Consumer medicine information

Sodium Valproate Wockhardt

Sodium valproate

BRAND INFORMATION

Brand name

Sodium Valproate Wockhardt

Active ingredient

Sodium valproate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sodium Valproate Wockhardt.

What is in this leaflet

This leaflet answers some common questions about Sodium Valproate Wockhardt.

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 using Sodium Valproate Wockhardt against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Sodium Valproate Wockhardt is used for

Sodium Valproate Wockhardt 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.

Sodium Valproate Wockhardt 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.

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

Sodium Valproate Wockhardt may be used alone or in combination with other medicines to treat your condition.

Sodium Valproate Wockhardt may be used short-term in place of oral sodium valproate tablets or liquid when the medicine cannot be given by mouth.

Your doctor, however, may have prescribed Sodium Valproate Wockhardt for another reason.

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

There is no evidence that Sodium Valproate Wockhardt is addictive.

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

Before you are given it

When you must not receive it

You should not receive Sodium Valproate Wockhardt 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 Sodium Valproate Wockhardt 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 girl or woman of childbearing age you must not be given Sodium Valproate Wockhardt unless you use an effective method of birth control (contraception) at all times during your treatment with Sodium Valproate Wockhardt Do not stop taking Sodium Valproate Wockhardt or your contraception until you have discussed this with your doctor. Your doctor will advise you further (see 'Before you start to take it')

You should not be given Sodium Valproate Wockhardt 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.

Before you are given it

Tell your doctor 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 Sodium Valproate Wockhardt during pregnancy.

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

Tell your doctor immediately if you are pregnant or intend to become pregnant. Sodium Valproate Wockhardt 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 Sodium Valproate Wockhardt throughout their pregnancy may be at risk of impaired cognitive development or withdrawal syndrome.

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 Sodium Valproate Wockhardt, 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 are given Sodium Valproate Wockhardt.

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 Sodium Valproate Wockhardt 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. 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. Sodium Valproate Wockhardt 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
  • antipsychotic medicines including clozapine (a medicine used to treat schizophrenia)
  • quetiapine or olanzapine (a medicine used to treat bipolar disorder and schizophrenia).
  • mefloquine (a medicine used to treat malaria)
  • propofol (a medicine used to help blood flow to the brain)
  • 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.
  • cholestyramine (Questran Lite)
  • acetazolamide (Diamox)

These medicines and others may be affected by Sodium Valproate Wockhardt, 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 they are given Sodium Valproate Wockhardt, 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 Sodium Valproate Wockhardt.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while being given Sodium Valproate Wockhardt.

How it is given

Sodium Valproate Wockhardt will be given to you as an infusion or injection into the veins.

Adults:

If you are currently taking an oral formulation of sodium valproate (tablets, liquid or syrup) and are now changing over to Sodium Valproate Wockhardt, the total daily dose of Sodium Valproate Wockhardt should remain the same. In these circumstances, Sodium Valproate Wockhardt may be given as several separate injections, drips or infusions throughout the day, or as one long continuous drip or infusion lasting 24 hours a day.

If you are not currently taking any other form of sodium valproate by mouth, your doctor will decide what dose you will receive, depending on your condition and other factors such as your weight.

Children:

The dose for children is usually 20 to 30mg for each kg of body weight every day. If epilepsy is not controlled the dose may be increased up to 40mg for each kg of body weight every day, as long as blood tests are done to check the amount of Sodium Valproate Wockhardt in the blood. If higher doses are needed, further blood tests must be done to check that Sodium Valproate Wockhardt is not causing side effects.

If you take too much (overdose)

Your doctor will decide what dose of Sodium Valproate Wockhardt you need, and this will be given under close supervision, usually in a hospital setting.

The risk of an overdosage in these circumstances is low. In the event of an overdose occurring, your doctor will decide on the treatment necessary.

While you are receiving it

Things to be careful of

Be careful when driving or operating machinery until you know how Sodium Valproate Wockhardt affects you. It may cause drowsiness in some people. Make sure you know how you react to Sodium Valproate Wockhardt before you drive a car, operate machinery or do anything else that could be dangerous if you are drowsy or light headed.

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

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 nurse as soon as possible if you do not feel well while Sodium Valproate Wockhardt is being given to you.

