Drugs and medications - Epilim Chrono

Severe liver damage resulting sometimes 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 young children under the age of 3 with severe seizure disorders, organic brain disease, and (or) congenital metabolic or degenerative disease associated with mental retardation. After the age of 3, the incidence of occurrence is significantly reduced and progressively decreases with age.

The concomitant use of salicylates should be avoided in children under 3 due to the risk of liver toxicity. Additionally, salicylates should not be used in children under 16 years (see Aspirin /salicylates 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 firs( 6 months of therapy, the period of maximum risk being 2-12 weeks.

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.

Patients (or their family or 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.

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

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

Confirmation of an abnormally low prothrombin rate, particularly in association with other biological abnormalities (significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases) requires cessation of Epilim" therapy. As a matter of precaution and in ruse 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 arc also transient.

More extensive biological investigations (including prothrombin rate) are recommended in these patients; a reduction in dosage may he 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 decrease 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, valproate should be discontinued.

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 Undesirable effects)

In patients with renal insufficiency, it may be necessary to decrease dosage. As monitoring of plasma concentrations may he misleading, dosage should be adjusted according to clinical monitoring (see Dosage and method of administration and Pharmacokinetic properties).

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 Undesirable effects).

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

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 Undesirable effect).

Women of childbearing potential should not be started on Epilim without specialist neurological advice. Epilim" is the antiepileptic of choice in patients with certain types of epilepsy such as generalized epilepsy ± myoclomis/photosensitivity. For partial epilepsy, Epilim should be used only in patients resistant to other treatment. women who are likely to get pregnant, should receive specialist advice because of the potential teratogenic risk to the foetus (see Pregnancy and lactation).

Valproate is eliminated mainly through the kidneys, partly in the form of ketone bodies; this may give false positives in the urine testing of possible diabetics.

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

Valproate increases phenorbarbital plasma concentrations (due to inhibition of hepatic catabolism) and sedation may occur, particularly in children. Therefore, clinical monitoring is recommended throughout the first 1 ; days of combined treatment with immediate reduction of phenobarbital doses d sedation occurs and determination of phenobarbital plasma levels when appropriate.

Valproate increases primidone plasma levels with exacerbation of its adverse effects (such as sedation, these signs cease with long term treatment. Clinical monitoring is recommended especially at the beginning of combined therapy with dosage adjustment when appropriate.

Valproate decreases phenytoin total plasma concentration. Moreover valproate 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 level, are determined, the free form should be evaluated.

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

Valproate may reduce lamotrigine metabolism and increase its mean half-life, dosages should be adjusted (lamotrigine dosage decreased) when appropriate. Co-administration of lamotrigine and Epilim' might increase the risk of rash.

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

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.

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