1. Name Of The Medicinal Product
Orlept 200mg Gastro-Resistant Tablets or Sodium Valproate 200mg Gastro-Resistant Tablets
2. Qualitative And Quantitative Composition
Sodium Valproate 200mg
For excipients, see 6.1
3. Pharmaceutical Form
Enteric coated tablets.
White to faintly yellowish round bevel edged tablets.
4. Clinical Particulars
4.1 Therapeutic Indications
Sodium valproate is used in the treatment of all forms of epilepsy.
4.2 Posology And Method Of Administration
Dosage requirements vary according to age and body weight and should be adjusted individually to achieve adequate seizure control. The tablets may be given in divided doses.
Monotherapy: usual requirements are as follows:
Adults: Dosage should start at 600mg daily increasing by 200mg at three day intervals until control is achieved. This is generally within the dosage range 1000mg to 2000mg per day i.e. 20-30mg/kg body weight daily. Where adequate control is not achieved within this range the dose may be further increased to a maximum of 2500mg per day.
Children over 20kg: Initial dosage should be 400mg/day increasing until control is achieved. This is usually within the range 20-30mg/kg body weight per day.
Children under 20kg: 20mg/kg of body weight per day; in severe cases this may be increased up to 40mg/kg/day.
Use in the elderly: Care should be taken when adjusting dosage in the elderly since the pharmacokinetics of sodium valproate are modified. Dosage should be determined by seizure control.
Use in renal impairment:
Mild to moderate - Reduce dose
Severe - Alter dose according to free serum valproic acid concentration
Combined Therapy: In certain cases it may be necessary to raise the dose by 5 to 10mg/kg/day when used in combination with liver enzyme inducing drugs such as phenytoin, phenobarbitone and carbamazepine.
4.3 Contraindications
Liver disease or family history of severe hepatic dysfunction
Hypersensitivity to valproate
Porphyria
4.4 Special Warnings And Precautions For Use
Suicidal ideation and behaviour
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for sodium valproate.
Therefore patients should be monitored for sings of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
Liver dysfunction
Clinical symptoms are a more sensitive indicator in the early stages of hepatic failure than laboratory investigations. The onset of an acute illness, especially within the first six months, which may include symptoms of fever, vomiting, lethargy or weakness, drowsiness, coma, oedema, anorexia, jaundice or loss of seizure control is an indication for immediate withdrawal of the drug.
Patients should be instructed to report any such signs to the clinician should they occur.
Routine measurement of liver function should be undertaken in those at risk before and during the first six months of therapy including children under three years, especially those with severe seizure disorders associated with mental retardation, organic brain disease, metabolic or degenerative disorder.
The drug should be discontinued if signs of liver damage occur or if serum amylase levels are elevated.
The risk of fatal hepatic failure is higher in children and is compounded by use of more than one anticonvulsant.
Combination with other antiepileptics may increase the risk of liver damage and should therefore be avoided if possible (see Section 4.5 Interactions with Other Medicaments).
Renal impairment
Consider dose adjustment in renal impairment (see Section 4.2 Posology and Method of Administration).
Pancreatitis
Severe pancreatitis, which may be fatal, has been reported. Medical evaluation (including measurement of serum amylase) should be undertaken in patients presenting with symptoms suggestive of pancreatitis (e.g. abdominal pain, nausea and vomiting) and valproate should be discontinued if pancreatitis is diagnosed. Patients should be advised to consult their doctor immediately if they develop symptoms suggestive of pancreatitis (See Section 4.8. Undesirable Effects).
Haematological
Valproic acid inhibits the second stage of platelet aggregation. If spontaneous bruising or bleeding occurs or the prothrombin time is abnormally prolonged, medication should be withdrawn. Concomitant salicylates should be stopped if coagulation is affected. It is recommended that patients receiving sodium valproate are monitored for platelet function and clotting time before major surgery. Patients should be told how to recognise signs of blood disorders and advised to seek immediate medical advice.
Doripenem
Concomitant administration of sodium valproate and doripenem should be avoided (refer to section 4.5).
Von Willebrand's disease
There have been reports of the development of symptoms of Von Willebrand's disease in children. Precaution should be taken during surgical intervention and after traumatic events.
Systemic Lupus Erythematosus
Caution is advised in patients with systemic lupus erythematosus.
