Consumer medicine information

Zonegran

Zonisamide

BRAND INFORMATION

Brand name

Zonegran

Active ingredient

Zonisamide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zonegran.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Zonegran hard capsules.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist. Keep this leaflet with the medicine. You may need to read it again.

WHAT ZONEGRAN IS USED FOR

The name of your medicine is Zonegran. The active ingredient in Zonegran is called zonisamide.

Zonegran is used to treat certain types of epilepsy in adults. Zonegran may be used:

  • On its own to treat seizures in adults.
  • With other antiepileptic medicines to treat seizures in adults.

Epilepsy is caused by a disruption in the electrical activity of the brain. The abnormal electrical impulses occur due to altered levels of some chemicals in the brain. Zonegran can control brain chemicals which send signals to nerves so that seizures do not happen.

Zonegran is used in partial seizures that affect only one part of the brain, with or without generalized seizures that may affect the whole brain.

Your doctor may have prescribed Zonegran for another use.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

There is no evidence that Zonegran is addictive.

This medicine is only available with a doctor’s prescription.

Zonegran capsules is not recommended for children and adolescents under 18 years of age as there is not enough information on its use in children and adolescents.

BEFORE YOU TAKE ZONEGRAN

When you must not take it

Do not take this medicine if you have an allergy to:

  • Zonisamide
  • Sulphonamide drugs including furosemide (Lasix) and bumetanide (Burinex) (diuretic medicines)
  • Any of the ingredients listed at the end of this leaflet (See “Ingredients”)

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not give this medicines to anyone who is unconscious or in a coma.

Do not give this medicine to anyone under the age of 18 years. Safety and effectiveness in children younger than 18 years have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If the medicine has expired or the packing is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

You must tell your doctor if:

  • You have had an allergic reaction to similar medicines (ask your doctor to check your records).
  • You are allergic to any other substances such as food preservatives or dyes
    (Zonegran 100mg capsules contain a yellow colour called sunset yellow FCF (E110) which may cause allergic reactions).
  • You are pregnant or intend to become pregnant.
    Like most antiepileptic medicines, Zonegran is not recommended for use during pregnancy. Your doctor will discuss with you the possible risks and benefits of using Zonegran capsules during pregnancy.
  • You are breast feeding, or wish to breastfeed.
    It is recommended that you do not breastfeed while taking or for one month after stopping Zonegran capsules. This medicine may pass into the breast milk and there is a possibility that your baby may be affected. Your doctor will discuss with you the possible risks and benefits of using Zonegran capsules during breastfeeding.
  • You have liver or kidney disease or kidney stones.
  • You have a reduced white blood cell count or have recently lost weight (or weigh less than 40 kg).
  • You have high blood levels of ammonia

If you have not told your doctor about any of the above, tell them before you start taking Zonegran.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may affect the way other medicines work. They may also react with Zonegran capsules resulting in untoward or sometimes dangerous side effects. Your doctor or pharmacist will be able to tell you which medicines are safe to take with Zonegran capsules.

Some other antiepileptic drugs such as phenytoin, carbamazepine and phenobarbitone may affect Zonegran, so tell your doctor if you are taking these drugs.

Your doctor or pharmacist will have more information on medicines that you need to be careful with or need to avoid while taking Zonegran capsules.

Before you start to take any other medicines, tell your doctor or pharmacist that you are taking Zonegran capsules.

HOW TO TAKE ZONEGRAN

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

When you take Zonegran on its own:
The usual starting dose is 100 mg daily taken once a day. This may be increased by up to 100 mg at intervals of two weeks. The usual daily dose is 300 mg once a day.

When you take Zonegran with other antiepileptic medicines:
The usual starting dose is 50mg daily taken in two divided doses. The dose will be gradually increased at intervals of one or two weeks, to a daily dose of between 300mg and 500mg per day. Some patients respond to lower doses.

If you have a kidney problem your doctor may start you on a lower dose and increase it more gradually to prevent unwanted side effects.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you. If you take the wrong dose, Zonegran may not work as well.

How to take it

Zonegran capsules may need to be taken once or twice a day.

Zonegran capsules must be swallowed whole with water. Do not chew the capsules.

Zonegran can be taken with or without food.

When to take Zonegran

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take Zonegran

Continue taking your medicine for as long as your doctor tells you. Do not stop unless your doctor advises you to.

Zonegran capsules help to control your condition, but does not cure it. Therefore, it is important that you keep taking Zonegran capsules every day. Your doctor will check your progress to make sure the medicine is working and will discuss with you how long your treatment should continue.

Zonegran is meant to be taken as a long-term medicine. Do not reduce your dose or stop your medicine unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not try and make up for the dose that you missed by taking more than one dose at a time. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Zonegran. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE TAKING ZONEGRAN

Things you must do

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise, your doctor may think that it was not working as it should and change your treatment unnecessarily.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Zonegran.

Tell any other doctors, dentists and pharmacists who treat you that you are taking Zonegran.

If you become pregnant while taking Zonegran, tell your doctor immediately. Do not stop treatment without first discussing it with your doctor. You must only take zonisamide during your pregnancy if your doctor tells you to. If you are a woman of childbearing age you must use adequate contraception while taking zonisamide and for one month after stopping zonisamide.

Your doctor will check your progress and may want to take some blood tests from time to time. This helps to prevent unwanted side effects.

Tell your doctor immediately if you have thoughts about killing yourself or if you are close to or care for someone using Zonegran capsules who talks about or shows signs of wanting to kill him or herself. Persons taking Zonegran capsules may be more likely to think about killing themselves or actually trying to do so, especially when Zonegran capsules are first started or the dose is changed.

