Consumer medicine information

Epilim [7858]

Sodium valproate

BRAND INFORMATION

Brand name

Epilim

Active ingredient

Sodium valproate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Epilim [7858].

What is in this leaflet

This leaflet answers some common questions about Epilim.

It does not contain all of 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 your taking Epilim against the benefits they expect it will have for you.

Please read this leaflet very carefully before you start to take your Epilim, even if you have taken Epilim before.

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 Epilim is used for

Epilim is a medicine used to for the treatment of epilepsy in adults and children.

Epilepsy is a condition where you have repeated seizures (fits). There are many different types of seizures, ranging from mild to severe.

Epilim belongs to a group of medicines called anticonvulsants.

These medicines are thought to work by controlling brain chemicals which send signals to nerves so that seizures do not happen.

Epilim may also be used to control mania, a mental condition with episodes of overactivity, elation or irritability.

Epilim may be used alone or in combination with other medicines to treat your condition.

Your doctor, however, may have prescribed Epilim for another reason.

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

There is no evidence that Epilim is addictive.

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

Before you take it

When you must not take it

Do not take it if you have or have had any of the following medical conditions:

  • liver disease (hepatic dysfunction) or severe hepatitis.
  • a family history of hepatitis, especially when caused by medicines. Medicines used in the treatment of epilepsy, including Epilim may have adverse effects on the liver and the kidneys.
  • a urea cycle disorder or a family history of urea cycle disorders.
  • a family history of unexplained infant deaths.
  • porphyria which is a rare blood disease of blood pigments
  • known ornithine transcarbamylase deficiency or a family history of ornithine transcarbamylase deficiency.
  • known or suspected of having a genetic problem causing a mitochondrial disorder.
  • you are pregnant, unless your doctor has determined no alternative treatment works for you.
    If you are a girl or woman of childbearing age, you must not take Epilim unless you use an effective method of birth control (contraception) at all times during your treatment with Epilim. Do not stop taking Epilim or your contraception until you have discussed this with your doctor. Your doctor will advise you further (see 'Before you start to take it').

Do not take Epilim if you are allergic to it or any of the ingredients listed at the end of this leaflet.

Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Do not take it after the expiry date (EXP) printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

  • any of the ingredients listed at the end of this leaflet
  • any other medicines
  • any other substances, such as foods, preservatives or dyes

If you are a female patient of child-bearing age, make sure that you talk to your doctor about the risks associated with taking Epilim during pregnancy.

If you are a parent or carer, tell your doctor when your child using Epilim experiences her first period.

Tell your doctor immediately if you are pregnant or intend to become pregnant.

Epilim can be harmful to unborn children when taken by a woman during pregnancy. It can cause serious birth defects and can affect the way in which the child develops as it grows. Also, children born to mothers who take Epilim throughout their pregnancy may be at risk of impaired cognitive development or withdrawal syndrome. However, do not stop taking Epilim unless your doctor says so as there are risks to the mother and child from uncontrolled epilepsy or uncontrolled mania episodes.

Your doctor may want to adapt your treatment and/or prescribe dietary supplements of folate.

Your doctor will discuss the risks and benefits of taking it if you are pregnant.

Tell your doctor if you are breastfeeding or planning to breastfeed. Medicines used in the treatment of epilepsy, including Epilim, pass into breast milk. Your doctor will discuss the risks and benefits of taking it if you are breastfeeding or planning to breastfeed.

Tell your doctor if you drink alcohol. If you have more than 2 drinks per day, you may be putting yourself at risk of a seizure, or fit.

Tell your doctor if you have or have had any medical conditions, especially the following:

  • liver problems (hepatic insufficiency, hepatic damage)
  • kidney problems
  • urea cycle disorders
  • ornithine transcarbamylase (OTC) deficiency
  • carnitine palmitoyltransferase (CPT) type II deficiency
  • systemic lupus erythematosus (a disease affecting the skin, joints and kidneys)
  • family history of a genetic problem causing mitochondrial disorder

Tell your doctor if you plan to have surgery.

If you have not told your doctor about any of the above, tell them before you take Epilim.

Taking other medicines

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

Some medicines and Epilim may interfere with each other. These include:

  • aspirin (and other salicylates)
  • medicines used to prevent clots (anticoagulants) e.g. warfarin
  • other medicines used to treat epilepsy e.g. phenobarbital (phenobarbitone), methylphenobarbitone, primidone, phenytoin, carbamazepine, clonazepam, felbamate, lamotrigine, topiramate, diazepam, lorazepam, oxcarbamazepine, rifunamide and ethosuximide
  • medicines used to treat depression e.g. monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants
  • benzodiazepines (medicines used as sedatives or to treat anxiety)
  • oral contraceptives. Epilim should have little effect on the oral contraceptive pill, however, you should let your doctor know that you are taking it
  • zidovudine or any other anti viral medications
  • neuroleptic agents including clozapine (a medicine used to treat schizophrenia)
  • quetiapine or olanzapine (medicines used to treat bipolar disorder and schizophrenia)
  • mefloquine (a medicine used to treat malaria)
  • propofol (a medicine used before and during general anaesthesia)
  • nimodipine (a medicine used to help blood flow to the brain)
  • cimetidine (used to treat stomach ulcers)
  • erythromycin, rifampicin and carbapenem antibiotics such as Invanz and Merrem
  • colestyramine (Questran Lite)
  • acetazolamide (Diamox)

These medicines and others may be affected by Epilim, or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines. Your doctor or pharmacist will advise you.

Tell your doctor or pharmacist if your child is taking any other medicines before you start giving them Epilim, for example, aspirin or any other drugs used to treat epilepsy. Children, especially young children, can be more sensitive to some of the side effects of Epilim.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking Epilim.

How to take it

How much to take

Your doctor will tell you how much to take, and in what form (liquids or tablets) you should take it. This may depend on your age, your condition and whether or not you are taking any other medicines.

Your doctor may recommend that you start with a low dose of Epilim and slowly increase the dose to the lowest amount needed to control your condition.

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, Epilim may not work as well.

How to take it

Epilim Tablets (white tablets)

Epilim tablets may be taken twice a day.

Swallow the tablets whole with a full glass of water or other liquid or take them with food.

The tablets may be crushed and taken with food or drinks

Do not take them with "fizzy" water, soda or soft drinks.

Epilim EC Tablets (lilac tablets)

Swallow the lilac tablets (EC200 and EC500) whole with a glass of water or other liquid.

Do not crush or chew the tablets. The lilac tablets have a special coating to stop them dissolving until they have gone through the stomach and into the intestines. If you chew them, the coating is destroyed.

Epilim Syrup and Liquid

Epilim Syrup and Sugar-Free Liquid should be taken 2-3 times a day.

Shake the bottle well and accurately pour the dose into a medicine measure before taking it. Shaking the bottle and using a medicine measure will make sure you get the correct dose. You can get a medicine measure from your pharmacist.

When to take it

Your doctor will advise you when to take Epilim.

Always follow your doctor's instructions.

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

If you are not sure when to take it, ask your doctor.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Epilim helps control your condition but does not cure it. Therefore you must take it every day.

If you forget to take it

Always remember to take your prescribed dose otherwise you may find that either your seizures or manic symptoms may return.

If you forget a dose, take your next dose as usual. Do not take a double dose to make up for the dose that you missed. This may increase the chance of your getting unwanted side effects.

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

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

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much Epilim.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much Epilim you may feel dizzy, drowsy or have cramps in the abdomen.

While you are taking it

Things you must do

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Epilim.

If you are about to be started on any new medicine, tell your doctor that you are taking Epilim.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking this medicine.

If you become pregnant while you are taking this medicine, tell your doctor immediately.

Be sure to keep all of your doctors' appointments so that your progress can be checked. Your doctor will check your progress and may want to take some tests from time to time. This helps prevent unwanted side effects.

Things you must not do

Do not take more than the recommended dose unless your doctor tells you to.

Do not give this medicine to anyone else, even if they have the same condition as you.

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

Do not stop taking Epilim, or lower the dosage, without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Epilim affects you. It may cause drowsiness or light-headedness in some people, especially at the beginning of treatment. Make sure you know how you react to it before you drive a car, operate machinery, or do anything else that could be dangerous if you are drowsy or light headed.

Children should not ride a bike, climb trees or do anything else that could be dangerous if they are feeling drowsy or sleepy.

Epilim may cause drowsiness, dizziness or sleepiness in some people and affect alertness.

Diabetics are advised that Epilim Syrup contains 3.6 g/5 mL of sucrose (sugar).

The effects of alcohol could be made worse while taking Epilim. Combining it and alcohol can make you more sleepy, dizzy or lightheaded. Your doctor may suggest you avoid alcohol while you are treated with Epilim.

What do I need to consider about contraception?

Epilim can seriously harm an unborn child when taken during pregnancy. If you are a girl or woman of childbearing age, you must use at least one effective method of birth control (contraception) without interruption during your entire treatment with Epilim. Your doctor should discuss with you the most appropriate method of contraception for you.

