Sodium Valproate 500mg Gastro-resistant Tablets Taj Pharma

Sodium Valproate 500mg  Gastro-resistant Tablets

1. Name of the medicinal product

Sodium Valproate 200mg  Gastro-resistant Tablets Taj Pharma
Sodium Valproate 500mg Gastro-resistant Tablets Taj Pharma

2. Qualitative and quantitative composition

Each Enteric coated tablet contains
Sodium Valproate                                               200mg
Excipients                                                            q.s
Colour: Ponceau 4R & Sunset Yellow FCF

Each Enteric coated tablet contains         
Sodium Valproate                                               500mg
Excipients                                                            q.s
Colour: Ponceau 4R & Sunset Yellow FCF

3. Pharmaceutical form

Gastro-resistant Tablet.

4. Clinical particulars

4.1 Therapeutic indications

In the treatment of generalised, partial or other epilepsy.

4.2 Posology and method of administration

Sodium Valproate 200mg Gastro-resistant Tablets are for oral administration.

Daily dosage requirements vary according to age and body weight.

Sodium valproate tablets may be given twice daily. The tablets should be swallowed whole and not crushed or chewed.

Dosage

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 – 2000mg per day, i.e. 20 – 30mg/kg body weight per day. Where adequate control is not achieved within this range the dose may be further increased to 2500mg per day.

Children over 20 kg

Initial dosage should be 400mg/day (irrespective of weight) with spaced increases until control is achieved; this is usually within the range 20 – 30mg/kg body weight per day. Where adequate control is not achieved within this range the dose may be increased to 35mg/kg body weight per day.

Children under 20 kg

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

Use in the elderly

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

In patients with renal insufficiency

It may be necessary to decrease the dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see section 5.2 Pharmacokinetic properties).

In patients with hepatic insufficiency

Salicylates should not be used concomitantly with valproate since they employ the same metabolic pathway (see also sections 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).

Liver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid (see sections 4.3 Contraindications and 4.4 Special Warnings and Precautions for Use).

Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye’s syndrome). In addition in conjunction with sodium valproate, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1 Special warnings).

Combined Therapy

When starting sodium valproate in patients already on other anti-convulsants, these should be tapered slowly; initiation of sodium valproate therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5 to 10mg/kg/day when used in combination with anti-convulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of sodium valproate. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced.

NB: In children requiring doses higher than 40mg/kg/day clinical chemistry and haematological parameters should be monitored.

Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2 Pharmacokinetic properties).

Female children, female adolescents and women of childbearing potential and pregnant women

Sodium Valproate should be initiated and supervised by a specialist experienced in the management of epilepsy. Treatment should only be initiated if other treatments are ineffective or not tolerated (see section 4.4 and 4.6) and the benefit and risk should be carefully reconsidered at regular treatment reviews. Preferably sodium valproate should be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation to avoid high peak plasma concentrations. The daily dose should be divided into at least two single doses.

4.3 Contraindications

• Active liver disease
• Personal or family history of severe hepatic dysfunction, especially drug related
• Patients with known urea cycle disorders (see section 4.4)
• Hypersensitivity to sodium valproate
• Porphyria
• Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome, and in children under two years of age who are suspected of having a POLG-related disorder (see section 4.4).

4.4 Special warnings and precautions for use

Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms. NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations.

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 signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

4.4.1 Special warnings

Liver dysfunction:

Conditions of occurrence:

Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported.

Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anti-convulsant therapy, are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age.

The concomitant use of salicylates should be avoided in children under 3 years due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye’s syndrome).

Monotherapy is recommended in children under the age of 3 years when prescribing sodium valproate, but the potential benefit of sodium valproate should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy

In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2 – 12 weeks.

Suggestive signs:

Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: ‘Conditions of occurrence’):

– non-specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain.

– in patients with epilepsy, recurrence of seizures.

These are an indication for immediate withdrawal of the drug.

Patients (or their family for children) should be instructed to report immediately any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediately.

Detection:

Liver function should be measured before therapy and then periodically monitored during the first 6 months of therapy, especially in those who seem most at risk, and those with a prior history of liver disease.

Amongst usual investigations, tests which reflect protein synthesis, particularly prothrombin rate, are most relevant.

Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of sodium valproate therapy.

As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.

As with most anti-epileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient.

More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary.

Pancreatitis:

Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anti-convulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, valproate should be discontinued.

Carbapenem agents:

The concomitant use of valproate and carbapenem agents is not recommended.

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, valproate-induced acute liver failure and liver-related deaths have been reported at a higher rate in patients with hereditary neurometabolic syndromes caused by mutations in the gene for the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, 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 (see section 4.3).

Aggravated convulsions:

As with other anti-epileptic 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).

4.4.2 Precautions

Haematological:

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 (see section 4.8 Undesirable Effects).

Renal insufficiency:

In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may be misleading, dosage should be adjusted according to clinical monitoring (see sections 4.2 Posology and Method of Administration and 5.2 Pharmacokinetic Properties).

Systemic lupus erythematosus:

Although immune disorders have only rarely been noted 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 (see also section 4.8 Undesirable Effects).

