ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Zonegran 25 mg hard capsules
2.
Each hard capsule contains 25 mg of zonisamide.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
A white opaque body and a white opaque cap printed with a logo and “ZONEGRAN 25” in black.
4.
Zonegran is indicated as adjunctive therapy in the treatment of adult patients with partial seizures, with
or without secondary generalisation.
Posology
Adults
Zonegran must be added to existing therapy and the dose should be titrated on the basis of clinical
effect. Doses of 300 mg to 500 mg per day have been shown to be effective, though some patients,
especially those not taking CYP3A4-inducing agents, may respond to lower doses.
The recommended initial daily dose is 50 mg in two divided doses. After one week the dose may be
increased to 100 mg daily and thereafter the dose may be increased at weekly intervals, in increments
of up to 100 mg.
Use of two weekly intervals should be considered for patients with renal or hepatic impairment and
patients not receiving CYP3A4-inducing agents (see section 4.5).
Zonegran can be administered once or twice daily after the titration phase.
Elderly
Caution should be exercised at initiation of treatment in elderly patients as there is limited information
on the use of Zonegran in these patients. Prescribers should also take account of the safety profile of
Zonegran (see section 4.8).
Paediatric population
The safety and efficacy of Zonegran in children and adolescents have not yet been established.
Currently available data are described in section 5.2 but no recommendation on a posology can be
made.
2
Patients with renal impairment
Caution must be exercised in treating patients with renal impairment, as there is limited information on
use in such patients and a slower titration of Zonegran might be required. Since zonisamide and its
metabolites are excreted renally, it should be discontinued in patients who develop acute renal failure
or where a clinically significant sustained increase in serum creatinine is observed.
In subjects with renal impairment, renal clearance of single doses of zonisamide was positively
correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in
subjects with creatinine clearance < 20 ml/min.
Patients with hepatic impairment
Use in patients with hepatic impairment has not been studied. Therefore use in patients with severe
hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to
moderate hepatic impairment, and a slower titration of Zonegran may be required.
Withdrawal of Zonegran
When Zonegran treatment is to be discontinued, it should be withdrawn gradually. In clinical studies,
dose reductions of 100 mg at weekly intervals have been used with concurrent adjustment of other
antiepileptic medicine doses.
Method of administration
Zonegran hard capsules are for oral use.
Effect of food
Zonegran may be taken with or without food (see section 5.2).
Hypersensitivity to the active substance, to any of the excipients or to sulphonamides.
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.
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.
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.
3
Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and
leucocytosis have been reported. There is inadequate information to assess the relationship, if any,
between dose and duration of treatment and these events.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic
medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The
mechanism of this risk is not known and the available data do not exclude the possibility of an
increased risk for Zonegran.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate
treatment should be considered. Patients (and caregivers of patients) should be advised to seek
medical advice should signs of suicidal ideation or behaviour emerge.
Kidney stones have occurred in patients treated with zonisamide. Zonegran should be used with
caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family
history of nephrolithiasis and hypercalcuria. Such patients may be at increased risk for renal stone
formation and associated signs and symptoms such as renal colic, renal pain or flank pain. In addition,
patients taking other medications associated with nephrolithiasis may be at increased risk. Increasing
fluid intake and urine output may help reduce the risk of stone formation, particularly in those with
predisposing risk factors.
Hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the
normal reference range in the absence of chronic respiratory alkalosis) is associated with Zonegran
treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of
zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of
Zonegran in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-
induced metabolic acidosis occurs early in treatment although cases can occur at any time during
treatment. The amounts by which bicarbonate is decreased are usually small – moderate (average
decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can
experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal
disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or
medicinal products) may be additive to the bicarbonate lowering effects of zonisamide.
The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger
patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in
patients taking zonisamide who have underlying conditions which might increase the risk of acidosis,
in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients
with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists,
consideration should be given to reducing the dose or discontinuing Zonegran (by gradual
discontinuation or reduction of a therapeutic dose). If the decision is made to continue patients on
Zonegran in the face of persistent acidosis, alkali treatment should be considered.
Zonegran should be used with caution in patients being treated concomitantly with carbonic anhydrase
inhibitors such as topiramate, as there are insufficient data to rule out a pharmacodynamic interaction
(see section 4.5).
Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric
patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Most reports
occurred during periods of warm weather. Patients or their carers must be warned to take care to
maintain hydration and avoid exposure to excessive temperatures. Caution should be used when
Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders;
these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.
In patients taking Zonegran who develop the clinical signs and symptoms of pancreatitis, it is
recommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the
4
absence of another obvious cause, it is recommended that discontinuation of Zonegran be considered
and appropriate treatment initiated.
In patients taking Zonegran, in whom severe muscle pain and/or weakness develop either in the
presence or absence of a fever, it is recommended that markers of muscle damage be assessed,
including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another
obvious cause such as trauma or grand mal seizures, it is recommended that Zonegran discontinuation
be considered and appropriate treatment initiated.
Women of child-bearing potential must use adequate contraception during treatment with Zonegran
and for one month after discontinuation (see section 4.6). Physicians treating patients with Zonegran
should try to ensure that appropriate contraception is used, and should use clinical judgement when
assessing whether oral contraceptives (OCs), or the doses of the OC components, are adequate based
on the individual patient’s clinical situation.
There is limited data from clinical studies in patients with a body weight of less than 40 kg. Therefore
these patients should be treated with caution.
Zonegran may cause weight loss. A dietary supplement or increased food intake may be considered if
the patient is losing weight or is underweight whilst on this medication. If substantial undesirable
weight loss occurs, discontinuation of Zonegran should be considered.