Epilim should have little effect on the oral contraceptive pill, however, you should let your doctor know that you are taking it.

Side effects

All medicines have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor or pharmacist has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Epilim.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • nausea or vomiting
  • bleeding, tender or enlarged gums
  • abdominal cramps or pain
  • changes in appetite
  • changes in your weight
  • irregular menstrual periods
  • diarrhoea
  • loss of bladder control
  • headache
  • unusual movements, including tremor and shaking
  • rapid uncontrollable movements of the eye or double vision
  • unsteadiness when walking, dizziness or light-headedness
  • depression
  • hair loss
  • feeling tired or drowsy
  • memory impairment
  • confusion
  • hallucinations
  • disturbance in attention
  • changes in behaviour including aggression and agitation
  • nail and nail bed disorders

These are the more common side effects of Epilim. Mostly these are mild and short-lived.

Tell your Doctor immediately or go to the Accident and Emergency department of your nearest hospital if you have any thoughts of harming yourself or committing suicide.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • more frequent or more severe seizures (fits)
  • blood clotting problems
  • spontaneous bruising or bleeding
  • rashes
  • signs of liver problems such as vomiting, loss of appetite, generally feeling unwell, tiredness, yellowing of the skin and/or eyes, dark urine or blood in urine, pain in the abdomen
  • swelling of the feet and legs, weight increase due to fluid build up
  • fainting
  • bizarre behaviour
  • suicidal thoughts
  • suicide attempts
  • severe upper stomach pain, often with nausea and vomiting.

These are very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also happen in some patients. Some of these side effects can only be found when your doctor does tests from time to time to check your progress.

Ask your doctor to answer any questions you may have.

After taking it

If you have any queries about any aspect of your medicine, or any questions regarding the information in this leaflet, discuss them with your doctor or pharmacist.

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the box or the blister pack they may not keep well.

Keep Epilim and Epilim EC tablets in a cool dry place where the temperature stays below 30°C.

Keep Epilim Syrup and Liquid in a cool dry place where the temperature stays below 25°C.

Do not store it or any other medicine in the bathroom, near a sink, or on a windowsill.

Do not leave it in the car. Heat and damp 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 Epilim, or the medicine has passed its expiry date, ask your pharmacist what to do with any that are left over.

Return any unused medicine to your pharmacist.

Product description

What it looks like

Epilim 100 mg Crushable tablets - White, round, scored tablets.

Epilim EC200 - Lilac, round, enteric-coated tablets.

Epilim EC500 - Lilac, round, enteric-coated tablets.

Epilim Syrup - Red, cherry flavoured syrup.

Epilim Liquid Sugar Free - Red, cherry flavoured liquid.

The tablets are available in boxes of 100 tablets.

Epilim Syrup and Liquid are available in 300 mL bottles.

Ingredients

Active Ingredient:

Epilim 100 mg Crushable tablets - 100 mg sodium valproate

Epilim EC200 - 200 mg sodium valproate

Epilim EC500 - 500 mg sodium valproate

Epilim Syrup - 200 mg/5 mL sodium valproate

Epilim Liquid Sugar Free - 200 mg/5 mL sodium valproate

Inactive Ingredients:

Epilim 100 mg Crushable tablets - Maize starch, silicon dioxide, kaolin, magnesium stearate

Epilim EC200 - Povidone, purified talc, magnesium stearate, calcium silicate, citric acid monohydrate, macrogol 6000, hypromellose, polyvinyl acetate phthalate, hyprolose, diethyl phthalate, stearic acid, amaranth aluminium lake, indigo carmine aluminium lake, titanium dioxide

Epilim EC500 - Povidone, purified talc, magnesium stearate, calcium silicate, citric acid monohydrate, macrogol 6000, hypromellose, polyvinyl acetate phthalate, hyprolose, diethyl phthalate, stearic acid, amaranth aluminium lake, indigo carmine aluminium lake, titanium dioxide

Epilim Syrup - Sucrose, sorbitol, saccharin sodium, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, brilliant scarlet 4R, imitation cherry flavour, purified water.

Epilim Liquid Sugar Free - Sorbitol, saccharin sodium, citric acid, hyetellose, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, brilliant scarlet 4R, imitation cherry flavour, purified water.

Manufacturer/Sponsor

Epilim is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113

This document was revised in March 2019

Australian Register Numbers:

Epilim 100 mg Crushable tablets - AUST R 15373

Epilim EC200 - AUST R 15369

Epilim EC500 - AUST R 15370

Epilim Syrup - AUST R 15372

Epilim Liquid Sugar Free - AUST R 74711

® Registered trademark

epilim-ccdsv25-cmiv15-19mar19

Published by MIMS June 2019

BRAND INFORMATION

Brand name

Epilim

Active ingredient

Sodium valproate

Schedule

S4

 

1 Name of Medicine

Sodium valproate.

2 Qualitative and Quantitative Composition

Crushable tablets, sodium valproate 100 mg.
Enteric-coated tablets, sodium valproate 200 mg.
Enteric-coated tablets, sodium valproate 500 mg.
Syrup, sodium valproate 200 mg/5 mL. Excipients of known effects: sucrose, saccharin sodium and sorbitol.
Sugar free liquid, sodium valproate 200 mg/5 mL. Excipients of known effects: saccharin sodium, sorbitol solution (70%) (non-crystallising), sodium methyl hydroxybenzoate and sodium propyl hydroxybenzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Crushable tablets, 100 mg (white, scored).
Tablets, 200 mg (lilac, enteric-coated).
Tablets, 500 mg (lilac enteric-coated).
Syrup, 200 mg/5 mL (red, cherry flavoured).
Sugar free liquid, 200 mg/5 mL (red, cherry flavoured).

4 Clinical Particulars

4.1 Therapeutic Indications

Epilepsy.

Primary generalised epilepsy (petit mal absences, various forms of myoclonic epilepsy and tonic-clonic grand mal seizures). Partial (focal) epilepsy either alone or as adjuvant therapy.

Mania.

For the treatment of mania where other therapy has proved inadequate or is inappropriate.

4.2 Dose and Method of Administration

Epilim tablets may be given twice daily. Uncoated tablets may be crushed if necessary. Epilim Syrup and Sugar-Free Liquid should be given in divided doses.
Epilim should preferably be taken with or after food: the enteric-coated tablet (lilac) must be swallowed whole, if necessary with a little water; the plain tablet (white, 100 mg) may be taken whole or crushed and swallowed with water (not aerated).
Epilim 500 mg enteric-coated tablets are recommended for patients requiring high doses. Where the possibility of dental caries represents a risk through long-term therapy with Epilim Syrup, it may be beneficial to consider Epilim Sugar-Free Liquid.
Epilim may take several days to show an initial effect and in some cases may take from 2 to 6 weeks to exhibit its maximum effect.

Epilepsy.

Monotherapy.

Usual requirements are as follows:

Adults.

Dosage should start with 600 mg daily increasing by 200 mg/day at three-day intervals until control is achieved. This is generally within the range 1,000 to 2,000 mg/day, (i.e. 20 to 30 mg/kg/day). Where adequate control is not achieved within this range the dose may be further increased to 2,500 mg/day.

Children > 20 kg.

Initial dosage should be 400 mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20 to 30 mg/kg/day.

Children < 20 kg.

20 mg/kg/day: in severe cases this may be increased but only in patients in whom plasma valproic acid levels can be monitored. Above 40 mg/kg/day, clinical chemistry and haematological parameters should be monitored.

General considerations.

Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected.

Combined therapy.

In certain cases it may be necessary to raise the dose by 5 to 10 mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital (phenobarbitone) and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Epilim. When barbiturates are being administered concomitantly, the dosage of barbiturate should be reduced if sedation is observed.

Mania.

Initially dosage should start with 600 mg daily increasing by 200 mg/day at three-day intervals until control is achieved. This is generally within the range 1,000 to 2,000 mg/day, (i.e. 20 to 30 mg/kg/day). Where adequate control is not achieved within this range the dose may be further increased to 2,500 mg/day.
The Bowden et al study (see Section 5.1 Pharmacodynamic Properties) provided strong support for the greater efficacy of serum levels above 45 microgram/mL (these levels achieved 20% or greater improvement on both subscales of the Mania Rating Scale). Bowden noted that > 125 microgram/mL had greater drug-related adverse events. Between these extremes there does not appear to be a clear dose-response relationship.

Use in hepatic impairment.

Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid or sodium valproate (see Section 4.4 Special Warnings and Precautions for Use).

Use in renal impairment.

Lower doses may be required since free drug levels may be high owing to lowered serum albumin and poor urinary excretion of free drug metabolites (see Section 4.4 Special Warnings and Precautions for Use).

Use in the elderly.

Although the pharmacokinetics of Epilim are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.

Use in female children, women of child bearing potential and pregnant women.