If you or someone you know demonstrates any of the following warning signs of suicide-related behaviour while taking Zonegran capsules, contact a healthcare provider immediately, or even go to the nearest hospital for treatment:

  • Thoughts or talk of death or suicide
  • Thoughts or talk of self-harm or harm to others
  • Any recent attempts of self-harm
  • New or worse depression
  • New or worse anxiety
  • Panic attacks
  • Trouble sleeping (insomnia)
  • Increase in aggressive behaviour, irritability or agitation
  • Acting on dangerous impulses
  • Extreme increase in activity and talking (mania)
  • Other unusual changes in behaviour or mood.

Keep all of your doctor’s appointments so that your progress can be checked.

Things you must not do

Do not use Zonegran to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if their symptoms seem similar to yours.

Do not stop taking your medicine or lower the dosage, even if you are feeling better, without checking with your doctor. If you stop taking Zonegran capsules suddenly, your condition may worsen or your chance of getting an unwanted side effect may increase. To prevent this, your doctor may gradually reduce the amount of Zonegran capsules you take each day before stopping the medicine completely.

Things to be careful of

Do not drive or operating machinery until you know how Zonegran affects you. As with other antiepileptic medicines, Zonegran capsules may cause drowsiness in some people. Make sure you know how you react to Zonegran capsules before you drive a car, operate machinery, or do anything else that could be dangerous.

Make sure you keep cool in hot weather and drink plenty of water. This will help reduce the risk of kidney stones.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Zonegran All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Contact your doctor immediately if you:

  • have difficulty breathing, a swollen face, lips or tongue, or a severe skin rash as these symptoms may indicate that you are having a severe allergic reaction.
  • have signs of overheating - high body temperature but little or no sweating, rapid heartbeat and breathing, muscle cramps, and confusion.
  • have thoughts of harming or killing yourself. A small number of people being treated with antiepileptics such as Zonegran have had thoughts of harming or killing themselves.
  • have pain in your muscles or a feeling of weakness, as this may be a sign of abnormal muscle breakdown which can lead to kidney problems.
  • get a sudden pain in your back or stomach, have pain on urinating (passing water) or notice blood in your urine, as this may be a sign of kidney stones.
  • develop visual problems such as eye pain or blurred vision while taking Zonegran.

Contact your doctor as soon as possible if you:

  • have an unexplained skin rash, as this could develop into a more severe skin rash or skin peeling.
  • feel unusually tired or feverish, have a sore throat, swollen glands, or find that you bruise more
  • easily, as this may mean you have a blood disorder.
  • have signs of increased acid level in the blood- headaches, drowsiness, shortness of breath
  • have signs of high blood ammonia levels. High ammonia in the blood can affect your mental activities, slow your alertness,
  • make you feel tired, or cause vomiting, and
  • loss of appetite. Your doctor may need to monitor or treat this.

Your doctor may decide that you should stop using Zonegran

The most common side effects of Zonegran are mild. They occur during the first month of treatment and usually decrease with continued treatment.

Very common side effects (may affect more than 1 in 10 people) are:

  • agitation, irritability, confusion, depression
  • poor muscle coordination, dizziness, poor memory, sleepiness, double vision
  • loss of appetite, decreased blood levels of bicarbonate (a substance that prevents your blood from becoming acidic)

Common side effects (may affect up to 1 in 10 people) are:

  • difficulty sleeping, strange or unusual thoughts, feeling anxious or emotional.
  • slowed thoughts, loss of concentration, speech abnormalities, abnormal skin sensation (pins and needles), tremor, involuntary movement of the eyes.
  • kidney stones.
  • skin rashes, itching, allergic reactions, fever, tiredness, flu-like symptoms, hair loss.
  • ecchymosis (a small bruise caused by blood leaking from broken blood vessels in the skin).
  • loss of weight, nausea, indigestion, stomach pains, diarrhoea (loose stools), constipation.
  • swelling of the feet and legs.

Uncommon side effects (may affect up to 1 in 100 people) are:

  • anger, aggression, thoughts of suicide, suicide attempt.
  • vomiting.
  • gall bladder inflammation, gallstones.
  • urinary stones.
  • lung infection / inflammation, urinary tract infections.
  • low blood potassium levels, convulsions/seizures.

Very rare side effects (may affect up to 1 in 10,000 people) are:

  • hallucinations, memory loss, coma, neuroleptic malignant syndrome (inability to move, sweating, fever, incontinence), status epilepticus (prolonged or repeated seizures).
  • breathing disorders, shortness of breath, inflammation of the lungs.
  • inflammations of the pancreas (severe pain in the stomach or back)
  • liver problems, kidney failure, increased blood levels of creatinine (a waste product that your kidneys should normally remove).
  • severe rashes or skin peeling (at the same time you may feel unwell or develop a fever).
  • abnormal muscle breakdown (you may feel pain or weakness in your muscles) which can lead to kidney problems.
  • swollen glands, blood disorders (reduction in the number of blood cells, which can make infection more likely and can make you look pale, feel tired and feverish, and bruise more easily).
  • decreased sweating, overheating.
  • glaucoma, which is a blockage of fluid in the eye causing increased pressure in the eye. Eye pain, blurred vision or decreased vision may occur and can be signs of glaucoma.
  • high blood ammonia levels which can affect your mental activities, slow your alertness, make you feel tired, or cause vomiting.

During your treatment with Zonegran capsules, your doctor may from time to time test your blood to look for any side effects which the medication could cause. Your doctor or pharmacist will have more information. Your doctor or pharmacist should discuss the possible side effects of Zonegran capsules with you.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist.

