ZONISAMIDE ACCORD

Posology Adults Dosage escalation and maintenance Zonisamide Capsules 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. 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 Week 1 + 2 Week 3 + 4 Week 5 + 6Monotherapy - Newly diagnosed adult patients 100 mg/day (once a day) 200 mg /day (once a day) 300 mg / day (once a day) 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. 5) 50 mg/day (in two divided doses) 100 mg /day (in two divided doses) Increase at weekly intervals in increments of 100 mg 300 to 500 mg per day (once a day or two divided doses).

Week 1 + 2 Week 3 + 4 Week 5 to 10- without CYP3A4-inducing agents; or with renal or hepatic impairment 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 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 Capsules in special patient populations Paediatric population (aged 6 years and above) Dosage escalation and maintenance Zonisamide Capsules 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. 4: Paediatric population).

Table 2. 5) 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 Weeks ≥ 3 - without CYP3A4-inducing agents 1mg/kg/day (once a day) Increase at two- weekly 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 55 kg. The dose regime is 6-8mg/kg/day up to a maximum dose of 500 mg/day. The safety and efficacy of Zonisamide Capsules 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 Capsules.

In these cases it is therefore recommended that 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. 4). 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 Capsules in these patients. 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 Capsules 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 Capsules may be required. Method of administration Zonisamide hard capsules are for oral use. 2).

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 Capsules is a benzisoxazole derivative, which contains a sulfonamide group. 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.

8 %. 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 infectionBlood and lymphati c 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 disorder s Anorexia Hypokalaemia Metabolic acidosis, Renal tubular acidosis Psychiatric Disorders Agitation, Irritability, Confusiona l state, Depression Affect lability, Anxiety, Insomnia , Psychoti c Anger, Aggression, Suicidal ideation, Suicide attempt Hallucination Nervous system disorders Ataxia, Dizziness, Memory impairment, Somnolence Bradyphrenia, Disturbance in attention, Nystagmus, Paraesthesia, Speech disorder, 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 mediastina l disorders Dyspnoea, Pneumonia aspiration, Respiratory disorder, Hypersensitivity-type Pneumonitis System Organ Class (MedDRA terminology Very Common Common Uncommon Very Rare Gastrointestinal disorders Abdominal pain, Constipatio n, Diarrhoea, Vomiting Pancreatitis Hepatobiliar y 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 Rhabdomyolysis Renal and urinary disorders Nephrolithiasis Calculus urinary Hydronephrosis, Renal failure, Urine abnormality General disorders and administratio n site conditions Fatigue, Influenza- like illness, Pyrexia, Oedema periphera lInvestigations Decreased bicarbonate Weight decreased Blood creatine phosphokinase increased, Blood creatinine increased, Blood urea increased, Liver function tests abnormal Injury, poisoning and procedural complication Heat stroke In addition there have been isolated cases of Sudden Unexplained Death in Epilepsy Patients (SUDEP) receiving zonisamide.

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 […]

Unexplained rash Serious rashes occur in association with Zonisamide Capsules therapy, including cases of Stevens-Johnson syndrome. Consideration must be given to discontinuing Zonisamide Capsules in patients who develop an otherwise unexplained rash.

All patients who develop a rash while taking Zonisamide Capsules 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 Capsules 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 Capsules. Therefore, withdrawal of concomitant anti-epileptic medicinal products must be undertaken with caution.

Sulfonamide reactions Zonisamide Capsules is a benzisoxazole derivative, which contains a sulfonamide group. Serious immune based adverse reactions that are associated with medicinal products containing a sulfonamide 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 Capsules.

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. e. decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis) is associated with Zonisamide Capsules 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 Capsules 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. 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.

Metabolic acidosis has the potential to lead to hyperammonaemia, which has been reported with or without encephalopathy during zonisamide treatment. 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. The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients.

Appropriate evaluation and monitoring of serum […]

1 or to sulfonamides.