4.1. Therapeutic indications

Zonisamide Aristo is indicated as:

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

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

4.2. Posology and method of administration

Posology - Adults

Dosage escalation and maintenance

Zonisamide Aristo 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When Zonisamide Aristo treatment is to be discontinued, it should be withdrawn gradually (see section 4.4).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

Week 3 + 4

Week 5 + 6

300 mg per day (once a day).

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

100 mg/day

(once a day)

200 mg /day

(once a day)

300 mg / day

(once a day)

Adjunctive therapy

- with CYP3A4- inducing agents

(see section 4.5)

Week 1

Week 2

Week 3 to 5

300 to 500 mg per day

(once a day or two divided doses).

50 mg/day

(in two

divided doses)

100 mg /day

(in two divided doses)

Increase at weekly intervals in increments of 100 mg

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

Week 1 + 2

Week 3 + 4

Week 5 to 10

300 to 500 mg per day

(once a day or two divided doses).

Some patients may respond to lower doses.

50 mg/day

(in two divided doses)

100 mg / day

(in two divided doses)

Increase at two-weekly intervals in increments of up to 100 mg

General dosing recommendations for Zonisamide Aristo in special patient populations

Paediatric population (aged 6 years and above)

Dosage escalation and maintenance

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

Physicians should draw the attention of paediatric patients and their parents/carers to the Patient Alert Box (in the package leaflet) on preventing heatstroke (see section 4.4: Paediatric population).

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

Treatment Regimen

Titration Phase

Usual Maintenance Dose

Adjunctive therapy

- with CYP3A4-inducing agents

(see section 4.5)

Week 1

Weeks 2 to 8

Patients of weight

20 to 55 kg

Patients of weight

> 55 kg

1 mg/kg/day

(once a day)

Increase at weekly intervals in increments of 1 mg/kg

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

- without CYP3A4-inducing agents

Week 1 + 2

Weeks ≥ 3

6 to 8 mg/kg/day

(once a day)

300 - 500 mg/day

(once a day)

1 mg/kg/day

(once a day)

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

Note:

a. To ensure a therapeutic dose is maintained the weight of a child should be monitored and the dose reviewed as weight changes occur up to a weight of 55kg. The dose regime is 6-8mg/kg/day up to a maximum dose of 500 mg/day.

The safety and efficacy of Zonisamide Aristo 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 Aristo. 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 Aristo (25 mg, 50 mg and 100 mg).

Withdrawal

When Zonisamide Aristo 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 down-titration schedule

Weight

Decrease at weekly intervals in increments of:

20 – 28 kg

25 to 50 mg / day*

29 – 41 kg

50 to 75 mg / day*

42 – 55 kg

100 mg / day*

>55 kg

100 mg / day*

Note:

* All doses are once daily.

Elderly

Caution should be exercised at initiation of treatment in elderly patients as there is limited information on the use of Zonisamide Aristo in these patients. Prescribers should also take account of the safety profile of Zonisamide Aristo (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 Zonisamide Aristo 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 Zonisamide Aristo may be required.

Method of administration

Zonisamide Aristo hard capsules are for oral use.

Effect of food

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

4.3. Contraindications

Hypersensitivity to the active substance, to Ponceau-4R, 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 Aristo therapy, including cases of Stevens-Johnson syndrome.

Consideration must be given to discontinuing Zonisamide Aristo in patients who develop an otherwise unexplained rash. All patients who develop a rash while taking Zonisamide Aristo 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 Aristo 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 Aristo has been achieved in the add-on situation, in order to reach monotherapy with Zonisamide Aristo. 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 behaviour

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for Zonisamide Aristo.

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 Aristo 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 Aristo (by gradual discontinuation or reduction of a therapeutic dose) as osteopenia may develop.

If the decision is made to continue patients on Zonisamide Aristo in the face of persistent acidosis, alkali treatment should be considered.

Metabolic acidosis has the potential to lead to hyperammonaemia, which has been reported with or without encephalopathy during zonisamide treatment. The risk for hyperammonaemia may be increased in patients concomitantly taking other medications that can cause hyperammonaemia (e.g. valproate), or who have an underlying urea cycle disorder or reduced hepatic mitochondrial activity. In patients who develop unexplained lethargy or changes in mental status during treatment with zonisamide, it is recommended to consider hyperammonaemic encephalopathy and to measure ammonia levels.

Zonisamide Aristo 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 Aristo 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 Aristo 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 Aristo be considered and appropriate treatment initiated.

Rhabdomyolysis

In patients taking Zonisamide Aristo, 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 Aristo discontinuation be considered and appropriate treatment initiated.

Women of child-bearing potential

Women of child-bearing potential must use effective contraception during treatment with Zonisamide Aristo and for one month after discontinuation (see section 4.6). Zonisamide Aristo must not be used in women of childbearing potential not using effective contraception unless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus. Specialist medical advice should be given to women treated with zonisamide who are of childbearing potential. The woman should be fully informed of and understand the possible effects of Zonisamide Aristo on the foetus and these risks should be discussed with the patient in relation to the benefits before starting treatment. Before the initiation of treatment with Zonisamide Aristo in a woman of childbearing potential, pregnancy testing should be considered. Women planning a pregnancy should meet with their specialists to reassess treatment with Zonisamide Aristo and to consider other therapeutic options prior to conception and before contraception is discontinued. Women of childbearing potential should be counselled to contact her doctor immediately if she becomes pregnant or thinks she may be pregnant and is taking Zonisamide Aristo. Physicians treating patients with Zonisamide Aristo should ensure that patients are fully informed about the need to use appropriate effective contraception, and should use clinical judgement when assessing whether oral contraceptives (OCs), or the doses of the OC components, are adequate based on the individual patient's clinical situation.

Body weight

Zonisamide Aristo 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 Aristo 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 Aristo 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 Aristo:

• 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 heatstroke, 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 Aristo should be considered.

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

Body weight

Weight loss leading to deterioration of general condition and failure to take anti-epilepsy medication has been related to a fatal outcome (see section 4.8). Zonisamide Aristo 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 Aristo 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 Aristo 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 Aristo should be discontinued.

Hepatic dysfunction

Increased levels of hepatobiliary parameters such as alanine aminotransferase (ALT), aspartate aminotransferease (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 Aristo 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.

Zonisamide Aristo 100 mg contains Ponceau 4 R (E124)

Ponceau 4 R (E124) may cause allergic reactions.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of Zonisamide Aristo 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 Aristo 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 Aristo to affect other medicinal products

Anti-epileptic medicinal products

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

Carbonic anhydrase inhibitors

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

Zonisamide Aristo 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 Aristo

In clinical studies co-administration of lamotrigine had no apparent effect on Zonisamide pharmacokinetics. The combination of Zonisamide Aristo 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 Zonisamide Aristo 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 Aristo 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 Aristo 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 Zonisamide Aristo dosing should not be necessary when co-administered with known CYP3A4 inhibitors.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Zonisamide Aristo must not be used in women of childbearing potential not using effective contraception unless clearly necessary and only if the potential benefit is considered to justify the risk to the foetus. Specialist medical advice should be given to women treated with zonisamide who are of childbearing potential. The woman should be fully informed of and understand the possible effects of Zonisamide Aristo on the foetus and these risks should be discussed with the patient in relation to the benefits before starting treatment. Pregnancy testing in women of childbearing potential should be considered prior to initiating treatment with zonisamide. Women planning a pregnancy should meet with their specialists to reassess treatment with zonisamide and to consider other therapeutic options prior to conception and before contraception is discontinued.

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

Pregnancy

There are limited data from the use of Zonisamide Aristo in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). In humans, the potential risk of major congenital malformation and neurodevelopmental disorders is unknown.

Data from a registry study suggest an increase in the proportion of babies born at a low birth weight (LBW), pre-term or small for gestational age (SGA). These increases are from about 5 % to 8 % for LBW, from about 8 % to 10 % for pre-term birth and from about 7 % to 12 % for SGA, all compared with mothers treated with lamotrigine monotherapy.

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

Breast-feeding

Zonisamide is excreted in human milk; the concentration in breast milk is similar to maternal plasma. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zonisamide Aristo therapy. Due to the long retention time of zonisamide in the body, breast-feeding must not be resumed until one month after Zonisamide Aristo 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 post-marketing surveillance are tabulated below. The frequencies are arranged according to the following scheme:

very common

≥ 1/10

common

≥ 1/100 to < 1/10

uncommon

≥ 1/1,000 to < 1/100

rare

≥ 1/10,000 to < 1/1,000

very rare

< 1/10,000

not known

cannot be estimated from the available data

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

System Organ Class (MedDRA terminology)

Very Common

Common

Uncommon

Very Rare

Infections and infestation

Pneumonia

Urinary tract infection

Blood and lymphatic system disorders

Ecchymosis

Agranulocytosis

Aplastic anaemia

Leucocytosis

Leucopoenia

Lymphadenopathy

Pancytopenia,

Thrombocytopenia

Immune system disorders

Hypersensitivity

Drug-induced hypersensitivity syndrome

Drug rash with eosinophilia and systemic symptoms

Metabolism and nutrition disorders

Anorexia

Hypokalaemia

Metabolic acidosis

Renal tubular acidosis

Psychiatric Disorders

Agitation

Irritability

Confusional state

Depression

Affect lability

Anxiety

Insomnia

Psychotic disorder

Anger

Aggression

Suicidal ideation

Suicide attempt

Hallucination

Nervous system disorders

Ataxia

Dizziness

Memory impairment

Somnolence

Bradyphrenia

Disturbance in attention

Nystagmus

Paraesthesia

Speech disorder

Tremor

Convulsion

Amnesia

Coma

Grand mal seizure

Myasthenic syndrome

Neuroleptic malignant syndrome

Status epilepticus

Eye disorders

Diplopia

Angle closure glaucoma

Eye pain

Myopia

Vision blurred

Visual acuity reduced

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Pneumonia aspiration

Respiratory disorder

Hypersensitivity-type

Pneumonitis

Gastrointestinal disorders

Abdominal pain

Constipation

Diarrhoea

Dyspepsia

Nausea

Vomiting

Pancreatitis

Hepatobiliary disorders

Cholecystitis

Cholelithiasis

Hepatocellular damage

Skin and subcutaneous tissue disorders

Rash

Pruritus

Alopecia

Anhidrosis

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Rhabdomyolysis

Renal and urinary disorders

Nephrolithiasis

Calculus urinary

Hydronephrosis

Renal failure

Urine abnormality

General disorders and administration site conditions

Fatigue

Influenza-like illness

Pyrexia

Oedema peripheral

Investigations

Decreased bicarbonate

Weightdecreased

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 zonisamide.

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

System Organ Class

(MedDRA terminology†)

Very Common

Common

Uncommon

Infections and infestation

Urinary tract infection

Pneumonia

Blood and lymphatic disorders

Leukopenia

Thrombocytopenia

Metabolism and nutrition disorders

Decreased appetite

Hypokalaemia

Psychiatric Disorders

Agitation

Depression

Insomnia

Mood swings

Anxiety

Confusional state

Acute psychosis

Aggression

Suicidal ideation

Hallucination

Nervous system disorders

Ataxia

Dizziness

Memory impairment

Somnolence

Bradyphrenia

Disturbance in attention

Paraesthesia

Nystagmus

Speech disorder

Tremor

Convulsion

Eye disorders

Diplopia

Respiratory, thoracic and mediastinal disorders

Respiratory disorder

Gastrointestinal disorders

Constipation

Diarrhoea

Dyspepsia

Nausea

Vomiting

Abdominal pain

Hepatobiliary disorders

Cholecystitis acute

Skin and subcutaneous tissue disorders

Rash

Pruritus

Ecchymosis

General disorders and administration site conditions

Fatigue

Pyrexia

Irritability

Investigations

Decreased bicarbonate

Weight decreased

Blood creatinine phosphokinase increased

Alanine aminotransferase increased

Aspartate aminotransferase increased

Urine analysis abnormal

† MedDRA version 13.1

Additional information on special populations

Elderly

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

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

Paediatric Population

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 Aristo 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.