This includes any side effects not listed in this leaflet.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

AFTER TAKING ZONEGRAN

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place away from light and where the temperature stays below 25°C.

Do not store Zonegran or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Zonegran capsules 25mg: a white opaque body and a white opaque cap and printed with “ZONEGRAN 25” in black on the capsule body. Capsule size No 4 containing white powder free from visible impurities.

Zonegran capsules 50mg: a white opaque body and a grey opaque cap and printed with “ZONEGRAN 50” in black on the capsule body. Capsule Size No 3 containing white powder free from visible impurities.

Zonegran capsules 100mg: a white opaque body and a red opaque cap and printed with “ZONEGRAN 100” in black on the capsule body. Capsule size No 1 containing white powder free from visible impurities.

Ingredients

Zonegran capsules 25mg

Active Ingredients: Zonisamide

Inactive Ingredients:

  • microcrystalline cellulose
  • hydrogenated vegetable oil
  • sodium laurylsulphate

Capsule shell:

  • gelatin
  • titanium dioxide (E171)
  • TekPrint SW-9008 Black Ink (ARTG No 2328)

Zonegran capsules 50mg

Active Ingredients: Zonisamide

Inactive Ingredients:

  • microcrystalline cellulose
  • hydrogenated vegetable oil
  • sodium laurylsulphate

Capsule shell:

  • gelatin
  • titanium dioxide (E171)
  • black iron oxide (E172)
  • TekPrint SW-9008 Black Ink (ARTG No 2328)

Zonegran capsules 100mg

Active Ingredients: Zonisamide

Inactive Ingredients:

  • microcrystalline cellulose
  • hydrogenated vegetable oil
  • sodium laurylsulphate

Capsule shell:

  • gelatin
  • titanium dioxide (E171)
  • allura red AC (E129)
  • sunset yellow FCF (E110)
  • TekPrint SW-9008 Black Ink (ARTG No 2328)

This medicine does not contain gluten, tartrazine or any other azo dyes.

SPONSOR

Amdipharm Mercury (Australia) Pty Ltd
Level 9, 76 Berry Street
North Sydney NSW 2060

Ph: 1800 627 680

This leaflet was prepared in 13 July 2022

Australian Registration Number

25mg capsules: AUST R 125869

50mg capsules: AUST R 125870

100mg capsules: AUST R 125871

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Zonegran

Active ingredient

Zonisamide

Schedule

S4

 

1 Name of Medicine

Zonisamide.

2 Qualitative and Quantitative Composition

Each Zonegran 25 mg hard capsule contains 25 mg zonisamide.
Each Zonegran 50 mg hard capsule contains 50 mg zonisamide.
Each Zonegran 100 mg hard capsule contains 100 mg zonisamide.
List of excipients with known effect: None.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsule.
Zonegran 25 mg hard capsules have a white opaque body and a white opaque cap and printed with "ZONEGRAN 25" in black on the capsule body. Capsule size No. 4 containing white powder free from visible impurities.
Zonegran 50 mg hard capsules have a white opaque body and a grey opaque cap and printed with "ZONEGRAN 50" in black on the capsule body. Capsule size No. 3 containing white powder free from visible impurities.
Zonegran 100 mg hard capsules have a white opaque body and a red opaque cap and printed with "ZONEGRAN 100" in black on the capsule body. Capsule size No. 1 containing white powder free from visible impurities.

4 Clinical Particulars

4.1 Therapeutic Indications

Zonegran is indicated as:
monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy who are intolerant to other agents or where other agents are contraindicated;
adjunctive therapy in the treatment of adult patients with partial seizures, with or without secondary generalisation.

4.2 Dose and Method of Administration

Zonegran capsules are for oral use.

Dosage.

Adults.

Zonegran 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.

Elderly.

Caution should be exercised at initiation of treatment in elderly patients as there is limited information on the use of Zonegran in these patients. Prescribers should also take account of the safety profile of Zonegran (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric use.

The safety and efficacy in children and adolescents under 18 years have not been established. Therefore, use in these patients is not recommended (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

Dosage adjustment in renal impairment.

Caution must be exercised in treating patients with renal impairment, as there is limited information on use in such patients and a slower titration of Zonegran might be required. Since zonisamide and its metabolites are excreted renally, it should be discontinued in patients who develop acute renal failure or where a clinically significant sustained increase in serum creatinine is observed.
In subjects with renal impairment, renal clearance of single doses of Zonegran was positively correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in subjects with creatinine clearance < 20 mL/min.

Dosage adjustment in hepatic impairment.

Use in patients with hepatic impairment has not been studied. Therefore, use in patients with severe hepatic impairment is not recommended. Caution must be exercised in treating patients with mild to moderate hepatic impairment, and a slower titration of Zonegran may be required.

Dosage adjustment in dialysis.

Use in patients undergoing dialysis has not been studied.

Dosage adjustment in concomitant disease.

Refer to information provided for dosage adjustment in renal and hepatic insufficiency.

Maximum tolerated daily dose and the maximum dose for an entire course of therapy.

Although in some studies higher doses were used, the maximum recommended daily dose is 500 mg.
There is no recommended maximum dose for an entire course of therapy.

Effect of food.

Zonegran may be taken with or without food.

Withdrawal of Zonegran.

When Zonegran treatment is to be discontinued, it should be withdrawn gradually (see Section 4.4 Special Warnings and Precautions for Use). In clinical studies of adult patients, dose reductions of 100 mg at weekly intervals have been used with concurrent adjustment of other antiepileptic drug doses (where necessary).

