Drug Class Description
Anti-manic agents

Generic Name
Valproic acid (as valproate semisodium)

Drug Description
Containing 269.10mg of valproate semisodium* per tablet (equivalent to 250mg of valproic acid).Containing 538.20mg of valproate semisodium* per tablet (equivalent to 500mg of valproic acid). *Valproate semisodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. It is also known as divalproex sodium (USAN).

Presentation
Gastro-resistant tablets.

Indications
Depakote is indicated for the acute treatment of a manic episode associated with bipolar disorder.

Adult Dosage
For oral administration. The tablets should be swallowed whole with a drink of water, and not crushed or chewed.The daily dosage should be established according to age and body weight. The wide variation in individual sensitivity to Depakote should also be considered.There is no clear correlation between daily dose, plasma concentration and therapeutic effect. Optimum dosage should be determined mainly by clinical response. Measurement of valproate plasma levels may be considered in addition to clinical monitoring when adequate therapeutic effect is not achieved or adverse effects are suspected.In mania it is generally agreed that plasma levels around 45 to 50µg/ml are needed to allow efficacy; most patients receiving Depakote during controlled clinical trials achieved a maximum plasma concentration of greater than 75µg/ml.DosageAdultsThe recommended initial dose is 750mg daily in 2 to 3 divided doses. From day 2 the dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. Daily doses usually range between 1000 and 2000mg (i.e. 20 – 30 mg/kg/day body weight). Where adequate control is not achieved within this range the dose may be increased.Patients receiving daily doses higher than 45mg/kg/day body weight should be carefully monitored.In patients with renal insufficiencyIt may be necessary to decrease dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading.In patients with hepatic insufficiencySalicylates should not be used concomitantly with Depakote since they employ the same metabolic pathwayLiver dysfunction, including hepatic failure resulting in fatalities, has occurred in patients whose treatment included valproic acid.Salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome). In addition in conjunction with Depakote, concomitant use in children under 3 years can increase the risk of liver toxicity.Combined TherapyWhen starting Depakote in patients, already on anticonvulsants, these should be tapered slowly; if clinically possible; initiation of Depakote therapy should then be gradual, with target dose being reached after about 2 weeks. Faster titration may be permissible if plasma level monitoring is available. In certain cases it may be necessary to raise the dose by 5 to 10mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, e.g. phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain control on a reduced dose of Depakote. When barbiturates are being administered concomitantly and particularly if sedation is observed the dosage of barbiturate should be reduced.When using Depakote with other psycotropics, a reduced dose may be required.Optimum dosage is mainly determined by control. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected.

Child Dosage
The safety and effectiveness of Depakote for the treatment of manic episodes have not been studied in individuals below the age of 18 years.

Elderly Dosage
Although the pharmacokinetics of Depakote are modified in the elderly, they have limited clinical significance and dosage should be determined on the basis of clinical response

Contra Indications
Active liver diseasePersonal or family history of severe hepatic dysfunction, drug relatedHypersensitivity to valproate semisodium or any other ingredient of the preparation.Porphyria

Special Precautions
To ensure the correct medication is prescribed for the patient's condition, care must be taken not to confuse Depakote with Epilim or sodium valproate. Patients with bipolar disorder and epilepsy are distinct populations. These differences are reflected in the patient information leaflets which clearly indicate specific indications for these differing medications.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.Special WarningsLiver 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 are infants and in particular young children under the age of 3 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, the incidence of occurrence is significantly reduced and progressively decreases with age.The concomitant use of salicylates should be avoided in children under 3 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).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 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 treatment. As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway.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 eva luation (including measurement of serum amylase).Young children are at particular risk; this risk decreases with increasing age. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Depakote should be discontinued.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 valproate semisodium.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.PrecautionsHaematological: 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.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.Systemic lupus erythematosus: Although immune disorders have only rarely been noted during the use of Depakote, the potential benefit of Depakote should be weighed against its potential risk in patients with systemic lupus erythematosus.Hyperammonaemia: When a urea cycle enzymatic deficiency is suspected, metabolic investigations should be performed prior to treatment because of the risk of hyperammonaemia with Depakote.Weight gain: Depakote 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.Pregnancy:Women of child-bearing potential should not be started on Depakote without specialist psychiatric advice. Adequate counselling should be made available to all women with bipolar disorder of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus.Diabetic patients: Depakote 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.