Hyperammonaemia:

When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with valproate.

Weight gain:

Sodium valproate very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8 Undesirable Effects).

Pregnancy:

Women of childbearing potential should not be started on sodium valproate without specialist neurological advice. Adequate counselling should be made available to all pregnant women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (see also section 4.6 Pregnancy and Lactation).

Diabetic patients:

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.

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

Alcohol:

Alcohol intake is not recommended during treatment with valproate.

4.5 Interaction with other medicinal products and other forms of interaction

4.5.1 Effects of Valproate on other drugs

– Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

Valproate may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of other psychotropics should be adjusted when appropriate.

In particular, a clinical study has suggested that adding olanzapine to valproate or lithium therapy may significantly increase the risk of certain adverse events associated with olanzapine e.g. neutropenia, tremor, dry mouth, increased appetite and weight gain, speech disorder and somnolence.

– Lithium

Sodium valproate has no effect on serum lithium levels.

– Olanzapine

Valproic acid may decrease the olanzapine plasma concentration.

– Phenobarbital

Valproate increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate.

– 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.

– Phenytoin

Valproate decreases phenytoin total plasma concentration. Moreover valproate increases phenytoin free form 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.

– Carbamazepine

Clinical toxicity has been reported when valproate was administered with carbamazepine as valproate may 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 the metabolism of lamotrigine and increases the lamotrigine mean half-life by nearly two fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore, clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate.

– Felbamate

Valproic acid may decrease the falbamate mean clearance by up to 16%.

– Rufinamide

Valproic acid may lead to an increase in plasma levels 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.

– Zidovudine

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

– Nimodipine

In patients concomitantly treated with sodium valproate and nimodipine the exposure to nimodipine can be increased by 50%. The nimodipine dose should therefore be decreased in case of hypotension.

– Vitamin K-dependent anticoagulants

The anticoagulant effect of warfarin and other coumarin anticoagulants may be increased following displacement from plasma protein binding sites by valproic acid. The prothrombin time should be closely monitored.

– Temozolomide

Co-administration of temozolomide and valproate may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.

4.5.2 Effects of other drugs on Valproate

Anti-epileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy.

Valproic acid metabolite levels may be increased in the case of concomitant use with phenytoin or phenobarbital. Therefore patients treated with those two drugs should be carefully monitored for signs and symptoms of hyperammonaemia.

On the other hand, combination of felbamate and valproate decreases valproic acid clearance by 22% – 50% and consequently increase the valproic acid plasma concentrations. Valproate dosage should be monitored.

Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of sodium valproate may need adjustment.

In case of concomitant use of valproate and highly protein bound agents (e.g. aspirin), free valproic acid plasma levels may be increased.

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

Carbapenem antibiotics such as panipenem, imipenem and meropenem: Decreases in blood levels of valproic acid have been reported when it is co-administered with carabapenem agents, resulting in a 60% – 100% decrease in valproic acid levels within two days,sometimes associated with convulsions. Due to the rapid onset and the extent of the decrease, co-administration of carbapenem agents in patients stabilised on valproic acid should be avoided (see section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood levels should be performed.

Protease inhibitors such as lopinavir and ritonavir decrease valproate plasma level when co-administered.

Cholestyramine may lead to a decrease in plasma level of valproate when co-administered.

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

4.5.3 Other interactions

Caution is advised when using sodium valproate in combination with newer anti-epileptics whose pharmacodynamics may not be well established.

Concomitant administration of valproate and topiramate or acetazolamide has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring for signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy.

– Quetiapine

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

Valproate usually has no enzyme-inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.

4.6 Fertility, pregnancy and lactation

Sodium Valproate should not be used in female children, in women of childbearing potential and in pregnant women unless other treatments are ineffective or not tolerated. Women of childbearing potential have to use effective contraception during treatment. In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible.

Pregnancy Exposure Risk related to valproate

Both valproate monotherapy and valproate polytherapy are associated with abnormal pregnancy outcomes. Available data suggest that anti-epileptic polytherapy including valproate is associated with a greater risk of congenital malformations than valproate monotherapy.

Congenital malformations

Data derived 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 and major malformations. The most common types of malformations include neural tube defects, facial dysmorphism, cleft lip and palate, craniostenosis, cardiac, renal and urogenital defects, limb defects (including bilateral aplasia of the radius), and multiple anomalies involving various body systems.

Developmental disorders

Data have 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 available 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 up to 30 – 40% experience delays in their early development such as talking and walking later, lower intellectual abilities, poor language skills (speaking and understanding) and memory problems.

Intelligence quotient (IQ) measured in school aged children (age 6) with a history of valproate exposure in utero was on average 7 – 10 points lower than those children exposed to other anti-epileptics. 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 are limited data on the long term outcomes.

Available data 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 with the general study population.

Limited data suggests that children exposed to valproate in utero may be more likely to develop symptoms of attention deficit/hyperactivity disorder (ADHD).