See Section 4.4 Special Warnings and Precautions for Use.
Epilim must be initiated and supervised by a specialist experienced in the management of epilepsy or bipolar disorder. Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation).
In the exceptional circumstances when valproate is the only treatment option during pregnancy in epileptic women, valproate should preferably be prescribed as monotherapy, at the lowest effective dose.
The daily dose of non-prolonged release formulations should be divided into at least two single doses during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

Estrogen containing products.

The enzyme inducing effect of valproate is appreciably less than that of certain other anticonvulsants and loss of efficacy of oral contraceptive agents does not appear to be a problem.
However, estrogen containing products, including estrogen containing hormonal contraceptives, may increase the clearance of valproate, which may result in decreased serum concentration of valproate and potentially decreased valproate efficacy. Prescribers should monitor clinical response (seizure control or mood control) when initiating, or discontinuing estrogen-containing products. Consider monitoring of valproate serum levels. (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

4.3 Contraindications

Epilim is contraindicated in the following situations:

Treatment of epilepsy.

In pregnancy unless there is no suitable alternative treatment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation).
In women of childbearing potential, unless the physician has provided information in regards to the potential effects of valproate during pregnancy and recommendations on the use of valproate.

Treatment of mania.

In pregnancy (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation).
In women of childbearing potential, unless the physician has provided information in regards to the potential effects of valproate during pregnancy and the recommendations on the use of valproate.

All indications.

Pre-existing, acute or chronic hepatic dysfunction or family history of severe hepatitis, particularly medicine related. Known hypersensitivity to the medicine. Known urea cycle disorders (see Section 4.4 Special Warnings and Precautions for Use). Known hepatic porphyria. Patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding mitochondrial enzyme polymerase γ (POLG e.g. Alpers-Huttenlocher Syndrome) and in children under two years of age who are suspected of having POLG-related disorder.

4.4 Special Warnings and Precautions for Use

Pregnancy and women of childbearing potential.

Valproate has a high teratogenic potential and children exposed in utero to valproate have a high risk for congenital malformations and neurodevelopmental disorders (see Section 4.6 Fertility, Pregnancy and Lactation).
Valproate should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation).
In the exceptional circumstance when valproate is the only treatment option available for women of childbearing potential, the physician must ensure that:
Individual circumstances are evaluated and discussed with the patient. This is to guarantee the patient's engagement and understanding of the therapeutic options together with the risks and the measures needed to mitigate the risks.
The potential for pregnancy is assessed for all female patients.
The patient understands the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero.
The patient understands the need to undergo pregnancy testing prior to initiation of treatment and during treatment, as needed.
The patient is counselled regarding contraception, and that the patient is capable of complying with the need to use effective contraception (see Section 4.4 Special Warnings and Precautions for Use, Pregnancy and women of childbearing potential, Contraception), without interruption during the entire duration of treatment with valproate.
The patient understands the need for regular (at least annual) review of treatment by a specialist experienced in the management of epilepsy, or bipolar disorders.
The patient understands the need to consult her physician as soon as she is planning pregnancy to ensure timely discussion and switching to alternative treatment options prior to conception, and before contraception is discontinued.
The patient understands the need to urgently consult her physician in case of pregnancy.
The patient is aware that a patient guide is available electronically through the QR code located on the carton (www.sanofi.com.au/valproate).
The patient understands the hazards and necessary precautions associated with valproate use.
These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.
Pharmacist or other healthcare professional must:
Review the CMI with the patient (or parent/caregiver) and confirm that she can access the educational tools available electronically through the QR code located on the carton (www.sanofi.com.au/valproate).
Advise the patient (or parent/caregiver) not to stop valproate medication and to immediately contact a specialist in case of planned or suspected pregnancy.

Female children.

The prescribers must ensure that parents/caregivers of female children understand the need to contact the specialist once the female child using valproate experiences menarche.
The prescriber must ensure that parents/caregivers of female children who have experienced menarche are provided with comprehensive information about the risks of congenital malformations and neurodevelopmental disorders including the magnitude of these risks for children exposed to valproate in utero.
In patients who experience menarche, the prescribing specialist must reassess the need for valproate therapy annually and consider alternative treatment options. If valproate is the only suitable treatment, the need for using effective contraception program should be discussed. Every effort should be made by the specialist to switch the female children to alternative treatment before they reach adulthood.

Pregnancy test.

Pregnancy must be excluded before the start of treatment with valproate. Treatment with valproate must not be initiated in women of child bearing potential without a negative pregnancy test (plasma pregnancy test) result, confirmed by a health care provider, to rule out unintended use in pregnancy.

Contraception.

Women of childbearing potential who are prescribed valproate must use effective contraception, without interruption during the entire duration of treatment with valproate. These patients must be provided with comprehensive information on pregnancy prevention. If they are not using effective contraception they should be referred for contraceptive advice.
At least one effective method of contraception (preferably a user-independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used.
Individual circumstances should be evaluated in consultation with the patient when choosing contraception method. This will increase patient engagement and compliance with the chosen contraceptive measures.
Even if patient has amenorrhea she must follow all the advice on effective contraception.

Annual treatment review.

The specialist should review, at least annually, whether valproate is the most suitable treatment for the patient.

Pregnancy planning.

For the epilepsy indication, if a patient on valproate is planning to become pregnant, a specialist experienced in the management of epilepsy must reassess the therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see Section 4.6 Fertility, Pregnancy and Lactation). If switching is not possible, the patient should receive further counselling regarding the risks of valproate for the unborn child to support her informed decision making regarding family planning.
For the bipolar disorder indication, if a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted. Treatment with valproate should be discontinued prior to conception, and before contraception is discontinued. If needed, alternative treatment options should be considered.

In case of pregnancy.

If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to re-evaluate treatment with valproate and consider alternative options. The patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in pre-natal medicine for evaluation and counselling regarding the exposed pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

Educational materials.

To reinforce the warnings and provide guidance regarding use of valproate in women of childbearing potential, educational materials are available electronically through a QR code on the carton (www.sanofi.com.au/valproate). A patient guide should be provided/available to all women of childbearing potential using valproate.

Hepatic dysfunction.

Conditions of occurrence.

Severe liver damage and/or hepatic failure resulting in fatalities have occurred in patients whose treatment included valproic acid or sodium valproate. Patients most at risk are those on multiple anticonvulsant therapy and children, particularly those under the age of 3 years and those with congenital metabolic or degenerative disorders, organic brain disease or severe seizure disorders associated with brain damage and/or mental retardation.
The incidents usually occurred during the first six months of therapy, the period of maximum risk being 2 to 12 weeks, and usually involved multiple anticonvulsant therapy. Monotherapy is to be preferred in this group of patients.

Suggestive signs.

Clinical symptoms are usually more helpful than laboratory investigations in the early stages of hepatic failure. Jaundice, serious or fatal hepatotoxicity may be preceded by nonspecific symptoms, usually of sudden onset, such as loss of seizure control, malaise, asthenia, weakness, lethargy, facial oedema, anorexia, vomiting, abdominal pain, drowsiness, jaundice. In patients with epilepsy, recurrence of seizures can occur. These are an indication for immediate withdrawal of the medicine. Patients should be monitored closely for the appearance of these symptoms. Patients (and their family and carers) should be instructed to immediately report any such signs to the clinician for investigation should they occur. Investigations including clinical examination and laboratory assessment of liver functions should be undertaken immediately.

Detection.

Although published evidence does not establish which, if any, investigation could predict this possible adverse effect, liver function tests should be performed (especially in patients at risk) prior to therapy and frequently thereafter until 6 months after the controlling dose is reached, when less frequent monitoring may be appropriate. It is also advisable to monitor tests which reflect protein synthesis, e.g. prothrombin time, serum fibrinogen and albumin levels, especially in those who seem most at risk and those with a prior history of hepatic disease.
As with most antiepileptic drugs, a slight increase in liver enzymes may be noted, particularly at the beginning of therapy. They are transient and isolated. More extensive biological investigations (including prothrombin rate) are recommended in those patients. An adjustment of dosage may be considered when appropriate and tests should be repeated as necessary.
Raised liver enzymes are not uncommon during treatment with Epilim, particularly if used in conjunction with other anticonvulsants, and are usually transient or respond to dosage reduction. Patients with such biochemical abnormalities should be reassessed clinically and tests of liver function should be monitored more frequently. An abnormally low prothrombin rate, particularly in association with other relevant abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases), requires cessation of treatment and the substitution of alternative medicines to avoid precipitating convulsions. Uneventful recovery has been recorded in several cases where therapy with Epilim has ceased, but death has occurred in some patients in spite of the medicine being withdrawn. Any concomitant use of salicylates should be stopped, since they employ the same metabolic pathway.

Pancreatitis.