Interactions
Effects of Depakote on other drugs- Clozapine, haloperidol, lithiumNo significant interaction was observed when clozapine and haloperidol were administered concurrently with Depakote. Co-administration of Depakote and lithium does not appear to affect the steady state kinetics of lithium.- Antipsychotics , MAO inhibitors, antidepressants and benzodiazepinesDepakote may potentiate the effect of other psychotropics such as antipsychotics, MAO inhibitors, antidepressants and benzodiazepines; therefore, clinical monitoring is advised and the dosage of the 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.- PhenobarbitalDepakote increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur. 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.- PrimidoneDepakote 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.- PhenytoinDepakote decreases phenytoin total plasma concentration. Moreover Depakote increases phenytoin free form with possible overdosage 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 eva luated.- CarbamazepineClinical toxicity has been reported when Depakote was administered with carbamazepine as Depakote may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.- LamotrigineDepakote may reduce the metabolism of lamotrigine and increase the mean half-life. Dose should be adjusted (lamotrigine dosage decreased) when appropriate. Co-administration of lamotrigine and Depakote might increase the risk of rash.- ZidovudineDepakote may raise zidovudine plasma concentration leading to increased zidovudine toxicity.- Vitamin K-dependent anticoagulantsThe 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.- TemozolomideCo-administration of temozolomide and Depakote may cause a small decrease in the clearance of temozolomide that is not thought to be clinically relevant.Effects of other drugs on DepakoteAntiepileptics with enzyme inducing effects (including phenytoin, phenobarbital, carbamazepine) decrease valproic acid plasma concentrations. Dosages should be adjusted according to blood levels in case of combined therapy. On the other hand, combination of felbamate and Depakote may increase valproic acid plasma concentration. Depakote dosage should be monitored.Mefloquine and Chloroquine increase valproic acid metabolism. Accordingly, the dosage of Depakote may need adjustment.In case of concomitant use of Depakote 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: Decrease in valproic acid blood level, sometimes associated with convulsions, has been observed when panipenem, imipenem or meropenem were combined. If these antibiotics have to be administered, close monitoring of valproic acid blood level is recommended.Colestyramine may decrease the absorption of Depakote.Other interactionsDepakote usually has no enzyme inducing effect; as a consequence, Depakote does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.

Adverse Reactions
The following adverse events have been described from experience of sodium valproate in epilepsy; no other adverse event that could be specifically associated with the use of Depakote in the treatment of manic episodes have been identified.Congenital and familial/genetic disorders:Hepato-biliary disorders: rare cases of liver dysfunctionSevere liver damage, including hepatic failure sometimes resulting in death, has been reported. Increased liver enzymes are common, particularly early in treatment, and may be transient.Gastrointestinal disorders: (nausea, gastralgia, diarrhoea) 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 Depakote Tablets with or after food.Very rare cases of pancreatitis, sometimes lethal, have been reported.Nervous system disorders: Sedation has been reported occasionally. In monotherapy it occurred early in treatment on rare occasions and is usually transient. Rare cases of lethargy and confusion 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 anticonvulsants, notably phenobarbital. They have usually been reversible on withdrawal of treatment or reduction of dosage.Very rare cases of reversible extrapyramidal symptoms including parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported. Dose-related ataxia and fine postural tremor have occasionally been reported.An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.Metabolic disorders:Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur frequently, but they 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 Depakote should be discontinued. Very rare cases of hyponatraemia have been reported.Hyperammonaemia associated with neurological symptoms has also been reported. In such cases further investigations should be considered.Blood and lymphatic system disorders: frequent occurrence of thrombocytopenia, rare cases of anaemia, leucopenia or pancytopenia. The blood picture returned to normal when the drug was discontinued.Isolated reduction of fibrinogen or reversible increase in bleeding time have been reported, usually without associated clinical signs and particularly with high doses (Depakote has an inhibitory effect on the second phase of platelet aggregation). Spontaneous bruising or bleeding is an indication for withdrawal of medication pending investigations.Skin and subcutaneous tissue disorders: cutaneous reactions such as exanthematous rash rarely occur with Depakote. In very rare cases, toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme have been reported.Transient hair loss, which may sometimes be dose-related, has often been reported. Regrowth normally begins within six months, although the hair may become more curly than previously. Hirsutism and acne have been very rarely reported.Reproductive system and breast disorders: Amenorrhea and irregular periods have been reported. Very rarely gynaecomastia has occurred.Vascular disorders: the occurrence of vasculitis has occasionally been reported.Ear disorders: hearing loss, either reversible or irreversible, has been reported rarely; however a cause and effect relationship has not been established.Renal and urinary disorders: there have been isolated reports of a reversible Fanconi's syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with Depakote therapy, but the mode of action is as yet unclear. Very rare cases of enuresis have been reported.Immune system disorders: allergic reactions (ranging from rash to hypersensitivity reactions) have been reportedGeneral disorders: very rare cases of non severe peripheral oedema have been reported.Increase in weight may also occur. Weight gain being a risk factor for polycystic ovary syndrome, it should be carefully monitored.

Manufacturer
Sanofi-Synthelabo

Drug Availability
(POM)

Updated
06 May 2009