potential

Women of childbearing potential must use effective contraception during treatment with Zonegran and 
for one month after discontinuation (see section 4.6). Zonegran 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 Zonegran 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 Zonegran
and to consider other therapeutic options. Physicians treating patients with Zonegran 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.

Body weight

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. Weight loss is potentially more 
serious in children (see section 4.4. Paediatric population).

Paediatric population

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

Heat stroke and dehydration
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 to 
brain damage and death. Children are most at risk especially in hot weather. 

When a child is taking Zonegran:
• The child should stay cool especially in hot weather 
• The child must avoid heavy exercise especially when the weather is hot 
• The child must drink plenty of cold water  
• The child must not take any of these medicines:
carbonic anhydrase inhibitors (like topiramate and acetazolamide), and anticholinergic agents (like 
clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).  

IF ANY OF THE FOLLOWING OCCUR, THE CHILD NEEDS URGENT MEDICAL
ATTENTION:
The skin feels very hot with little or no sweating, or the child becomes confused or has muscle cramps, 
or the child’s heartbeat or breathing become rapid.  

 Take the child to a cool, shaded place 
 Keep the child's skin cool with water
 Give the child cold water to drink



48

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 Zonegran should be considered.

Zonegran should not be used as co-medication in paediatric patients with other medicinal products that 
predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal 
products with anticholinergic activity.

Body weight
Weight loss leading to deterioration of general condition and failure to take anti-epilepsy medication 
has been related to a fatal outcome (see section 4.8). Zonegran is not recommended for paediatric 
patients who are underweight (definition in accordance with the WHO age adjusted BMI categories)
or have a decreased appetite.

The incidence of decreased body weight is consistent across age groups (see section 4.8); however,
given the potential seriousness of weight loss in children, weight should be monitored in this 
population. A dietary supplement or increased food intake should be considered if the patient is failing 
to gain weight in accordance with growth charts, otherwise Zonegran should be discontinued. 

There are limited data from clinical studies in patients with a body weight of less than 20 kg. 
Therefore children aged 6 years and above with a body weight of less than 20 kg should be treated 
with caution. The long term effect of weight loss in the paediatric population on growth and 
development is unknown.

Metabolic 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 (see section 4.4 - Metabolic acidosis for full warning; see 
section 4.8 for incidence of low bicarbonate). The long term effect of low bicarbonate levels on 
growth and development is unknown. 

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

Kidney stones
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 for 
renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. 
Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone 
formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can 
reliably predict stone formation during zonisamide treatment.
Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in 
those with predisposing risk factors. Renal ultrasound should be performed at the discretion of the 
physician. In the event kidney stones are detected, Zonegran should be discontinued.

Hepatic dysfunction



49

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 Zonegran 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.   

Excipients

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

4.5 Interaction with other medicinal products and other forms of interaction

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 adult patients treated concomitantly with carbonic anhydrase 
inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible 
pharmacodynamic interaction (see section 4.4).

Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydrase 
inhibitors 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 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 



50

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, 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.  

Paediatric population
Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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 contraception 
unless 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 childbearing 
potential. Women planning a pregnancy should meet with their specialists to reassess treatment with 
zonisamide and to consider other therapeutic options.

As with all antiepileptic medicines, sudden discontinuation of zonisamide should be avoided as this 
may lead to breakthrough seizures that could have serious consequences for the woman and the 
unborn child. 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.

Pregnancy

There are limited 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.

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 compared 
with mothers treated with lamotrigine monotherapy.



51

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

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.

Fertility

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

4.7 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.

4.8 Undesirable effects

Summary of the safety profile

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. The most common adverse reactions in a randomised, controlled monotherapy 
trial comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate, 
decreased appetite, and decreased weight. The incidence of markedly abnormally low serum 
bicarbonate (a decrease to less than 17 mEq/l and by more than 5 mEq/l) was 3.8%. The incidence of 
marked decreases in weight of 20% or more was 0.7%.