Female children and women of childbearing potential (see above and section 4.4)

If a Woman wants to plan a Pregnancy

• During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia may carry a particular risk of death for mother and the unborn child.
• In women planning to become pregnant or who are pregnant, valproate therapy should be reassessed
• In women planning to become pregnant all efforts should be made to switch to appropriate alternative treatment prior to conception, if possible (see section 4.6).

Valproate therapy should not be discontinued without a reassessment of the benefits and risks of the treatment with valproate for the patient by a physician experienced in the management of epilepsy. If based on a careful evaluation of the risks and the benefits valproate treatment is continued during the pregnancy, it is recommended to:

– Use the lowest effective dose and divide the daily dose 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.

– Folate supplementation before the pregnancy may decrease the risk of neural tube defects common to all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.

– To institute specialised prenatal monitoring in order to detect the possible occurrence of neural tube defects or other malformations.

Risk in the neonate

– Cases of haemorrhagic syndrome have been reported very rarely in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to thrombocytopenia, hypofibrinogenemia and/or to a decrease in other coagulation factors. Afibrinogenemia has also been reported and may be fatal. However, this syndrome must be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and enzymatic inducers. Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.

– Cases of hypoglycaemia have been reported in neonates whose mothers have taken valproate during the third trimester of their pregnancy.

– Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy.

– Withdrawal syndrome (such as, in particular, agitation, irritability, hyper-excitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur in neonates whose mothers have taken valproate during the last trimester of their pregnancy.

Breast-feeding

Valproate is excreted in human milk with a concentration ranging from 1% – 10% of maternal serum levels. Haematological disorders have been shown in breastfed newborns/infants of treated women (see section 4.8).

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from sodium valproate therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Amenorrhoea, polycystic ovaries and increased testosterone levels have been reported in women using valproate (see section 4.8). Valproate administration may also impair fertility in men (see section 4.8). Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.

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 licence.

Patients should be warned of the risk of transient drowsiness, especially in cases of anti-convulsant polytherapy or association with benzodiazepines (see section 4.5 Interactions with Other Medicaments and Other Forms of Interaction).

4.8 Undesirable effects

The following CIOMS frequency rating is used, when applicable: Very common ≥ 1 %; Common ≥ 1 % and ≤ 10 %; Uncommon ≥ 0.1 % and ≤ 1 %; Rare ≥ 0.01 % and ≤ 0.1 %; Very rare ≥ 0.01 %, Unknown (cannot be estimated from available data).

Congenital malformations and developmental disorders (see section 4.4 and section 4.6).

Hepatobiliary disorders:

Common: liver injury (see section 4.4.1 Warnings)

Severe liver damage, including hepatic failure sometimes resulting in death, has been reported (see also sections 4.2, 4.3 and 4.4.1). Increased liver enzymes are common, particularly early in treatment, and may be transient (see section 4.4.1).

Gastrointestinal disorders:

Very common: nausea

Common: vomiting, gingival disorder (mainly gingival hyperplasia), stomatitis, gastralgia, diarrhoea

The above adverse events frequently occur at the start of treatment, but they usually disappear after a few days without discontinuing treatment. These problems can usually be overcome by taking sodium valproate with or after food.

Uncommon: pancreatitis, sometimes lethal (see section 4.4 Special Warnings and Special Precautions for Use)

Nervous system disorders:

Very common: tremor

Common: extrapyramidal disorder, stupor, somnolence, convulsion, memory impairment, headache, nystagmus

Uncommon: coma, encephalopathy, lethargy (see below), reversible parkinsonism, ataxia, paraesthesia, aggravated convulsions (see section 4.4)

Rare: reversible dementia associated with reversible cerebral atrophy, cognitive disorder

Sedation has been reported occasionally, usually when in combination with other anti-convulsants. In monotherapy it occurred early in treatment on rare occasions and is usually transient.

Rare cases of lethargy occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation or concomitant use of other anti-convulsants, notably phenobarbital or topiramate. They have usually been reversible on withdrawal of treatment or reduction of dosage.

An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.

Psychiatric disorder:

Common: confusional state, hallucinations, aggression*, agitation*, disturbance in attention*

Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disorder*

*These ADRs are principally observed in the paediatric population.

Metabolism and nutrition disorders:

Common: hyponatraemia, weight increased*

*Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4).

Rare: hyperammonaemia (see section 4.4.2 Precautions), obesity

Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, are usually transient and should not cause treatment discontinuation. However, they may present clinically as vomiting, ataxia, and increasing clouding of consciousness. Should these symptoms occur sodium valproate should be discontinued.

Hyperammonaemia associated with neurological symptoms has also been reported (see section 4.4.2 Precautions). In such cases further investigations should be considered.

Endocrine Disorders

Uncommon: Syndrome of inappropriate secretion of ADH (SIADH), hyperandrogenism (hirsutism, virilism, acne, male pattern alopecia, and/or androgen increase)

Rare: hypothyroidism (see section 4.6 Fertility, pregnancy and lactation)

Blood and lymphatic system disorders:

Common: anaemia, thrombocytopenia (see section 4.4.2 Precautions)

Uncommon: pantoctyopenia, leucopenia

The blood picture returned to normal when the drug was discontinued.