Withdrawal
Withdrawal of sodium valproate or transition to another antiepileptic should be made gradually to avoid precipitation of an increase in seizure frequency.
Diabetic patients
Sodium valproate may give false positives for ketone bodies in the urine testing of diabetics.
Weight gain
Sodium valproate very commonly causes weight gain, which may be marked and progressive. All patients should be warned of this risk at the initiation of therapy and appropriate strategies adopted to minimise weight gain.
Monitor body weight during sodium valproate therapy.
Pregnancy
Women of childbearing potential should not be started on sodium valproate without specialist neurological advice. Women of child-bearing potential have to use effective contraception during treatment. Sodium valproate is the antiepileptic of choice in patients with certain types of epilepsy such as generalised epilepsy ± myoclonus/photosensitivity. For partial epilepsy, sodium valproate should be used only in those resistant to other treatment. Women who are likely to get pregnant should receive specialist advice because of the potential teratogenic risk to the foetus (see also section 4.6 Pregnancy and Lactation).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Other antiepileptics:
Co-administration with other antiepileptics may be associated with enhanced effects, increased sedation, reduced plasma concentrations and enhanced toxicity (especially hepatic, see Section 4.4 Special Warnings and Precautions for Use), and can complicate monitoring of treatment.
Antiepileptics which have an effect on valproate
Concomitant use of hepatic enzyme inducers (e.g. barbiturates, carbamazepine, phenytoin) may enhance metabolism of valproic acid.
Antiepileptics affected by valproate
Valproic acid has been reported to have variable effects on blood levels of other hepatically metabolised or highly protein bound agents. Plasma levels of lamotrigine, primidone, phenobarbital, ethosuximide, and active metabolites of primidone and carbamazepine may be increased. Plasma levels of phenytoin may be increased or reduced. Plasma levels of an active metabolite of oxcarbazepine are sometimes lowered.
Other drugs affecting clotting:
Caution is recommended when administering with other drugs affecting clotting (e.g. warfarin, aspirin). Aspirin may increase the effects of valproate (See Section 4.4 Special Warnings and Precautions for Use).
Other hepatotoxic drugs:
Concomitant use of sodium valproate and topimarate may result in reversible hepatic impairment.
Other hepatotoxic drugs should be avoided (including aspirin in children).
Antacids:
Absorption of sodium valproate may be increased when administered with aluminium and magnesium hydroxides.
Antidepressants and antipsychotics:
Antidepressants and antipsychotics may lower the threshold for convulsions and higher doses of sodium valproate may be needed. Valproate has the potential to increase the plasma concentration of amitriptyline and nortriptyline.
Valproate may decrease the plasma level of clozapine.
Diazepam, lorazepam and bupropion plasma levels may be raised by sodium valproate.
Concomitant use of clonazepam with sodium valproate may increase the risk of side effects.
Antimalarials:
Chloroquine and mefloquine antagonise the anticonvulsant effect of valproate.
Antiulcer drugs:
Cimetidine has been reported to decrease clearance.
Antivirals:
Plasma concentration of zidovudine possibly increased (risk of toxicity).
Antibacterials:
Plasma concentrations of valproate may be reduced by meropenem.
An interaction with a combination of panipenem and betamipron, resulting in a marked reduction in valproate serum levels has been reported rarely.
It has been shown that co-administration of doripenem and valproic acid significantly reduces serum valproate levels below the therapeutic range. The lowered valproic acid levels can lead to inadequate seizure control. In an interaction study, the serum concentrations of valproic acid were markedly reduced (AUC was reduced by 63%) following co-administration of doripenem and valproic acid. The interaction had a fast onset. Since patients were administered only four doses of doripenem, a further decrease of valproic acid levels with longer concomitant administration cannot be excluded.
Lipid-lowering agents:
Cholestyramine may decrease valproate absorption; separate dosage by three hours.
Sodium valproate may reduce the effects of sodium benzoate and sodium phenylbutyrate.
4.6 Pregnancy And Lactation
Pregnancy
From experience in treating mothers with epilepsy, the risk associated with the use of valproate during pregnancy has been described as follows:
Risk associated with epilepsy and antiepileptics
In offspring born to mothers with epilepsy receiving any anti-epileptic treatment, the overall rate of malformations has been demonstrated to be 2 to 3 times higher than the rate (approximately 3%) reported in the general population. Although an increased number of children with malformations has been reported in cases of multiple drug therapy, the respective role of treatments and disease in causing the malformations has not been formally established. Malformations most frequently encountered are cleft lip and cardiovascular malformations.