Effect of Zonegran on cytochrome P450 enzymes
In vitro
studies using human liver microsomes show no or little (<25%) inhibition of cytochrome P450
isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at zonisamide levels approximately two-
fold or greater than clinically relevant unbound serum concentrations. Therefore, Zonegran is not
expected to affect the pharmacokinetics of other medicinal products via cytochrome P450-mediated
mechanisms, as demonstrated for carbamazepine, phenytoin, ethinylestradiol and desipramine
in vivo
.
Potential for Zonegran to affect other medicinal products
Anti-epileptic medicinal products
In epileptic patients, steady-state dosing with Zonegran resulted in no clinically relevant
pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.
Oral contraceptives
In clinical studies in healthy subjects, steady-state dosing with Zonegran did not affect serum
concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.
Carbonic anhydrase inhibitors
Zonegran should be used with caution in patients treated concomitantly with carbonic anhydrase
inhibitors such as topiramate, as there are insufficient data to rule out a possible pharmacodynamic
interaction t (see section 4.4).
P-gp substrate
An
in vitro
study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC
50
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).
5
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.
Women of childbearing potential
Women of childbearing potential must use adequate contraception during treatment with Zonegran,
and for one month after discontinuation.
Pregnancy
There are no adequate data from the use of Zonegran in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Zonegran must not be used during pregnancy unless clearly necessary, in the opinion of the physician,
and only if the potential benefit is considered to justify the risk to the foetus. The need for anti-
epileptic treatment should be reviewed in patients planning to become pregnant. If Zonegran is
prescribed, careful monitoring is recommended.
Specialist advice should be given to women who are likely to become pregnant in order to consider the
optimal treatment during pregnancy. Women of childbearing potential should be given specialist
advice regarding possible effects of Zonegran on the foetus and the risk should be discussed with the
patient in relation to the benefits before starting treatment. The risk of birth defect is increased by
factor 2 to 3 in the offspring of mothers treated with an antiepileptic medicinal product The most
frequently reported are cleft lip, cardiovascular malformations and neural tube defect. Multiple
antiepileptic medicinal product therapy may be associated with a higher risk of congenital
malformations than monotherapy.
No sudden discontinuation of anti-epileptic therapy should be undertaken as this may lead to
breakthrough seizures, which could have serious consequences for both mother and child.
Breast-feeding
Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from
6
Zonegran therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not
be resumed until one month after Zonegran therapy is completed.
No studies on the effects on the ability to drive and use machines have been performed. However,
given that some patients may experience drowsiness or difficulty with concentration, particularly early
in treatment or after a dose increase, patients must be advised to exercise caution during activities
requiring a high degree of alertness, e.g., driving or operating machines.
Zonegran has been administered to over 1,200 patients in clinical studies, more than 400 of whom
received Zonegran for at least 1 year. In addition there has been extensive post-marketing experience
with zonisamide in Japan since 1989 and in the USA since 2000.
It should be noted that Zonegran is a benzisoxazole derivative, which contains a sulphonamide group.
Serious immune based adverse reactions that are associated with medicinal products containing a
sulphonamide group include rash, allergic reaction and major haematological disturbances including
aplastic anaemia, which very rarely can be fatal (see section 4.4).
The most common adverse reactions in controlled adjunctive-therapy studies were somnolence,
dizziness and anorexia. Adverse reactions associated with Zonegran obtained from clinical studies
and post-marketing surveillance are tabulated below. The frequencies are arranged according to the
following scheme:
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
not known
cannot be estimated from the available data
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
Metabolism and
nutrition
disorders
Anorexia
Hypokalaemia
Metabolic acidosis
Renal tubular acidosis
7
very rare
< 1/10,000
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
Respiratory,
thoracic and
mediastinal
disorders
Dyspnoea
Pneumonia aspiration
Respiratory disorder
Gastrointestinal
disorders
Abdominal pain
Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting
Pancreatitis
Hepatobiliary
disorders
Cholecystitis
Cholelithiasis
Hepatocellular damage
Skin and
subcutaneous
tissue disorders
Rash
Anhidrosis
Erythema multiforme
Pruritis
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
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.
8
Additional information on special populations:
Review of post-marketing data suggests that patients aged 65 years or older report a higher frequency
than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug
Induced Hypersensitivity syndrome (DIHS).
There have been cases of accidental and intentional overdose in adult and paediatric patients. In some
cases, the overdoses were asymptomatic, particularly where emesis or lavage was prompt. In other
cases, the overdose was followed by symptoms such as somnolence, nausea, gastritis, nystagmus,
myoclonus, coma, bradycardia, reduced renal function, hypotension and respiratory depression. A
very high plasma concentration of 100.1 μg/ml zonisamide was recorded approximately 31 hours after
a patient took an overdose of Zonegran and clonazepam; the patient became comatose and had
respiratory depression, but recovered consciousness five days later and had no sequelae.
Treatment
No specific antidotes for Zonegran overdose are available. Following a suspected recent overdose,
emptying the stomach by gastric lavage or by induction of emesis may be indicated with the usual
precautions to protect the airway. General supportive care is indicated, including frequent monitoring
of vital signs and close observation. Zonisamide has a long elimination half-life so its effects may be
persistent. Although not formally studied for the treatment of overdose, haemodialysis reduced
plasma concentrations of zonisamide in a patient with reduced renal function, and may be considered
as treatment of overdose if clinically indicated.
5.
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.
Clinical efficacy
Efficacy has been demonstrated with Zonegran in 4 double-blind, placebo-controlled studies of
periods of up to 24 weeks with either once or twice daily dosing. These studies show that the median
reduction in partial seizure frequency is related to Zonegran dose with sustained efficacy at doses of
300-500 mg per day.
Pharmacodynamic effects
The anticonvulsant activity of zonisamide has been evaluated in a variety of models, in several species
with induced or innate seizures, and zonisamide appears to act as a broad-spectrum anti-epileptic in
these models. Zonisamide prevents maximal electroshock seizures and restricts seizure spread,
including the propagation of seizures from cortex to sub-cortical structures and suppresses
epileptogenic focus activity. Unlike phenytoin and carbamazepine however, zonisamide acts
preferentially on seizures originating in the cortex.
Mechanism of action
The mechanism of action of zonisamide is not fully elucidated, but it appears to act on
voltage-sensitive sodium and calcium channels, thereby disrupting synchronised neuronal firing,
reducing the spread of seizure discharges and disrupting subsequent epileptic activity. Zonisamide
also has a modulatory effect on GABA-mediated neuronal inhibition.
9
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 C
max
values increased almost linearly after single dose over the dose range of
100-800 mg and after multiple doses over the dose range of 100-400 mg once daily. The increase at
steady state was slightly more than expected on the basis of dose, probably due to the saturable
binding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater
than expected accumulation occurs relative to single dosing.
Distribution
Zonisamide is 40 - 50 % bound to human plasma proteins, with
in vitro
studies showing that this is
unaffected by the presence of various 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.
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.
10
Other characteristics
No clear Zonegran dose-concentration-response relationship has been defined. When comparing the
same dose level, subjects of higher total body weight appear to have lower steady-state serum
concentrations, but this effect appears to be relatively modest. Age (≥ 12 years) and gender, after
adjustment for body weight effects, have no apparent effect on zonisamide exposure in epileptic
patients during steady-state dosing.
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.
6.
6.1 List of excipients
Capsule contents
Microcrystalline cellulose
Hydrogenated vegetable oil
Sodium laurilsulfate
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.
11
6.6 Special precautions for disposal
No special requirements.
7.
Eisai Limited
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire, AL10 9SN
United Kingdom
8.
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: 10/03/2005
Date of latest renewal:
10/03/2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency: http://www.ema.europa.eu
12
1.
Zonegran 50 mg hard capsules.
2.
Each hard capsule contains 50 mg of zonisamide.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
A white opaque body and a grey opaque cap printed with a logo and “ZONEGRAN 50” in black.
4.
Zonegran is indicated as adjunctive therapy in the treatment of adult patients with partial seizures, with
or without secondary generalisation.
Posology
Adults
Zonegran must be added to existing therapy and the dose should be titrated on the basis of clinical
effect. Doses of 300 mg to 500 mg per day have been shown to be effective, though some patients,
especially those not taking CYP3A4-inducing agents, may respond to lower doses.
The recommended initial daily dose is 50 mg in two divided doses. After one week the dose may be
increased to 100 mg daily and thereafter the dose may be increased at weekly intervals, in increments
of up to 100 mg.
Use of two weekly intervals should be considered for patients with renal or hepatic impairment and
patients not receiving CYP3A4-inducing agents (see section 4.5).
Zonegran can be administered once or twice daily after the titration phase.
Elderly
Caution should be exercised at initiation of treatment in elderly patients as there is limited information
on the use of Zonegran in these patients. Prescribers should also take account of the safety profile of
Zonegran (see section 4.8).
Paediatric population
The safety and efficacy of Zonegran in children and adolescents have not yet been established.
Currently available data are described in section 5.2 but no recommendation on a posology can be
made.
13
Patients with renal impairment
Caution must be exercised in treating patients with renal impairment, as there is limited information on
use in such patients and a slower titration of Zonegran might be required. Since zonisamide and its
metabolites are excreted renally, it should be discontinued in patients who develop acute renal failure
or where a clinically significant sustained increase in serum creatinine is observed.
In subjects with renal impairment, renal clearance of single doses of zonisamide was positively
correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in
subjects with creatinine clearance < 20 ml/min.
Patients with hepatic impairment
Use in patients with hepatic impairment has not been studied. Therefore use in patients with severe
hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to
moderate hepatic impairment, and a slower titration of Zonegran may be required.
Withdrawal of Zonegran
When Zonegran treatment is to be discontinued, it should be withdrawn gradually. In clinical studies,
dose reductions of 100 mg at weekly intervals have been used with concurrent adjustment of other
antiepileptic medicine doses.
Method of administration
Zonegran hard capsules are for oral use.
Effect of food
Zonegran may be taken with or without food (see section 5.2).
Hypersensitivity to the active substance, to any of the excipients or to sulphonamides.
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.
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.
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
14
rash, allergic reaction and major haematological disturbances, including aplastic anaemia, which very
rarely can be fatal.
Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and
leucocytosis have been reported. There is inadequate information to assess the relationship, if any,
between dose and duration of treatment and these events.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic
medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The
mechanism of this risk is not known and the available data do not exclude the possibility of an
increased risk for Zonegran.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate
treatment should be considered. Patients (and caregivers of patients) should be advised to seek
medical advice should signs of suicidal ideation or behaviour emerge.
Kidney stones have occurred in patients treated with zonisamide. Zonegran should be used with
caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family
history of nephrolithiasis and hypercalcuria. Such patients may be at increased risk for renal stone
formation and associated signs and symptoms such as renal colic, renal pain or flank pain. In addition,
patients taking other medications associated with nephrolithiasis may be at increased risk. Increasing
fluid intake and urine output may help reduce the risk of stone formation, particularly in those with
predisposing risk factors.
Hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the
normal reference range in the absence of chronic respiratory alkalosis) is associated with Zonegran
treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of
zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of
Zonegran in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-
induced metabolic acidosis occurs early in treatment although cases can occur at any time during
treatment. The amounts by which bicarbonate is decreased are usually small – moderate (average
decrease of approximately 3.5 mEq/l at daily doses of 300mg 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). If the decision is made to continue patients on
Zonegran in the face of persistent acidosis, alkali treatment should be considered.
Zonegran should be used with caution in patients being treated concomitantly with carbonic anhydrase
inhibitors such as topiramate, as there are insufficient data to rule out a pharmacodynamic interaction
(see section 4.5).
Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric
patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Most reports
occurred during periods of warm weather. Patients or their carers must be warned to take care to
maintain hydration and avoid exposure to excessive temperatures. Caution should be used when
Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders;
these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.
15
In patients taking Zonegran who develop the clinical signs and symptoms of pancreatitis, it is
recommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the
absence of another obvious cause, it is recommended that discontinuation of Zonegran be considered
and appropriate treatment initiated.
In patients taking Zonegran, in whom severe muscle pain and/or weakness develop either in the
presence or absence of a fever, it is recommended that markers of muscle damage be assessed,
including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another
obvious cause such as trauma or grand mal seizures, it is recommended that Zonegran discontinuation
be considered and appropriate treatment initiated.
Women of child-bearing potential must use adequate contraception during treatment with Zonegran
and for one month after discontinuation (see section 4.6). Physicians treating patients with Zonegran
should try to ensure that appropriate contraception is used, and should use clinical judgement when
assessing whether oral contraceptives (OCs), or the doses of the OC components, are adequate based
on the individual patient’s clinical situation.
There is limited data from clinical studies in patients with a body weight of less than 40 kg. Therefore
these patients should be treated with caution.
Zonegran may cause weight loss. A dietary supplement or increased food intake may be considered if
the patient is losing weight or is underweight whilst on this medication. If substantial undesirable
weight loss occurs, discontinuation of Zonegran should be considered.
Effect of Zonegran on cytochrome P450 enzymes
In vitro
studies using human liver microsomes show no or little (<25%) inhibition of cytochrome P450
isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at zonisamide levels approximately two-
fold or greater than clinically relevant unbound serum concentrations. Therefore, Zonegran is not
expected to affect the pharmacokinetics of other medicinal products via cytochrome P450-mediated
mechanisms, as demonstrated for carbamazepine, phenytoin, ethinylestradiol and desipramine
in vivo
.
Potential for Zonegran to affect other medicinal products
Anti-epileptic medicinal products
In epileptic patients, steady-state dosing with Zonegran resulted in no clinically relevant
pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.
Oral contraceptives
In clinical studies in healthy subjects, steady-state dosing with Zonegran did not affect serum
concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.
Carbonic anhydrase inhibitors
Zonegran should be used with caution in patients treated concomitantly with carbonic anhydrase
inhibitors such as topiramate, as there are insufficient data to rule out a possible pharmacodynamic
interaction (see section 4.4).
P-gp substrate
An
in vitro
study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC
50
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).
16
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.
Women of childbearing potential
Women of childbearing potential must use adequate contraception during treatment with Zonegran,
and for one month after discontinuation.
Pregnancy
There are no adequate data from the use of Zonegran in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Zonegran must not be used during pregnancy unless clearly necessary, in the opinion of the physician,
and only if the potential benefit is considered to justify the risk to the foetus. The need for anti-
epileptic treatment should be reviewed in patients planning to become pregnant. If Zonegran is
prescribed, careful monitoring is recommended.
Specialist advice should be given to women who are likely to become pregnant in order to consider the
optimal treatment during pregnancy. Women of childbearing potential should be given specialist
advice regarding possible effects of Zonegran on the foetus and the risk should be discussed with the
patient in relation to the benefits before starting treatment. The risk of birth defect is increased by
factor 2 to 3 in the offspring of mothers treated with an antiepileptic medication. The most frequently
reported are cleft lip, cardiovascular malformations and neural tube defect. Multiple antiepileptic
medicinal product therapy may be associated with a higher risk of congenital malformations than
monotherapy.
No sudden discontinuation of anti-epileptic therapy should be undertaken as this may lead to
breakthrough seizures, which could have serious consequences for both mother and child.
Breast-feeding
Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from
17
Zonegran therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not
be resumed until one month after Zonegran therapy is completed.
No studies on the effects on the ability to drive and use machines have been performed. However,
given that some patients may experience drowsiness or difficulty with concentration, particularly early
in treatment or after a dose increase, patients must be advised to exercise caution during activities
requiring a high degree of alertness, e.g., driving or operating machines.
Zonegran has been administered to over 1,200 patients in clinical studies, more than 400 of whom
received Zonegran for at least 1 year. In addition there has been extensive post-marketing experience
with zonisamide in Japan since 1989 and in the USA since 2000.
It should be noted that Zonegran is a benzisoxazole derivative, which contains a sulphonamide group.
Serious immune based adverse reactions that are associated with medicinal products containing a
sulphonamide group include rash, allergic reaction and major haematological disturbances including
aplastic anaemia, which very rarely can be fatal (see section 4.4).
The most common adverse reactions in controlled adjunctive-therapy studies were somnolence,
dizziness and anorexia. Adverse reactions associated with Zonegran obtained from clinical studies
and post-marketing surveillance are tabulated below. The frequencies are arranged according to the
following scheme:
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
not known
cannot be estimated from the available data
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
Metabolism and
nutrition
disorders
Anorexia
Hypokalaemia
Metabolic acidosis
Renal tubular acidosis
18
very rare
< 1/10,000
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
Respiratory,
thoracic and
mediastinal
disorders
Dyspnoea
Pneumonia aspiration
Respiratory disorder
Gastrointestinal
disorders
Abdominal pain
Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting
Pancreatitis
Hepatobiliary
disorders
Cholecystitis
Cholelithiasis
Hepatocellular damage
Skin and
subcutaneous
tissue disorders
Rash
Anhidrosis
Erythema multiforme
Pruritis
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
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.
19
Additional information on special populations:
Review of post-marketing data suggests that patients aged 65 years or older report a higher frequency
than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug
Induced Hypersensitivity syndrome (DIHS).
There have been cases of accidental and intentional overdose in adult and paediatric patients. In some
cases, the overdoses were asymptomatic, particularly where emesis or lavage was prompt. In other
cases, the overdose was followed by symptoms such as somnolence, nausea, gastritis, nystagmus,
myoclonus, coma, bradycardia, reduced renal function, hypotension and respiratory depression. A
very high plasma concentration of 100.1 μg/ml zonisamide was recorded approximately 31 hours after
a patient took an overdose of Zonegran and clonazepam; the patient became comatose and had
respiratory depression, but recovered consciousness five days later and had no sequelae.
Treatment
No specific antidotes for Zonegran overdose are available. Following a suspected recent overdose,
emptying the stomach by gastric lavage or by induction of emesis may be indicated with the usual
precautions to protect the airway. General supportive care is indicated, including frequent monitoring
of vital signs and close observation. Zonisamide has a long elimination half-life so its effects may be
persistent. Although not formally studied for the treatment of overdose, haemodialysis reduced
plasma concentrations of zonisamide in a patient with reduced renal function, and may be considered
as treatment of overdose if clinically indicated.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Anti-epileptics, other antiepileptics, ATC code: N03AX15
Zonisamide is a benzisoxazole derivative. It is an anti-epileptic medicine with weak carbonic
anhydrase activity
in-vitro
. It is chemically unrelated to other anti-epileptic agents.
Clinical efficacy
Efficacy has been demonstrated with Zonegran in 4 double-blind, placebo-controlled studies of
periods of up to 24 weeks with either once or twice daily dosing. These studies show that the median
reduction in partial seizure frequency is related to Zonegran dose with sustained efficacy at doses of
300-500 mg per day.
Pharmacodynamic effects
The anticonvulsant activity of zonisamide has been evaluated in a variety of models, in several species
with induced or innate seizures, and zonisamide appears to act as a broad-spectrum anti-epileptic in
these models. Zonisamide prevents maximal electroshock seizures and restricts seizure spread,
including the propagation of seizures from cortex to sub-cortical structures and suppresses
epileptogenic focus activity. Unlike phenytoin and carbamazepine however, zonisamide acts
preferentially on seizures originating in the cortex.
Mechanism of action
The mechanism of action of zonisamide is not fully elucidated, but it appears to act on
voltage-sensitive sodium and calcium channels, thereby disrupting synchronised neuronal firing,
reducing the spread of seizure discharges and disrupting subsequent epileptic activity. Zonisamide
also has a modulatory effect on GABA-mediated neuronal inhibition.
20
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 C
max
values increased almost linearly after single dose over the dose range of
100-800 mg and after multiple doses over the dose range of 100-400 mg once daily. The increase at
steady state was slightly more than expected on the basis of dose, probably due to the saturable
binding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater
than expected accumulation occurs relative to single dosing.
Distribution
Zonisamide is 40 - 50 % bound to human plasma proteins, with
in vitro
studies showing that this is
unaffected by the presence of various 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.
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.
21
Other characteristics
No clear Zonegran dose-concentration-response relationship has been defined. When comparing the
same dose level, subjects of higher total body weight appear to have lower steady-state serum
concentrations, but this effect appears to be relatively modest. Age (≥ 12 years) and gender, after
adjustment for body weight effects, have no apparent effect on zonisamide exposure in epileptic
patients during steady-state dosing.
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.
6.
6.1 List of excipients
Capsule contents
Microcrystalline cellulose
Hydrogenated vegetable oil
Sodium laurilsulfate
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.
22
6.6 Special precautions for disposal
No special requirements.
7.
Eisai Limited
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire, AL10 9SN
United Kingdom
8.
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: 10/03/2005
Date of latest renewal:
10/03/2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency: http://www.ema.europa.eu
23
1.
Zonegran 100 mg hard capsules
2.
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).
For a full list of excipients, see section 6.1.
3.
Hard capsule.
A white opaque body and a red opaque cap printed with a logo and “ZONEGRAN 100” in black.
4.
Zonegran is indicated as adjunctive therapy in the treatment of adult patients with partial seizures, with
or without secondary generalisation.
Posology
Adults
Zonegran must be added to existing therapy and the dose should be titrated on the basis of clinical
effect. Doses of 300 mg to 500 mg per day have been shown to be effective, though some patients,
especially those not taking CYP3A4-inducing agents, may respond to lower doses.
The recommended initial daily dose is 50 mg in two divided doses. After one week the dose may be
increased to 100 mg daily and thereafter the dose may be increased at weekly intervals, in increments
of up to 100 mg.
Use of two weekly intervals should be considered for patients with renal or hepatic impairment and
patients not receiving CYP3A4-inducing agents (see section 4.5).
Zonegran can be administered once or twice daily after the titration phase.
Elderly
Caution should be exercised at initiation of treatment in elderly patients as there is limited information
on the use of Zonegran in these patients. Prescribers should also take account of the safety profile of
Zonegran (see section 4.8).
24
Paediatric population
The safety and efficacy of Zonegran in children and adolescents have not yet been established.
Currently available data are described in section 5.2 but no recommendation on a posology can be
made.
Patients with renal impairment
Caution must be exercised in treating patients with renal impairment, as there is limited information on
use in such patients and a slower titration of Zonegran might be required. Since zonisamide and its
metabolites are excreted renally, it should be discontinued in patients who develop acute renal failure
or where a clinically significant sustained increase in serum creatinine is observed.
In subjects with renal impairment, renal clearance of single doses of zonisamide was positively
correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in
subjects with creatinine clearance < 20 ml/min.
Patients with hepatic impairment
Use in patients with hepatic impairment has not been studied. Therefore use in patients with severe
hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to
moderate hepatic impairment, and a slower titration of Zonegran may be required.
Withdrawal of Zonegran
When Zonegran treatment is to be discontinued, it should be withdrawn gradually. In clinical studies,
dose reductions of 100 mg at weekly intervals have been used with concurrent adjustment of other
antiepileptic medicine doses.
Method of administration
Zonegran hard capsules are for oral use.
Effect of food
Zonegran may be taken with or without food (see section 5.2).
Hypersensitivity to the active substance, to any of the excipients or to sulphonamides.
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.
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.
Zonegran is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based
adverse reactions that are associated with medicinal products containing a sulphonamide group include
rash, allergic reaction and major haematological disturbances, including aplastic anaemia, which very
rarely can be fatal.
Cases of agranulocytosis, thrombocytopenia, leukopenia, aplastic anaemia, pancytopenia and
leucocytosis have been reported. There is inadequate information to assess the relationship, if any,
between dose and duration of treatment and these events.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in
several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic
medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The
mechanism of this risk is not known and the available data do not exclude the possibility of an
increased risk for Zonegran.
Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate
treatment should be considered. Patients (and caregivers of patients) should be advised to seek
medical advice should signs of suicidal ideation or behaviour emerge.
Kidney stones have occurred in patients treated with zonisamide. Zonegran should be used with
caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family
history of nephrolithiasis and hypercalcuria. Such patients may be at increased risk for renal stone
formation and associated signs and symptoms such as renal colic, renal pain or flank pain. In addition,
patients taking other medications associated with nephrolithiasis may be at increased risk. Increasing
fluid intake and urine output may help reduce the risk of stone formation, particularly in those with
predisposing risk factors.
Hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the
normal reference range in the absence of chronic respiratory alkalosis) is associated with Zonegran
treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of
zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of
Zonegran in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-
induced metabolic acidosis occurs early in treatment although cases can occur at any time during
treatment. The amounts by which bicarbonate is decreased are usually small – moderate (average
decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can
experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal
disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or
medicinal products) may be additive to the bicarbonate lowering effects of zonisamide.
The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger
patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in
patients taking zonisamide who have underlying conditions which might increase the risk of acidosis,
in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients
with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists,
consideration should be given to reducing the dose or discontinuing Zonegran (by gradual
discontinuation or reduction of a therapeutic dose). If the decision is made to continue patients on
Zonegran in the face of persistent acidosis, alkali treatment should be considered.
Zonegran should be used with caution in patients being treated concomitantly with carbonic anhydrase
inhibitors such as topiramate, as there are insufficient data to rule out a pharmacodynamic interaction
(see section 4.5).
Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric
patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Most reports
26
occurred during periods of warm weather. Patients or their carers must be warned to take care to
maintain hydration and avoid exposure to excessive temperatures. Caution should be used when
Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders;
these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.
In patients taking Zonegran who develop the clinical signs and symptoms of pancreatitis, it is
recommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the
absence of another obvious cause, it is recommended that discontinuation of Zonegran be considered
and appropriate treatment initiated.
In patients taking Zonegran, in whom severe muscle pain and/or weakness develop either in the
presence or absence of a fever, it is recommended that markers of muscle damage be assessed,
including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another
obvious cause such as trauma or grand mal seizures, it is recommended that Zonegran discontinuation
be considered and appropriate treatment initiated.
Women of child-bearing potential must use adequate contraception during treatment with Zonegran
and for one month after discontinuation (see section 4.6). Physicians treating patients with Zonegran
should try to ensure that appropriate contraception is used, and should use clinical judgement when
assessing whether oral contraceptives (OCs), or the doses of the OC components, are adequate based
on the individual patient’s clinical situation.
There is limited data from clinical studies in patients with a body weight of less than 40 kg. Therefore
these patients should be treated with caution.
Zonegran may cause weight loss. A dietary supplement or increased food intake may be considered if
the patient is losing weight or is underweight whilst on this medication. If substantial undesirable
weight loss occurs, discontinuation of Zonegran should be considered.
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.
Effect of Zonegran on cytochrome P450 enzyme
In vitro
studies using human liver microsomes show no or little (<25%) inhibition of cytochrome P450
isozymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A4 at zonisamide levels approximately two-
fold or greater than clinically relevant unbound serum concentrations. Therefore, Zonegran is not
expected to affect the pharmacokinetics of other medicinal products via cytochrome P450-mediated
mechanisms, as demonstrated for carbamazepine, phenytoin, ethinylestradiol and desipramine
in vivo
.
Potential for Zonegran to affect other medicinal products
Anti-epileptic medicinal products
In epileptic patients, steady-state dosing with Zonegran resulted in no clinically relevant
pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.
Oral contraceptives
In clinical studies in healthy subjects, steady-state dosing with Zonegran did not affect serum
concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.
Carbonic anhydrase inhibitors
Zonegran should be used with caution in patients treated concomitantly with carbonic anhydrase
inhibitors such as topiramate, as there are insufficient data to rule out a possible pharmacodynamic
interaction (see section 4.4).
27
P-gp substrate
An
in vitro
study shows that zonisamide is a weak inhibitor of P-gp (MDR1) with an IC
50
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.
Women of childbearing potential
Women of childbearing potential must use adequate contraception during treatment with Zonegran,
and for one month after discontinuation.
Pregnancy
There are no adequate data from the use of Zonegran in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Zonegran must not be used during pregnancy unless clearly necessary, in the opinion of the physician,
and only if the potential benefit is considered to justify the risk to the foetus. The need for anti-
epileptic treatment should be reviewed in patients planning to become pregnant. If Zonegran is
prescribed, careful monitoring is recommended.
Specialist advice should be given to women who are likely to become pregnant in order to consider the
optimal treatment during pregnancy. Women of childbearing potential should be given specialist
advice regarding possible effects of Zonegran on the foetus and the risk should be discussed with the
patient in relation to the benefits before starting treatment. The risk of birth defect is increased by
factor 2 to 3 in the offspring of mothers treated with an antiepileptic medication. The most frequently
reported are cleft lip, cardiovascular malformations and neural tube defect. Multiple antiepileptic
28
medicinal product therapy may be associated with a higher risk of congenital malformations than
monotherapy.
No sudden discontinuation of anti-epileptic therapy should be undertaken as this may lead to
breakthrough seizures, which could have serious consequences for both mother and child.
Breast-feeding
Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from
Zonegran therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not
be resumed until one month after Zonegran therapy is completed.
No studies on the effects on the ability to drive and use machines have been performed. However,
given that some patients may experience drowsiness or difficulty with concentration, particularly early
in treatment or after a dose increase, patients must be advised to exercise caution during activities
requiring a high degree of alertness, e.g., driving or operating machines.
Zonegran has been administered to over 1,200 patients in clinical studies, more than 400 of whom
received Zonegran for at least 1 year. In addition there has been extensive post-marketing experience
with zonisamide in Japan since 1989 and in the USA since 2000.
It should be noted that Zonegran is a benzisoxazole derivative, which contains a sulphonamide group.
Serious immune based adverse reactions that are associated with medicinal products containing a
sulphonamide group include rash, allergic reaction and major haematological disturbances including
aplastic anaemia, which very rarely can be fatal (see section 4.4).
The most common adverse reactions in controlled adjunctive-therapy studies were somnolence,
dizziness and anorexia. Adverse reactions associated with Zonegran obtained from clinical studies
and post-marketing surveillance are tabulated below. The frequencies are arranged according to the
following scheme:
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
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
29
System Organ
Class
(MedDRA
terminology)
Very
Common
Common
Uncommon
Very Rare
Immune system
disorders
Hypersensitivity
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
Respiratory,
thoracic and
mediastinal
disorders
Dyspnoea
Pneumonia aspiration
Respiratory disorder
Gastrointestinal
disorders
Abdominal pain
Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting
Pancreatitis
Hepatobiliary
disorders
Cholecystitis
Cholelithiasis
Hepatocellular damage
Skin and
subcutaneous
tissue disorders
Rash
Anhidrosis
Erythema multiforme
Pruritis
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
Investigations
Decreased
bicarbonate
Weight
decreased
Blood creatine
phosphokinase increased
Blood creatinine increased
Blood urea increased
Liver function tests
abnormal
30
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.
Additional information on special populations:
Review of post-marketing data suggests that patients aged 65 years or older report a higher frequency
than the general population of the following events: Stevens-Johnson syndrome (SJS) and Drug
Induced Hypersensitivity syndrome (DIHS).
There have been cases of accidental and intentional overdose in adult and paediatric patients. In some
cases, the overdoses were asymptomatic, particularly where emesis or lavage was prompt. In other
cases, the overdose was followed by symptoms such as somnolence, nausea, gastritis, nystagmus,
myoclonus, coma, bradycardia, reduced renal function, hypotension and respiratory depression. A
very high plasma concentration of 100.1 μg/ml zonisamide was recorded approximately 31 hours after
a patient took an overdose of Zonegran and clonazepam; the patient became comatose and had
respiratory depression, but recovered consciousness five days later and had no sequelae.
Treatment
No specific antidotes for Zonegran overdose are available. Following a suspected recent overdose,
emptying the stomach by gastric lavage or by induction of emesis may be indicated with the usual
precautions to protect the airway. General supportive care is indicated, including frequent monitoring
of vital signs and close observation. Zonisamide has a long elimination half-life so its effects may be
persistent. Although not formally studied for the treatment of overdose, haemodialysis reduced
plasma concentrations of zonisamide in a patient with reduced renal function, and may be considered
as treatment of overdose if clinically indicated.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
Anti-epileptics, other antiepileptics, ATC code: N03AX15
Zonisamide is a benzisoxazole derivative. It is an anti-epileptic medicine with weak carbonic
anhydrase activity
in-vitro
. It is chemically unrelated to other anti-epileptic agents.
Clinical efficacy
Efficacy has been demonstrated with Zonegran in 4 double-blind, placebo-controlled studies of
periods of up to 24 weeks with either once or twice daily dosing. These studies show that the median
reduction in partial seizure frequency is related to Zonegran dose with sustained efficacy at doses of
300-500 mg per day.
Pharmacodynamic effects
The anticonvulsant activity of zonisamide has been evaluated in a variety of models, in several species
with induced or innate seizures, and zonisamide appears to act as a broad-spectrum anti-epileptic in
31
these models. Zonisamide prevents maximal electroshock seizures and restricts seizure spread,
including the propagation of seizures from cortex to sub-cortical structures and suppresses
epileptogenic focus activity. Unlike phenytoin and carbamazepine however, zonisamide acts
preferentially on seizures originating in the cortex.
Mechanism of action
The mechanism of action of zonisamide is not fully elucidated, but it appears to act on
voltage-sensitive sodium and calcium channels, thereby disrupting synchronised neuronal firing,
reducing the spread of seizure discharges and disrupting subsequent epileptic activity. Zonisamide
also has a modulatory effect on GABA-mediated neuronal inhibition.
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 C
max
values increased almost linearly after single dose over the dose range of
100-800 mg and after multiple doses over the dose range of 100-400 mg once daily. The increase at
steady state was slightly more than expected on the basis of dose, probably due to the saturable
binding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater
than expected accumulation occurs relative to single dosing.
Distribution
Zonisamide is 40 - 50 % bound to human plasma proteins, with
in vitro
studies showing that this is
unaffected by the presence of various 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.
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.).
32
Patients with an impaired liver function:
The pharmacokinetics of zonisamide in patients with
impaired liver function have not been adequately studied.
Elderly:
No clinically significant differences were observed in the pharmacokinetics between young
(aged 21-40 years) and elderly (65-75 years).
Children and Adolescents (5-18 years):
Limited data indicate that pharmacokinetics in children and
adolescents dosed to steady state at 1, 7 or 12 mg/kg daily, in divided doses, are similar to those
observed in adults, after adjustment for bodyweight.
Other characteristics
No clear Zonegran dose-concentration-response relationship has been defined. When comparing the
same dose level, subjects of higher total body weight appear to have lower steady-state serum
concentrations, but this effect appears to be relatively modest. Age (≥ 12 years) and gender, after
adjustment for body weight effects, have no apparent effect on zonisamide exposure in epileptic
patients during steady-state dosing.
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.
6.
6.1 List of excipients
Capsule contents
Microcrystalline cellulose
Hydrogenated vegetable oil
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.
33
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.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Eisai Limited
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire, AL10 9SN
United Kingdom
8.
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: 10/03/2005
Date of latest renewal:
10/03/2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency: http://www.ema.europa.eu
34
1.
6.
FURTHER INFORMATION
What Zonegran contains
The active substance in Zonegran is zonisamide. Zonegran 25 mg orodispersible tablets contain
25 mg of zonisamide. Zonegran 50 mg orodispersible tablets contain 50 mg of zonisamide. Zonegran
100 mg orodispersible tablets contain 100 mg zonisamide. Zonegran 300 mg orodispersible tablets
contain 300 mg zonisamide.
•
The other ingredients that are present in the 25 mg, 50 mg, and 100 mg orodispersible tablets are:
fish gelatin, mannitol (E421), aspartame (E951), and orange flavour.
•
The other ingredients that are present in the 300 mg orodispersible tablets are: bovine gelatin,
mannitol (E421), aspartame (E951), and orange flavour.
See Section 2 for important information about the ingredient, aspartame (E951).
116
What Zonegran looks like and contents of the pack
Zonegran orodispersible tablets are white to off-white, circular tablets, debossed with the tablet
strength (“25”, “50”, “100” or “300”).
Zonegran orodispersible tablets are packaged in blister packs supplied in boxes containing:
•
25 mg: 14 and 28 orodispersible tablets
•
50 mg: 14 and 28 orodispersible tablets
•
100 mg: 56 and 98 orodispersible tablets
•
300 mg: 28 and 98 orodispersible tablets
Not all pack sizes may be available.
Marketing Authorisation Holder
Eisai Ltd., Mosquito Way, Hatfield, Herts AL10 9SN, United Kingdom.
Manufacturer
Eisai Manufacturing Ltd, Mosquito Way, Hatfield, Herts AL10 9SN, United Kingdom.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Eisai Europe Ltd.
Tél/Tel: +32 (0) 2 735 45 34
Luxembourg/Luxemburg
Eisai Europe Ltd.
Tél/Tel: +32 (0) 2 735 45 34
(Belgique/Belgien)
България
Eisai Ltd.
Teл.: +359 2 810 39 96
Magyarország
Eisai GesmbH
Tel.:+36 1 230 43 20
Česká republika
Eisai GesmbH organizační složka
Tel.: +420 242 485 839
Malta
Associated Drug Company Ltd.
Tel: + 356 2124 2751
Danmark
Eisai AB
Tlf: +46 (0)8 501 01 600
(Sverige)
Nederland
Eisai Europe Ltd.
Tél/Tel: +32 (0) 2 735 45 34
(België /Belgique)
Deutschland
Eisai GmbH
Tel: + 49 (0) 696 65 850
Norge
Eisai AB
Tlf: + 46 (0)8 501 01 600
(Sverige)
Eesti
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
(Ühendkuningriik)
Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0
Ελλάδα
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
Polska
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(Wielka Brytania)
117
España
Eisai Farmacéutica, S.A.
Tel: +(34) 91 455 94 55
Portugal
Eisai Farmacêutica, Unipessoal Lda
Tel: +351 214 875 540
France
Eisai SAS
Tél: + (33) 1 47 67 00 05
România
Eisai Ltd.
Tel: +40 21 301 7469
Ireland
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(United Kingdom)
Slovenija
Eisai Ltd.
Tel: + 386 (0) 1 426 7015
Ísland
Eisai AB
Sími: + 46 (0) 8 501 01 600
(Svíþjóð)
Slovenská republika
Eisai GesmbH organizační 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
Latvija
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(Lielbritānija)
United Kingdom
Eisai Ltd.
Tel: +44 (0) 208 600 1400
Lietuva
Eisai Ltd.
Tel: + 44 (0)208 600 1400
(Jungtinė Karalystė)
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
118
Source: European Medicines Agency
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