Cases of life-threatening pancreatitis have been reported in both children and adults receiving sodium valproate. Some cases have occurred shortly after initial use while others have occurred after several years of use. There have also been cases in which pancreatitis recurred after rechallenge with sodium valproate. Some of the cases have been described as haemorrhagic with a rapid progression from initial symptoms to death. In clinical trials, there were two cases of pancreatitis without alternative aetiology in 2416 patients, representing 1044 patient-years experience. Young children are at particular risk but this risk decreases with increasing age.
Severe seizures, neurological impairment or anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome.
Patients and guardians should be warned that acute abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical attention. If pancreatitis is diagnosed, sodium valproate should be discontinued and alternative treatment for the underlying medical condition initiated as clinically indicated.

Use in renal impairment.

Lower doses may be required since free drug levels may be high owing to lowered serum albumin and poor urinary excretion of free drug metabolites. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring.

Diabetes.

Care should be taken when treating diabetic patients with Epilim syrup which contains sucrose 3.6 g/5 mL. In such patients, Epilim Sugar-Free Liquid would be a preferable medication. Also see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests.

Dilutions.

If it is necessary to dilute the syrup, the recommended diluent is Syrup BP. Syrup containing sulfur dioxide as a preservative should not be used. The diluted product will have a 14-day shelf-life. The Sugar-Free Liquid should not be diluted.

Lupus erythematosus.

Although immune disorders have been noted only exceptionally during the use of Epilim, the potential benefit of Epilim should be weighed against its potential risk in patients with systemic lupus erythematosus.

Hyperammonaemia.

When urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate.
Hyperammonaemia, which may be present in the absence of abnormal liver function tests, can occur in patients during treatment with sodium valproate. This may occasionally present clinically, with or without lethargy or coma, as vomiting, ataxia and increasing clouding of consciousness. Should these symptoms occur, hyperammonaemic encephalopathy should be considered (see Section 4.4 Special Warnings and Precautions for Use, Urea cycle disorders (UCD)) and Epilim should be discontinued.

Urea cycle disorders (UCD).

Hyperammonaemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency.
Prior to the initiation of valproate therapy, evaluation for UCD should be considered in the following patients:
1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine;
2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance;
3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males);
4) those with other signs or symptoms of UCD.
Patients who develop symptoms of unexplained hyperammonaemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders.

Ornithine transcarbamylase (OTC) deficiency.

The females who are heterozygous for OTC deficiency have a spectrum of clinical and biochemical findings, depending on the extent of inactivation of the X chromosome. Females may show a range of symptoms due to hyperammonaemia which may be episodic and, therefore, difficult to diagnose. The acute symptoms include headaches, vomiting, irritability, bizarre behaviour, lethargy, ataxia, tremors, seizures (generalised tonic-clonic or focal) and coma.
Valproate may precipitate hyperammonaemia symptoms in those who have pre-existing OTC deficiency. As the symptoms may include seizures, any female with valproate-associated symptomatic hyperammonaemia should be evaluated for OTC deficiency. Investigations should include measurement of plasma amino acids and the immediate cessation of valproate should result in clinical improvement.

Surgery.

Prolongation of bleeding time, sometimes with thrombocytopenia, has occurred with Epilim therapy. Platelet function should be monitored before surgery is undertaken in patients receiving Epilim.

Other.

Blood tests (blood cell count, including platelet count, bleeding time and coagulation tests) are recommended prior to initiation of therapy or before surgery, and in case of spontaneous bruising or bleeding.

Suicidal behaviour and ideation.

Antiepileptic drugs, including sodium valproate increase the risk of suicidal thoughts or behaviour in patients taking these drugs for any indication. Patients treated with any antiepileptic drug (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, and appropriate treatment should be considered.
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 1 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 sodium valproate 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 the treating doctor.

Abrupt withdrawal.

The possible risk of fits after sudden cessation of Epilim should be borne in mind. If it is the only anticonvulsant used and has to be withdrawn for more than 12 hours because of surgery, control of epilepsy may be lost.

Carbapenem antibiotics.

The concomitant use of sodium valproate and carbapenem antibiotics is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Pharmaceutical precautions.

Epilim tablets are hygroscopic and must be kept in protective foil until taken. See Section 6.4 Special Precautions for Storage.

Patients with known or suspected mitochondrial disease.

Valproate may trigger or worsen clinical signs of underlying mitochondrial diseases caused by mutations of mitochondrial DNA as well as the nuclear-encoded POLG gene. In particular, acute liver failure and liver-related deaths have been associated with valproate treatment at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial enzyme polymerase γ (POLG e.g. Alpers-Huttenlocher Syndrome).
POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders.

Aggravated convulsion.

As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately (see Section 4.8 Adverse Effects (Undesirable Effects)).

Thrombocytopenia.

Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. Evidence of haemorrhage, bruising or a disorder of haemostasis/coagulation is an indication for reduction of Epilim dosage or withdrawal of therapy.

Ornithine transcarbamylase (OTC) deficiency.

A familial history of infant mortality or patient history of OTC deficiency, or of seizures or coma in the presence of mental retardation suggests the need to exclude OTC deficiency.

Weight gain.

Patients should be warned of the risk of weight gain at the initiation of therapy, and appropriate strategies should be adopted to minimise the risk.

Carnitine palmitoyltransferase (CPT) type II deficiency.

Patients with an underlying carnitine palmitoyltransferase (CPT) type II deficiency should be warned of the greater risk of rhabdomyolysis when taking valproate.

Estrogen containing products.

The enzyme inducing effect of valproate is appreciably less than that of certain other anticonvulsants and loss of efficacy of oral contraceptive agents does not appear to be a problem.
However, estrogen containing products, including estrogen containing hormonal contraceptives, may increase the clearance of valproate, which may result in decreased serum concentration of valproate and potentially decreased valproate efficacy. Prescribers should monitor clinical response (seizure control or mood control) when initiating, or discontinuing estrogen-containing products. Consider monitoring of valproate serum levels (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

Although the pharmacokinetics of Epilim are modified in the elderly, they have limited clinical significance and dosage should be determined by seizure control. The volume of distribution is increased in the elderly and because of decreased binding to serum albumin, the proportion of free drug is increased. This will affect the clinical interpretation of plasma valproic acid levels.

Paediatric use.

The potential benefit of Epilim should be weighed against the risk of pancreatitis or liver damage in such patients prior to initiation of therapy (see Section 4.4 Special Warnings and Precautions for Use). The concomitant use of salicylates should be avoided in children under 3 due to the risk of liver toxicity and the concomitant use of barbiturates may require dosage adjustment (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Monotherapy is recommended in children under 3 years of age, when prescribing Epilim. Young children are at particular risk for pancreatitis, however this risk decreases with increasing age.

Effects on laboratory tests.

Epilim is eliminated mainly through the kidneys, partly in the form of ketone bodies. This may give false positives in the urine testing of possible diabetics.
There have been reports of altered thyroid function test results associated with sodium valproate. The clinical significance of this is unknown.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of valproate on other medicines.

Sodium valproate is an inhibitor of a variety of hepatic enzymes, including cytochrome P450, glucuronyl transferase and epoxide hydrolase, and may displace various drugs from plasma protein binding sites. The following list provides information about potential effects of valproate co-administration on a range of commonly prescribed medications. The list is not exhaustive, as new interactions may be reported.

Alcohol.

Valproic acid may potentiate the CNS depressant activity of alcohol. Alcohol intake is not recommended during treatment with valproate.

Antiepileptic drugs.

Several antiepileptic drugs often used in conjunction with valproate (e.g. phenytoin, carbamazepine, phenobarbital (phenobarbitone) have the ability to increase the intrinsic clearance of valproate, presumably by enzymatic induction of metabolism.

Carbamazepine.

Valproate may displace carbamazepine from protein binding sites and may inhibit the metabolism of both carbamazepine and its metabolite carbamazepine 10, 11 epoxide and consequently potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy, with dosage adjustment when appropriate.

Lamotrigine.

Sodium valproate reduces lamotrigine metabolism and increases its mean half-life. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Clinical monitoring is recommended and lamotrigine dosage should be decreased as appropriate.

Phenobarbital (phenobarbitone).

Sodium valproate blocks the metabolism of barbiturates causing an increase in phenobarbital (phenobarbitone) plasma levels, which, particularly in children, may be associated with sedation. Combination of sodium valproate and phenobarbital (phenobarbitone) can cause CNS depression without significant elevation of serum level of either drug. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment. A reduction in the dose of phenobarbital (phenobarbitone) and/or valproate may be necessary and this should also be borne in mind if medicines which are metabolised to phenobarbital (phenobarbitone) (e.g. primidone, methylphenobarbitone) are given with sodium valproate.

Phenytoin.

