Section 4.2 - Addition of the Following sentances / paragraphs:
“Where adequate control is not achieved within this range the dose may be increased.
Combined Therapy
When starting Depakote in patients, already on anticonvulsants, these should be tapered slowly; if clinically possible; initiation of Depakote 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 Once known enzyme inducers have been withdrawn it may be possible to maintain control on a reduced dose of Depakote. When barbiturates are being administered concomitantly and particularly if sedation is observed the dosage of barbiturate should be reduced.
When using Depakote with other psycotropics, a reduced dose may be required, (see 4.5.1 Effects of Depakote 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).”
Section 4.4 - Addition of the following paragraphs:
“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.”
“Pregnancy:. . .. Adequate counselling should be made available to all women with bipolar disorder 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).”
Section 5.1 - Addition of the following paragraph:
“- Antipsychotics , MAO inhibitors, antidepressants and benzodiazepines
. . . 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.
- 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.”
Section 4.6 - Rewording:
“Women of child-bearing potential should not be started on Depakote without specialist psychiatric advice.
Adequate counselling should be made available to all women with bipolar disorder 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 Depakote and who may become pregnant should
receive specialist psychiatric advice and the benefits of its use should be
weighed against the risks.
If pregnancy is planned, consideration should be given to cessation of
Depakote treatment, if appropriate.
When Depakote 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”)
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. 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.
Epidemiological studies have suggested an association between in-utero exposure to Depakote and a risk of developmental delay. Developmental delay has been reported in children born to mothers with epilepsy. It is not possible to differentiate what may be due to genetic, social, environmental factors, maternal epilepsy or antiepileptic treatment.
Notwithstanding those potential risks, no sudden discontinuation in the bipolar therapy should be undertaken as this may lead to an immediate relapse of the underlying symptoms.”
“- Risk associated with valproate
. . . In humans: 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%. An increased incidence of minor or major malformations including neural tube defects, craniofacial defects, malformation of the limbs, cardiovascular malformations, hypospadias and multiple anomalies involving various body systems has been reported in offspring born to mothers treated with valproate.
Some data from studies, of women with epilepsy, have suggested an association between in-utero exposure to valproate and the risk of developmental delay (frequently associated with craniofacial abnormalities), particularly of verbal IQ.
- In view of the above data
When a woman is planning pregnancy, this provides an opportunity to review the need for treatment. . . “
Section 4.8 - Addition of the following side-effects:
- Metabolic Disorders - Very Rare cases of hyponatraemia
- Renal and Urinary Disorders - Very Rare cases of enuresis have been reported
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