Tabulated list of adverse reactions

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: 

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



52

Table 4. Adverse reactions associated with Zonegran obtained from adjunctive use clinical 
studies and post-marketing surveillance
System Organ 
Class
(MedDRA 
terminology)

Very 
Common

Common Uncommon Very Rare

Infections and 
infestation

Pneumonia
Urinary tract 
infection

Blood and 
lymphatic 
system disorders

Ecchymosis Agranulocytosis
Aplastic anaemia
Leucocytosis
Leucopoenia
Lymphadenopathy
Pancytopenia,
Thrombocytopenia

Immune system 
disorders

Hypersensitivity Drug-induced 
hypersensitivity syndrome
Drug rash with eosinophilia 
and systemic symptoms

Metabolism and 
nutrition 
disorders

Anorexia Hypokalaemia Metabolic acidosis
Renal tubular acidosis

Psychiatric 
Disorders

Agitation 
Irritability
Confusional 
state
Depression

Affect lability
Anxiety
Insomnia
Psychotic 
disorder

Anger
Aggression 
Suicidal ideation
Suicide attempt

Hallucination

Nervous system 
disorders

Ataxia
Dizziness
Memory 
impairment
Somnolence

Bradyphrenia
Disturbance in 
attention
Nystagmus
Paraesthesia
Speech disorder
Tremor

Convulsion Amnesia
Coma
Grand mal seizure
Myasthenic syndrome
Neuroleptic malignant
syndrome
Status epilepticus

Eye disorders Diplopia Angle closure glaucoma
Eye pain
Myopia
Vision blurred
Visual acuity reduced

Respiratory, 
thoracic and 
mediastinal 
disorders

Dyspnoea 
Pneumonia aspiration 
Respiratory disorder
Hypersensitivity-type 
Pneumonitis

Gastrointestinal 
disorders

Abdominal pain
Constipation
Diarrhoea
Dyspepsia
Nausea

Vomiting Pancreatitis

Hepatobiliary 
disorders

Cholecystitis
Cholelithiasis

Hepatocellular damage



53

System Organ 
Class
(MedDRA 
terminology)

Very 
Common

Common Uncommon Very Rare

Skin and 
subcutaneous 
tissue disorders

Rash
Pruritus
Alopecia

Anhidrosis
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis

Musculoskeletal 
and connective 
tissue disorders

Rhabdomyolysis

Renal and 
urinary 
disorders

Nephrolithiasis Calculus urinary Hydronephrosis
Renal failure
Urine abnormality

General 
disorders and 
administration 
site conditions

Fatigue
Influenza-like 
illness
Pyrexia
Oedema 
peripheral

Investigations Decreased 
bicarbonate

Weight 
decreased

Blood creatine 
phosphokinase increased
Blood creatinine increased
Blood urea increased
Liver function tests 
abnormal

Injury, 
poisoning and 
procedural 
complications

Heat stroke

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 comparing 
zonisamide with carbamazepine prolonged release

System Organ Class
(MedDRA terminology†)

Very Common Common Uncommon

Infections and 
infestation

Urinary tract infection
Pneumonia

Blood and lymphatic 
disorders

Leukopenia
Thrombocytopenia

Metabolism and 
nutrition disorders

Decreased appetite Hypokalaemia

Psychiatric Disorders Agitation
Depression
Insomnia
Mood swings
Anxiety

Confusional state
Acute psychosis
Aggression
Suicidal ideation
Hallucination



54

System Organ Class
(MedDRA terminology†)

Very Common Common Uncommon

Nervous system 
disorders

Ataxia
Dizziness
Memory impairment
Somnolence
Bradyphrenia
Disturbance in attention 
Paraesthesia

Nystagmus
Speech disorder
Tremor
Convulsion

Eye disorders Diplopia
Respiratory, thoracic 
and mediastinal 
disorders

Respiratory disorder

Gastrointestinal 
disorders

Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting

Abdominal pain

Hepatobiliary disorders Cholecystitis acute
Skin and subcutaneous 
tissue disorders

Rash Pruritus
Ecchymosis

General disorders and 
administration site 
conditions

Fatigue
Pyrexia
Irritability

Investigations Decreased 
bicarbonate

Weight decreased
Blood creatinine 
phosphokinase increased
Alanine aminotransferase 
increased
Aspartate aminotransferase 
increased

Urine analysis 
abnormal

† MedDRA version 13.1

Additional information on special populations:

Elderly
A pooled analysis of safety data on 95 elderly subjects has shown a relatively higher reporting 
frequency 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 frequency 
than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug 
Induced Hypersensitivity syndrome (DIHS).



55

Paediatric population
The adverse event profile of zonisamide in paediatric patients aged 6 to 17 years in placebo-controlled 
clinical studies was consistent with that of adults. Among 465 subjects in the paediatric safety 
database (including a further 67 subjects from the extension phase of the controlled clinical trial) there 
were 7 deaths (1.5%; 14.6/1000 person-years): 2 cases of status epilepticus, of which one was related 
to severe weight loss (10% within 3 months) in an underweight subject and subsequent failure to take 
medication; 1 case of head injury/haematoma, and 4 deaths in subjects with pre-existing functional 
neurological deficits for various causes (2 cases of pneumonia-induced sepsis/organ failure, 1 SUDEP 
and 1 head injury). A total of 70.4% of paediatric subjects who received ZNS in the controlled study 
or its open label extension had at least one treatment-emergent bicarbonate measurement below 22 
mmol/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 237 
subjects aged 12 to 16 years with a mean duration of exposure of approximately 12 months) has 
shown 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 the 
adult 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 body 
weight of 10% or more was 10.7% (see section 4.4). In some cases of weight decrease there was a 
delay in transition to the next Tanner stage and in bone maturation.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


56

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.  

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.

Clinical efficacy and safety

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 newly 
diagnosed partial seizures with or without secondary generalised tonic-clonic seizures. Subjects were 
randomised to carbamazepine and zonisamide received treatment for a duration of up to 24 months 
depending on response. Subjects were titrated to the initial target dose of 600 mg carbamazepine or 
300 mg of zonisamide. Subjects who experienced a seizure were titrated to the next target dose i.e. 800 
mg carbamazepine or 400 mg of zonisamide. Subjects who experienced a further seizure were titrated 
to the maximal target dose of 1200 mg carbamazepine or 500 mg zonisamide. Subjects who were 
seizure-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 Carbamazepine
n (ITT population) 281 300

Six months seizure freedom Diff CI
95%

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 
baseline period

71.7% 75.7% -4.0% -11.7% ; 3.7%

> 4 seizures during 3 month 
baseline period

52.9% 68.9% -15.9% -37.5% ; 5.6%

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 
baseline period

57.4% 64.7% -7.2% -15.7% ; 1.3%

> 4 seizures during 3 month 
baseline period

44.1% 48.9% -4.8% -26.9% ; 17.4%

Seizure Sub-type (6 month 
seizure 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%



57

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 in 
adults

In adults, 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.

Paediatric population

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

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

Specific safety issues that were encountered in the paediatric studies were: decreased appetite and 
weight loss, decreased bicarbonate levels, increased risk of kidney stones and dehydration. All these 
effects 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 and 
development are limited.

5.2 Pharmacokinetic properties

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 Cmax 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 antiepileptic 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.



58

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.

Linearity/non-linearity

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 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. There is no need for dose adjustment with any of the 
AEDs including CYP3A4 inducers.

Pharmacokinetic/pharmacodynamic relationship

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 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.

5.3 Preclinical safety data

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.



59

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.

In a repeated-dose oral toxicity study in juvenile rats, at exposure levels similar to those observed in 
paediatric patients at the maximum recommended dose, decreases in body weight and changes in renal 
histopathology and clinical pathology parameters and behavioural changes were observed. Changes in 
renal histopathology and clinical pathology parameters were considered to be related to carbonic 
anhydrase inhibition by zonisamide. The effects at this dose level were reversible during the recovery 
period. At a higher dose level (2-3-fold systemic exposure compared to therapeutic exposure) renal 
histopathological effects were more severe and only partially reversible. Most adverse effects 
observed in the juvenile rats were similar to those seen in the repeated-dose toxicity studies of 
zonisamide in adult rats, but renal tubular hyaline droplets and transitional hyperplasia were observed 
in 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 decreased 
body 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 levels 
equivalent to the maximum therapeutic dose in humans; irregular oestrus cycles and a decreased 
number of live foetuses were observed at exposure levels three times higher.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents
Microcrystalline cellulose 
Hydrogenated vegetable oil (from soyabean)
Sodium laurilsulfate