There have been reports of breakthrough seizures occurring with the combination of sodium valproate and phenytoin. Sodium valproate decreases total plasma phenytoin concentration, however, increases in total phenytoin levels have been reported. An initial fall in total phenytoin levels with subsequent increase in phenytoin levels has also been reported. In addition, a decrease in total serum phenytoin with an increase in the free versus protein bound phenytoin levels has been reported with possible overdose symptoms (valproic acid displaces phenytoin from its plasma protein binding sites and reduces its hepatic catabolism). Therefore, clinical monitoring is recommended. When phenytoin plasma levels are determined, the free form should be evaluated. The dosage of phenytoin may require adjustment when given in conjunction with valproate as required by the clinical situation.

Medicines with extensive protein binding.

The concomitant administration of sodium valproate with medicines that exhibit extensive protein binding (e.g. aspirin, carbamazepine, phenytoin, warfarin) may result in alteration of serum drug levels.

Anticoagulants.

The effect of Epilim on anticoagulants which modify platelet function is unknown (see Section 4.8 Adverse Effects (Undesirable Effects)). Caution is recommended when administering anticoagulants and other products which have anticoagulant properties (e.g. warfarin and aspirin).

Ethosuximide.

The interaction between ethosuximide and valproate is not normally of clinical significance. There is evidence that sodium valproate may inhibit ethosuximide metabolism, especially in the presence of other anticonvulsants. Patients receiving this combination should be monitored clinically.

Oral contraceptives.

The enzyme inducing effect of valproate is appreciably less than that of certain other anticonvulsants and loss of efficacy of oral contraceptive agents does not appear to be a problem.

Psychotropic agents.

Epilim may potentiate the effects of other psychotropics such as MAOIs, neuroleptics, benzodiazepines and other antidepressants, therefore clinical monitoring is advised and the dose of these medicines should be reduced accordingly.

Clonazepam.

The concomitant use of sodium valproate and clonazepam may produce absence status.

Clozapine.

Caution is advised during concomitant administration as competitive protein binding may potentiate an increase in clozapine or valproate levels.

Diazepam.

Sodium valproate displaces diazepam from its plasma binding sites and inhibits its metabolism. Monitoring of free diazepam levels may be necessary if the patient becomes sedated.

Lorazepam.

A decrease in lorazepam plasma clearance may occur with concomitant administration of sodium valproate.

Midazolam.

Free plasma midazolam may increase in patients receiving valproate. It appears likely that sodium valproate displaces midazolam from its plasma binding sites, potentially leading to an increase of the midazolam response.

Primidone.

Valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation); these signs cease with long-term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

Zidovudine.

Valproate may raise zidovudine plasma concentrations leading to increased zidovudine toxicity.

Tricyclic antidepressants.

Sodium valproate may inhibit the metabolism of tricyclic antidepressants. Clinical monitoring of free antidepressant levels may be necessary.

Olanzapine.

Valproic acid may decrease the olanzapine plasma concentration.

Felbamate.

Valproic acid may decrease the felbamate mean clearance.

Rufinamide.

Valproic acid may lead to an increase ion plasma level of rufinamide. This increase is dependent on concentration of valproic acid. Caution should be exercised, in particular in children as this effect is larger in this population.

Propofol.

Valproic acid may lead to an increased blood level of propofol. When co-administered with valproate, a reduction of the dose of propofol should be considered.

Nimodipine.

Concomitant treatment of nimodipine with valproic acid may increase nimodipine plasma concentration.

Other medicines.

There was no notable interaction between valproate and lithium.

Effects of other medicines on valproate.

The dosage of Epilim may need to be increased by 5 to 10 mg/kg/day when used in combination with medicines which induce hepatic enzymes and thereby increase the clearance of valproate. In contrast, medicines that are inhibitors of cytochrome P450 may be expected to have only a minor effect on valproate clearance as cytochrome P450 mediated microsomal oxidation is a relatively minor secondary metabolic pathway to glucuronidation and β-oxidation. The list is not exhaustive, as new interactions may be reported.

Aspirin.

Concomitant administration of sodium valproate and aspirin may result in displacement of valproate from protein binding sites, resulting in a rise in free levels. In addition, aspirin appears to inhibit the metabolism of valproate. Thus caution is advisable when patients on sodium valproate are prescribed aspirin. Furthermore, patients requiring long-term aspirin therapy may require a reduction in dosage of sodium valproate.

Felbamate.

Felbamate may decrease valproic acid clearance and consequently increase valproate serum concentrations. Valproate dosage should be monitored when given in combination with felbamate.

Phenobarbital (phenobarbitone), phenytoin and carbamazepine.

These medicines can decrease steady-state valproate levels in patients by increasing the intrinsic clearance of valproate, presumably through enzymic induction of metabolism. The half-life is significantly reduced in patients on polytherapy with these medicines. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.
Valproic acid metabolite levels may be increased in case of concomitant use with phenytoin or phenobarbital (phenobarbitone). Therefore patients treated with either of these two drugs should be carefully monitored for signs and symptoms of hyperammonemia.

Antidepressants.

Antidepressants (including MAOIs, tricyclic antidepressants and SSRIs) may have the potential to inhibit the metabolism of valproate via the cytochrome P450 system. However, there is not expected to be any significant interaction within normal therapeutic doses. Antidepressants can lower the seizure threshold of non-stabilised epileptic patients, and so careful and regular monitoring of their condition is indicated.

Clozapine.

Caution is advised during concomitant administration as competitive protein binding may potentiate an increase in clozapine or valproate levels.

Chlorpromazine.

Chlorpromazine may inhibit the metabolism of valproate.

Fluoxetine.

Fluoxetine may inhibit the metabolism of valproate as it does with tricyclic antidepressants, carbamazepine and diazepam.

Mefloquine.

Mefloquine increases valproic acid metabolism and has a convulsing effect; therefore epileptic seizures may occur in cases of combined therapy.

Cimetidine or erythromycin.

Valproate serum levels may be increased (as a result of reduced hepatic metabolism) in case of concomitant use with cimetidine or erythromycin.

Carbapenem antibiotics.

Decrease in valproate blood level sometimes associated with convulsions has been observed when valproate and carbapenem antibiotics (panipenem, meropenem, imipenem, ertapenem, biapenem) were combined. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem antibiotics in patients stabilised on valproic acid should be avoided (see Section 4.4 Special Warnings and Precautions for Use). If treatment with these antibiotics cannot be avoided, close monitoring of valproate blood level should be performed.

Vitamin K dependent factor anticoagulant.

Close monitoring of prothrombin rate should be performed in case of concomitant use of vitamin K dependent factor anticoagulant.

Rifampicin.

Rifampicin may decrease the valproate blood levels resulting in a lack of therapeutic effect. Therefore, valproate dosage adjustment may be necessary when it is co-administered with rifampicin.

Protease inhibitors.

Protease inhibitors such as lopinavir, ritonavir decrease valproate plasma levels when co-administered.

Colestyramine.

Colestyramine may lead to a decrease in plasma levels of valproate when co-administered.

Medicines with extensive protein binding.

The concomitant administration of sodium valproate with medicines that exhibit extensive protein binding (e.g. aspirin, carbamazepine, phenytoin, warfarin) may result in alteration of valproic acid free serum levels.

Estrogen containing products.

Estrogen containing products, including estrogen containing hormonal contraceptives, may increase the clearance of valproate, which may result in decreased serum concentration of valproate and potentially decreased valproate efficacy. Prescribers should monitor clinical response (seizure control or mood control) when initiating, or discontinuing estrogen-containing products. Consider monitoring of valproate serum levels.
The enzyme inducing effect of valproate is appreciably less than that of certain other anticonvulsants and loss of efficacy of oral contraceptive agents does not appear to be a problem.

Other interactions.

Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonemia. Patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonemic encephalopathy.

Quetiapine.

Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see Section 4.8 Adverse Effects (Undesirable Effects)). Valproate administration may also impair fertility in men (see Section 4.8 Adverse Effects (Undesirable Effects)).
(Category D)
Valproate is contraindicated as treatment for epilepsy during pregnancy unless there is no suitable alternative.
Valproate is contraindicated for use in women of childbearing potential unless the physician has provided education on the potential effects of valproate during pregnancy (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Valproate is contraindicated as treatment for bipolar disorder during pregnancy.

Teratogenicity and developmental effects.

Valproate was shown to cross the placental barrier both in animal species and in humans (see Section 5.2 Pharmacokinetic Properties).

Animal data.

Teratogenic effects (malformation of multiple organ systems) have been demonstrated in mice, rats, and rabbits.
In published literature, behavioural abnormalities have been reported in first generation offspring of mice and rats after in utero exposure to clinically relevant doses/exposure of valproate. In mice, behavioural changes have also been observed in the 2nd and 3rd generations, albeit less pronounced in the 3rd generation, following an acute in utero exposure of the first generation. The relevance of these findings for humans is unknown.

Pregnancy exposure risk related to valproate.

Both valproate monotherapy and valproate polytherapy including other antiepileptics, are frequently associated with abnormal pregnancy outcomes. Available data suggest that antiepileptic polytherapy including valproate may be associated with a greater risk of congenital malformations than valproate monotherapy.
In animals teratogenic effects have been demonstrated in mice, rats and rabbits.

