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Effects of other drugs on Valproate
Antiepileptics with enzyme inducing effect (including phenytoin, phenobarbital, and carbamazepine) decrease valproic acid serum concentrations. Dosages should be adjusted according to blood levels in case of combined therapy.
On the other hand, combination of felbamate and valproate may increase valproate serum concentration. Valproate 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 valproate and highly protein bound agents (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 and meropenem: Decrease in valproic acid blood level, sometimes associated with convulsion, has been observed when imipenem or meropenem were combined. If these antibiotics have to be administered, close monitoring of valproic acid levels is recommended.
Cholestyramine may decrease the absorption of valproate.
Other interactions
Caution is advised when using Epilim in combination with newer anti-epileptics whose pharmacodynamics may not be well established.
Valproate usually has no enzyme-inducing effect; as a consequence, valproate does not reduce efficacy of oestroprogestative agents in women receiving hormonal contraception, including the oral contraceptive pill.
Pregnancy and lactation
Pregnancy
From experience in treating mothers with epilepsy, the risk associated with the use of valproate during pregnancy has been described as follows:
Risk associated with epilepsy and antiepileptics
In offspring born to mothers with epilepsy receiving any antiepileptic treatment, the overall rate of malformations has been demonstrated to be 2 to 3 times higher than the rate (approximately 3%) reported in the general population. Although an increased number of children with malformations have been reported in case of multiple drug therapy, the respective role of treatments and disease in causing the malformation has not been formally established. Malformations most frequently encountered are labial clefts and cardiovascular malformations.
Epidemiological studies have suggested an association between in-utero exposure to sodium valproate and a risk developmental delay. Many factors including maternal epilepsy may also contribute to this risk but it is difficult to quantity the relative contributions of these or of maternal anti-epileptic treatment. Notwithstanding those potential risks, 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.
Risk associated with valproate
In animals: teratogenic effects have been demonstrated in the mouse, rat and rabbit. There is animal experimental evidence that high plasma peak levels and the size of an individual dose are associated with neural tube defects.
In humans: an increased incidence of congenital abnormalities (including cases of facial dysmorphia, hypospadias and multiple malformations, particularly of the limbs) has been demonstrated in offspring born to mothers with epilepsy treated with valproate.
Valproate use is associated with neural tube defects such as myelomeningocele and spina bifida. The frequency of this effect is estimated to be 1 to 2%.
In view of the above data
When a women is planning pregnancy, this provides an opportunity to review the need for anti-epileptic treatment. Women of childbearing age should be informed of the risks and benefits of continuing anti-epileptic treatment throughout pregnancy.
Folate supplementation, prior to pregnancy, has been demonstrated to reduce the incidence of neural tube defects in the offspring of women of high risk. Although no direct evidence exists of such effects in woman receiving anti-epileptic drugs, woman should be advised to start taking folic acid supplementation (5mg) as soon as contraception is discontinued. The available evidence suggests that anticonvulsant monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose.
The incidence of neural tube defect rises with increasing dosage, particularly above 1000mg daily. The administration in several divided doses over the day and the use of prolonged release formulation is preferable in order to avoid high peak plasma levels.
During pregnancy, valproate anti-epileptic treatment should not he discontinued if it has been effective. Nevertheless, specialized prenatal monitoring should be instituted in order to detect the possible occurrence of a neural tube detect or any other malformation. Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate (see Special warning and special precaution for use).
Risk in the neonate
Very rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken valproate during pregnancy. This haemorrhagic syndrome is related to hypofibrinogenemia; afibrinogenernia has also been reported and may be fatal. These are possibly associated with a decrease of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbitone and other anti-epileptic enzyme inducing drugs.
Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.
Lactation
Excretion of valproate in breast milk is low, with a concentration between 1% to 10% of total maternal serum levels; up to now children breast fed that have been monitored during the neonatal period have not experienced clinical effects. There appears to be no contraindication to breast feeding by patients on valproate.
Effects on ability to drive and to use machines
Use of Epilim may provide seizure control such that the patient may be eligible to hold a driving license. Patients should be warned of the risk of transient drowsiness, especially in cases of anticonvulsant polytherapy or association with benzodiazepines (see Interactions with other medicaments and other loans of interactions).
Undesirable effects
Congenital and familial/genetic disorders. (see Pregnancy and lactation)
Hepato-biliary disorders: rare cases of liver dysfunction (see Warnings) Severe
liver damage, including hepatic failure sometimes resulting in death, has been reported (see Dosage and method of administration, Contraindications and Special warnings). Increased liver enzymes are common, particularly early in treatment, and may be transient (see Special warnings).
Gastrointestinal disorders (nausea, gastralgin, diarrhoea) frequently occur at the start of treatment. These problems can usually be overcome by taking Epilim with or after food or by using Enteric Coated Epilim. Very rare case of pancreatitis, sometimes lethal, have been reported (See Special warnings and special precaution for use).
Nervous system disorder:
Sedation has been reported occasionally, usually when in combination with other anticonvulsants. In monotherapy it occurred early in treatment on rare occasions and is usually transient. Rare cases of lethargy and confusion occasionally progressing to stupor, sometimes with associated hallucinations or convulsions have been reported. Encephalopathy and coma have very rarely been observed. These cases have often been associated with too high a starting dose or too rapid a dose escalation of concomitant use of other anticonvulsants, notably phenobarbitone. They have usually been reversible on withdrawal of treatment or reduction of dosage.
Very rare cases of reversible extrapyramidal symptoms including parkinsonism, or reversible dementia associated with reversible cerebral atrophy have been reported. Dose-related ataxia and fine postural tremor have occasionally been reported.
An increase in alertness may occur; this is generally beneficial but occasionally aggression, hyperactivity and behavioural deterioration have been reported.
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