Capsule shells
Gelatin 
Titanium dioxide (E171) 
Allura red AC (E129) 
Sunset yellow FCF (E110) 
Shellac 
Propylene glycol 
Potassium hydroxide 
Black iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

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



60

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7. MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 

8. MARKETING AUTHORISATION NUMBER(S)

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

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10/03/2005
Date of latest renewal: 21/12/2009

10. DATE OF REVISION OF THE TEXT

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



61

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT



62

A MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Zonegran Capules:

Eisai Manufacturing Ltd
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire, AL10 9SN
United Kingdom

Or

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
o At the request of the European Medicines Agency;
o Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 



63

ANNEX III

LABELLING AND PACKAGE LEAFLET



64

A. LABELLING



65

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Zonegran 25 mg hard capsules
zonisamide

2. STATEMENT OF ACTIVE SUBSTANCE

Each hard capsule contains 25 mg zonisamide.

3. LIST OF EXCIPIENTS

Hydrogenated vegetable oil (from soyabean)

4. PHARMACEUTICAL FORM AND CONTENTS

14 hard capsules
28 hard capsules
56 hard capsules
84 hard capsules

5. METHOD AND ROUTE OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNINGS, IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30ºC.



66

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/307/001 14 capsules
EU/1/04/307/005 28 capsules
EU/1/04/307/002 56 capsules
EU/1/04/307/013 84 capsules

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Zonegran 25 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN: 
NN: 



67

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister Pack

1. NAME OF THE MEDICINAL PRODUCT

Zonegran 25 mg hard capsules
zonisamide

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Eisai 

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



68

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Zonegran 50 mg hard capsules
zonisamide

2. STATEMENT OF ACTIVE SUBSTANCE

Each hard capsule contains 50 mg zonisamide.

3. LIST OF EXCIPIENTS

Hydrogenated vegetable oil (from soyabean)

4. PHARMACEUTICAL FORM AND CONTENTS

14 hard capsules
28 hard capsules
56 hard capsules
84 hard capsules

5. METHOD AND ROUTE OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNINGS, IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30ºC.



69

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/307/010 14 capsules
EU/1/04/307/009 28 capsules
EU/1/04/307/003 56 capsules
EU/1/04/307/012 84 capsules

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Zonegran 50 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN: 
NN: 



70

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister Pack

1. NAME OF THE MEDICINAL PRODUCT

Zonegran 50 mg hard capsules
zonisamide

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Eisai 

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



71

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

OUTER CARTON

1. NAME OF THE MEDICINAL PRODUCT

Zonegran 100 mg hard capsules
zonisamide

2. STATEMENT OF ACTIVE SUBSTANCE

Each hard capsule contains 100 mg zonisamide.

3. LIST OF EXCIPIENTS

Contains also hydrogenated vegetable oil (from soyabean), sunset yellow FCF (E110) and allura red 
AC (E129). See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

28 hard capsules
56 hard capsules
84 hard capsules
98 hard capsules
196 hard capsules

5. METHOD AND ROUTE OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNINGS, IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Do not store above 30ºC.



72

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/04/307/006 28 capsules
EU/1/04/307/004 56 capsules
EU/1/04/307/011 84 capsules
EU/1/04/307/007 98 capsules
EU/1/04/307/008 196 capsules

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Zonegran 100 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN: 
NN: 



73

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister Pack

1. NAME OF THE MEDICINAL PRODUCT

Zonegran 100 mg hard capsules
zonisamide

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Eisai 

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



74

B. PACKAGE LEAFLET



75

Package leaflet: Information for the user

Zonegran 25 mg, 50 mg, and 100 mg hard capsules
zonisamide

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or your pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet:
1. What Zonegran is and what it is used for 
2. What you need to know before you take Zonegran
3. How to take Zonegran
4. Possible side effects
5. How to store Zonegran
6. Contents of the pack and other information

1. What Zonegran is and what it is used for

Zonegran contains the active substance zonisamide, and is used as an antiepileptic medicine.  