4.3 Contraindications

Hypersensitivity to zonisamide, to sulphonamides or any of the excipients.

4.4 Special Warnings and Precautions for Use

Suicidal ideation and behaviour.

Antiepileptic drugs, including Zonegran, increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behaviour, and/or any unusual changes in mood or behaviour.
Pooled analyses of 199 placebo controlled clinical trials (mono and adjunctive therapy) of 11 different AEDs showed that patients randomised to one of the AEDs had approximately twice the risk (adjusted relative risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviour compared to patients randomised to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behaviour or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behaviour for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behaviour with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behaviour beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behaviour was generally consistent among drugs in the data analysed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analysed.
Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
The relative risk for suicidal thoughts or behaviour was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Zonegran or any other AED must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behaviour. Should suicidal thoughts and behaviour emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviour and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behaviour, or the emergence of suicidal thoughts, behaviour, or thoughts about self harm. Behaviours of concern should be reported immediately to healthcare providers (see Section 4.4 Special Warnings and Precautions for Use, Cognitive adverse events).

Withdrawal seizures.

In accordance with current clinical practice, discontinuation of Zonegran in patients with epilepsy must be accomplished by gradual dose reduction, to reduce the possibility of seizures on withdrawal. There are insufficient data for the withdrawal of concomitant antiepileptic medications once seizure control with Zonegran has been achieved in the add-on situation, in order to reach monotherapy with Zonegran. Therefore withdrawal of concomitant antiepileptic agents must be undertaken with caution.

Sulfonamide reactions.

Potentially fatal reactions to sulfonamides.

Fatalities have occurred, although rarely, as a result of severe reactions to sulfonamides (zonisamide is a sulfonamide) including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Such reactions may occur when a sulfonamide is readministered irrespective of the route of administration. If signs of hypersensitivity or other serious reactions occur, discontinue Zonegran immediately.

Serious skin reactions.

Serious rashes have occurred in association with Zonegran therapy, including isolated cases of Stevens-Johnson syndrome.
Consideration must be given to discontinuing Zonegran in patients who develop an otherwise unexplained rash. All patients who develop a rash while taking Zonegran must be closely supervised, with additional levels of caution applied to those patients receiving concomitant antiepileptic agents that may independently induce skin rashes.

Serious haematological events.

Isolated 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.

Hyperammonaemia and encephalopathy.

Hyperammonaemia and encephalopathy have been reported with the postmarketing use of zonisamide. Zonisamide treatment inhibits carbonic anhydrase activity, which may cause metabolic acidosis that is associated with an increased risk for developing hyperammonaemia. Hyperammonaemia resulting from zonisamide can also be asymptomatic.
The risks of hyperammonaemia and various manifestations of encephalopathy may be increased in patients treated with zonisamide and concomitantly taking other medications that can cause hyperammonaemia, including valproic acid or topiramate. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonaemia with or without encephalopathy and this risk may be increased by zonisamide use.
Measure serum ammonia concentration if signs or symptoms (e.g. unexplained change in mental status, vomiting, or lethargy) of encephalopathy occur. Hyperammonaemia resulting from zonisamide resolves when zonisamide is discontinued. Hyperammonaemia from zonisamide may resolve or decrease in severity with a decrease of the daily dose.

Metabolic acidosis.

Zonegran can cause a hyperchloraemic, non-anion gap, metabolic acidosis (i.e. decreased serum bicarbonate below the normal reference range in the absence of chronic respiratory alkalosis). Metabolic acidosis is often asymptomatic. Metabolic acidosis can also increase the risk for hyperammonaemia, particularly in the presence of drugs which can cause hyperammonaemia.
Signs and symptoms of acute or chronic metabolic acidosis may include hyperventilation, nonspecific symptoms such as fatigue and anorexia or more severe sequelae including cardiac arrhythmias or stupor. The risk of development of zonisamide induced metabolic acidosis appears to be greater at higher doses of Zonegran, but can occur with doses as low as 25 mg daily.
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 postmarketing period. Generally, zonisamide induced metabolic acidosis occurs early in treatment although cases can occur at any time during treatment.
The risk of zonisamide induced metabolic acidosis appears to be more frequent and severe in younger patients.
Data from one paediatric clinical trial shows a higher incidence of metabolic acidosis compared to data from trials of Zonegran in adults. Chronic metabolic acidosis in paediatric patients can reduce growth rates, resulting in a reduction in the maximal height achieved. The specific effects of zonisamide on growth and bone have not been investigated. Appropriate evaluation and monitoring of serum bicarbonate levels should be carried out in patients taking Zonegran 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.
Serum bicarbonate should be measured pretreatment (baseline), on commencement of maintenance dosing, when dosage is increased and when strong CYP3A4 inhibitors are newly coprescribed with Zonegran and at a minimum 6 monthly from the adoption of a maintenance regimen. Although acidosis has been demonstrated to be dose dependent it can present at any time. In addition, if signs or symptoms of metabolic acidosis are observed, serum bicarbonate should be measured. 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.
Bicarbonate decrements are usually mild-moderate (average decrease of approximately 3.5 mEq/L at daily doses of 300 mg in adults); rarely patients can experience more severe decrements. Conditions or therapies that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhoea, surgery, ketogenic diet, or other drugs, e.g. acetazolamide) may be additive to the bicarbonate lowering effects of zonisamide. Therefore, combination of Zonegran with a ketogenic diet in the management of epilepsy is not advisable as it may increase the risk of metabolic acidosis.
Chronic, untreated metabolic acidosis may result in osteomalacia (referred to as rickets in paediatric patients) and/or osteoporosis with an increased risk for fractures. Of potential relevance, zonisamide treatment was associated with reductions in serum phosphorus and increases in serum alkaline phosphatase, changes that may be related to metabolic acidosis and osteomalacia (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).
Although the effects of metabolic acidosis from zonisamide on the fetus are not clearly known, metabolic acidosis in pregnancy (due to other causes) may affect fetal development (i.e. decreased fetal growth, decreased fetal oxygenation and fetal death) and the ability of the fetus to tolerate labour. In addition, significant amounts of zonisamide can appear in the breast milk of nursing women taking zonisamide, and the effects of this exposure on the infant from metabolic acidosis, or any other cause, are unknown.
In a Zonegran monotherapy study (see Section 4.8 Adverse Effects (Undesirable Effects)), 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%. Reductions from baseline in serum bicarbonate of > 3.5 mmol/L occurred in 121/237 (51.1%) patients given Zonegran.

