Epilim Chrono 500mg - Summary of Product Characteristics (SPC

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Epilim side effects
Epilim Chrono 500mg - Summary of Product Characteristics (SPC

Conditions of occurrence : Severe liver damage, including hepatic failure sometimes resulting in fatalities, has been very rarely reported. Experience in epilepsy has indicated that patients most at risk, especially in cases of multiple anticonvulsant therapy, are infants and in particular young children under the age of 3 years and those with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3 years, the incidence of occurrence is significantly reduced and progressively decreases with age. The concomitant use of salicylates should be avoided in children under 3 years due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years (see aspirin/salicylate product information on Reye's syndrome). Monotherapy is recommended in children under the age of 3 years when prescribing Epilim, but the potential benefit of Epilim should be weighed against the risk of liver damage or pancreatitis in such patients prior to initiation of therapy In most cases, such liver damage occurred during the first 6 months of therapy, the period of maximum risk being 2-12 weeks. Suggestive signs : Clinical symptoms are essential for early diagnosis. In particular the following conditions, which may precede jaundice, should be taken into consideration, especially in patients at risk (see above: 'Conditions of occurrence'): - non specific symptoms, usually of sudden onset, such as asthenia, malaise, anorexia, lethargy, oedema and drowsiness, which are sometimes associated with repeated vomiting and abdominal pain. - in patients with epilepsy, recurrence of seizures. These are an indication for immediate withdrawal of the drug. Patients (or their family for children) should be instructed to report immediay any such signs to a physician should they occur. Investigations including clinical examination and biological assessment of liver function should be undertaken immediay. 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 Epilim therapy. As a matter of precaution and in case they are taken concomitantly salicylates should also be discontinued since they employ the same metabolic pathway. As with most antiepileptic drugs, increased liver enzymes are common, particularly at the beginning of therapy; they are also transient. More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may be considered when appropriate and tests should be repeated as necessary. Pancreatitis: Pancreatitis, which may be severe and result in fatalities, has been very rarely reported. Patients experiencing nausea, vomiting or acute abdominal pain should have a prompt medical evaluation (including measurement of serum amylase).Young children are at particular risk; this risk decreases with increasing age. Severe seizures and severe neurological impairment with combination anticonvulsant therapy may be risk factors. Hepatic failure with pancreatitis increases the risk of fatal outcome. In case of pancreatitis, Epilim should be discontinued. Women of childbearing potential (see section 4.6): This medicine should not be used in women of child-bearing potential unless clearly necessary (i.e. in situations where other treatments are ineffective or not tolerated). This assessment is to be made before Epilim is prescribed for the first time, or when a women of child bearing potential treated with Epilim plans a pregnancy. Women of child-bearing potential must use effective contraception during treatment. Suicidal ideation and behaviour:

Each tablet contains 333mg Sodium Valproate and 145mg Valproic Acid equivalent to 500mg sodium valproate. 3. Pharmaceutical form Prolonged Release Tablet 4. Clinical particulars 4.1 Therapeutic indications Treatment of generalised, partial or other epilepsy. 4.2 Posology and method of administration Epilim Chrono Controlled Release Tablets are for oral administration. Epilim Chrono is a prolonged release formulation of Epilim which reduces peak concentration and ensures more even plasma concentrations throughout the day. Epilim Chrono 500 may be given once or twice daily. The tablets should be swallowed whole and not crushed or chewed. Daily dosage requirements vary according to age and body weight. In patients where adequate control has been achieved Epilim Chrono formulations are interchangeable with other Epilim conventional or prolonged release formulations on an equivalent daily dosage basis. Dosage.

Last Updated on eMC 06-Feb-2014 View changes| SANOFI Contact details Epilim Chrono (PIL).

Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, carbamazepine ) decrease valproic acid plasma concentrations. Dosages should be adjusted according to clinical response and blood levels in case of combined therapy. On the other hand, combination of felbamate and Epilim decreases valproic acid clearance by 22% to 50% and consequently increase the valproic acid plasma concentrations. Epilim dosage should be monitored. Mefloquine and chloroquine increase valproic acid metabolism and may lower the seizure threshold; therefore epileptic seizures may occur in cases of combined therapy. Accordingly, the dosage of Epilim may need adjustment. In case of concomitant use of Epilim 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 imipenem panipenem 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 levels should be performed. Colestyramine may decrease the absorption of Epilim. 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.

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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 Epilim, the potential benefit of Epilim 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 Epilim. Weight gain: Epilim very commonly causes weight gain, which may be marked and progressive. Patients should be warned of the risk of weight gain at the initiation of therapy and appropriate strategies should be adopted to minimise it (see section 4.8 Undesirable Effects). Pregnancy: Women of childbearing potential should not be started on Epilim without specialist neurological advice. Adequate counselling should be made available to all pregnant women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (see also section 4.6 Pregnancy and Lactation). Diabetic patients: Epilim 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. Alcohol: Alcohol intake is not recommended during treatment with valproate 4.5 Interaction with other medicinal products and other forms of interaction 4.5.1 Effects of Epilim on other drugs.

Haematological: Blood tests (blood cell count, including plaet 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:

- Antipsychoticss, MAO inhibitors, antidepressants and benzodiazepines Epilim 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. - Lithium.

Usual requirements are as follows: Adults.

It may be necessary to decrease the dosage. Dosage should be adjusted according to clinical monitoring since monitoring of plasma concentrations may be misleading (see section 5.2 Pharmacokinetic Properties). In patients with hepatic insufficiency.

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

Valproic acid may decrease the felbamate mean clearance by up to 16%. - Zidovudine Epilim may raise zidovudine plasma concentration leading to increased zidovudine toxicity. - 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 Epilim 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 Epilim.

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

Epilim has no effect on serum lithium levels - Phenobarbital Epilim increases phenobarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 15 days of combined treatment with immediate reduction of phenobarbital doses if sedation occurs and determination of phenobarbital plasma levels when appropriate. - Primidone Epilim 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 Epilim decreases phenytoin total plasma concentration. Moreover Epilim 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 Epilim was administered with carbamazepine as Epilim may potentiate toxic effects of carbamazepine. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate. - Lamotrigine Epilim reduces the metabolism of lamotrigine and increases the lamotrigine mean half life by nearly to fold. This interaction may lead to increased lamotrigine toxicity, in particular serious skin rashes. Therefore clinical monitoring is recommended and dosages should be adjusted (lamotrigine dosage decreased) when appropriate. - Felbamate.

When starting Epilim in patients already on other anticonvulsants, these should be tapered slowly; initiation of Epilim therapy should then be gradual, with target dose being reached after about 2 weeks. In certain cases it may be necessary to raise the dose by 5 to 10mg/kg/day when used in combination with anticonvulsants which induce liver enzyme activity, eg phenytoin, phenobarbital and carbamazepine. Once known enzyme inducers have been withdrawn it may be possible to maintain seizure control on a reduced dose of Epilim. When barbiturates are being administered concomitantly and particularly if sedation is observed (particularly in children) the dosage of barbiturate should be reduced. NB: In children requiring doses higher than 40mg/kg/day clinical chemistry and haematological parameters should be monitored. Optimum dosage is mainly determined by seizure control and routine measurement of plasma levels is unnecessary. However, a method for measurement of plasma levels is available and may be helpful where there is poor control or side effects are suspected (see section 5.2 Pharmacokinetic Properties). 4.3 Contraindications - Active liver disease - Personal or family history of severe hepatic dysfunction, especially drug related - Hypersensitivity to sodium valproate - Porphyria 4.4 Special warnings and precautions for use Although there is no specific evidence of sudden recurrence of underlying symptoms following withdrawal of valproate, discontinuation should normally only be done under the supervision of a specialist in a gradual manner. This is due to the possibility of sudden alterations in plasma concentrations giving rise to a recurrence of symptoms. NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations. 4.4.1 Special warnings Liver dysfunction:

The concomitant use of valproate and carbapenem agents is not recommended. 4.4.2 Precautions.

Epilim Chrono 500 Controlled Release 2. Qualitative and quantitative composition Active Constituents.

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An alternative formulation of Epilim should be used in this group of patients, due to the tablet size and need for dose titration. Epilim Liquid (sugar-free) or Epilim Syrup are alternatives. Elderly.

Caution is advised when using Epilim in combination with newer anti-epileptics whose pharmacodynamics may not be well established. Concomitant administration of valproate and topiramate has been associated with encephalopathy and/or hyperammonaemia. In patients taking these two drugs, careful monitoring of signs and symptoms is advised in particularly at-risk patients such as those with pre-existing encephalopathy. Epilim usually has no enzyme-inducing effect; as a consequence, Epilim does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill. 4.6 Fertility, pregnancy and lactation Women of childbearing potential should not be started on Epilim without specialist neurological advice. Adequate counselling should be made available to all women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (See also section 4.6.1).Women who are taking Epilim and who may become pregnant should receive specialist neurological advice and the benefits of its use should be weighed against the risks. Epilim is the antiepileptic of choice in patients with certain types of epilepsy such as generalised epilepsy ± myoclonus/photosensitivity. For partial epilepsy, Epilim should be used only in patients resistant to other treatment. If pregnancy is planned, consideration should be given to cessation of Epilim treatment, if appropriate. When Epilim treatment is deemed necessary, precautions to minimize the potential teratogenic risk should be followed. (See also section 4.6.1 paragraph entitled “In view of the above”) 4.6.1 Pregnancy.

Salicylates should not be used concomitantly with Epilim 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 Epilim, concomitant use in children under 3 years can increase the risk of liver toxicity (see section 4.4.1 Special warnings). Combined Therapy.

In offspring born to mothers with epilepsy receiving any anti-epileptic treatment, the overall rate of malformations has been demonstrated to be higher than the rate (approximay 3 %) reported in the general population. An increased number of children with malformations have been reported in cases of multiple drug therapy. Malformations most frequently encountered are cleft lip and cardio-vascular malformations. No sudden discontinuation in the anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both the mother and the foetus. Antiepileptic drugs should be withdrawn under specialist supervision. - Risk associated with seizures.

Dosage should start at 600mg daily increasing by 200mg at three-day intervals until control is achieved. This is generally within the dosage range 1000mg to 2000mg per day, ie 20-30mg/kg/day body weight. Where adequate control is not achieved within this range the dose may be further increased to 2500mg per day. Children over 20kg.

- Risk associated with epilepsy and antiepileptics.

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for sodium valproate. Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. Carbapenem agents:

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