Syonell

Syonell 500 mg Gastro-Resistant Tablets

Containing 538.12mg 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.

For a full list of excipients, see section 6.1

Gastro-resistant tablet.

500mg: Pink, oval shaped, biconvex coated tablet with slight vanilla flavour, imprinted with '500' on one side and plain on other side.

Treatment of manic episode in bipolar disorder when lithium is contraindicated or not tolerated. The continuation of treatment after manic episode could be considered in patients who have responded to valproate semisodium for acute mania.

Posology

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 valproate semisodium should also be considered.

Dosage

Manic episodes in bipolar disorder:

Adults

The daily dosage should be established and controlled individually by the treating physician. The initial recommended daily dose is 750 mg. In addition, in clinical trials a starting dose of 20 mg valproate/kg body weight has also shown an acceptable safety profile. Prolonged-release formulations can be given once or twice daily. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect. The daily dose should be adapted to the clinical response to establish the lowest effective dose for the individual patient. The mean daily dose usually ranges between 1000 and 2000 mg valproate. Patients receiving daily doses higher than 45mg/kg/day body weight should be carefully monitored.

Continuation of treatment of manic episodes in bipolar disorder should be adapted individually using the lowest effective dose.

Elderly

Although the pharmacokinetics of valproate semisodium are modified in the elderly, they have limited clinical significance and dosage should be determined on the basis of clinical response.

Children and adolescents

The safety and efficacy of valproate semisodium for the treatment of manic episodes in bipolar disorder have not been evaluated in patients aged less than 18 years.

In patients with renal insufficiency

It may be necessary to decrease 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 semisodium 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 valproate semisodium, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1 Special warnings).

Female children and women of childbearing potential

Valproate semisodium must be initiated and supervised by a specialist experienced in the management of bipolar disorder. Valproate semisodium should not be used in female children and women of childbearing potential unless other treatments are ineffective or not tolerated.

Valproate semisodium is prescribed and dispensed according to the Valproate Pregnancy Prevention Programme (sections 4.3 and 4.4).

Valproate semisodium should preferably be prescribed as monotherapy and at the lowest effective dose, if possible as a prolonged release formulation. The daily dose should be divided into at least two single doses (see section 4.6).

Combined Therapy

When starting Syonell in patients already on anticonvulsants, these should be tapered slowly; if clinically possible; initiation of Syonell 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 Syonell. When barbiturates are being administered concomitantly and particularly if sedation is observed the dosage of barbiturate should be reduced.

When using Syonell with other psychotropics, a reduced dose may be required, (see 4.5.1 Effects of Syonell on other drugs).

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 (see section 5.2 Pharmacokinetic Properties).

Syonell is contraindicated in the following situations:

• In pregnancy (see section 4.4 and 4.6).

• In women of childbearing potential, unless the conditions of the pregnancy prevention programme are fulfilled (see section 4.4 and 4.6).

• Active liver disease

• Personal or family history of severe hepatic dysfunction, drug related

• Patients with known urea cycle disorders (see section 4.4).

• Hypersensitivity to valproate semisodium or any other ingredient of the preparation.

• 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).

To ensure the correct medication is prescribed for the patient's condition, care must be taken not to confuse Syonell 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.

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 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).

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 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 evaluation (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, valproate semisodium should be discontinued.

Female children, Women of childbearing potential and pregnant women:

Aggravated convulsions:

As with other antiepileptic drugs, some patients may experience, instead of an improvement, a reversible worsening of convulsion frequency and severity (including status epilepticus), or the onset of new types of convulsions with valproate. In case of aggravated convulsions, the patients should be advised to consult their physician immediately (see section 4.8).

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 (see section 4.3).

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 valproate semisodium the potential benefit of valproate semisodium 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 semisodium.

Weight gain:

Valproate semisodium 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:

See section 4.6 Pregnancy and Lactation.

Diabetic patients

: Valproate semisodium 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 Valproate semisodium.

Alcohol:

Alcohol intake is not recommended during treatment with valproate.

4.5.1 Effects of valproate semisodium on other drugs

- Antipsychotics, MAO inhibitors, antidepressants and benzodiazepines

Valproate semisodium 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 valproate semisodium.

- Lithium

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

- Phenobarbital

Valproate semisodium 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

Valproate semisodium 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 semisodium decreases phenytoin total plasma concentration. Moreover, valproate semisodium 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 evaluated.

- Carbamazepine

Clinical toxicity has been reported when valproate semisodium was administered with carbamazepine as valproate semisodium may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

- Lamotrigine

Valproate semisodium 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%.

- Zidovudine

Valproate semisodium 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 semisodium 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 semisodium

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.

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

Mefloquine

and Chloroquine increase valproic acid metabolism. Accordingly, the dosage of valproate semisodium may need adjustment.

In case of concomitant use of valproate semisodium 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 (section 4.4). If treatment with these antibiotics cannot be avoided, close monitoring of valproic acid blood level should be performed.

Colestyraminee

may decrease the absorption of valproate semisodium

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 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 valproate semisodium and quetiapine may increase the risk of neutropenia/leucopenia.

Valproate semisodium usually has no enzyme inducing effect; as a consequence, valproate semisodium 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.

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).

Female children, female adolescents and woman of childbearing potential (see above and section 4.4).

If a Woman wants to plan 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 (see sections 4.3 and 4.4).

If a woman using valproate becomes pregnant, she must be immediately referred to a specialist to consider alternative treatment options

All patients with a valproate exposed pregnancy and their partners should be referred to a specialist experienced in in prenatal medicine for evaluation and counselling regarding the exposed pregnancy. Specialized 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 which may occur in all pregnancies. However the available evidence does not suggest it prevents the birth defects or malformations due to valproate exposure.

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 bipolar disorder. 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 specialized 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.

Breastfeeding

Valproate is excreted in human milk with a concentration ranging from 1% to 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 valproate semisodium therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

FertilityAmenorrhoea, 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.

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

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 valproate semisodium in the treatment of manic episodes have been identified.

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

Hepato-biliary disorders:

Common: liver injury (see section 4.4.1 Special 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 Special Warnings).

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 valproate semisodium with or after food.

Uncommon: pancreatitis, sometimes lethal, (see section 4.4 Special Warnings and 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, paresthesia, convulsions (see section 4.4).

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 disorder:

Common: confusional state, aggression*, agitation*, disturbance in attention* Rare: abnormal behaviour*, psychomotor hyperactivity*, learning disorder*

*These ADRs are principally observed in the paediatric population.

Metabolic 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, 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 valproate semisodium 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 increased).

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: pancytopenia, leucopenia.

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

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

Investigations:

Common: Weight increased*.

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), biotin deficiency/biotinidase deficiency.

*Weight increase should be carefully monitored since it is a factor for polycystic ovary syndrome (see section 4.4.2 Precautions).

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 (valproate semisodiumhas 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 Fertility, 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

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 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 oedema peripheral have been reported.

Musculoskeletal and connective tissue disorders:

Uncommon: bone mineral density decreased, osteopenia, osteoporosis and fractures in patients on long-term therapy with valproate semisodium. The mechanism by which valproate semisodium 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

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 Website: 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 to 20 times maximum therapeutic levels, usually include CNS depression, or coma with muscular hypotonia, hyporeflexia, miosis, impaired respiratory functions and metabolic acidosis. 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 Syonell 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 to 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.

Valproate semisodium exerts its effects mainly on the central nervous system.

The most likely mode of action for valproate semisodium 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 valproate semisodium in acute mania was demonstrated in two, 3-week, double-blind, placebo-controlled trials conducted in bipolar patients. Valproate semisodium was initiated at a dose of 250mg tid and subsequently titrated up to a maximum daily dose not exceeding 2500mg; 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 behaviour in mania.

Absorption

Following oral administration of valproate semisodium the absolute bioavailability of valproic acid approaches 100%.

Distribution

Mean terminal half life is about 14 hours, steady state conditions usually being achieved within 3 to 4 days. Peak plasma concentrations are achieved within 3 to 5 hours. Administration with food increases Tmax by about 4 hours but does not modify the extent of absorption. Plasma protein binding of valproate semisodium ranges from 85 to 94% over plasma drug concentrations of 40 to 100 mcg/ml. It is concentration-dependent and the free fraction increases non-linearly with plasma drug concentration.

Biotransformtion

valproate semisodium is extensively metabolised in the liver through β-oxidation (up to 45% of the dose) and glucuronidation (up to 60% of the dose) pathways.

Elimination

Valproate semisodium 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 to 0.6L/h and is independent of hepatic blood flow.

Elderly

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.

Core:

Microcrystalline cellulose

Starch pregelatinised

Silicone dioxide, colloidal

Magnesium stearate

Hydroxypropylcellulose, low-substituted

Coating:

Hypromellose (E464)

Hydroxypropylcellulose (E463)

Hypromellose phthalate

Titanium dioxide (E171)

Triethyl citrate

Allura Red FD&C 40 (E129)

Indigo Carmine FD&C Blue 2 (E132)

Vanillin

Ink:

Shellac Glaze (modified) (E904)

Isopropyl alcohol

Black iron oxide (E172)

N-butyl alchol

Propylene glycol (E1520)

Ammonium hydroxide (E527)

Not applicable.

2 years.

Do not store above 25°C.

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

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

Not all pack sizes may be marketed

No special requirements.

Lupin Healthcare (UK) Limited

The Urban Building, 2^nd floor,

3-9 Albert Street, Slough, Berkshire,

SL1 2BE, United Kingdom.

PL 35507/0192

19/01/2018

December 2019.