Tell your doctor 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
  • 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 Sodium Valproate Wockhardt. 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 if you notice any of the following:

  • more frequent or more severe seizures (fits)
  • blood clotting problems
  • spontaneous bruising or bleeding
  • skin 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, vomiting and/or loss of appetite especially when prolonged

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

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 receiving 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

If you need to store Sodium Valproate Wockhardt before taking it to hospital, make sure it is stored in a dry place where the temperature does not exceed 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 ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Sodium Valproate Wockhardt, 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

Sodium Valproate Wockhardt comes as a clear colourless solution in glass ampoules.

Each box of Sodium Valproate Wockhardt contains one, five or ten glass ampoules.

Ingredients

Each ampoule contains the active ingredient sodium valproate 100 mg/mL. Each 4 mL ampoule contains 400 mg sodium valproate and each 10 mL ampoule contains 1000 mg sodium valproate.

Sponsor

Wockhardt Bio Pty Limited
Suite 103,
39 East Esplanade,
MANLY NSW 2095, Australia

Distributed in Australia by

InterPharma Pty Ltd
PO Box 115,
MANLY, NSW, 1655
Australia

This document was updated in October 2019.

Australian Register Numbers:

400 mg/4 mL
AUST R 279248

1000 mg/10 mL
AUST R 279285

Published by MIMS January 2020

BRAND INFORMATION

Brand name

Sodium Valproate Wockhardt

Active ingredient

Sodium valproate

Schedule

S4

 

Notes

Distributed by InterPharma Pty Ltd

1 Name of Medicine

Sodium valproate.

2 Qualitative and Quantitative Composition

Sodium Valproate Wockhardt solution for injection is available in ampoules containing the active ingredient sodium valproate 100 mg/mL.
Each 4 mL ampoule contains 400 mg sodium valproate and each 10 mL ampoule contains 1000 mg sodium valproate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Is a clear and colourless solution for injection in a Type I glass ampoule.

4 Clinical Particulars

4.1 Therapeutic Indications

Sodium Valproate Wockhardt is used for the treatment of patients with epilepsy or mania, who would normally be maintained on oral sodium valproate, and for whom oral therapy is temporarily not possible.

4.2 Dose and Method of Administration

Sodium Valproate Wockhardt may be given by direct slow intravenous injection or by slow intravenous infusion in 0.9% NaCl (normal saline), 5% glucose solution or glucose saline, using a separate intravenous line. The recommended concentration of the intravenous infusion solution is 4 mg/mL, with 8 mg/mL being the maximum concentration.
Sodium Valproate Wockhardt should not be administered at the same time as other intravenous additives via the same IV line. The intravenous solution is suitable for infusion by PVC, polyethylene or glass containers.
Sodium Valproate Wockhardt should be replaced by oral sodium valproate therapy (available from other brands) as soon as practicable.
Each ampoule of Sodium Valproate Wockhardt is for single dose injection only. To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary hold at 2 to 8°C for not more than 24 hours. Sodium Valproate Wockhardt is intended for use in one patient on one occasion only, any unused portion should be discarded. Never administer Sodium Valproate Wockhardt other than by the intravenous route (see Section 4.3 Contraindications).

Monotherapy.

Daily dosage requirements vary according to age and body weight.

Adults.

Patients already satisfactorily treated with sodium valproate may be continued at their current dosage using continuous infusion. For example, a patient stabilised on 25 mg/kg administered daily should be continued with an infusion at the rate of 1 mg/kg/hr.
Other patients may be given a slow intravenous injection over 3-5 minutes, usually 400-800 mg depending on body weight (up to 10 mg/kg) followed by continuous infusion of 1-2 mg/kg/hr up to a maximum of 2500 mg/day, according to the patient's clinical response.

Use in children.

The daily requirement for children is usually in the range 20-30 mg/kg/day and method of administration is as above. Where adequate control is not achieved within this range the dose may be increased up to 40 mg/kg/day 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.

Use in the elderly.

Although the pharmacokinetics of sodium valproate are modified in the elderly, they have limited clinical significance and dosage should be determined by control of symptoms. 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 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). Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading.

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

(See Section 4.4 Special Warnings and Precautions for Use.)
Valproate 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; Section 4.4; Section 4.6).
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).

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).

General considerations.

Optimum dosage is mainly determined by control of symptoms 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.