Epidemiological studies have suggested an association between in-utero exposure to sodium valproate and a risk of development delay. Many factors including maternal epilepsy may also contribute to this risk but it is difficult to quantify the relative contributions of these or of maternal anti-epileptic treatment. Notwithstanding those potential risks, no sudden discontinuation in the anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures, which could have serious consequences for both the mother and the foetus.
Risk associated with valproate
In animals: teratogenic effects have been demonstrated in the mouse, rat and rabbit. There is animal experimental evidence that high plasma peak levels and the size of an individual dose are associated with neural tube defects.
In humans: an increased incidence of congenital abnormalities (including cases of facial dysmorphia, hypospadias and multiple malformations, particularly of the limbs) has been demonstrated in offspring born to mothers with epilepsy treated with valproate.
Valproate use is associated with neural tube defects such as myelomeningocele and spina bifida. The frequency of this effect is estimated to be 1 to 2%.
Hepatotoxicity and hypoglycaemia have been reported in newborns exposed to valproate in utero.
In view of the above data
Women of child-bearing potential have to use effective contraception during treatment.
When a woman is planning pregnancy, this provides as opportunity to review the need for anti-epileptic treatment. Women of childbearing age should be informed of the risks and benefits of continuing anti-epileptic treatment throughout pregnancy.
Folate supplementation, prior to pregnancy, has been demonstrated to reduce the incidence of neural tube defects in the offspring of women at high risk. Although no direct evidence exists of such effects in women receiving anti-epileptic drugs, women should be advised to start taking folic acid supplementation (5mg) as soon as contraception is discontinued.
The available evidence suggests that anticonvulsant monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1000 mg daily. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable in order to avoid high peak plasma levels. During pregnancy, valproate anti-epileptic treatment should not be discontinued if it has been effective. Nevertheless, specialist prenatal monitoring should be instituted in order to detect the possible occurrence of a neural tube defect or any other malformation. Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate (see Section 4.4 Special Warnings and Special Precautions for use).
Risk in the neonate
Very rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to hypofibrinogenaemia; afibrinogenaemia has also been reported and may be fatal. These are possibly associated with a decrease of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbitone and other anti-epileptic enzyme inducing drugs.
Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Valproate withdrawal symptoms including irritability, jitteriness, hypertonia, seizures and feeding problems have been noted in newborns.
Lactation
Excretion of valproate in breast milk is low, with a concentration between 1% to 10% of total maternal serum levels; up to now breast fed children that have been monitored during the neonatal period have not experienced clinical effects. There appears to be no contraindication to breast feeding by patients on valproate.
4.7 Effects On Ability To Drive And Use Machines
Sodium valproate in appropriate doses may not impair driving skills but driving should be restricted to patients whose seizures are adequately controlled. Administration of the drug may occasionally induce drowsiness.
4.8 Undesirable Effects
Blood and lymphatic system disorders
Inhibition of platelet aggregation, reduced fibrinogen, reversible prolongation of bleeding time, red cell hypoplasia, thrombocytopenia, leucopenia and bone marrow depression have been reported (see Section 4.4 Special Warnings and Precautions for Use). Reports of Von Willebrand's disease symptoms have been reported in children.
Immune system disorders
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome.
Metabolism and nutrition disorders
Hyperammonaemia without liver failure (sometimes associated with neurological symptoms), and hyperglycinaemia have been reported.
Less commonly, increased appetite.
Psychiatric disorders
Confusion. Anorexia has also been reported.
Nervous system disorders
Occasionally, neurological side effects (often with too high a dose or other antiepileptics), including sedation, extrapyramidal symptoms, drowsiness, headache, lethargy, and, more rarely, encephalopathy, coma and reversible dementia associated with cerebral atrophy.
Increased alertness may occur, but occasionally aggression, hyperactivity and behavioural disturbances in children.
Ear and labyrinth disorders
Rarely, hearing loss has been reported.
Gastrointestinal disorders
Most frequently, gastrointestinal disturbances (nausea), particularly on initiation of therapy.
Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as haemorrhagic with a rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use (see Section 4.4 Special Warnings and Precautions for Use).
Hepatobiliary disorders
Impaired liver function has been reported.
Transient elevation of liver enzyme levels is common and dose related. Liver dysplasia and hepatic failure (occurs most commonly in children; is rarely fatal) occurs occasionally, usually in the first few months, necessitating withdrawal.
Hepatic failure may be preceded by a combination of symptoms from the following: fever, vomiting, lethargy or weakness, drowsiness, coma, oedema, anorexia, jaundice or loss of seizure control. (Please refer to section 4.4 Special Warnings and Precautions).
Carnitine deficiency may occur and may be a factor in valproate-induced hepatotoxicity.
Reye's-like syndrome has been reported.
Skin and subcutaneous tissue disorders
Occasionally, rashes (risk increased with concomitant lamotrigine), including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), transient alopecia with regrowth of curly hair, change in hair texture, acne and hirsutism.
Renal and urinary disorders
Rarely, reversible defects in renal tubular function (Fanconi's syndrome), urinary incontinence and enuresis have been reported.
Reproductive system and breast disorders
Rarely, gynaecomastia, menstrual irregularity and amenorrhoea have been reported.
Increase in weight may also occur. Weight gain, being a risk factor for polycystic ovary syndrome, should be carefully monitored (see section 4.4 Special Warnings and Precautions for Use).
Congenital, familial and genetic disorders
Congenital malformations have been reported in women receiving anti-epileptic agents including sodium valproate during pregnancy.
General disorders and administration site conditions
Oedema
4.9 Overdose
Treatment of overdose consists primarily of supportive and symptomatic measures.
The value of gastric decontamination following overdose is uncertain since valproic acid and its salts are rapidly absorbed. Activated charcoal may be tried if the patient presents within 1 hour of a potentially life-threatening overdose; alternatively gastric lavage may be considered in similar circumstances.
Haemodialysis or tandem haemodialysis and hemoperfusion, may result in significant reductions in valproate serum concentrations.
Maintenance of adequate urinary output must be ensured. Naloxone has been administered to counteract severe CNS depression, but is also theoretically reverses the anticonvulsant effect and should be used with caution.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
The mode of action of valproic acid in epilepsy is not fully understood but may involve an elevation of gamma-amino butyric acid levels in the brain.
5.2 Pharmacokinetic Properties
Sodium valproate is rapidly and completely absorbed after oral administration; the rate of absorption is delayed by administration as enteric coated tablets.
Sodium valproate is extensively metabolised in the liver, it is excreted in the urine almost entirely in the form of its metabolites.
Sodium valproate is extensively bound to plasma protein. Peak plasma levels are attained 1-4 hours after oral dosing and the half-life is of the order of 8-22 hours.
Sodium valproate crosses the blood brain barrier and small amounts are excreted in milk. Data from animal studies indicate that sodium valproate crosses the placenta.
5.3 Preclinical Safety Data
There are no additional preclinical data of relevance to the prescriber that have not been included in the main body of the text.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Microcrystalline cellulose anhydrous
Methylated colloidal anhydrous silica
Enzymatically hydrolysed gelatin
Calcium behenate
Talc
Tablet Coating
Methacrylic acid copolymer
Talc
Triacetin
Titanium Dioxide
Polyethylene Glycol 6000
6.2 Incompatibilities
None known
6.3 Shelf Life
24 months in polypropylene or polyethylene container or glass bottles.
24 months in blister strips of PVC/PVDC and aluminium foil.
6.4 Special Precautions For Storage
Do not store above 25°C.
Store in the original package in order to protect from moisture.
6.5 Nature And Contents Of Container
Polypropylene or polyethylene containers or glass bottles containing 100 tablets.
Blister strips of rigid PVC/PVDC film and aluminium foil of 10 tablets used in multiples of 5, 6 or 10 giving pack sizes of 10, 50, 60 or 100 tablets.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
Wockhardt UK Ltd
Ash Road North
Wrexham Industrial Estate
Wrexham LL13 9UF
United Kingdom
8. Marketing Authorisation Number(S)
PL 29831/0189
9. Date Of First Authorisation/Renewal Of The Authorisation
24/07/2007
10. Date Of Revision Of The Text
6th October 2011.