Congenital malformations.

Data from a meta-analysis (including registries and cohort studies) has shown that 10.73% of children of epileptic women exposed to valproate monotherapy during pregnancy suffer from congenital malformations (95% CI: 8.16-13.29). This is a greater risk of major malformations than for the general population, for whom the risk is about 2-3%. The risk is dose dependent but a threshold dose below which no risk exists cannot be established.
Available data show an increased incidence of minor or major malformations. The most common include: neural tube defects, facial dysmorphism, cleft lip palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.
In utero exposure to valproate may also result in hearing impairment/loss due to ear and/or nose malformations (secondary effect) and/or to direct toxicity on the hearing function. Cases describe both unilateral and bilateral deafness or hearing impairment. Outcomes were not reported for all cases. When outcomes were reported, the majority of the cases had not resolved. Monitoring of signs and symptoms of ototoxicity is recommended.
Data has shown an incidence of congenital malformations in children born to epileptic women exposed to valproate monotherapy during pregnancy. This is a greater risk of major malformations than for the general population. Mothers taking more than one anticonvulsant medicine might have a higher risk of having a baby with a malformation than mothers taking one medicine.
Sodium valproate (valproic acid), if taken in the first trimester of pregnancy, is suspected of causing an increased risk of neural tube defects (especially spina bifida) in the exposed foetus. This has been estimated to be in the region of 1-2%.
This risk is dose dependent but a threshold dose below which no risk exists cannot be established.

Developmental disorders.

Data has shown that exposure to valproate in utero can have adverse effects on mental and physical development of the exposed children. The risk seems to be dose-dependent but a threshold dose below which no risk exists, cannot be established based on data. The exact gestational period of risk for these effects is uncertain and the possibility of a risk throughout the entire pregnancy cannot be excluded.
Studies in preschool children exposed in utero to valproate show that some children may experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.
Some data have suggested an association between in utero valproate exposure and the risk of developmental delay (frequently associated with craniofacial abnormalities), particularly of verbal IQ. IQ measured in school aged children with a history of valproate exposure in utero, was lower than those children exposed to other antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ. There is limited data on the long term outcomes.
Developmental delay has been very rarely reported in children born to mothers with epilepsy. It is not possible to differentiate what may be due to genetic, social, environmental factors, maternal epilepsy or antiepileptic treatment.
Available data from a study conducted using registries in Denmark show that children exposed to valproate in utero are at increased risk of autistic spectrum disorder (approximately 3-fold) and childhood autism (approximately 5-fold) compared to the unexposed population in the study.
Available data from a study conducted using registries in Denmark show that children exposed to valproate in utero are at increased risk of developing attention deficit/hyperactivity disorder (ADHD) (approximately 1.5-fold) compared to the unexposed population in the study.

Valproate therapy in pregnancy.

The enzyme inducing effect of valproate is appreciably less than that of certain other anticonvulsants and loss of efficacy of oral contraceptive agents does not appear to be a problem.
However, estrogen containing products, including estrogen containing hormonal contraceptives, may increase the clearance of valproate, which may result in decreased serum concentration of valproate and potentially decreased valproate efficacy. Prescribers should monitor clinical response (seizure control or mood control) when initiating, or discontinuing estrogen-containing products. Consider monitoring of valproate serum levels.
Women taking sodium valproate (valproic acid) who become or wish to become pregnant should be encouraged to consider routine ultrasound and amniocenteses for prenatal diagnosis of such abnormalities. As folic acid may have a role in the prevention of neural tube defects in infants of women taking antiepileptic therapy, such women are recommended to take folic acid supplementation (5 mg daily) four weeks prior to and 12 weeks after conception.
Notwithstanding the potential risks, no sudden discontinuation of antiepileptic therapy should be undertaken, without reassessment of the risks and benefits, as this may lead to breakthrough seizures which could have serious consequences for both the mother and the foetus. If after careful evaluation of the risks and benefits, sodium valproate treatment is to be continued during pregnancy, it is recommended to use sodium valproate in divided doses over the day at the lowest effective dose. The use of a prolonged release formulation may be preferable to any other treatment form.
It is recommended that:
in bipolar disorders indication, cessation of valproate therapy should be considered;
women on antiepileptic drugs (AEDs) receive prepregnancy counselling with regard to the risk of foetal abnormalities;
AEDs should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose as risk of abnormality is greater in women taking combined medication;
if appropriate, folic acid supplementation (5 mg) should be commenced four weeks prior to and continue for twelve weeks after conception as it may minimize the risk of neural tube defects;
specialist prenatal diagnosis, including detailed mid-trimester ultrasound, should be offered in order to detect the possible occurrence of neural tube defects or other malformations.
Before Epilim is prescribed for use in women with epilepsy of any form, who could become pregnant, they should receive specialist advice. Due to the potential risks to the foetus, the benefits of its use should be weighed against the risks. When treatment with Epilim is deemed necessary, precautions to minimise the potential teratogenic risk should be followed (see above recommendations).

If a woman plans a pregnancy.

For the epilepsy indication, if a woman is planning to become pregnant, a specialist experienced in the management of epilepsy must reassess the valproate therapy and consider alternative treatment options. Every effort should be made to switch to appropriate alternative treatment prior to conception, and before contraception is discontinued (see Section 4.4 Special Warnings and Precautions for Use). If switching is not possible, the woman should receive further counselling regarding the valproate risks for the unborn child to support her informed decision making regarding family planning.
For the bipolar disorder indication, if a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted. Treatment with valproate should be discontinued prior to conception, and before contraception is discontinued. If needed, alternative treatment options should be considered.
Folate supplementation (5 mg daily) before the pregnancy may decrease the risk of neural tube defects which may occur in all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.

Pregnant women.

Valproate as treatment for epilepsy is contraindicated in pregnancy unless there is no suitable alternative treatment (see Section 4.4 Special Warnings and Precautions for Use).
If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options. During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
If, despite the known risks of valproate in pregnancy and after careful consideration of alternative treatment, in exceptional circumstances a pregnant woman must receive valproate for epilepsy, it is recommended to:
Use the lowest effective dose and divide the daily dose of valproate into several small doses to be taken throughout the day.
Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy.
All patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in pre-natal medicine for evaluation and counselling regarding the exposed pregnancy.
Specialised prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations.
Folate supplementation (5 mg daily) before the pregnancy may decrease the risk of neural tube defects which may occur in all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.

Risk in the neonate.

There have been rare reports of haemorrhagic syndrome in neonates whose mothers have taken sodium valproate during pregnancy. This syndrome is related to thrombocytopenia, hypofibrinaemia, and/or to a decrease in other coagulation factors. Afibrinaemia has also been reported and may be fatal. Hypofibrinaemia is possibly associated with a decrease of coagulation factors. Haemorrhagic syndrome must be distinguished from the decrease of the vitamin K factors induced by phenobarbital (phenobarbitone) and other enzyme inducers. Platelet count, fibrinogen plasma level and coagulation status should be investigated in neonates.
Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of the pregnancy.
Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.
Withdrawal syndrome (such as, in particular, agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of pregnancy.
Epilim is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentration. It is not known what effect this would have on a breastfed infant. As a general rule, breastfeeding should not be undertaken whilst a patient is receiving Epilim.

4.7 Effects on Ability to Drive and Use Machines

Use of Epilim may provide seizure control such that the patient may be eligible to hold a driving licence. However, patients should be warned of the risk of drowsiness, especially in cases of anticonvulsant polytherapy, too high a starting dose, too rapid a dose escalation or when used in association with benzodiazepines.

4.8 Adverse Effects (Undesirable Effects)

In epilepsy.

The incidence of adverse reactions to marketed medicines such as Epilim is difficult to reliably assess due to the nature of spontaneous reporting systems and the problems associated with estimating the total exposure to the medicine. With these limitations in mind, adverse events received by the Australian Drug Reactions Committee (ADRAC) on sodium valproate products for the twenty-year period 1977-1997 are presented, summarised in Table 2. The data are presented in accordance with system organ class and include all adverse events reported, independent of drug causality i.e. adverse events classified as certain, probable or possible.

In mania.

No new or unexpected adverse events have been reported in clinical trials of Epilim in mania. The frequencies of adverse events (%) reported on valproate (as divalproex) in the largest controlled clinical trial described (see Section 5.1 Pharmacodynamic Properties) are summarised in Table 3.
In this study, there were differences with placebo for vomiting only for divalproex (45% vs 14%), fever was more common for lithium (14%) than for divalproex (1%) and placebo (4%), pain was less common with lithium (3%) than with either divalproex (19%) or placebo (20%).

List of adverse effects by system organ class.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Myelodysplastic syndrome is rare.

Blood and lymphatic system disorders.