Rare: bone marrow failure, including red cell aplasia, agranulocytosis, macrocytic anaemia, macrocytosis

Isolated findings of a reduction in blood fibrinogen and/or an increase in prothrombin time have been reported, usually without associated clinical signs and particularly with high doses (sodium valproate has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations (see also section 4.6 Pregnancy and Lactation).

Skin and subcutaneous tissue disorders:

Common: Hypersensitivity, transient and/or dose related alopecia (hair loss), nail and nail bed disorders. Regrowth normally begins within six months, although the hair may become more curly than previously.Uncommon: angioedema, rash, hair disorder (such as abnormal hair texture, hair colour changes, abnormal hair growth)

Rare: toxic epidermal necrolysis, Stevens-Johnson, syndrome, erythema multiforme, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome

Reproductive system and breast disorders:

Common: dysmenorrhea

Uncommon: amenorrhea

Rare: male infertility, polycystic ovaries

Very rarely gynaecomastia has occurred.

Vascular disorders:

Common: haemorrhage (see section 4.4.2 Precautions and 4.6 Fertility, pregnancy and lactation)

Uncommon: vasculitis

Ear and labyrinth disorders:

Common: deafness, a cause and effect relationship has not been established.

Renal and urinary disorders:

Uncommon: renal failure

Rare: enuresis, tubulointerstitial nephritis, reversible Fanconi’s syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with sodium valproate therapy, but the mode of action is as yet unclear.

General disorders and administration site conditions:

Uncommon: hypothermia, non-severe peripheral oedema

Musculoskeletal and connective tissue disorders:

Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with sodium valproate. The mechanism by which sodium valproate affects bone metabolism has not been identified.

Rare: systemic lupus erythematosus, rhabdomyolysis (see section 4.4.2 Precautions)

Respiratory, thoracic and mediastinal disorders:

Uncommon: pleural effusion

Investigations:

Rare: coagulation factors decreased (at least one), abnormal coagulation tests (such as prothrombin time prolonged, activated partial thromboplastin time prolonged, thrombin time prolonged, INR prolonged) (see sections 4.4 and 4.6).

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

Rare: myelodysplastic syndrome

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

Cases of accidental and deliberate valproate overdose have been reported. At plasma concentrations of up to 5 – 6 times the maximum therapeutic levels, there are unlikely to be any symptoms other than nausea, vomiting and dizziness.

Signs of acute massive overdose, i.e. plasma concentration 10 – 20 times maximum therapeutic levels, usually include CNS depression or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, metabolic acidosis, hypotension and circulatory collapse/shock. A favourable outcome is usual, however some deaths have occurred following massive overdose.

Symptoms may however be variable and seizures have been reported in the presence of very high plasma levels (see also section 5.2 Pharmacokinetic Properties). Cases of intracranial hypertension related to cerebral oedema have been reported.

The presence of sodium in the sodium valproate formulations may lead to hypernatraemia when taken in overdose.

Hospital management of overdose should be symptomatic, including cardio-respiratory monitoring. Gastric lavage may be useful up to 10 – 12 hours following ingestion.

Haemodialysis and haemoperfusion have been used successfully.

Naloxone has been successfully used in a few isolated cases, sometimes in association with activated charcoal given orally.

In case of massive overdose, haemodialysis and haemoperfusion have been used successfully.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Sodium valproate and valproic acid are anti-convulsants.

In certain in-vitro studies it was reported that sodium valproate could stimulate HIV replication but studies on peripheral blood mononuclear cells from HIV-infected subjects show that sodium valproate does not have a mitogen-like effect on inducing HIV replication. Indeed the effect of sodium valproate on HIV replication ex-vivo is highly variable, modest in quantity, appears to be unrelated to the dose and has not been documented in man.

5.2 Pharmacokinetic properties

The half-life of sodium valproate is usually reported to be within the range 8 – 20 hours. It is usually shorter in children.

In patients with severe renal insufficiency it may be necessary to alter dosage in accordance with free serum valproic acid levels.

The reported effective therapeutic range for plasma valproic acid levels is 40 – 100mg/litre (278 – 694 micromol/litre). This reported range may depend on time of sampling and presence of co-medication. The percentage of free (unbound) drug is usually between 6% and 15% of the total plasma levels. An increased incidence of adverse effects may occur with plasma levels above the effective therapeutic range.

The pharmacological (or therapeutic) effects of sodium valproate may not be clearly correlated with the total or free (unbound) plasma valproic acid levels.

5.3 Preclinical safety data

Not applicable.

6. Pharmaceutical particulars

6.1 List of excipients

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

6.2 Incompatibilities

There are no major incompatibilities.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Sodium valproate is hygroscopic. The tablets should not be removed from their foil until immediately before they are taken. Where possible, blister strips should not be cut. Store in a dry place below 30°C.

6.5 Nature and contents of container

Sodium Valproate 200mg/500mg  Gastro-resistant Tablets are supplied in blister packs further packed into a cardboard carton. Pack sizes 100 and 112 tablets.

6.6 Special precautions for disposal and other handling

None.

7. Manufactured By:
   Taj Pharmaceuticals Ltd.
   at: Plot. No. 220, Mahagujarat
   Industrial Estate, At & Post-Moraiya,
   Tal-Sanand, Dist- Ahmedabad Gujarat (India)

   PATIENT INFORMATION LEAFLET

   Sodium valproate 200mg and 500mg gastro-resistant tablets

   This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get.

   Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

   • Keep this leaflet. You may need to read it
   • If you have further questions, please ask your doctor or
   • This medicine has been prescribed for you only. Do not pass it onto others. It may harm them even if their symptoms are the same as
   • If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section

    

   What is in this leaflet

   1. What sodium valproate is and what is it used for
   2. What you need to know before you take sodium valproate
   3. How to take sodium valproate
   4. Possible side effects
   5. How to store sodium valproate
   6. Contents of the pack and other information

    

   1. What sodium valproate is and what it is used for

    

   The name of your medicine is Sodium Valproate   200mg or 500mg Gastro-resistant Tablets (called sodium valproate throughout this leaflet). This belongs to a group of medicines called anti- convulsants or anti-epileptic agents. It works by controlling the activity of the brain which causes fits or seizures.

   It is used to treat epilepsy (fits) in adults and children.

   2. What you need to know before you take sodium valproate

    

   Do not take sodium valproate and tell your doctor if:

   Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue.

7. 7. • You have liver problems or a family history of liver problems
      • You have a rare illness called porphyria which affects your metabolism
      • You have a known metabolic disorder i.e. a urea cycle disorder
      • You have a genetic problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome)

       

      Talk to your doctor or pharmacist before taking sodium valproate if:

      • You have diabetes. This medicine may affect the results of urine tests
      • You have a carnitine palmitoyltransferase type II
      • You have kidney problems – you may need a lower dose
      • You have a ‘urea cycle disorder’ – where too much ammonia builds up in the body
      • You have an illness called “lupus” – a disease of the immune system which affects the skin, bones, joints, lungs and kidneys
      • You know that there is a genetic problem caused by a mitochondrial disorder in your family Talk to your doctor or pharmacist before taking sodium valproate if you have these conditions. Do this even if you no longer have them, but have had them in the

      Sodium valproate can increase your appetite and may make you put on weight. Talk to your doctor about how this will affect you.

      Your doctor may wish to do blood tests before you start taking sodium valproate and during the first six months of treatment.

       

      Warnings and precautions

      • A small number of people being treated with anti-epileptics such as sodium valproate have had thoughts of harming or killing themselves. If at any time you have these thoughts, immediately contact your
      • As with other antiepileptic drugs, convulsions may become worse or happen more frequently whilst taking this medicine. If this happens contact your doctor

       

      Other medicines and sodium valproate

      Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. This includes herbal medicines. This is because sodium valproate can affect the way some other medicines work. Also some medicines can affect the way sodium valproate works.

      In particular, check with your doctor or pharmacist if you are taking any of the following medicines:

      • Anti-psychotic agents such as quetiapine and olanzapine – for mental health problems. Sodium valproate may increase the effects of these drugs. In particular, when taken with the medicine olanzapine the following effects occur: neutropenia (a blood problem which reduces the chance of fighting infection), tremor, dry mouth, increased appetite and weight gain, problems with speech, sleepiness or extreme
      • Medicines for depression – including monoamine oxidase inhibitors (MAOI) such as
      • Benzodiazepines (such as Diazepam) – used as sleeping tablets and for
      • Some medicines for epilepsy such as phenytoin, carbamazepine, rufinamide, topiramate, acetazolamide, phenobarbital, lamotrigine, primidone,
      • Medicines for thinning the blood such as
      • Salicylates such as aspirin
      • Cholestyramine – for high blood lipid (fat)
      • Cimetidine – for stomach
      • Carbapenem agents (antibiotics used to treat bacterial infections) such as imipenem, meropenem, rifampicin and The combination of sodium valproate and carbapenems should be avoided because it may decrease the effect of your medicine.
      • Mefloquine and chloroquine – used to prevent and treat malaria. Taking these with sodium valproate may increase the chance of a Before travelling to a malaria area, ask your doctor or pharmacist about the best malaria prevention tablets for you.
      • Zidovudine and protease inhibitors such as lopinavir and ritonavir – for HIV and
      • Temozolomide – for
      • Propofol – used for

       

      Taking sodium valproate with food and drink

      Take sodium valproate with or after food. This will help to stop the feelings of sickness that may happen after taking the tablets.

      Alcohol intake is not recommended during treatment.