Zonegran is used to treat seizures that affect one part of the brain (partial seizure), which may or may 
not be followed by a seizure affecting all of the brain (secondary generalisation). 

Zonegran may be used:
 On its own to treat seizures in adults.
 With other antiepileptic medicines to treat seizures in adults, adolescents, and children aged 

6 years and above. 

2. What you need to know before you take Zonegran 

Do not take Zonegran:
 if you are allergic to zonisamide or any of the other ingredients of this medicine (listed in section 

6),
 if you are allergic to other sulphonamide medicines. Examples include: sulphonamide antibiotics, 

thiazide diuretics, and sulfonylurea antidiabetes medicines,
 if you are allergic to peanut or soya, do not use this medicinal product.

Warnings and precautions
Zonegran belongs to a group of medicines (sulphonamides) which can cause severe allergic reactions, 
severe skin rashes, and blood disorders, which very rarely can be fatal (see section 4. Possible side 
effects).

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

Talk to your doctor or pharmacist before taking Zonegran if you: 



76

 are younger than 12 years old, as you may be at greater risk of decreased sweating, heat stroke, 
pneumonia and liver problems. If you are younger than 6 years old, Zonegran is not recommended 
for you.  

 are elderly, as your dose of Zonegran may need adjusting, and you may be more likely to develop 
an allergic reaction, severe skin rash, swelling of the feet and legs, and itchiness when taking 
Zonegran (see section 4 Possible side effects). 

 suffer from liver problems, as your dose of Zonegran may need adjusting. 
 have eye problems such as glaucoma.
 suffer from kidney problems as your dose of Zonegran may need adjusting. 
 have previously suffered from kidney stones, as you may be at increased risk of developing more 

kidney stones. Reduce the risk of kidney stones by drinking sufficient water.
 live in a place or are on holiday in a place where the weather is warm. Zonegran can make you 

perspire less, which can cause your body temperature to increase. Reduce the risk of overheating 
by drinking sufficient water and keeping cool.

 are underweight, or have lost a lot of weight as Zonegran can cause you to lose more weight. Tell 
your doctor as this may need to be monitored.

 are pregnant or could become pregnant (see section ‘pregnancy, breast-feeding and fertility’ for 
further information).

If any of these applies to you, tell your doctor before you take Zonegran.

Children and adolescents
Talk to your doctor about the following risks:

Preventing overheating and dehydration in children

Zonegran can cause your child to sweat less and overheat and if your child is not treated this can lead 
to brain damage and death. Children are most at risk especially in hot weather. 

When your child is taking Zonegran:
• Keep your child cool especially in hot weather 
• Your child must avoid heavy exercise especially when the weather is hot 
• Give your child plenty of cold water to drink 
• Your child must not take these medicines:
carbonic anhydrase inhibitors (like topiramate and acetazolamide), and anticholinergic agents (like 
clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin).  

If your child’s skin feels very hot with little or no sweating, becomes confused, has muscle cramps, or 
your child’s heartbeat or breathing becomes rapid: 
 Take your child to a cool, shaded place 
 Sponge your child’s skin with cool (not cold) water
 Give your child cold water to drink
 Seek urgent medical assistance.

 Body weight: You should monitor your child’s weight every month and see your doctor as soon as 
possible if your child is not gaining enough weight. Zonegran is not recommended for children 
who are underweight or have a small appetite, and should be used with caution in those below 20 
kg.

 Increased acid level in the blood and kidney stones: Reduce these risks by ensuring that your child 
drinks enough water and is not taking any other medicine which could cause kidney stones (see 
Other medicines). Your doctor will monitor your child’s blood bicarbonate levels and kidneys (see 
also section 4).

Do not give this medicine to children below the age of 6 years because it is not known for this age 
group whether the potential benefits are greater than the risks.



77

Other medicines and Zonegran 
Please tell your doctor or pharmacist if you are taking, or have recently taken, any other medicines,
including medicines obtained without a prescription. 
 Zonegran should be used carefully in adults when taken with medicines that can cause kidney 

stones, like topiramate or acetazolamide. In children, this combination is not recommended
 Zonegran could possibly increase your blood levels of medicines like digoxin and quinidine, and 

so a reduction in their dose may be required.
 Other medicines like phenytoin, carbamazepine, phenobarbitone and rifampicin can decrease your 

blood levels of Zonegran, which may require an adjustment of your dose of Zonegran.