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.

Kidney stones.

Kidney stones have occurred in patients treated with zonisamide. In some cases, calculi were accompanied by urine abnormalities, hydronephrosis, haematuria, bladder stenosis or urinary tract infection. Zonegran should be used with caution in patients who have risk factors for nephrolithiasis, including prior stone formation, a family history of nephrolithiasis and hypercalciuria. Such patients may be at increased risk of stone formation and associated signs and symptoms such as renal colic, renal pain or flank pain. In addition, patients taking other medications associated with nephrolithiasis may be at increased risk. Increasing fluid intake and urine output may help reduce the risk of stone formation, particularly in those with predisposing risk factors.
Among 991 patients treated during the development of zonisamide, 40 patients (4.0%) with epilepsy receiving zonisamide developed clinically possible or confirmed kidney stones (e.g. clinical symptomology, sonography, etc), a rate of 34 per 1000 patient years of exposure (40 patients with 1168 years of exposure). Of these, 12 were symptomatic, and 28 were described as possible kidney stones based on sonographic detections. In nine patients, the diagnosis was confirmed by a passage of a stone or by a definitive sonograph finding. The rate of occurrence of kidney stones was 28.7 per 1000 patient years of exposure in the first six months, 62.6 per 1000 patients years of exposure between 6 and 12 months, and 24.3 per 1000 patients years of exposure after 12 months of use. There are no normative sonographic data available for either the general population or patients with epilepsy. Although the clinical significance of the sonographic findings may not be certain, the development of nephrolithiasis may be related to metabolic acidosis. The analysed stones were composed of calcium or urate salts.

Abnormal liver function tests.

Findings not observed in clinical studies, but seen in the dog at exposure levels similar to clinical use, were liver changes (enlargement, dark brown discoloration, mild hepatocyte enlargement with concentric lamellar bodies in the cytoplasm and cytoplasmic vacuolation) associated with increased metabolism.

Carbonic anhydrase inhibitors.

Zonegran should be used with caution in patients being treated concomitantly with carbonic anhydrase inhibitors such as topiramate, as this combination may increase the severity of metabolic acidosis and may also increase the risks of hyperammonaemia and kidney stone formation. Therefore, if Zonegran is given concomitantly with another carbonic anhydrase inhibitor, the patient should be monitored for the appearance or worsening of metabolic acidosis (see Section 4.4 Special Warnings and Precautions for Use, Metabolic acidosis).

Oligohidrosis and hyperthermia.

Cases of decreased sweating and elevated body temperature have been reported mainly in paediatric patients. Heat stroke requiring hospital treatment was diagnosed in some cases. Most reports occurred during periods of warm weather. Patients or their carers must be warned to take care to maintain hydration and avoid exposure to excessive temperatures. Caution should be used when Zonegran is prescribed with other medicinal products that predispose patients to heat related disorders; these include carbonic anhydrase inhibitors and medicinal products with anticholinergic activity.

Pancreatitis.

In patients taking Zonegran who develop the clinical signs and symptoms of pancreatitis, it is recommended that pancreatic lipase and amylase levels are monitored. If pancreatitis is evident, in the absence of another obvious cause, it is recommended that discontinuation of Zonegran be considered and appropriate treatment initiated.

Muscle weakness.

In patients taking Zonegran, in whom severe muscle pain and/or weakness develop either in the presence or absence of a fever, it is recommended that markers of muscle damage be assessed, including serum creatine phosphokinase and aldolase levels. If elevated, in the absence of another obvious cause such as trauma or grand mal seizures, it is recommended that Zonegran discontinuation be considered and appropriate treatment initiated.

Women of childbearing potential.

Women of child-bearing potential must use adequate contraception during treatment with Zonegran and for one month after discontinuation (see Section 4.6 Fertility, Pregnancy and Lactation).

Allergic reactions.

Zonegran 100 mg hard capsules contain a yellow colour called sunset yellow FCF (E110), which may cause allergic reactions.

Low bodyweight.

There is limited data from clinical studies in patients with a bodyweight of less than 40 kg. Therefore these patients should be treated with caution.

Weight loss.

Zonegran may cause weight loss. A dietary supplement or increased food intake may be considered if the patient is losing weight or is underweight whilst on this medication. If substantial undesirable weight loss occurs, discontinuation of Zonegran should be considered.

Discontinuation.

No sudden discontinuation of antiepileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both mother and child.

Cognitive adverse events.

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 machinery.

Use in the elderly.

Caution should be exercised at initiation of treatment in elderly patients as there is limited information on the use of Zonegran in these patients. Prescribers should also take account of the safety profile of Zonegran (see Section 4.8 Adverse Effects (Undesirable Effects)).

Paediatric use.

