- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Posology - Adults
Dosage escalation and maintenanceZonegran 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.
WithdrawalWhen Zonegran treatment is to be discontinued, it should be withdrawn gradually (see section 4.4). In clinical studies of adult patients, dose reductions of 100 mg at weekly intervals have been used with concurrent adjustment of other antiepileptic medicine doses (where necessary). 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.
(once a day)
|200 mg /day
(once a day)|
|300 mg / day
(once a day)
- with CYP3A4-inducing agents (see section 4.5)
|Week 1||Week 2||Week 3 to 5|
300 to 500 mg per day (once a day or two divided doses).
|50 mg/day (in two divided doses)||100 mg /day (in two divided doses)||Increase at weekly intervals in increments of 100 mg|
|- without CYP3A4-inducing agents; or with renal or hepatic impairment||Week 1 + 2||Week 3 + 4||Week 5 to 10|
300 to 500 mg per day (once a day or two divided doses). Some patients may respond to lower doses.
|50 mg/day (in two divided doses)
|100 mg / day (in two divided doses)
|Increase at two-weekly intervals in increments of up to 100 mg
General dosing recommendations for Zonegran in special patient populations
Paediatric population (aged 6 years and above)
Dosage escalation and maintenanceZonegran must be added to existing therapy for paediatric patients aged 6 years and above. The dose should be titrated on the basis of clinical effect. Recommended escalation and maintenance doses are given in Table 2. Some patients, especially those not taking CYP3A4-inducing agents, may respond to lower doses.Physicians should draw the attention of paediatric patients and their parents/carers to the Patient Alert Box (in the package leaflet) on preventing heatstroke (see section 4.4: Paediatric population). Table 2. Paediatric population (aged 6 years and above) recommended dosage escalation and maintenance regimen
|Treatment Regimen||Titration Phase||Usual Maintenance Dose|
|Adjunctive therapy- with CYP3A4-inducing agents (see section 4.5)||Week 1||Weeks 2 to 8||Patients of weight 20 to 55 kga||Patients of weight > 55 kg|
|1 mg/kg/day (once a day)||Increase at weekly intervals in increments of 1 mg/kg||6 to 8 mg/kg/day (once a day)||300 - 500 mg/day (once a day)|
|- without CYP3A4-inducing agents||Week 1 + 2||Weeks ≥ 3|
6 to 8 mg/kg/day
(once a day)
300 - 500 mg/day
(once a day)
(once a day)
Increase at two-weekly intervals in increments of 1 mg/kg
Note:a. To ensure a therapeutic dose is maintained the weight of a child should be monitored and the dose reviewed as weight changes occur up to a weight of 55kg. The dose regime is 6-8 mg/kg/day up to a maximum dose of 500 mg/day. The safety and efficacy of Zonegran in children aged below 6 years or those below 20 kg have not yet been established. There are limited data from clinical studies in patients with a body weight of less than 20 kg. Therefore children aged 6 years and above and with a body weight less than 20 kg should be treated with caution. It is not always possible to precisely achieve the calculated dose with the commercially available capsule strengths of Zonegran. In these cases it is therefore recommended that the Zonegran total dose should be rounded up or down to the nearest available dose that can be achieved with commercially available capsule strengths of Zonegran (25 mg, 50 mg and 100 mg).
WithdrawalWhen Zonegran treatment is to be discontinued, it should be withdrawn gradually (see section 4.4). In clinical studies of paediatric patients, down-titration was completed by dose reductions at weekly intervals in increments of about 2 mg/kg (i.e. in accordance with the schedule in Table 3). Table 3. Paediatric population (aged 6 years and above) recommended down-titration schedule
|Weight||Decrease at weekly intervals in increments of:|
|20 28 kg||25 to 50 mg / day*|
|29 41 kg||50 to 75 mg / day*|
|42 55 kg||100 mg / day*|
|>55 kg||100 mg / day*|
ElderlyCaution should be exercised at initiation of treatment in elderly patients as there is limited information on the use of Zonegran in these patients. Prescribers should also take account of the safety profile of Zonegran (see section 4.8).
Patients with renal impairmentCaution 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 impairmentUse in patients with hepatic impairment has not been studied. Therefore use in patients with severe hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to moderate hepatic impairment, and a slower titration of Zonegran may be required.
Method of administrationZonegran hard capsules are for oral use.
Effect of foodZonegran may be taken with or without food (see section 5.2).
|Serious rashes occur in association with Zonegran therapy, including cases of Stevens-Johnson syndrome.|
Withdrawal seizuresIn accordance with current clinical practice, discontinuation of Zonegran in patients with epilepsy must be accomplished by gradual dose reduction, to reduce the possibility of seizures on withdrawal. There are insufficient data for the withdrawal of concomitant antiepileptic medicines once seizure control with Zonegran has been achieved in the add-on situation, in order to reach monotherapy with Zonegran. Therefore, withdrawal of concomitant anti-epileptic medicinal products must be undertaken with caution.
Sulphonamide reactionsZonegran 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.
Suicide ideation and behaviourSuicidal 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 stonesSome 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 acidosisHyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with Zonegran treatment. This metabolic acidosis is caused by renal bicarbonate loss due to the inhibitory effect of zonisamide on carbonic anhydrase. Such electrolyte imbalance has been observed with the use of Zonegran in placebo-controlled clinical trials and in the post-marketing period. Generally, zonisamide-induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment. The amounts by which bicarbonate is decreased are usually small moderate (average decrease of approximately 3.5 mEq/l at daily doses of 300 mg in adults); rarely patients can experience more severe decreases. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or medicinal products) may be additive to the bicarbonate lowering effects of zonisamide. The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in patients taking zonisamide who have underlying conditions which might increase the risk of acidosis, in patients who are at an increased risk of adverse consequences of metabolic acidosis and in patients with symptoms suggestive of metabolic acidosis. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing Zonegran (by gradual discontinuation or reduction of a therapeutic dose) as osteopenia may develop.If the decision is made to continue patients on Zonegran in the face of persistent acidosis, alkali treatment should be considered.Zonegran should be used with caution in adult patients being treated concomitantly with carbonic anhydrase inhibitors such as topiramate or acetazolamide, as there are insufficient data to rule out a pharmacodynamic interaction (see also section 4.4 Paediatric population and section 4.5).
Heat strokeCases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients (see section 4.4 Paediatric population for full warning). Caution should be used in adults when Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity (see also section 4.4 Paediatric population).
PancreatitisIn 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.
RhabdomyolysisIn patients taking Zonegran, in whom severe muscle pain and/or weakness develop either in the presence or absence of a fever, it is recommended that markers of muscle damage be assessed, including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another obvious cause such as trauma or grand mal seizures, it is recommended that Zonegran discontinuation be considered and appropriate treatment initiated.
Women of childbearing potentialWomen of childbearing potential have to use effective 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.
Body weightZonegran may cause weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight or is underweight whilst on this medication. If substantial undesirable weight loss occurs, discontinuation of Zonegran should be considered. Weight loss is potentially more serious in children (see section 4.4. Paediatric population).
Paediatric populationThe 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 childrenZonegran can cause children to sweat less and overheat and if the child is not treated this can lead to brain damage and death. Children are most at risk especially in hot weather. When a child is taking Zonegran: The child should stay cool especially in hot weather The child must avoid heavy exercise especially when the weather is hot The child must drink plenty of cold water The child must not take any of these medicines: carbonic anhydrase inhibitors (like topiramate and acetazolamide), and anticholinergic agents (like clomipramine, hydroxyzine, diphenhydramine, haloperidol, imipramine and oxybutynin). IF ANY OF THE FOLLOWING OCCUR, THE CHILD NEEDS URGENT MEDICAL ATTENTION:The skin feels very hot with little or no sweating, or the child becomes confused or has muscle cramps, or the child's heartbeat or breathing become rapid. • Take the child to a cool, shaded place • Keep the child's skin cool with water • Give the child cold water to drink|
Body weightWeight loss leading to deterioration of general condition and failure to take anti-epilepsy medication has been related to a fatal outcome (see section 4.8). Zonegran is not recommended for paediatric patients who are underweight (definition in accordance with the WHO age adjusted BMI categories) or have a decreased appetite.The incidence of decreased body weight is consistent across age groups (see section 4.8); however, given the potential seriousness of weight loss in children, weight should be monitored in this population. A dietary supplement or increased food intake should be considered if the patient is failing to gain weight in accordance with growth charts, otherwise Zonegran should be discontinued. There are limited data from clinical studies in patients with a body weight of less than 20 kg. Therefore children aged 6 years and above with a body weight of less than 20 kg should be treated with caution. The long term effect of weight loss in the paediatric population on growth and development is unknown.
Metabolic acidosisThe risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in paediatric and adolescent patients. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in this population (see section 4.4 - Metabolic acidosis for full warning; see section 4.8 for incidence of low bicarbonate). The long term effect of low bicarbonate levels on growth and development is unknown. Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide (see section 4.5).
Kidney stonesKidney stones have occurred in paediatric patients (see section 4.4 Kidney stones for full warning). Some patients, especially those with a predisposition to nephrolithiasis, may be at increased risk for renal stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. Nephrolithiasis may lead to chronic kidney damage. Risk factors for nephrolithiasis include prior stone formation, a family history of nephrolithiasis and hypercalciuria. None of these risk factors can reliably predict stone formation during zonisamide treatment.Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in those with predisposing risk factors. Renal ultrasound should be performed at the discretion of the physician. In the event kidney stones are detected, Zonegran should be discontinued.