Zonegran with food and drink
Zonegran can be taken with or without food.

Pregnancy, breast-feeding and fertility
If you are a woman of childbearing age you must use adequate contraception while taking and for one 
month after stopping Zonegran.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. You should not stop your treatment without 
discussing this with your doctor.
You must only take Zonegran during your pregnancy if your doctor tells you to. Research has shown 
an increased risk of birth defects in children of women taking anti-epileptic medicines. A study 
showed that babies born to mothers using zonisamide during pregnancy were smaller than expected 
for their age at birth, compared with babies born to mothers treated with lamotrigine monotherapy. 
Make sure you are fully informed about the risks and the benefits of using zonisamide for epilepsy 
during pregnancy.

Do not breast-feed whilst taking, or for one month after stopping Zonegran.

There are no clinical data available on the effects of zonisamide on human fertility. Studies in animals 
have shown changes in fertility parameters.

Driving and using machines
Zonegran may affect your concentration, ability to react/respond, and may make you feel sleepy, 
particularly at the beginning of your treatment or after your dose is increased. Be especially careful 
while driving or operating machinery, if Zonegran affects you in this way.

Important information about some of the ingredients of Zonegran

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

Zonegran contains soya oil. If you are allergic to peanut or soya, do not use this medicinal product.

3. How to take Zonegran  

Always take this medicine exactly as your doctor has told you. You should check with your doctor or 
pharmacist if you are not sure.

The recommended adult dose

When you take Zonegran on its own:
 The starting dose is 100 mg taken once a day.
 This may be increased by up to 100 mg at intervals of two weeks.
 The recommended dose is 300 mg once a day.



78

When you take Zonegran with other antiepileptic medicines:
 The starting dose is 50 mg daily taken in two equal doses of 25 mg.
 This may be increased by up to 100 mg at intervals of one to two weeks.
 The recommended daily dose is between 300 mg and 500 mg.
 Some people respond to lower doses. The dose may be increased more slowly if you experience 

side effects, are elderly or if you suffer from kidney or liver problems.

Use in children (aged 6 to 11 years) and adolescents (aged 12 to 17 years) weighing at least 20 kg:
 The starting dose is 1 mg per kg of body weight taken once a day.
 This may be increased by 1 mg per kg of body weight at intervals of one to two weeks.
 The recommended daily dose is 6 to 8 mg per kg for a child with a body weight of up to 55 kg or 

300 to 500 mg for a child with a body weight more than 55 kg (which ever dose is lower) taken 
once a day.

Example: A child who weighs 25 kg should take 25 mg once a day for the first week, and then increase 
the daily dose by 25 mg at the start of each week until a daily dose between 150 to 200 mg is reached.

If you feel that the effect of Zonegran is too strong or too weak, talk to your doctor or pharmacist.

 Zonegran capsules must be swallowed whole with water.
 Do not chew the capsules.
 Zonegran can be taken once or twice daily, as instructed by your doctor.
 It you take Zonegran twice a day, take half the daily dose in the morning and half in the evening.

If you take more Zonegran than you should
If you may have taken more Zonegran than you should, tell a carer (relative or friend), your doctor or 
pharmacist immediately, or contact your nearest hospital casualty department, taking your medicine 
with you. You may become sleepy and could lose consciousness. You might also feel sick, have a sore 
stomach, muscle twitches, eye movement, feel faint, have a slowed heart beat, and reduced breathing 
and kidney function. Do not try to drive.

If you forget to take Zonegran
 If you forget to take a dose, don’t worry: take the next dose when it is due.
 Do not take double the dose to make up for the forgotten dose.

If you stop taking Zonegran
 Zonegran is meant to be taken as a long-term medicine. Do not reduce your dose or stop your 

medicine unless your doctor tells you to.
 If your doctor advises you to stop taking Zonegran your dose will be reduced gradually to lower

the risk of more seizures.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.



79

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Zonegran belongs to a group of medicines (sulphonamides) that can cause severe allergic reactions, 
severe skin rashes, and blood disorders, which very rarely can be fatal.

Contact your doctor immediately if you:
 have difficulty breathing, a swollen face, lips or tongue, or a severe skin rash as these symptoms 

may indicate that you are having a severe allergic reaction.
 have signs of overheating - high body temperature but little or no sweating, rapid heartbeat and 

breathing, muscle cramps, and confusion. 
 have thoughts of harming or killing yourself. A small number of people being treated with anti-

epileptics such as Zonegran have had thoughts of harming or killing themselves.
 have pain in your muscles or a feeling of weakness, as this may be a sign of abnormal muscle 

breakdown which can lead to kidney problems.
 get a sudden pain in your back or stomach, have pain on urinating (passing water) or notice blood 

in your urine, as this may be a sign of kidney stones. 
 develop visual problems such as eye pain or blurred vision while taking Zonegran

Contact your doctor as soon as possible if you:
 have an unexplained skin rash, as this could develop into a more severe skin rash or skin peeling.
 feel unusually tired or feverish, have a sore throat, swollen glands, or find that you bruise more 

easily, as this may mean you have a blood disorder. 
 have signs of increased acid level in the blood- headaches, drowsiness, shortness of breath and 

loss of appetite. Your doctor may need to monitor or treat this.

Your doctor may decide that you should stop using Zonegran.

The most common side effects of Zonegran are mild. They occur during the first month of treatment 
and usually decrease with continued treatment. In children ages 6 – 17 years old, side effects were 
consistent with those described below with the following exceptions: pneumonia, dehydration, 
sweating decreased (common) and abnormal liver enzymes (uncommon).

Very common side effects (may affect more than 1 in 10 people):
 agitation, irritability, confusion, depression
 poor muscle coordination, dizziness, poor memory, sleepiness, double vision
 loss of appetite, decreased blood levels of bicarbonate (a substance that prevents your blood from 

becoming acidic)

Common side effects (may affect up to 1 in 10 people):
 difficulty sleeping, strange or unusual thoughts, feeling anxious or emotional.
 slowed thoughts, loss of concentration, speech abnormalities, abnormal skin sensation (pins and 

needles), tremor, involuntary movement of the eyes.
 kidney stones.
 skin rashes, itching, allergic reactions, fever, tiredness, flu-like symptoms, hair loss.
 ecchymosis (a small bruise caused by blood leaking from broken blood vessels in the skin).
 loss of weight, nausea, indigestion, stomach pains, diarrhoea (loose stools), constipation.
 swelling of the feet and legs.

Uncommon side effects (may affect up to 1 in 100 people):
 anger, aggression, thoughts of suicide, suicide attempt.
 vomiting.
 gall bladder inflammation, gallstones.
 urinary stones.
 lung infection / inflammation, urinary tract infections.



80

 low blood potassium levels, convulsions/seizures. 

Very rare side effects (may affect up to 1 in 10,000 people):
 hallucinations, memory loss, coma, neuroleptic malignant syndrome (inability to move, sweating, 

fever, incontinence), status epilepticus (prolonged or repeated seizures).
 breathing disorders, shortness of breath, inflammation of the lungs.
 inflammations of the pancreas (severe pain in the stomach or back)
 liver problems, kidney failure, increased blood levels of creatinine (a waste product that your 

kidneys should normally remove).
 severe rashes or skin peeling (at the same time you may feel unwell or develop a fever).
 abnormal muscle breakdown (you may feel pain or weakness in your muscles) which can lead to 

kidney problems.
 swollen glands, blood disorders (reduction in the number of blood cells, which can make infection 

more likely and can make you look pale, feel tired and feverish, and bruise more easily).
 decreased sweating, overheating.
 glaucoma, which is a blockage of fluid in the eye causing increased pressure in the eye. Eye pain, 

blurred vision or decreased vision may occur and can be signs of glaucoma.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store Zonegran 

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and the carton after EXP. 
The expiry date refers to the last day of that month.

Do not store above 30°C.

Do not use this medicine if you notice any damage to the capsules, blister or carton or any visible 
signs of deterioration in the medicine. Return the pack to your pharmacist.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Zonegran contains
The active substance in Zonegran is zonisamide.  