The safety and efficacy of Zonegran in children under 18 years of age have not been established. The use of Zonegran in this age group is not recommended. Cases of oligohidrosis and hyperpyrexia have been reported. Zonegran commonly causes metabolic acidosis in paediatric patients (see Section 4.4 Special Warnings and Precautions for Use, Metabolic acidosis). Chronic untreated metabolic acidosis in paediatric patients may cause nephrolithiasis and/or nephrocalcinosis, osteoporosis and/or osteomalacia (potentially decrease the maximal height achieved). The effect of zonisamide on growth and bone related sequelae has not been systematically investigated.

Effects on laboratory tests.

Please refer to the warning regarding impact of zonisamide on bicarbonate levels (see Section 4.4 Special Warnings and Precautions for Use, Metabolic acidosis).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Antiepileptic drugs.

In epileptic patients, steady-state dosing with zonisamide resulted in no clinically relevant pharmacokinetic effects on carbamazepine, lamotrigine, phenytoin or sodium valproate. The effect of zonisamide on phenobarbitone pharmacokinetics has not been studied.

Oral contraceptives.

In clinical studies in healthy subjects, steady-state dosing with zonisamide did not affect serum concentrations of ethinylestradiol or norethisterone in a combined oral contraceptive.

Carbonic anhydrase inhibitors.

Patients taking a combination of carbonic anhydrase inhibitors may be at increased risk of metabolic acidosis, nephrolithiasis and hyperammonaemia. These combinations are not recommended. If Zonegran is given concomitantly with another carbonic anhydrase inhibitor such as topiramate, the patient should be monitored for the appearance or worsening of metabolic acidosis (see Section 4.4 Special Warnings and Precautions for Use).

Potential medicinal product interactions affecting Zonegran.

In clinical studies coadministration 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-acetyltransferases 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 antiepileptic 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 coadministration 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 nonspecific CYP3A4 inhibitors appear to have no clinically relevant effect on zonisamide pharmacokinetic exposure parameters. Steady-state dosing of either ketoconazole (400 mg/day) or cimetidine (1200 mg/day) had no clinically relevant effects on the single dose pharmacokinetics of zonisamide given to healthy subjects. Therefore, modification of Zonegran dosing should not be necessary when coadministered with known CYP3A4 inhibitors.

4.6 Fertility, Pregnancy and Lactation

Women of childbearing potential.

Women of childbearing potential must use effective contraception during treatment with Zonegran, and for one month after discontinuation (see Section 4.4 Special Warnings and Precautions for Use).
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.
Zonegran 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 advice should be given to women who are of childbearing potential regarding the possible effects of Zonegran on the foetus and these risks should be discussed with the patient in relation to the benefits before starting treatment. Women planning a pregnancy should meet with their specialists to reassess treatment with Zonegran and to consider other therapeutic options.

Effects on fertility.

The effect on human fertility is unknown. Rats treated orally with zonisamide before mating and during early gestation had reduced numbers of corpora lutea, implantations and live fetuses at a dose similar to the human therapeutic dose, on a mg/m2 basis.
(Category D)
Zonisamide is teratogenic in mice, rats and dogs and embryolethal in monkeys when administered orally during the period of organogenesis. Administration to dogs was associated with increased incidences of fetal cardiovascular malformations (ventricular septal defects, cardiomegaly, valvular and arterial anomalies) at peak maternal plasma concentrations similar to those at the maximal recommended clinical dose. The incidence of skeletal malformations was also increased at peak maternal plasma concentrations of twice the maximal anticipated clinical concentration. Administration to cynomolgus monkeys was associated with increased incidences of embryofetal deaths at peak maternal plasma concentrations lower than the maximal anticipated clinical concentration. Administration to mice was associated with increased incidences of skeletal and/or craniofacial defects at doses similar to and greater than the maximal recommended clinical dose on a mg/m2 basis. Administration to rats was associated with increased incidences of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, reduced skeletal ossification) at doses ranging from less than to greater than the maximal clinical dose on a mg/m2 basis.
Oral administration to rats from late gestation to weaning was associated with delayed behavioural development at doses similar to the maximal clinical dose on a mg/m2 basis.
Zonegran must not be used in pregnancy unless clearly necessary and only if the potential benefit is considered to justify the risk to the fetus. The need for antiepileptic 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.
There are limited data from the use of Zonegran in pregnant women. Data from a registry study suggest a higher proportion of babies born at a low birth weight (LBW), pre-term or small for gestational age (SGA) in mothers treated with zonisamide (n = 98) compared to mothers treated with lamotrigine monotherapy (n = 1581). The approximate risks with zonisamide are 8% for LBW (5% with lamotrigine), 10% for pre-term birth (8% with lamotrigine) and 12% for SGA (7% with lamotrigine).
 Zonisamide is excreted in human milk at a concentration similar to that in plasma. Oral administration of zonisamide to rats from late gestation to weaning was associated with delayed behavioural development at doses similar to the maximal clinical dose on a mg/m2 basis. A decision must be made whether to discontinue breastfeeding or to discontinue/ abstain from Zonegran therapy. Due to the long retention time of zonisamide in the body, breastfeeding must not be resumed until one month after Zonegran therapy is completed.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
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 Adverse Effects (Undesirable Effects)

Zonegran has been administered to over 1,200 patients in clinical studies, more than 400 of whom received Zonegran for at least 1 year. In addition there has been extensive postmarketing experience with zonisamide in Japan since 1989 and in the USA since 2000.

Adverse event incidence in controlled clinical trials.

Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation in adults.

The most common adverse reactions in controlled adjunctive therapy studies were somnolence, dizziness and anorexia.
Table 3 lists treatment emergent adverse events occurring in ≥ 1% of zonisamide treated patients and greater than placebo.

Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults with newly diagnosed epilepsy.

A monotherapy study conducted in 583 adult subjects with newly diagnosed partial seizures with or without secondary generalised tonic-clonic seizures showed that 60.5% in the Zonegran group and 61.7% in the carbamazepine prolonged release (PR) group experienced adverse effects. Serious adverse effects were experienced by 5.3% in the Zonegran group and 5.7% in the carbamazepine PR group. Subjects treated with Zonegran were more likely to experience loss of appetite (7.8% versus 1.7%) and weight loss (6.8% versus 0%); 13.2% of subjects lost ≥ 10% of their body weight, and 0.7% lost ≥ 20%.
There were more reports of psychiatric disorders (9.3% versus 4.7%), and fewer reports of dizziness (3.9% versus 7.7%) and rash (2.1% versus 4.3%) in subjects treated with Zonegran compared to those treated with carbamazepine PR. See Table 4.
Other adverse reactions associated with zonisamide obtained from clinical studies and post-marketing surveillance of Zonegran treated patients is included in Table 5.
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 including isolated reports.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There have been cases of accidental and intentional overdose in adult and paediatric patients. In some cases, the overdoses were asymptomatic, whereas 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 microgram/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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

Treatment.

No specific antidotes for Zonegran overdose are available. General supportive care is indicated, including frequent monitoring of vital signs and close observation. Zonisamide has a long elimination half-life so its effects may be persistent. Although not formally studied for the treatment of overdose, haemodialysis reduced plasma concentrations of zonisamide in a patient with reduced renal function, and may be considered as treatment of overdose if clinically indicated.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Zonisamide is a benzisoxazole derivative. It is an antiepileptic medicine with weak carbonic anhydrase inhibiting activity in vitro. It is chemically unrelated to other antiepileptic agents.

Mechanism of action.

Zonisamide exhibits broad spectrum anticonvulsant activity in a variety of animal models characterised by induced or innate seizures; it is effective against tonic (but not clonic) seizures, raises generalised seizure threshold, shortens cortical focal seizure duration, and suppresses interictal spikes and secondarily generalised seizures. Zonisamide restricts seizure spread, including propagation of seizures from the cortex to subcortical structures, and suppresses epileptogenic focus activity. Unlike phenytoin and carbamazepine, zonisamide acts preferentially on seizures originating in the cortex.
The mechanism of action of zonisamide has not been 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, and facilitates dopaminergic and serotonergic neurotransmission.

Clinical trials.

Monotherapy in the treatment of partial seizures, with or without secondary generalisation, in adults.

Efficacy of Zonegran as monotherapy was established in a double blind, parallel group, noninferiority 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 PR (N = 301; 600 to 1200 mg/day, twice daily) or Zonegran (N = 282; 300 to 500 mg/day, once daily), and 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 Zonegran. Subjects who experienced a seizure were titrated to the next target dose, i.e. 800 mg carbamazepine or 400 mg of Zonegran. Subjects who experienced a further seizure were titrated to the maximal target dose of 1200 mg carbamazepine or 500 mg Zonegran. Subjects who were seizure free for 26 weeks at a target dose level continued on this dose for another 26 weeks.
Six month seizure freedom was achieved in 79.4% of Zonegran-treated subjects and 83.7% of carbamazepine PR treated subjects (in the per protocol population). The adjusted absolute difference between treatments was -4.5% (95% CI: -12.2%, 3.1%). More than half of the subjects remained seizure free at 12 months (67.6% Zonegran versus 74.7%).
Main outcomes of this study are presented in Table 6.

Adjunctive therapy in the treatment of partial seizures, with or without secondary generalisation in adults.

In adults, efficacy has been demonstrated with zonisamide in 4 double blind, 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 zonisamide dose with sustained efficacy at doses of 300-500 mg per day.
The pivotal clinical study was a double blind, placebo controlled, randomised, parallel group study conducted at 54 sites in 19 countries comparing Zonegran at 100 mg (n = 56), at 300 mg (n = 55), at 500 mg (n = 118) and placebo (n = 120). After a prospective baseline period of 12 weeks, patients were randomised to one of the four treatment groups above. The treatment period consisted of a 6 week up-titration period and a 2 week stabilisation period followed by a 16 week fixed dose evaluation period, during which concomitant anti-epileptic drug regimens were held constant. Patients then underwent 4 week down titration period or were included in an open label extension of the study.
The primary measure of effectiveness was the median percent reduction in seizure frequency from baseline. Secondary outcomes included the percentage of responders (patients with a greater than 50% reduction in seizure frequency from baseline). The results of the analyses of this study are provided in Tables 7 and 8.

5.2 Pharmacokinetic Properties

Absorption.

Zonisamide is almost completely absorbed after oral administration, generally reaching peak serum or plasma concentrations within 2 to 5 hours of dosing. First-pass metabolism is believed to be negligible. Absolute oral bioavailability is estimated to be approximately 100% and is not affected by food, although peak plasma and serum concentrations may be delayed.
Zonisamide plasma AUC and Cmax values increased almost linearly after a 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 following a single dose and at steady state were 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 of a change in dose. Concentrations of zonisamide at steady state are up to sixfold higher than following an equivalent single dose at the recommended dosing interval.

Distribution.