Hepatic dysfunctionIncreased 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 Zonegran should be considered.
CognitionCognitive 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. ExcipientsZonegran 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 enzymesIn 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 productsIn epileptic patients, steady-state dosing with Zonegran resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin, or sodium valproate.
Oral contraceptivesIn 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 inhibitorsZonegran should be used with caution in adult patients treated concomitantly with carbonic anhydrase inhibitors such as topiramate and acetazolamide, as there are insufficient data to rule out a possible pharmacodynamic interaction (see section 4.4).Zonegran should not be used as co-medication in paediatric patients with other carbonic anhydrase inhibitors such as topiramate and acetazolamide (see section 4.4 Paediatric population).
P-gp substrateAn 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 ZonegranIn clinical studies co-administration of lamotrigine had no apparent effect on zonisamide pharmacokinetics. The combination of Zonegran with other medicinal products that may lead to urolithiasis may enhance the risk of developing kidney stones; therefore the concomitant administration of such medicinal products should be avoided.Zonisamide is metabolised partly by CYP3A4 (reductive cleavage), and also by N-acetyl-transferases and conjugation with glucuronic acid; therefore, substances that can induce or inhibit these enzymes may affect the pharmacokinetics of zonisamide:- Enzyme induction: Exposure to zonisamide is lower in epileptic patients receiving CYP3A4-inducing agents such as phenytoin, carbamazepine, and phenobarbitone. These effects are unlikely to be of clinical significance when Zonegran is added to existing therapy; however, changes in zonisamide concentrations may occur if concomitant CYP3A4-inducing anti-epileptic or other medicinal products are withdrawn, dose adjusted or introduced, an adjustment of the Zonegran dose may be required. Rifampicin is a potent CYP3A4 inducer. If co-administration is necessary, the patient should be closely monitored and the dose of Zonegran and other CYP3A4 substrates adjusted as needed.- CYP3A4 inhibition: Based upon clinical data, known specific and non-specific CYP3A4 inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposure parameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1200 mg/day) had no clinically relevant effects on the single-dose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of Zonegran dosing should not be necessary when co-administered with known CYP3A4 inhibitors.
Paediatric populationInteraction studies have only been performed in adults.
Women of childbearing potentialWomen of childbearing potential have to use effective contraception during treatment with Zonegran, and for one month after discontinuation.
PregnancyThere are limited data from the use of Zonegran in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.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-feedingZonisamide 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.
FertilityThere 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).
Summary of the safety profileZonegran has been administered to over 1,200 patients in clinical studies, more than 400 of whom received Zonegran for at least 1 year. In addition there has been extensive post-marketing experience with zonisamide in Japan since 1989 and in the USA since 2000.It should be noted that Zonegran is a benzisoxazole derivative, which contains a sulphonamide group. Serious immune based adverse reactions that are associated with medicinal products containing a sulphonamide group include rash, allergic reaction and major haematological disturbances including aplastic anaemia, which very rarely can be fatal (see section 4.4).The most common adverse reactions in controlled adjunctive-therapy studies were somnolence, dizziness and anorexia. The most common adverse reactions in a randomised, controlled monotherapy trial comparing zonisamide with carbamazepine prolonged release were decreased bicarbonate, decreased appetite, and decreased weight. The incidence of markedly abnormally low serum bicarbonate (a decrease to less than 17 mEq/l and by more than 5 mEq/l) was 3.8%. The incidence of marked decreases in weight of 20% or more was 0.7%.
Tabulated list of adverse reactionsAdverse reactions associated with Zonegran obtained from clinical studies and post-marketing surveillance are tabulated below. The frequencies are arranged according to the following scheme:
|very common||≥ 1/10|
|common||≥ 1/100 to < 1/10|
|uncommon||≥ 1/1,000 to < 1/100|
|rare||≥ 1/10,000 to < 1/1,000|
|very rare||< 1/10,000|
|not known||cannot be estimated from the available data|
Table 4. Adverse reactions associated with Zonegran obtained from adjunctive use clinical studies and post-marketing surveillance
|System Organ Class(MedDRA terminology)||Very Common||Common||Uncommon||Very Rare|
|Infections and infestation||Pneumonia Urinary tract infection|
|Blood and lymphatic system disorders||Ecchymosis||Agranulocytosis Aplastic anaemia Leucocytosis Leucopoenia Lymphadenopathy Pancytopenia, Thrombocytopenia|
|Immune system disorders||Hypersensitivity||Drug-induced hypersensitivity syndrome Drug rash with eosinophilia and systemic symptoms|
|Metabolism and nutrition disorders||Anorexia||Hypokalaemia||Metabolic acidosis Renal tubular acidosis|
|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|
|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 Pruritis Alopecia||Anhidrosis Erythema multiforme Stevens-Johnson syndrome Toxic epidermal necrolysis|
|Musculoskeletal and connective tissue disorders||Rhabdomyolysis|
|Renal and urinary disorders||Nephrolithiasis||Calculus urinary||Hydronephrosis Renal failure Urine abnormality|
|General disorders and administration site conditions||Fatigue Influenza-like illness Pyrexia Oedema peripheral|
|Investigations||Decreased bicarbonate||Weight decreased||Blood creatine phosphokinase increased Blood creatinine increased Blood urea increased Liver function tests abnormal|
|Injury, poisoning and procedural complications||Heat stroke|
|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|
|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|
Additional information on special populations:
ElderlyA 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 populationThe 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 reactionsReporting 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard
TreatmentNo 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.
Mechanism of actionThe 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 effectsThe 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 generalisationEfficacy 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 (ITT population)||281||300|
|Six months seizure freedom||Diff||CI95%|
|PP-population*||79.4%||83.7%||-4.5%||-12.2% ; 3.1%|
|ITT-population||69.4%||74.7%||-6.1%||-13.6% ; 1.4%|
|< 4 seizures during 3 month baseline period||71.7%||75.7%||-4.0%||-11.7% ; 3.7%|
|> 4 seizures during 3 month baseline period||52.9%||68.9%||-15.9%||-37.5% ; 5.6%|
|Twelve months seizure freedom|
|PP-population||67.6%||74.7%||-7.9%||- 17.2% ; 1.5%|
|ITT-population||55.9%||62.3%||-7.7%||- 16.1% ; 0.7%|
|< 4 seizures during 3 month baseline period||57.4%||64.7%||-7.2%||-15.7% ; 1.3%|
|> 4 seizures during 3 month baseline period||44.1%||48.9%||-4.8%||-26.9% ; 17.4%|
|Seizure Sub-type (6 month seizure freedom-PP population)|
|All partial||76.4%||86.0%||-9.6%||-19.2% ; 0.0%|
|Simple partial||72.3%||75.0%||-2.7%||-20.0% ; 14.7%|
|Complex partial||76.9%||93.0%||-16.1%||-26.3% ; -5.9%|
|All generalized Tonic-Clonic||78.9%||81.6%||-2.8%||-11.5% ; 6.0%|
|Secondary Tonic-Clonic||77.4%||80.0%||-2.6%||-12.4% ; 7.1%|
|Generalized Tonic-Clonic||85.7%||92.0%||-6.3%||-23.1% ; 10.5%|
PP = Per Protocol Population; ITT = Intent To Treat Population
Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation in adultsIn adults, efficacy has been demonstrated with Zonegran in 4 double-blind, placebo-controlled studies of periods of up to 24 weeks with either once or twice daily dosing. These studies show that the median reduction in partial seizure frequency is related to Zonegran dose with sustained efficacy at doses of 300-500 mg per day.
Paediatric populationAdjunctive 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.
AbsorptionZonisamide is almost completely absorbed after oral administration, generally reaching peak serum or plasma concentrations within 2 to 5 hours of dosing. The first-pass metabolism is believed to be negligible. Absolute bioavailability is estimated to be approximately 100%. Oral bioavailability is not affected by food, although peak plasma and serum concentrations may be delayed.Zonisamide AUC and Cmax values increased almost linearly after single dose over the dose range of 100-800 mg and after multiple doses over the dose range of 100-400 mg once daily. The increase at steady state was slightly more than expected on the basis of dose, probably due to the saturable binding of zonisamide to erythrocytes. Steady state was achieved within 13 days. Slightly greater than expected accumulation occurs relative to single dosing.
DistributionZonisamide 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.
BiotransformationZonisamide 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.
EliminationApparent 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-linearityZonisamide 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 relationshipZonisamide lowers the 28-day average seizure frequency and the decrease is proportional (log-linear) to zonisamide average concentration.
Special patient groupsIn 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.
Capsule contentsMicrocrystalline cellulose Hydrogenated vegetable oil Sodium laurilsulfateCapsule shells (25 mg and 50 mg hard capsules)Gelatin Titanium dioxide (E171) Shellac Propylene glycol Potassium hydroxide Black iron oxide (E172)Capsule shells (100 mg hard capsules)Gelatin Titanium dioxide (E171) Allura red AC (E129) Sunset yellow FCF (E110) Shellac Propylene glycol Potassium hydroxide Black iron oxide (E172)
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