Zonegran 25 mg hard capsules contain 25 mg of zonisamide. Zonegran 50 mg hard capsules contain 
50 mg zonisamide. Zonegran 100 mg hard capsules contain 100 mg zonisamide.  

 The other ingredients that are present in the capsule contents are: microcrystalline cellulose, 
hydrogenated vegetable oil (from soyabean) and sodium laurilsulfate.

 The capsule shell contains: gelatin, titanium dioxide (E171), shellac, propylene glycol, potassium 
hydroxide, black iron oxide (E172). Additionally the 100 mg capsule shell contains sunset yellow 
FCF (E110) and allura red (E129).

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


81

See Section 2 for important information about the ingredients: sunset yellow FCF (E110) and 
allura red AC (E129) and hydrogenated vegetable oil (from soyabean).

What Zonegran looks like and contents of the pack
- Zonegran 25 mg hard capsules have a white opaque body and a white opaque cap and are 

printed with a logo and “ZONEGRAN 25” in black.  
- Zonegran 50 mg hard capsules have a white opaque body and a grey opaque cap and are printed 

with a logo and “ZONEGRAN 50” in black. 
- Zonegran 100 mg hard capsules have a white opaque body and a red opaque cap and are printed 

with a logo and “ZONEGRAN 100” in black.  

Zonegran capsules are packaged in blister packs supplied in boxes containing:

- 25 mg: 14, 28, 56 and 84 capsules
- 50 mg: 14, 28, 56 and 84 capsules
- 100 mg: 28, 56, 84, 98 and 196 capsules.

Not all pack sizes may be available.

Marketing Authorisation Holder
Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 
e-mail: medinfo_de@eisai.net

Manufacturer
Eisai Manufacturing Ltd
European Knowledge Centre,
Mosquito Way
Hatfield
Herts
AL10 9SN
United Kingdom.

Or

Eisai GmbH
Edmund-Rumpler-Straße 3   
60549 Frankfurt am Main
Germany 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
Eisai SA/NV
Tél/Tel: +32 (0)800 158 58

Lietuva
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Vokietija)

България
Eisai GmbH
Teл.: + 49 (0) 69 66 58 50
(Германия)

Luxembourg/Luxemburg
Eisai SA/NV
Tél/Tel: +32 (0)800 158 58
(Belgique/Belgien)



82

Česká republika
Eisai GesmbH organizačni složka
Tel: + 420 242 485 839

Magyarország
Ewopharma Hungary Ltd.
Tel: +36 1 200 46 50

Danmark
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)

Malta
Associated Drug Co. Ltd
Tel: + 356 2277 8000

Deutschland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50

Nederland
Eisai B.V.
Tel: + 31 (0) 900 575 3340

Eesti
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Saksamaa)

Norge
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)

Ελλάδα
Arriani Pharmaceutical S.A.
Τηλ: + 30 210 668 3000

Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0

España
Eisai Farmacéutica, S.A.
Tel: + (34) 91 455 94 55

Polska
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Niemcy)

France
Eisai SAS
Tél: + (33) 1 47 67 00 05

Portugal
Eisai Farmacêtica, Unipessoal Lda
Tel: + 351 214 875 540

Hrvatska
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Njemačka)

România
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Germania)

Ireland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Germany)

Slovenija
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Nemčija)

Ísland
Eisai AB
Sími: + 46 (0)8 501 01 600
(Svíþjóð)

Slovenská republika
Eisai GesmbH organizačni složka
Tel.: + 420 242 485 839
(Česká republika)

Italia
Eisai S.r.l.
Tel: + 39 02 5181401

Suomi/Finland
Eisai AB
Puh/Tel: + 46 (0) 8 501 01 600
(Ruotsi)

Κύπρος
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
(Ελλάδα)

Sverige
Eisai AB
Tel: + 46 (0) 8 501 01 600



83

Latvija
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
(Vācija)

United Kingdom
Eisai Europe Ltd.
Tel: +44 (0)208 600 1400

This leaflet was last revised in

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


	SUMMARY OF PRODUCT CHARACTERISTICS
	A MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET