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ZONISAMIDE 50 MG CAPSULES HARD

Active substance(s): ZONISAMIDE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Zonisamide 50 mg, capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 50 mg of Zonisamide
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Hard capsule
Gray-White opaque coloured hard gelatin capsules of size “3” imprinted with “I” on
cap and “21” on body with black ink containing white to off white powder.
Capsule size approximately 15.80 mm ± 0.4 mm.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Zonisamide is indicated as:


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



4.2

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

Posology and method of administration
Posology
Dosage escalation and maintenance
Zonisamide 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When Zonisamide treatment is to be discontinued, it should be withdrawn gradually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).

Table 1. Adults – recommended dosage escalation and maintenance regimen
Treatment Regimen

Titration Phase

Usual Maintenance Dose

Monotherapy
Newly
diagnosed
adult patients

Week 1 + 2
100 mg/day
(once a day)

Week 3 + 4
200 mg /day
(once a day)

Week 5 + 6
300 mg / day
(once a day)

Adjunctive therapy
- with CYP3A4inducing agents
(see section 4.5)

Week 1
50 mg/day
(in two divided
doses)

Week 2
100 mg /day
(in two divided
doses)

-without CYP3A4inducing agents; or
with renal or hepatic
impairment

Week 1 + 2
50 mg/day
(in two divided
doses)

Week 3 + 4
100 mg / day
(in two divided
doses)

Week 3 to 5
Increase
at
weekly intervals
in increments of
100 mg
Week 5 to 10
Increase at twoweekly intervals
in increments of
up to 100 mg

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.
300 to 500 mg per day
(once a day or two divided
doses).

300 to 500 mg per day
(once a day or two divided
doses).
Some patients may respond
to lower doses.

General dosing recommendations for Zonisamide in special patient populations
Paediatric population (aged 6 years and above)

Dosage escalation and maintenance
Zonisamide 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
Adjunctive therapy
-with CYP3A4-inducing
agents
(see section 4.5)

- without CYP3A4inducing agents

Titration Phase
Week 1

Weeks 2 to 8

Usual Maintenance Dose
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)

Week 1 + 2
1 mg/kg/day
(once a day)

Weeks ≥ 3
Increase at twoweekly intervals in
increments of 1
mg/kg

6 to 8 mg/kg/day
(once a day)

300 - 500 mg/day
(once a day)

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 6-8mg/kg/day up to a maximum dose of 500 mg/day.
The safety and efficacy of Zonisamide 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 Zonisamide. In these cases it is therefore
recommended that the Zonisamide total dose should be rounded up or down to the
nearest available dose that can be achieved with commercially available capsule
strengths of Zonisamide (25 mg, 50 mg and 100 mg).

Withdrawal
When Zonisamide 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 Tablet 3).

Table 3. Paediatric population (aged 6 years and above) – recommended downtitration schedule

Weight

Decrease at weekly intervals in increments of:

20 – 28 kg
29 – 41 kg
42 – 55 kg
>55 kg

25 to 50 mg / day*
50 to 75 mg / day*
100 mg / day*
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 /…/ in these patients. Prescribers should also take
account of the safety profile of /…/ (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 /…/ 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 /…/ may be required.
Method of administration
Zonisamide hard capsules are for oral use.
Effect of food
Zonisamide 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.

4.4

Special warnings and precautions for use
Unexplained rash

Serious rashes occur in association with Zonisamide therapy, including cases
of Stevens-Johnson syndrome.
Consideration must be given to discontinuing Zonisamide in patients who develop an
otherwise unexplained rash. All patients who develop a rash while taking Zonisamide
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 Zonisamide 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 Zonisamide has been
achieved in the add-on situation, in order to reach monotherapy with Zonisamide.
Therefore, withdrawal of concomitant anti-epileptic medicinal products must be
undertaken with caution.
Sulphonamide reactions

Zonisamide 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 behavior
Suicidal ideation and behavior have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebocontrolled trials of anti-epileptic medicinal products has also shown a small increased
risk of suicidal ideation and behavior. The mechanism of this risk is not known and
the available data do not exclude the possibility of an increased risk for Zonisamide.
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 Zonisamide 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 Zonisamide
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
Zonisamide (by gradual discontinuation or reduction of a therapeutic dose) as
osteopenia may develop.
If the decision is made to continue patients on Zonisamide in the face of persistent
acidosis, alkali treatment should be considered.
Zonisamide 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 Zonisamide 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 Zonisamide 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 Zonisamide be considered and appropriate
treatment initiated.
Rhabdomyolysis
In patients taking Zonisamide, 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 Zonisamide discontinuation be considered and
appropriate treatment initiated.
Women of child-bearing potential
Women of child-bearing potential have to use effective contraception during
treatment with Zonisamide and for one month after discontinuation (see section 4.6).
Physicians treating patients with Zonisamide 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.
Body weight
Zonisamide 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
Zonisamide 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

Zonisamide 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 Zonisamide:





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 Zonisamide should be considered.
Zonisamide 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 antiepilepsy medication has been related to a fatal outcome (see section 4.8). Zonisamide
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 Zonisamide 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.
Zonisamide 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,
Zonisamide 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
Zonisamide 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 Zonisamide 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, Zonisamide 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 Zonisamide to affect other medicinal products
Anti-epileptic medicinal products
In epileptic patients, steady-state dosing with Zonisamide 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 Zonisamide did not
affect serum concentrations of ethinylestradiol or norethisterone in a combined oral
contraceptive.
Carbonic anhydrase inhibitors
Zonisamide 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 t (see section
4.4).

Zonisamide 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 Zonisamide
In clinical studies co-administration of lamotrigine had no apparent effect on
Zonisamide pharmacokinetics. The combination of zonisamide with other medicinal
products that may lead to urolithiasis may enhance the risk of developing kidney
stones; therefore the concomitant administration of such medicinal products should be
avoided.
Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by Nacetyl-transferases and conjugation with glucuronic acid; therefore, substances that
can induce or inhibit these enzymes may affect the pharmacokinetics of Zonisamide:
-

Enzyme induction: Exposure to Zonisamide is lower in epileptic patients
receiving CYP3A4-inducing agents such as phenytoin, carbamazepine, and
phenobarbitone. These effects are unlikely to be of clinical significance when
zonisamide 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 zonisamide 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 zonisamide and other CYP3A4 substrates
adjusted as needed.

-

CYP3A4 inhibition: Based upon clinical data, known specific and nonspecific 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 zonisamide 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 have to use effective contraception during treatment
with zonisamide, and for one month after discontinuation.
Pregnancy
There are limited data from the use of zonisamide in pregnant women. Studies in
animals have shown reproductive toxicity (see section 5.3). The potential risk for
humans is unknown.
Zonisamide 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 zonisamide 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 zonisamide
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.
Breastfeeding
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 zonisamide therapy. Due to the long retention time of
zonisamide in the body, breast-feeding must not be resumed until one month after
zonisamide 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
Zonisamide has been administered to over 1,200 patients in clinical studies, more
than 400 of whom received zonisamide 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 zonisamide 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 zonisamide obtained from clinical studies and postmarketing 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 zonisamide obtained from adjunctive
use clinical studies and post-marketing surveillance
System
Class

Organ Very
Common

Common

Uncommon

Very Rare

(MedDRA
terminology)
Infections
infestations

Pneumonia

and

Urinary tract
infection

Blood
and
lymphatic system
disorders

Ecchymosis

Agranulocytosis
Aplastic anaemia
Leucocytosis
Leucopoenia
Lymphadenopathy
Pancytopenia,

Immune system
disorders

Hypersensitivity

Drug-induced
hypersensitivity
syndrome

Thrombocytopenia

Drug rash with
eosinophilia
and
systemic symptoms
Metabolism and
nutrition
disorders

Anorexia

Psychiatric
disorders

Agitation
Irritability
Confusional
state

Hypokalaemia

Renal
acidosis

Depression
Nervous system Ataxia
Dizziness
disorders
Memory
impairment

Somnolence

Affect lability
Anxiety
Insomnia

Psychotic
disorder
Bradyphrenia
Disturbance in
attention
Nystagmus
Paraesthesia
Speech disorder

Anger
Aggression
Suicidal
ideation
Suicide
attempt
Convulsion

Tremor
Eye disorders

tubular

Hallucination

Amnesia
Coma
Grand mal seizure
Myasthenic syndrome
Neuroleptic malignant
syndrome

Status epilepticus
Angle
closure
glaucoma
Eye pain
Myopia
Vision blurred
Visual
acuity
reduced

Diplopia

Dyspnoea
Pneumonia aspiration
Respiratory disorder

Respiratory,
thoracic
and
mediastinal
disorders
Gastrointestinal

Metabolic acidosis

Hypersensitivitytype Pneumonitis
Abdominal pain

Vomiting

Pancreatitis

Constipation
Diarrhoea
Dyspepsia

disorders

Nausea
Cholecystitis
Cholelithiasis

Hepatobiliary
disorders
Skin
and
subcutaneous
tissue disorders

Rash
Pruritus

Alopecia

Hepatocellular
damage
Anhidrosis
Erythema multiforme
Stevens-Johnson
syndrome

Toxic
epidermal
necrolysis
Rhabdomyolysis

Musculoskeletal
and
connective
tissue disorders
Renal
and
urinary disorders

Nephrolithiasis

Calculus
urinary

Hydronephrosis
Renal failure
Urine abnormality

Fatigue
Influenza-like
illness
Pyrexia

General disorders
and
administration
site conditions

Oedema
peripheral
Decreased
bicarbonate

Investigations

Weight
decreased

Injury, poisoning
and procedural
complications

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

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

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

System Organ Class

(MedDRA
terminology†)
Infections and infestation

Very
Common

Common

Uncommon

Urinary
infection

tract

Pneumonia
Blood and
disorders

lymphatic

Leukopenia
Thrombocytopenia

Metabolism and nutrition
disorders

Decreased appetite

Hypokalaemia

Psychiatric Disorders

Agitation
Depression
Insomnia
Mood swings

Confusional state
Acute psychosis
Aggression
Suicidal ideation
Hallucination
Nystagmus
Speech disorder
Tremor
Convulsion

Anxiety
Ataxia
Dizziness
Memory impairment
Somnolence
Bradyphrenia
Disturbance
in
attention

Nervous system disorders

Paraesthesia
Diplopia

Eye disorders
Respiratory, thoracic and
mediastinal disorders
Gastrointestinal disorders

Respiratory disorder
Constipation
Diarrhoea
Dyspepsia
Nausea
Vomiting

Hepatobiliary disorders
Skin and subcutaneous
tissue disorders
General disorders
administration
conditions
Investigations

Rash

and
site
Decreased
bicarbonate

Abdominal pain

Cholecystitis acute
Pruritus
Ecchymosis

Fatigue
Pyrexia
Irritability
Weight decreased
Urine
Blood
creatinine abnormal
phosphokinase
increased
Alanine
aminotransferase
increased
Aspartate
aminotransferase
increased

analysis

† 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: StevensJohnson 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 preexisting functional neurological deficits for various causes (2 cases of pneumoniainduced 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 Yellow Card Scheme, website www.mhra.gov.uk/yellowcard.

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 zonisamide 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 zonisamide 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 generalization
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
N

Zonisamide Carbamazepine
n (ITT population)
Six months seizure freedom
PP-population*
ITT-population
< 4 seizures during 3 month baseline
period
> 4 seizures during 3 month baseline
period
Twelve months seizure freedom
PP-population
ITT-population
< 4 seizures during 3 month baseline
period
> 4 seizures during 3 month baseline
period
Seizure Sub-type (6 month seizure
freedom-PP population)
All partial
Simple partial
Complex partial
All generalized Tonic-Clonic
Secondary Tonic-Clonic
Generalized Tonic-Clonic

281

300

79.4%
69.4%
71.7%

83.7%
74.7%
75.7%

Diff
-4.5%
-6.1%
-4.0%

CI95%
-12.2% ; 3.1%
-13.6% ; 1.4%
-11.7% ; 3.7%

52.9%

68.9%

-15.9%

-37.5% ; 5.6%

67.6%
55.9%
57.4%

74.7%
62.3%
64.7%

-7.9%
-7.7%
-7.2%

-17.2% ; 1.5%
-16.1% ; 0.7%
-15.7% ; 1.3%

44.1%

48.9%

-4.8%

-26.9% ; 17.4%

76.4%
72.3%
76.9%
78.9%
77.4%
85.7%

86.0%
75.0%
93.0%
81.6%
80.0%
92.0%

-9.6%
-2.7%
-16.1%
-2.8
-2.6%
-6.3%

-19.2% ; 0.0%
-20.0% ; 14.7%
-26.3% ; -5.9%
-11.5% ; 6.0%
-12.4% ; 7.1%
-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 zonisamide in 4 double-blind, placebocontrolled 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
zonisamide 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 100400 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.).
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
Cellulose Microcrystalline
Hydrogenated Vegetable Oil
Sodium Laurilsulfate
Silica Colloidal Anhydrous
Capsule shells
Gelatin
Water
Iron Oxide Black (E172)
Titanium Dioxide (E171)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage condition.

6.5

Nature and contents of container
Clear PVC /PVdC/ Aluminum blister pack of 14, 28, 56, 84 and 98 hard capsules
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
WARREN GENERICS s.r.o.
U Staré tvrze 285/21,
196 00 Praha 9,
Czech Republic

8

MARKETING AUTHORISATION NUMBER(S)
PL 42831/0026

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/10/2016

10

DATE OF REVISION OF THE TEXT
28/04/2017

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