When starting Sodium Valproate Wockhardt in patients already on other anticonvulsants, these should be tapered slowly: initiation of sodium valproate therapy should be gradual, with the target dose being reached after about 2 weeks. 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, phenobarbitone and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain symptom control on a reduced dose of sodium valproate. When barbiturates are being administered concomitantly the dosage of barbiturate should be reduced if sedation is observed (particularly in children). (See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

4.3 Contraindications

Valproate is contraindicated in the following situations:

Treatment of epilepsy.

In pregnancy, unless there is no suitable alternative treatment (see Section 4.4; Section 4.6).
In women of childbearing potential, unless the physician has provided information in regard to the potential effects of valproate during pregnancy and recommendations on the use of valproate.

Treatment of mania.

In pregnancy (see Section 4.4; Section 4.6).
In women of childbearing potential, unless the physician has provided information in regard 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 eg Alpers-Huttenlocher Syndrome) and in children under two years of age who are suspected of having POLG-related disorder.
Sodium valproate IV should not be injected intramuscularly as it may produce tissue necrosis.

4.4 Special Warnings and Precautions for Use

Identified precautions.

1. Use with caution in the following circumstances.

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.

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 and 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 sodium valproate, 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 sodium valproate 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.

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.

Lupus erythematosus.

Although immune disorders have been noted only exceptionally during the use of sodium valproate, the potential benefit of sodium valproate 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 Urea cycle disorders (UCD)) and sodium valproate 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 sodium valproate therapy. Platelet function should be monitored before surgery is undertaken in patients receiving sodium valproate.

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 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 sodium valproate 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 (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

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 un-explained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, 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 convulsions.

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)).

2. Check the following before use.

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 sodium valproate 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.

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).
Valproate should not be used in female children, and women of child-bearing potential unless other treatments are ineffective or not tolerated (see Section 4.3; Section 4.4; Section 4.6).
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 subsection contraception of this warning), 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 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) which can be accessed online at www.interpharma.com.au.
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 childbearing 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). 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).

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 sodium valproate are modified in the elderly, they have limited clinical significance and dosage should be determined by control of symptoms. 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 sodium valproate 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 sodium valproate. Young children are at particular risk for pancreatitis, however this risk decreases with increasing age.

Effects on laboratory tests.

Sodium valproate 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, 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.

Phenobarbitone.

Sodium valproate blocks the metabolism of barbiturates causing an increase in phenobarbitone plasma levels, which, particularly in children, may be associated with sedation. Combination of sodium valproate and 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 phenobarbitone and/or valproate may be necessary and this should also be borne in mind if medicines which are metabolised to 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 sodium valproate 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.

Sodium valproate 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 sodium valproate 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.
Valproic acid metabolite levels may be increase in case of concomitant use with phenytoin or phenobarbital. Therefore patients treated with either of these two drugs should be carefully monitored for signs and symptoms of hyperammonemia.

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.

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.

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.

Cholestyramine.

Cholestyramine 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; Section 4.4).
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, behavioral 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, behavioral 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. Women treated with valproate have a potentially increased risk of giving birth to a baby with an abnormality due to the higher Cmax of the intravenous formulation compared with the oral formulation.
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 three-fold) and childhood autism (approximately five-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 pre-pregnancy 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 valproate 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 valproate 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). 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).
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. The use of a prolonged release formulation may be preferable to other treatment formulations in order to avoid high peak plasma concentrations.
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 decreased 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.
 Sodium valproate 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 breast-fed infant. As a general rule, breastfeeding should not be undertaken whilst a patient is receiving sodium valproate.

4.7 Effects on Ability to Drive and Use Machines

Use of sodium valproate may provide seizure control such that the patient may be eligible to hold a driving license. However, patients should be warned of the risk of transient 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 valproate 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.

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. Hirsutism, acne and male pattern alopecia are uncommon (see Endocrine disorders). 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. Angiodema, 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, and Stevens Johnson Syndrome have been rarely reported. Nail and nail bed disorders have been commonly reported.

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.

Endocrine disorders.

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

Reproductive system and breast disorders.

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

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).

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 Check the following before 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. 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.
Bone marrow failure, including pure red cell aplasia, agranulocytosis, anaemia macrocytic and macrocytosis have rarely been reported.

Hepatobiliary disorders.

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). Liver injury is common.

Metabolism and nutrition disorders.

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.
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.

Nervous system disorders.

The true incidence of drowsiness and sedation with valproate is difficult to assess, as mostly it was administered in combination with other medicines. Sodium valproate, 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.
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.
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.
When using sodium valproate intravenously, dizziness may occur a few minutes after injection; it disappears spontaneously within a few minutes.
Rare cases of reversible dementia associated with reversible cerebral atrophy and cognitive disorder have been reported.
Common cases of extrapyramidal disorder which may not be reversible, including reversible parkinsonism has been reported.

Eye disorders.

Not known - diplopia.

Psychiatric disorders.

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

Ear and labyrinth disorders.

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

Immune system disorders.

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

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

Myelodysplastic syndrome is rare.

Respiratory, thoracic and mediastinal disorders.

Pleural effusion has uncommonly been reported.

Renal and urinary disorders.

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

Vascular disorders.

Haemorrhage is common and the occurrence of vasculitis is uncommon.

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.

General disorders and administration site conditions.

Oedema has been reported. Non-severe peripheral oedema and hypothermia are uncommon. Increase in appetite may occur.
The adverse events expected for the intravenous formulation of sodium valproate are identical to those expected for the oral formulations currently available with the exception of local administration site reactions.

In mania.

No new or unexpected adverse events have been reported in clinical trials of sodium valproate 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, Clinical trials) 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%).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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. Haemodialysis and haemoperfusion have been used successfully. Intravenous naloxone has also been used sometimes in association with activated charcoal given orally when used in cases of overdosage with oral formulations.
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 Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

Class.

Anticonvulsant, antipsychotic.

5.1 Pharmacodynamic Properties

Mechanism of action.

Site and mode of action.

The mode of action of sodium valproate 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, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic transmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase and/or succinic semi-aldehyde dehydrogenase and/or by inhibiting the reuptake of GABA by neuronal cells.
Sodium valproate exhibits marked anticonvulsant activity in animals, demonstrated by the various tests used to detect antiepileptic activity.
Sodium valproate 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.

In epilepsy.

Sodium valproate 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.
Sodium valproate 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.

Sodium valproate'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.

The pharmacokinetic profile of sodium valproate powder for IV Injection differs from that of oral sodium valproate preparations. As expected, after intravenous and oral dosage (enteric-coated tablets) of sodium valproate (400 mg), Tmax is reached sooner following intravenous administration (7.3 ± 2.6 min) than after oral administration (227.7 ± 59.2 min) and Cmax is higher after intravenous dosage (55.4 ± 9.38 microgram/mL) than after oral administration (39.1 ± 3.51 microgram/mL). The bioavailability of sodium valproate enteric-coated (EC) tablets is only slightly less than that of intravenous sodium valproate with a mean AUC ratio of 100:87 for intravenous to oral forms respectively. The distribution, metabolism, excretion and elimination of intravenous sodium valproate are not different to orally administered sodium valproate.
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.
Sodium valproate 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. Sodium valproate may displace phenobarbitone or phenytoin from plasma protein binding sites.
Saliva levels of sodium valproate 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.

Sodium valproate 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.

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

The inactive ingredients present are dibasic sodium phosphate dodecahydrate sodium phosphate - monobasic dihydrate and water for injections. Phosphoric acid and sodium hydroxide may be present to adjust the pH.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store in a dry place below 25°C.
For intravenous use, the reconstituted solution should be used as soon as practicable after reconstitution, to reduce microbiological hazard. If storage is necessary, hold at 2 to 8°C for not more than 24 hours and discard any remaining solution.

6.5 Nature and Contents of Container

Sodium Valproate Wockhardt solution for injection or infusion is a clear and colourless sterile solution available in a Type I glass ampoule and contains 100 mg of sodium valproate in each mL. Each 4 mL ampoule contains 400 mg sodium valproate and each 10 mL ampoule contains 1000 mg sodium valproate.
Sodium Valproate Wockhardt is available in cartons containing 1, 5 or 10 ampoules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Sodium valproate is a white, odourless, crystalline powder with a saline taste. It is highly soluble in water and alcohol. Its molecular weight is 166. 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 structure.


CAS number.

1069-66-5.

Chemical name.

Sodium di-n-propylacetic acid.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes