Revised SPCs: Epilim (sodium valproate) products

SPS commentary:

In November 2023, the MHRA issued a National Patient Safety Alert asking organisations to put a plan in place to implement new regulatory measures for valproate/valproic acid preparations, following a comprehensive review of safety data and advice from CHM.

The SPC now notes that valproate should not be prescribed in female children and women of childbearing potential aged under 55 years unless two specialists independently consider and document that there is no other effective or tolerated treatment. Where possible, existing female children and women of childbearing potential aged under 55 years should be switched to another treatment unless two specialists independently consider and document there is no other effective or tolerated treatment.

No new male children or men aged under 55 years should be initiated on valproate unless two specialists independently consider and document that there is no other effective or tolerated treatment or the risk of infertility or potential risk of testicular toxicity are not applicable. The specialist should discuss and complete the risk acknowledgement form with the patient and/or carer at initiation to ensure all male children and men aged under 55 years are aware of the risk of infertility in males and of the data available showing testicular toxicity in animals exposed to valproate and the uncertain clinical relevance.

The SPC has been updated throughout to note that the risk of neuro-developmental disorders in children exposed to valproate in utero may lead to permanent disability.

Other changes to the SPC include the following:

• Further information on testicular toxicity has been added.
  
  
• Use of sodium valproate is now contraindicated in those with uncorrected systemic primary carnitine deficiency. Further information on those at risk of hypocarnitinaemia (including those with mitochondrial disorders) is included.
  
  
• Information has been added on concomitant use with other medicines that increases the risk of liver damage (e.g. cannabidiol; multiple anticonvulsant therapy; salicylates [should be avoided in those <3 years of age]).

• Upon changes in concomitant medicinal products (dose increase or additions) that are known to impact the liver, liver monitoring should be restarted as appropriate.
  
  
• Concomitant use of valproate and pivalate-conjugated medicines (e.g. such as cefditoren pivoxil, adefovir dipivoxil, pivmecillinam and pivampicillin) should be avoided due to increased risk of carnitine depletion.

• Some case reports describe a significant decrease in valproate serum levels after methotrexate administration, with occurrence of seizures. Prescribers should monitor clinical response (seizure control) and consider monitoring valproate serum levels as appropriate.

The risk minimisation materials have been updated and an interactive male risk acknowledgement form, which should be completed by men under 55 years with their specialist when starting valproate, is now available.