Valproic acid inhibits the second stage of platelet aggregation. Reversible prolongation of bleeding time, as well as thrombocytopenia, have been reported but have usually been associated with doses above those recommended (see Section 4.4 Special Warnings and Precautions for Use).
Common cases of thrombocytopaenia and anaemia have been reported.
Uncommon cases of leucopenia and pancytopaenia with or without bone marrow depression have been reported.
Bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic and macrocytosis have rarely been reported.
Isolated cases of decreased blood fibrinogen and prolonged prothrombin time have been reported.
Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigation (see Section 4.4 Special Warnings and Precautions for Use).
Red cell hypoplasia, neutropenia and leucopenia have also been reported. In most cases the blood picture returned to normal when the medicine was discontinued.

Immune system disorders.

Angioedema, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome and allergic reactions have been observed.

Endocrine disorders.

Hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increased) and Syndrome of Inappropriate Secretion of ADH (SIADH) is uncommon.
Hypothyroidism is rare.

Metabolism and nutrition disorders.

Common cases of hyponatremia have been reported.
Increased weight is common and since this is a risk factor for polycystic ovary syndrome, it should be carefully monitored.
Obesity has been reported rarely.
Hyperammonaemia is rare. This has been reported in association with valproate therapy and may be present despite normal liver function tests.
Hyperammonaemia associated with neurological symptoms has been reported. In patients who develop unexplained lethargy and vomiting or changes in mental status, further investigations and hyperammonaemic encephalopathy should be considered. In these patients, EEG and ammonia level should be checked and, if ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonaemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders (see Section 4.4 Special Warnings and Precautions for Use).
Asymptomatic elevations of ammonia are more common and, when present, require close monitoring of plasma ammonia levels. If the elevation is significant (above 3N) and persists, discontinuation of valproate therapy should be considered.

Psychiatric disorders.

Confusional state, hallucinations, aggression, agitation, disturbance in attention, abnormal behaviour, psychomotor hyperactivity and learning disorder have been commonly reported.

Nervous system disorders.

The true incidence of drowsiness and sedation with Epilim is difficult to assess, as mostly it was administered in combination with other medicines. Epilim, however, may have an intrinsic sedative action in addition to potentiating sedative effects of other anticonvulsants (e.g. barbiturates, clonazepam) and CNS depressants, including alcohol.
Very common cases of tremor have been reported.
Common cases of stupor, somnolence, convulsion, memory impairment, headache, nystagmus and dizziness have been reported.
Common cases of extrapyramidal disorder which may not be reversible, including reversible parkinsonism has been reported.
Uncommon cases of ataxia, coma, encephalopathy, aggravated convulsions (see Section 4.4 Special Warnings and Precautions for Use), lethargy, paresthesia and reversible parkinsonism have been reported. Diplopia and depression have occurred rarely and usually in association with other anticonvulsants. Excitement, hyperactivity and behavioural disorders have been rarely reported, usually in children at the start of treatment.
Rare cases of reversible dementia associated with reversible cerebral atrophy and cognitive disorder have been reported.
Stupor and lethargy sometimes leading to transient coma/encephalopathy, either isolated or in conjunction with recurrence of seizures, may occur and were most often associated with polytherapy, too high a starting dose or too rapid a dose escalation.

Eye disorders.

Not known: diplopia.

Ear and labyrinth disorders.

Deafness, either reversible or irreversible, has been reported commonly.

Vascular disorders.

Haemorrhage is common and the occurrence of vasculitis is uncommon.

Respiratory, thoracic and mediastinal disorders.

Pleural effusion has uncommonly been reported.

Gastrointestinal disorders.

Nausea is very common.
Vomiting is common. Upper abdominal pain, diarrhoea, gingival disorder (mainly gingival hyperplasia) and stomatitis are common and frequently occur at the start of treatment and usually disappear after a few days without discontinuing treatment.
Vomiting, abdominal cramp, upper abdominal pain, anorexia, increased appetite and diarrhoea are usually transient and rarely require discontinuation of therapy or limitation of dose.
The overall incidence of adverse GI effects are reported to be 9 to 16% in adults and over 22% in children when plain tablets are prescribed. GI side effects may be minimised by taking the tablets with or after food or by substituting the enteric-coated tablets. As some of these symptoms may also indicate early stage hepatic dysfunction, patients should be monitored closely for the appearance of these symptoms. Patients should be instructed to report such signs to the clinician for investigation should they occur (see Section 4.4 Special Warnings and Precautions for Use).
There have been uncommon reports of pancreatitis, sometimes lethal, occurring in patients receiving valproic acid or sodium valproate, usually within the first 6 months of therapy. Patients experiencing acute abdominal pain should have the serum amylase estimated promptly; if these levels are elevated the medicine should be withdrawn (see Section 4.4 Special Warnings and Precautions for Use).

Hepatobiliary disorders.

Liver injury is common.
Hepatic dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid or sodium valproate (see Section 4.4 Special Warnings and Precautions for Use).

Skin and subcutaneous tissue disorders.

Hypersensitivity and transient and/or dose related alopecia has been commonly observed. This effect does not appear to be dose-related and regrowth may occur, although the hair may become more curly than previously.
Nail and nail bed disorders have been commonly reported.
Hirsutism, acne and male pattern alopecia are uncommon (see Section 4.8 Adverse Effects (Undesirable Effects), List of adverse effects by system organ class, Endocrine disorders). Angioedema, rash and hair disorder (such as hair texture abnormal, hair colour changes, hair growth abnormal) are uncommon.
Toxic epidermal necrolysis, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome, Stevens Johnson Syndrome have been rarely reported.
Dermatological reactions consistent with immune adverse reactions such as pruritus, urticaria have been noted. Caution should be observed when using the medicine in patients with systemic lupus erythematosus.

Musculoskeletal and connective tissue disorders.

Decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with valproate have been uncommon. The mechanism by which valproate affects bone metabolism has not been identified.
Systemic lupus erythematosus and rhabdomyolysis are rare.

Renal and urinary disorders.

Urinary incontinence is common.
Renal failure is uncommon.
Rare cases of enuresis and tubulointerstitial nephritis have been reported.
Rare cases of reversible Fanconi's syndrome associated with valproate therapy have been reported but the mode of action is as yet unclear.

Reproductive system and breast disorders.

Dysmenorrhoea is common and amenorrhoea is uncommon.
There have been rare reports of male infertility and polycystic ovaries.
There have been reports of irregular menses and secondary amenorrhoea and rare cases of breast enlargement and galactorrhoea.

General disorders and administration site conditions.

Non-severe peripheral oedema and hypothermia are uncommon.
Oedema has been reported. Increase in appetite may occur.

Investigations.

Coagulation factors decreased, abnormal coagulation tests (such as prolonged prothrombin time, activated partial thromboplastin time, thrombin time and INR) and biotin deficiency/biotinidase deficiency have rarely been reported.

Reporting of suspected adverse reactions.

Reporting of 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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Cases of accidental and suicidal overdosage have been reported. Fatalities are rare.

Symptoms.

Symptoms of overdosage may include serious CNS depression and impairment of respiration. In cases of overdose, long half-lives up to 30 hours have been reported. Signs of an acute massive overdose usually include coma, with muscular hypotonia, hyporeflexia and miosis, impaired respiratory functions and metabolic acidosis, hypotension and circulatory collapse/shock. Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels. Cases of intracranial hypertension related to cerebral oedema have been reported. Deaths have occurred following massive overdose; nevertheless, a favourable outcome is usual. The presence of sodium content in the valproate formulations may lead to hypernatraemia when taken in overdose.

Treatment.

Establish airway and breathing and evaluate circulatory status. Assisted mechanical ventilation may be required in cases of respiratory depression. Activated charcoal may reduce the absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube, once the airway is protected. Haemodialysis and haemoperfusion have been used successfully. Intravenous naloxone has also been used sometimes in association with activated charcoal given orally.
Provided that adequate supportive treatment is given, full recovery usually occurs. Particular attention should be given to the maintenance of an adequate urinary output. Hepatic and pancreatic function should be monitored.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiepileptics, ATC Code: N03AG01.
Class: Anticonvulsant, antipsychotic.

Mechanism of action.

Site and mode of action.

The mode of action of Epilim has not been fully established. Its anticonvulsant effect is attributed to the blockade of voltage dependent Na+ channels and increased brain levels of γ-aminobutyric acid (GABA). The GABA-ergic effect is also believed to possibly contribute towards the antimanic properties of sodium valproate.
In animals, Epilim raises cerebral and cerebellar levels of the inhibitory synaptic transmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase and/or succinic semialdehyde dehydrogenase and/or by inhibiting the reuptake of GABA by neuronal cells.
Epilim exhibits marked anticonvulsant activity in animals, demonstrated by the various tests used to detect antiepileptic activity.
Epilim appears to have no significant hypnotic effect (an incidence of about 0.2% was noted for drowsiness in a survey of unwanted effects), nor does it have any significant action on the autonomic nervous system, respiration, blood pressure, renal function or body temperature. It does have a spasmolytic action on the isolated ileum preparation but no effect on the nictitating membrane.

Pharmacodynamics.

In epilepsy.

Epilim has been shown to be effective in the treatment of absence seizures (petit mal), tonic-clonic seizures (grand mal) and myoclonic seizures. It has also been shown to be effective in patients with partial (focal) seizures. Epilim appears to have less sedative effect than conventional antiepileptic drugs and this, together with the reduction in fit frequency in children, has often led to improvements in alertness and performance in school.

In mania.

In one study valproate has been shown to be significantly more effective than placebo in the treatment of acute mania and has been reported to be comparable to lithium. Potential medicine interactions likely to be relevant to valproate in the management of patients with mania are outlined (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Although the dosage of sodium valproate varied considerably among the controlled studies, a fixed initial dose was used after which dosage was determined by serum levels.

Clinical trials.

In epilepsy.

Epilim's efficacy in this therapeutic indication is widely known and recognised.

In mania.

There have been at least five double-blind trials comparing sodium valproate or the bioequivalent active, divalproex sodium with either placebo and/or lithium in the treatment of mania. Only one of these trials was of adequate size. Bowden et al (1994) demonstrated most convincingly the superior effectiveness of valproate as compared to placebo in the treatment of acute mania. Marked improvement, defined as at least 50% improvement on the Manic Syndrome Subscale of the Mania Rating Scale occurred in 48% of valproate-treated patients and 25% of placebo-treated patients respectively (p=0.0040). Comparable efficacy to lithium in this study was reported. Marked improvement, defined as at least 50% improvement on the Manic Syndrome Subscale of the Mania Rating Scale, occurred in a similar number of patients receiving sodium valproate and lithium, 48% and 49%, respectively.

5.2 Pharmacokinetic Properties

Absorption.

Valproic acid is rapidly and almost completely absorbed in fasting patients following oral dosing with Epilim plain tablets, syrup and sugar-free liquid, with peak blood levels occurring within 1 to 4 hours. Absorption of valproic acid from the enteric-coated tablets given to fasting subjects is delayed with peak blood levels occurring within 3 to 7 hours. Overall absorption is not significantly altered by co-administration with milk products, but is delayed if the medicine is taken with food. However, the extent of absorption is not affected. Local gastric irritation may occur with the plain tablets, sugar-free liquid or syrup when administered on an empty stomach, due to transformation of sodium valproate into valproic acid. Gastric irritation is less likely to occur with the enteric-coated tablets.
In most adult patients, daily doses of 1,200 to 1,500 mg result in therapeutic plasma levels of 50 to 100 microgram/mL (0.35 to 0.69 mmol/L). However, correlation between the daily dose per bodyweight and plasma levels of drug has been poor.

Distribution.

Distribution of sodium valproate is rapid and most likely restricted to the circulation and rapidly exchangeable extracellular water. CSF and breast milk levels were found to be 5 to 15% and about 1 to 10% of plasma levels, respectively.
Valproic acid shows non-linear kinetics, due to concentration-dependent plasma protein binding as well as a relatively short half-life.
Epilim is approximately 90% bound to plasma proteins but only 60% to albumin. However, if the plasma level of valproic acid rises above 120 microgram/mL or if the serum albumin concentration is lowered, the binding sites may become saturated, causing the amount of free drug to rise rapidly, out of proportion to any increase in dosage. Epilim may displace phenobarbital (phenobarbitone) or phenytoin from plasma protein binding sites.
Saliva levels of Epilim are poorly correlated with those in plasma in contrast to the good correlation found for other antiepileptics.
Placental transfer (see Section 4.6 Fertility, Pregnancy and Lactation).
Valproate crosses the placental barrier in animal species and in humans:
In animal species, valproate crosses the placenta, to a similar extent as in humans.
In humans, several publications assessed the concentration of valproate in the umbilical cord of neonates at delivery. Valproate serum concentration in the umbilical cord, representing that in the fetuses, was similar to or higher than that in the mothers.

Metabolism.

Its metabolism is complex; the major elimination pathway is via glucuronidation (40-60%). The remainder is largely metabolised via oxidation pathways, β-oxidation accounting for 30-40% and w-oxidation (cytochrome P450 dependent), the remaining fraction. Only 1 to 3% of the ingested dose is found to be excreted unchanged in the urine.

Excretion.

Sodium valproate is almost completely metabolised prior to excretion. Plasma half-life is variable but generally appears to be 8 to 12 hours (range 3.84 to 15.77 hours). It may be shorter in patients receiving other anticonvulsants or in children and patients receiving the medicine for long periods. In cases of overdose, long half-lives up to 30 hours have been reported. Antipsychotic agents or antidepressants including MAOIs, tricyclics and SSRIs co-administered with sodium valproate may result in competitive metabolism or enzyme inhibition, thereby increasing valproate levels (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

5.3 Preclinical Safety Data

Genotoxicity.

Valproate was not mutagenic in bacteria (Ames test), or mouse lymphoma L5178Y cells at thymidine kinase locus (mouse lymphoma assay), and did not induce DNA repair activity in primary culture of rat hepatocytes. After oral administration, valproate did not induce either chromosome aberrations in rat bone marrow, or dominant lethal effects in mice.
Statistically significant higher incidences of sister-chromatid exchange (SCE) have been observed in patients exposed to valproate as compared to healthy subjects not exposed to valproate. However, these data may have been impacted by confounding factors. Two published studies examining SCE frequency in epileptic patients treated with valproate versus untreated epileptic patients, provided contradictory results. The biological significance of an increase in SCE frequency is not known.

Toxicology.

No significant toxic effects were seen in rats receiving 270 mg/kg/day for 3 months or in dogs receiving 90 mg/kg/day for 12 months. At higher doses sedation, ataxia and various histopathological effects (testicular atrophy and reduction in lymphoid tissue) were observed at levels of 256 to 568 microgram/mL (1.78 to 3.94 mmol/L).

Testicular function.

Epilim has been shown to cause atrophy of the seminiferous epithelium with impairment of spermatogenesis, and to cause a decrease of the testicular weight of adult rats and of offspring of female rats, when administered in high doses. On the other hand, reproductive studies carried out in rats with similarly high doses in both sexes has not shown any evidence of impaired fertility. The relevance of these findings to humans is not clear.

Carcinogenicity.

Carcinogenesis.

Sodium valproate was administered in the diet to Sprague-Dawley rats and ICR (HA/ICR) mice at approximate dosage levels of 0, 80 and 160 mg/kg/day for up to 2 years. There was equivocal evidence of an increased incidence of subcutaneous fibrosarcomas in male rats and of bronchoalveolar adenomas in male mice. The presence of these tumours was not considered to be biologically significant because of the published variable incidence of spontaneously occurring fibrosarcomas and pulmonary adenomas in rats and mice respectively and the fact that statistical significance of tumour incidence was only attained in males. The significance of these findings for humans is unknown at present.

6 Pharmaceutical Particulars

6.1 List of Excipients

Crushable tablets.

Maize starch, kaolin, silicon dioxide and magnesium stearate.

Enteric-coated.

Povidone, purified talc, magnesium stearate, calcium silicate, citric acid monohydrate, macrogol 6000, hypromellose, hyprolose, polyvinyl acetate phthalate, diethyl phthalate, stearic acid, amaranth aluminium lake, indigo carmine aluminium lake, titanium dioxide.

Syrup.

Sucrose, sorbitol, saccharin sodium, brilliant scarlet 4R, purified water, flavour imitation cherry 17.40.0740, sodium methyl hydroxybenzoate and sodium propyl hydroxybenzoate.

Sugar-free liquid.

Hyetellose, saccharin sodium, sorbitol solution (70%) (non-crystallising), citric acid, brilliant scarlet 4R, purified water, flavour imitation cherry 17.40.0740, sodium methyl hydroxybenzoate and sodium propyl hydroxybenzoate.

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

Epilim tablets are hygroscopic and must be kept in protective foil until taken.

Crushable tablets.

Store below 30°C. Store in a dry place.

Enteric-coated tablets.

Store below 30°C. Store in a dry place.

Syrup.

Store below 25°C. Store away from direct sunlight.

Sugar free liquid.

Store below 25°C. Store away from direct sunlight.

6.5 Nature and Contents of Container

Crushable tablets.

Aluminium/aluminium blister packs of 100 tablets.

Enteric-coated tablets.

Aluminium/aluminium blister packs of 10#, 20# and 100 tablets.

Syrup.

300 mL amber glass bottle.

Sugar free liquid.

300 mL amber glass bottle.
# Presentations not marketed.

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

Sodium valproate is a white, odourless, crystalline powder with a saline taste. It is highly soluble in water and alcohol. It is quite dissimilar to other established anticonvulsants such as barbiturates, hydantoins, succinamides, oxazolidinediones and acetylureas in that it has no nitrogen or aromatic moiety.
Chemical name: Sodium di-n-propylacetic acid.
Its molecular weight is 166.

Chemical structure.


CAS number.

1069-66-5.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

Summary Table of Changes