Zonisamide is 40-50% bound to human plasma proteins, with in vitro studies showing that this is unaffected by the presence of various antiepileptic medicinal products (i.e. phenytoin, phenobarbitone, carbamazepine, and sodium valproate). The apparent volume of distribution is about 1.1-1.7 L/kg in adults indicating that zonisamide is extensively distributed to tissues. Zonisamide binds saturably to erythrocytes, and erythrocyte/ plasma Cmax ratios are about 11 at low drug concentrations in plasma and about 3 at therapeutic concentrations.

Metabolism.

Zonisamide is metabolised primarily through reductive cleavage of the benzisoxazole ring of the parent drug by CYP3A4 to form 2-sulphamoylacetylphenol (SMAP) and also by N-acetylation to form N-acetyl zonisamide. 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.

Excretion.

Apparent clearance of zonisamide from plasma 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 concomitant therapy with CYP3A4 inducers. However, the apparent clearance is increased by up to 2-fold in patients also receiving the antiepileptic drugs phenobarbitone, phenytoin, carbamazepine and/or sodium valproate, and elimination half-life is reduced by up to 50%. The elimination half-life is independent of dose and not affected by repeat administration. Fluctuation in serum or plasma zonisamide concentrations over a dosing interval is low (< 30%). The rate of clearance from erythrocytes is approximately 0.3 L/h at steady state. The main route of excretion of zonisamide metabolites and unchanged drug is via the urine. In healthy volunteers, 62% of the dose was recovered in urine and a further 3% in faeces over 10 days. Renal clearance of unchanged zonisamide is relatively low (approximately 3.5 mL/min); about 15-30% of the dose is eliminated unchanged, with the remainder being excreted as metabolites.

Effect of zonisamide on cytochrome P450 enzymes.

In vitro studies using human liver microsomes show no or little (< 25%) inhibition of cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 or 3A4 at zonisamide concentrations approximately twofold or greater than clinically relevant unbound serum concentrations. Clinical studies have demonstrated that zonisamide does not significantly affect the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, sodium valproate, levonorgestrel, norethindrone, ethinylestradiol and desipramine in vivo. The potential effects of zonisamide on the pharmacokinetics of other compounds, including phenobarbitone, are unknown.

Special patient groups.

In subjects with renal impairment.

Renal clearance of single doses of zonisamide was positively correlated with creatinine clearance. The plasma AUC of zonisamide was increased by 35% in subjects with creatinine clearance < 20 mL/min.

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).

Adolescents (12-18 years).

Limited data indicate that pharmacokinetics in adolescents dosed to steady state at 1, 7 or 12 mg/kg daily, in divided doses, are similar to those observed in adults, after adjustment for bodyweight.

Other characteristics.

No clear zonisamide dose concentration response relationship has been defined. When comparing the same dose level, subjects of higher total bodyweight appear to have lower steady state serum concentrations, but this effect appears to be relatively modest. Age (≥ 12 years) and gender, after adjustment for bodyweight effects, have no apparent effect on zonisamide exposure in epileptic patients during steady state dosing.

5.3 Preclinical Safety Data

Zonisamide is teratogenic in mice, rats and dogs and embryolethal in monkeys when administered orally during the period of organogenesis. Administration to dogs was associated with increased incidences of fetal cardiovascular malformations (ventricular septal defects, cardiomegaly, valvular and arterial anomalies) at peak maternal plasma concentrations similar to those at the maximal recommended clinical dose. The incidence of skeletal malformations was also increased at peak maternal plasma concentrations of twice the maximal anticipated clinical concentration.
Administration to cynomolgus monkeys was associated with increased incidences of embryofetal deaths at peak maternal plasma concentrations lower than the maximal anticipated clinical concentration. Administration to mice was associated with increased incidences of skeletal and/or craniofacial defects at doses similar to and greater than the maximal recommended clinical dose on a mg/m2 basis. Administration to rats was associated with increased incidences of malformations (cardiovascular defects) and variations (persistent cords of thymic tissue, reduced skeletal ossification) at doses ranging from less than to greater than the maximal clinical dose on a mg/m2 basis.
Oral administration to rats from late gestation to weaning was associated with delayed behavioural development at doses similar to the maximal clinical dose on a mg/m2 basis.

Genotoxicity.

The genotoxicity of zonisamide has been studied in an adequate range of in vitro and in vivo assays, and the weight of evidence suggests that it is unlikely to cause genetic toxicity at therapeutic levels of exposure.

Carcinogenicity.

Zonisamide did not display carcinogenic activity in lifetime studies in mice or rats following dietary administration at doses similar to the maximal recommended clinical dose on a mg/m2 basis.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients in Zonegran are microcrystalline cellulose, hydrogenated vegetable oil and sodium lauryl sulphate. The hard capsule shells contain gelatin, titanium dioxide, iron oxide black (only in 50 mg capsules), sunset yellow FCF (only in 100 mg capsules) and allura red AC (only in 100 mg capsules) and TekPrint SW-9008 Black Ink (ARTG No 2328).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Zonegran 25 mg (AUST R 125869) hard capsules are available in PVC/PVDC/Aluminium blister packs of 14 and 56 hard capsules.
Zonegran 50 mg (AUST R 125870) hard capsules are available in PVC/PVDC/Aluminium blister packs of 56 hard capsules.
Zonegran 100 mg (AUST R 125871) hard capsules are available in PVC/PVDC/Aluminium blister packs of 56 hard capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Zonisamide forms white to pale yellow crystals or a crystalline powder. It is freely soluble in acetone, sparingly soluble in methanol, slightly soluble in ethanol and very slightly soluble in water, diethyl ether and chloroform.

Chemical structure.

Zonisamide has a molecular formula C8H8N2O3S and a molecular weight of 212.23. The chemical structure is:

CAS number.

68291-97-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes