Depakote

Overdose

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 functions and 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 in epileptic patients. Cases of intracranial hypertension related to cerebral oedema have been reported.

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

Hospital management of overdose should be symptomatic, including cardio-respiratogastric 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.

Shelf life

3 years.

Depakote price

Incompatibilities

Not applicable.

List of excipients

Silicone dioxide

Starch pregelatinised

Povidone

Titanium dioxide (E171)

Hypromellose

Polyethylene glycol 6000

Methacrylic acid- ethyl acrylate copolymer (1:1)

Triethyl citrate

Ponceau 4R aluminium lake (E124)

Indigotine aluminium lake (E132)

Vanillin.

Undesirable effects

The following CIOMS frequency rating is used, when applicable: Very common (> 1/10); Common (> 1/100 to < 1/ 10); Uncommon (> 1/1,000 to <1/100); Rare (> 1/10,000 to <1/1,000); Very rare (<1/10,000), not known (cannot be estimated from available data).

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 malformations and developmental disorders.

Hepatobiliary disorders:

Common: liver injury

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 Depakote Tablets with or after food.

)

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

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

Sedation has been reported occasionally. 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 anticonvulsants, 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 disorders:

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.

Rare: hyperammonaemia* , obesity

*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, 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.

Hyperammonaemia associated with neurological symptoms has also been reported. 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)

)

Blood and lymphatic system disorders:

Common: anaemia, thrombocytopenia

Uncommon: pancytopenia, leucopenia

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

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

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 (Depakote has an inhibitory effect on the second phase of platelet aggregation).).

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:

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 syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with Epilim 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 Depakote. The mechanism by which Depakote affects bone metabolism has not been identified.

Rare: systemic lupus erythematosus, rhabdomyolysis

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)

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. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics; Antipsychotics; Other Antipsychotics, ATC Code: N05AX.

Depakote exerts its effects mainly on the central nervous system.

The most likely mode of action for Depakote is potentiation of the inhibitory action of gamma amino butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.

The effectiveness of Depakote in acute mania was demonstrated in two 3 week, double-blind, placebo-controlled trials conducted in bipolar patients. Depakote was initiated at a dose of 250 mg tid and subsequently titrated up to a maximum daily dose not exceeding 2500 mg; the concomitant use of a benzodiazepine was allowed during the first 10 days of treatment to manage associated symptoms such as severe agitation.

Pharmacological studies have demonstrated activity in experimental models of animal behavior in mania.

Pharmacokinetic properties

Following oral administration of Depakote the absolute bioavailability of valproic acid approaches 100%. Mean terminal half-life is about 14 hours, steady state conditions usually being achieved within 3 - 4 days. Peak plasma concentrations are achieved within 3 - 5 hours. Administration with food increases Tmax by about 4 hours but does not modify the extent of absorption.

Depakote is extensively metabolised in the liver with less than 3% of an administered dose excreted unchanged in the urine. Principal metabolites found in urine are those originating from β-oxidation (up to 45% of the dose) and glucuronidation (up to 60% of the dose). Plasma clearance ranges from 0.4 - 0.6L/h and is independent of hepatic blood flow.

Plasma protein binding of Depakote ranges from 85 - 94% over plasma drug concentrations of 40 - 100 mcg/ml. It is concentration-dependent and the free fraction increases non-linearly with plasma drug concentration.

In elderly patients and those with liver cirrhosis (including alcoholic), acute hepatitis or renal failure the elimination of valproic acid is reduced. Reduction in intrinsic clearance and protein binding are reported. Thus, monitoring of total concentrations may be misleading and dosage adjustment may need to be considered according to clinical response.

Haemodialysis reduces serum valproic acid concentrations by about 20%.

Date of revision of the text

30/04/2018

Marketing authorisation holder

An Annual Risk Acknowledgement Form needs to be used at time of treatment initiation and during each annual review of valproate treatment by the specialist.

Valproate therapy should only be continued after a reassessment of the benefits and risks of the treatment with valproate for the patient by a specialist experienced in the management of bipolar disorder.

Aggravated convulsions:

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

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 does 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.

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.

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

Renal insufficiency:

In patients with renal insufficiency, it may be necessary to decrease dosage.2. Pharmacokinetic Properties).

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.

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.

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

Alcohol:

Alcohol intake is not recommended during treatment with valproate.

4.5.1 Effects of Depakote on other drugs

- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

Depakote 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.

- Clozapine and haloperidol,

No significant interaction was observed when clozapine and haloperidol were administered concurrently with Depakote.

- Lithium

Co-administration of Depakote and lithium does not appear to affect the steady state kinetics of lithium. Depakote has no effect on serum lithium levels.

- Olanzapine

Valproic acid may decrease the olanzapine plasma concentration.

- Phenobarbital

Depakote 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.

- Primidone

Depakote 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

Depakote decreases phenytoin total plasma concentration. Moreover Depakote 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 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.

- Lamotrigine

Depakote 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 dosage should be adjusted (lamotrigine dosage decreased) when appropriate.

- Felbamate

Valproic acid may decrease the felbamate 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

Depakote 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 Depakote 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 Depakote

Antiepileptics with enzyme inducing effects (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 Depakote decreases valproic acid clearance by 22% - 50% and consequently increase the valproic acid plasma concentrations. 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): Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem 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. If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood level 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

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 Depakote and quetiapine may increase the risk of neutropenia/leucopenia.

Depakote 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.

Pregnancy exposure risk related to valproate

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

Teratogenicity and developmental effects

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 antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.

There 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).

)

If a woman plans a pregnancy

If a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued, and if needed switched to an alternative treatment prior to conception and before contraception is discontinued.

Pregnant women

Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy. If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.

If a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued, and if needed switched to an alternative treatment prior to conception and before contraception is discontinued.

Pregnant women

Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy. If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.

All patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialised prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation 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.

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.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Depakote 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. Valproate administration may also impair fertility in men. Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.

The following CIOMS frequency rating is used, when applicable: Very common (> 1/10); Common (> 1/100 to < 1/ 10); Uncommon (> 1/1,000 to <1/100); Rare (> 1/10,000 to <1/1,000); Very rare (<1/10,000), not known (cannot be estimated from available data).

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 malformations and developmental disorders.

Hepatobiliary disorders:

Common: liver injury

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 Depakote Tablets with or after food.

)

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

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

Sedation has been reported occasionally. 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 anticonvulsants, 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 disorders:

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.

Rare: hyperammonaemia* , obesity

*Cases of isolated and moderate hyperammonaemia without change in liver function tests may occur, 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.

Hyperammonaemia associated with neurological symptoms has also been reported. 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)

)

Blood and lymphatic system disorders:

Common: anaemia, thrombocytopenia

Uncommon: pancytopenia, leucopenia

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

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

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 (Depakote has an inhibitory effect on the second phase of platelet aggregation).).

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:

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 syndrome (a defect in proximal renal tubular function giving rise to glycosuria, amino aciduria, phosphaturia, and uricosuria) associated with Epilim 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 Depakote. The mechanism by which Depakote affects bone metabolism has not been identified.

Rare: systemic lupus erythematosus, rhabdomyolysis

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)

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. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 functions and 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 in epileptic patients. Cases of intracranial hypertension related to cerebral oedema have been reported.

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

Hospital management of overdose should be symptomatic, including cardio-respiratogastric 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.

Pharmacotherapeutic group: Psycholeptics; Antipsychotics; Other Antipsychotics, ATC Code: N05AX.

Depakote exerts its effects mainly on the central nervous system.

The most likely mode of action for Depakote is potentiation of the inhibitory action of gamma amino butyric acid (GABA) through an action on the further synthesis or further metabolism of GABA.

The effectiveness of Depakote in acute mania was demonstrated in two 3 week, double-blind, placebo-controlled trials conducted in bipolar patients. Depakote was initiated at a dose of 250 mg tid and subsequently titrated up to a maximum daily dose not exceeding 2500 mg; the concomitant use of a benzodiazepine was allowed during the first 10 days of treatment to manage associated symptoms such as severe agitation.

Pharmacological studies have demonstrated activity in experimental models of animal behavior in mania.

Following oral administration of Depakote the absolute bioavailability of valproic acid approaches 100%. Mean terminal half-life is about 14 hours, steady state conditions usually being achieved within 3 - 4 days. Peak plasma concentrations are achieved within 3 - 5 hours. Administration with food increases Tmax by about 4 hours but does not modify the extent of absorption.

Depakote is extensively metabolised in the liver with less than 3% of an administered dose excreted unchanged in the urine. Principal metabolites found in urine are those originating from β-oxidation (up to 45% of the dose) and glucuronidation (up to 60% of the dose). Plasma clearance ranges from 0.4 - 0.6L/h and is independent of hepatic blood flow.

Plasma protein binding of Depakote ranges from 85 - 94% over plasma drug concentrations of 40 - 100 mcg/ml. It is concentration-dependent and the free fraction increases non-linearly with plasma drug concentration.

In elderly patients and those with liver cirrhosis (including alcoholic), acute hepatitis or renal failure the elimination of valproic acid is reduced. Reduction in intrinsic clearance and protein binding are reported. Thus, monitoring of total concentrations may be misleading and dosage adjustment may need to be considered according to clinical response.

Haemodialysis reduces serum valproic acid concentrations by about 20%.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Silicone dioxide

Starch pregelatinised

Povidone

Titanium dioxide (E171)

Hypromellose

Polyethylene glycol 6000

Methacrylic acid- ethyl acrylate copolymer (1:1)

Triethyl citrate

Ponceau 4R aluminium lake (E124)

Indigotine aluminium lake (E132)

Vanillin.

Not applicable.

3 years.

None.

Aluminium/aluminium blister packs containing 30, 60 or 90 tablets.

Not all pack sizes may be marketed

No special requirements

Aventis Pharma Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

or trading as:-

Sanofi-aventis or Sanofi

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Special precautions for storage

None.

Nature and contents of container

Aluminium/aluminium blister packs containing 30, 60 or 90 tablets.

Not all pack sizes may be marketed

Marketing authorisation number(s)

PL 04425/0200

Fertility, pregnancy and lactation

Pregnancy exposure risk related to valproate

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

Teratogenicity and developmental effects

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 antiepileptics. Although the role of confounding factors cannot be excluded, there is evidence in children exposed to valproate that the risk of intellectual impairment may be independent from maternal IQ.

There 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).

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If a woman plans a pregnancy

If a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued, and if needed switched to an alternative treatment prior to conception and before contraception is discontinued.

Pregnant women

Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy. If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.

If a woman is planning to become pregnant, a specialist experienced in the management of bipolar disorder must be consulted and treatment with valproate should be discontinued, and if needed switched to an alternative treatment prior to conception and before contraception is discontinued.

Pregnant women

Valproate as treatment for bipolar disorder is contraindicated for use during pregnancy. If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options.

All patients with valproate-exposed pregnancy and their partners should be referred to a specialist experienced in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialised prenatal monitoring should take place to detect the possible occurrence of neural tube defects or other malformations. Folate supplementation 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.

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.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Depakote 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. Valproate administration may also impair fertility in men. Case reports indicate that fertility dysfunctions are reversible after treatment discontinuation.

Special precautions for disposal and other handling

No special requirements

Date of first authorisation/renewal of the authorisation

Date of first authorisation: 4 February 2009

Date of latest renewal: 24 March 2009

Interaction with other medicinal products and other forms of interaction

4.5.1 Effects of Depakote on other drugs

- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

Depakote 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.

- Clozapine and haloperidol,

No significant interaction was observed when clozapine and haloperidol were administered concurrently with Depakote.

- Lithium

Co-administration of Depakote and lithium does not appear to affect the steady state kinetics of lithium. Depakote has no effect on serum lithium levels.

- Olanzapine

Valproic acid may decrease the olanzapine plasma concentration.

- Phenobarbital

Depakote 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.

- Primidone

Depakote 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

Depakote decreases phenytoin total plasma concentration. Moreover Depakote 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 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.

- Lamotrigine

Depakote 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 dosage should be adjusted (lamotrigine dosage decreased) when appropriate.

- Felbamate

Valproic acid may decrease the felbamate 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

Depakote 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 Depakote 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 Depakote

Antiepileptics with enzyme inducing effects (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 Depakote decreases valproic acid clearance by 22% - 50% and consequently increase the valproic acid plasma concentrations. 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): Decreases in blood levels of valproic acid have been reported when it is co-administered with carbapenem 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. If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood level 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

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 Depakote and quetiapine may increase the risk of neutropenia/leucopenia.

Depakote 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.