      Pregnancy, breast feeding and fertility Important advice for women

      • Valproate can be harmful to unborn children when taken by a woman during
      • Whether taken on its own or with another epilepsy medicine, valproate seems to carry a higher risk if taken during pregnancy than other epilepsy medicines. The higher the dose, the higher the risks but all doses carry a risk. It can cause serious birth defects and can affect the way in which the child develops as it grows. Birth defects which have been reported include spina bifida (where the bones of the spine are not properly developed); facial and skull malformations; heart, kidney, urinary tract and sexual organ malformations; limb
      • If you take valproate during pregnancy you have a higher risk than other women of having a child with birth defects that require medical treatment. Because valproate has been used for many years we know that in women who take valproate around 10 babies in every 100 will have birth defects. This compares to 2-3 babies in every 100 born to women who don’t have
      • It is estimated that up to 30-40% of preschool children whose mothers took valproate during pregnancy may have problems with early childhood development. Children affected can be slow to walk and talk , intellectually less able than other children, and have difficulty with language and
      • Autistic spectrum disorders are more often diagnosed in children exposed to valproate and there is some evidence children may be more likely to develop symptoms of Attention Deficit Hyperactivity Disorder (ADHD).
      • If you are a woman capable of becoming pregnant your doctor should only prescribe valproate for you if nothing else works for
      • Before prescribing this medicine to you, your doctor will have explained what might happen to your baby if you become pregnant whilst taking valproate. If you decide later you want to have a child you should not stop taking your medicine until you have discussed this with your doctor and agreed a plan for switching you onto another product if this is
      • Ask your doctor about taking folic acid when trying for a baby. Folic acid can lower the general risk of spina bifida and early miscarriage that exists with all pregnancies. However, it is unlikely that it will reduce the risk of birth defects associated with valproate

       

      FIRST PRESCRIPTION

      If this is the first time you have been prescribed valproate your doctor will have explained the risks to an unborn child if you become pregnant. Once you are of childbearing age, you will need to make sure you use an effective method of contraception throughout your treatment. Talk to your doctor or family planning clinic if you need advice on contraception.

      Key messages:

      • Make sure you are using an effective method of
      • Tell your doctor at once if you are pregnant or think you might be

       

      CONTINUING TREATMENT AND NOT TRYING FOR A BABY

      If you are continuing treatment with valproate but you don’t plan to have a baby make sure you are using an effective method of contraception. Talk to your doctor or family planning clinic if you need advice on contraception.

      Key messages:

      • Make sure you are using an effective method of contraception
      • Tell your doctor at once if you are pregnant or think you might be

       

      CONTINUING TREATMENT AND CONSIDERING TRYING FOR A BABY

      If you are continuing treatment with valproate and you are now thinking of trying for a baby you must not stop taking either your valproate or your contraceptive medicine until you have discussed this with your prescriber. You should talk to your doctor well before you become pregnant so that you can put several actions in place so that your pregnancy goes as smoothly as possible and any risks to you and your unborn child are reduced as much as possible.

      Your doctor may decide to change the dose of valproate or switch you to another medicine before you start trying for a baby.

      If you do become pregnant you will be monitored very closely both for the management of your underlying condition and to check how your unborn child is developing.

      Ask your doctor about taking folic acid when trying for a baby. Folic acid can lower the general risk of spina bifida and early miscarriage that exists with all pregnancies. However, it is unlikely that it will reduce the risk of birth defects associated with valproate use.

      Key messages:

      • Do not stop using your contraception before you have talked to your doctor and worked together on a plan to ensure your epilepsy is controlled and the risks to your baby are
      • Tell your doctor at once when you know or think you might be

       

      UNPLANNED PREGNANCY WHILST CONTINUING TREATMENT

      Babies born to mothers who have been on valproate are at serious risk of birth defects and problems with development which can be seriously debilitating. If you are taking valproate and you think you are pregnant or might be pregnant contact your doctor at once. Do not stop taking your medicine until your doctor tells you to.

      Ask your doctor about taking folic acid. Folic acid can lower the general risk of spina bifida and early miscarriage that exists with all pregnancies. However, it is unlikely that it will reduce the risk of birth defects associated with valproate use.

      Key messages:

      • Tell your doctor at once if you know you are pregnant or think you might be
      • Do not stop taking valproate unless your doctor tells you

      Make sure you read the patient booklet and sign the Acknowledgement of Risk form which should be given to you and discussed with you by your doctor or pharmacist.

       

      Breast-feeding

      Very little sodium valproate gets into the breast milk. However, talk to your doctor about whether you should breastfeed your baby. Ask your doctor or pharmacist for advice before taking any medicine.

       

      Driving and using machines

      You may feel sleepy:

      • When you first start taking sodium
      • If you are taking it with other medicines, such as other antiepileptic drugs or benzodiazepines. If this happens to you, do not drive or use any tools or

       

      Important information about some the ingredients of sodium valproate tablets

      These tablets contain:

      • The colouring agent amaranth lake, which may cause an allergic reaction in some people.
      • 6mg sodium per 200mg dose and 69mg sodium per 500mg dose. To be taken into consideration by patients on a controlled sodium diet.

       

      3. How to take sodium valproate

       

      Always take sodium valproate exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

      Sodium valproate treatment must be started and supervised by a doctor specialised in the treatment of epilepsy.

      Taking this medicine

      • Swallow the tablets whole with a drink of water
      • Do not crush or chew
      • Take with or just after a meal. This will help reduce the chances of getting certain side effects such as nausea or upset

       

      How much to take Adults

      • The usual dose of sodium valproate is between 1000mg and 2000mg each
      • This may be increased to 2500mg each
      • Take this in 2 separate doses – half in the morning and half in the

      Children over 20kg:

      • The dose of sodium valproate is based on the child’s
      • The usual dose is between 20 and 30mg for each kg of body
      • This may be increased to 35mg for each kg of body weight each
      • Take this in 2 separate doses – half in the morning and half in the

       

      Children under 20kg:

      • The usual dose of sodium valproate is based on the child’s
        • The usual dose is 20mg for each kg of body
        • Give in 2 separate doses – half in the morning and half in the

      People with kidney problems

      If you or your child have kidney problems, your doctor may prescribe a lower dose.

      Do not change the dose you have been prescribed without first discussing with your doctor.

      When treatment is first started

      At first you may be prescribed a lower dose. This is because some patients need less sodium valproate than others to control their fits. Your doctor will then increase the dosage until your condition is controlled.

      • Because of this it is very important that you follow your doctor’s instructions about how much to
      • Blood tests may be needed to check how well the medicine is
      • You may be taking other medicines for epilepsy at the same time as sodium valproate. If so, your doctor may increase the dose of sodium valproate by 5-10mg for each kg of body weight each

      Appointments

      Make sure you keep your regular appointments for a check-up. They are very important as your dose may need to be changed. If you go into hospital or visit another doctor or a dentist, tell them you are taking sodium valproate.

      If you take more sodium valproate than you should

      An overdose of this medicine may be dangerous. If you think you may have taken more sodium valproate tablets than you should (or someone else has taken some), talk to a doctor, pharmacist or go to the nearest hospital casualty department straight away. Take the carton and any sodium valproate tablets left with you so that the doctors know what you have taken.

      The following effects may happen: feeling sick or being sick, pupils of the eye become smaller, dizziness, loss of consciousness, weak muscles and poor reflexes, breathing problems, headaches, fits (seizures), confusion, memory loss and unusual or inappropriate behaviour.

      If you forget to take sodium valproate

      If you forget to take a dose at the right time, take it as soon as you remember, unless it is nearly time for your next dose. Then go on as before. Do not take a double dose to make up for a forgotten dose.

      If you stop taking sodium valproate

      Do not stop taking sodium valproate without first discussing this with your doctor, even if you feel better. This is because stopping suddenly may lead to your fits coming back.

       

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

      4. Possible side effects

       

      Like all medicines, sodium valproate can cause side effects, although not everybody gets them. Usually they are not serious, and may stop if you change to another medicine.

      Stop taking sodium valproate and see a doctor or go to a hospital straight away if:

      • You get swelling of the face, lips or throat which may cause difficulty in swallowing or breathing. Hands, feet or genitals may also be affected. More severe allergic reactions can lead to lymph node enlargement and possible impairment of other organs. You could also notice an itchy, lumpy rash (hives) nettle rash (urticaria), joint pain or fever (systemic lupus erythematosus). This may mean you are having an allergic reaction to sodium valproate

       

      Tell your doctor straight away if you notice any of the following serious side effects – you may need urgent medical treatment.

      • Liver problems and problems of the pancreas may show as a sudden illness which may happen in the first six months of treatment. This is a common side effect in people taking sodium valproate. It includes feeling and being sick many times, being very tired, sleepy and weak, stomach pain including very bad upper stomach pain, jaundice (yellowing of the skin or whites of the eyes), leg swelling, worsening of your epilepsy or a general feeling of being unwell. Your doctor may tell you to stop taking sodium valproate if you have these

       

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

      • Breathing difficulty and pain due to inflammation of lungs (pleural effusion)
      • An increase in the number and severity of convulsions

       

      Rare side effects (may affect up to 1 in 1,000 people)

      • You have a skin rash or skin lesions with a pink/red ring and a pale centre which may be itchy, scaly or filled with fluid. The rash may appear especially on the palms or soles of your feet. These could be signs of a serious allergy to the medicine called ‘erythema multiforme’
      • Blistering or bleeding of the skin around the lips, eyes, mouth, nose and genitals. Also flu-like symptoms and fever. This may be something called ‘Stevens-Johnson syndrome’
      • Severe blistering rash where layers of the skin peel off to leave large areas of raw exposed skin over the body. Also a feeling of being generally unwell, fever, chills and aching muscles. This may be something called ‘Toxic epidermal necrolysis’
      • Bruising more easily and getting more infections than usual. This could be a blood problem called ‘thrombocytopenia.’ It can also be due to a fall in the number of white blood cells, bone marrow depression or another condition that affects red blood cells, white blood cells and platelets (pantocytopenia)
      • Blood problems such as blood clotting problems (bleeding for longer than normal), bruising or bleeding for no reason or getting infections more easily than usual. These blood problems could include bone marrow depression or how the blood
      • Changes in mood, loss of memory, lack of concentration and deep loss of consciousness (coma)
      • Underactive thyroid gland, which may cause tiredness or weight gain (hypothyroidism)

       

      Tell your doctor as soon as possible if you have any of the following side effects:

      • Very unusual behaviour including being very alert, and sometimes also aggressive, hyper-active and showing bad behaviour. This can be associated with more frequent or severe fits, and loss of drive. This is more likely if phenobarbital and topiramate is taken at the same time or if the sodium valproate dose has been suddenly
      • Sleepy or unsteady when walking or jerky muscle movements. This is a common side effect (may affect up to 1 in 10 people)
      • Feeling tired, confused, with loss of consciousness (coma) sometimes accompanied by hallucinations or fits. This is a common side effect (may affect up to 1 in 10 people)
      • Rapid, uncontrollable movement of the eyes. This is a common side effect (may affect up to 1 in 10 people)
      • Blisters with the skin flaking away. This is a rare side effect (may affect up to 1 in 10,000 people)
      • Changes in the amount of ammonia in the blood. Symptoms of this condition are being sick, problems with balance and co-ordination, feeling lethargic or less alert. This is a rare side effect (may affect up to 1 in 10,000 people)

       

      Tell your doctor or pharmacist if any of the following side effects get serious or lasts longer than a few days, or if you notice any side effects not listed in this leaflet: 

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

      • Feeling sick (nausea) especially when starting treatment. Feeling sick may be made better by taking the tablet with or after
      • Feeling shaky (tremor)

      Common (may affect up to 1 in 10 people)

      • Being sick (vomiting), stomach ache or diarrhoea, especially when starting
      • Swelling of gums or sore mouth
      • Hearing problems
      • Nail and nail bed disorders
      • Loss of hair which is usually temporary. When it grows back it may be more curly than before
      • Weight gain – as your appetite may be increased
      • Headache
      • Seeing or hearing things that are not there (hallucinations)
      • Aggression, agitation and disturbance in attention
      • Painful periods

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

      • Feeling tired, confused, having hallucinations or changes in mood and loss of consciousness (coma)
      • Inflamed blood vessels (vasculitis) – you may notice pain, redness or itching
      • Changes in women’s periods absence of periods
      • Swelling of the feet and legs (oedema)
      • Severe stomach pain which may reach through to your back. This could be a sign of pancreatitis.
      • Tingling or numbness in the hands and feet
      • Hair disorders (changes in texture, colour or growth)
      • Increased levels of some hormones (androgens), which may lead to increased hair growth on the face, breasts or chest, acne or thinning
      • Kidney disease
      • Lowering of normal body temperature

      Rare side effects (may affect up to 1 in 1,000 people)

      • Abnormal blood clotting factors
      • Abnormal behaviour, restlessness/hyperactivity and learning disorder
      • Kidney problems, bedwetting or increased need to pass urine
      • Blood in the urine
      • Skin problems such as rashes. These happen rarely, but more often in people also taking lamotrigine
      • Muscle pain and weakness (rhabdomyolysis)
      • Male infertility, polycystic ovaries
      • Obesity

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

      • Increased breast growth in men

      Frequency unknown (cannot be estimated from available data)

      • Fainting

      These effects usually get better when you stop taking sodium valproate.

      Bone disorders

      There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the bone) and fractures. Check with your doctor or pharmacist if you are on long-term antiepileptic medication, have a history of osteoporosis, or take steroids.

      Sodium valproate may decrease blood sodium. This can make you feel tired, weak, dizzy or faint. You may also feel or be sick and have muscle cramps.

      Less commonly you may be bloated with swelling and tightness of the hands and feet, feel confused and have fits. Sometimes it can cause changes in the blood. Here you may notice unusual bleeding or bruising more easily, severe stomach pains, feeling shaky or problems with balance.

      Male fertility

      Taking sodium valproate can be a contributing factor in male infertility.

      Reporting of side effects

      If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

      5. How to store sodium valproate
      • Keep out of the sight and reach of
      • Do not take this medicine after the expiry date shown on the
      • Store this medicine below 30ºC and in a dry
      • Store this medicine in the original container. It is important to keep sodium valproate tablets in their foil pack until you are ready to take them or they may
      • Ask your pharmacist how to dispose of medicines no longer required. Do not dispose of medicines by flushing down a toilet or sink or by throwing out with your normal household rubbish. This will help to protect the

       

      6. Contents of the pack and other information

       

      What Sodium Valproate Tablets contain

      Each tablet contains 200mg or 500mg of sodium valproate as the active substance.

      The other ingredients are: Povidone, talc, magnesium stearate, calcium silicate, polyvinyl acetate phthalate, citric acid, hypromellose, macrogol 6000, diethyl phthalate, stearic acid, titanium dioxide, amaranth lake, indigo carmine lake and hydroxypropyl cellulose.

      What Sodium Valproate Tablets look like and contents of the pack

      Sodium Valproate 200mg and 500mg Tablets are round, lilac gastro-resistant tablets. They are available in blister packs of 100 tablets.

       

      7. Manufactured By:
         Taj Pharmaceuticals Ltd.
         at: Plot. No. 220, Mahagujarat
         Industrial Estate, At & Post-Moraiya,
         Tal-Sanand, Dist- Ahmedabad Gujarat (India)