Valproate


 

Sodium Valproate, Valproic Acid [as Semisodium Salt]

  Issues for Surgery


For treatment of epilepsy – precipitation of rebound seizures or status epilepticus if omitted.

For treatment of manic episodes associated with bipolar disorder – risk of mania if omitted.

For migraine prophylaxis [unlicensed] – risk of acute migraine attack if omitted.


  Advice in the Perioperative period


Elective and Emergency Surgery


Continue.  

Check full blood count and ensure no undue potential for bleeding pre-operatively1, 2, 3 (see Further Information).

Epilepsy
Patients should be advised to take their regular medications on the day of surgery1, 4, 5.

Abrupt withdrawal of any anticonvulsant drug should be avoided1.

Confirm with the patient if they need to be maintained on a specific manufacturer’s product (see Further Information).

Mania
Confirm with the patient if they need to be maintained on a specific manufacturer’s product (see Further Information).

Post-operative Advice

Regular dosing of the patient’s usual oral medication should be re-established as early as possible post-operatively4, 5.

If it is anticipated that patients will be immobilised for a prolonged period post-operatively, consider commencing vitamin D supplementation1 (see Further Information).

Sodium Valproate
If patients are unable to take their regular oral medication post-operatively, consider using the intravenous route. The intravenous dose and frequency should be the same as the established oral dose1.

Valproic Acid 
Valproic acid is only available as oral preparations. If patient cannot resume their usual oral medication post-operatively, the advice of a Neurologist/ Psychiatrist should be sought to determine the most appropriate antiepileptic / anti-manic preparation, dose, route and frequency to be used.


  Interaction(s) with Common Anaesthetic Agents


For general information regarding the use of anaesthetic agents in patients with epilepsy – see Antiepileptics – A General Overview.

Propofol

Cautious dosing of propofol is advised as valproate potentially increases the concentration of propofol in the plasma2, 6, 7

Benzodiazepines

Sodium valproate has been reported to displace diazepam from plasma-protein binding sites leading to increased diazepam concentrations and increased sedative effects7, 8. Use of valproate semisodium with lorazepam has resulted in raised concentrations of lorazepam due to inhibition of glucuronidation of lorazepam leading to a possible increase in sedative effects7, 8. This interaction may occur with other benzodiazepines2, 7.


  Interaction(s) with other Common Medicines used in the Perioperative Period


For general information regarding the use of antiemetics in patients with epilepsy – see ‘Antiepileptics – A General Overview.

Antimicrobials

Carbapenems
Dramatic decreases in plasma concentrations of valproate to subtherapeutic levels (and sometimes with loss of seizure control) have been noted in patients during concomitant treatment with ertapenem, imipenem, or meropenem1, 2, 3, 6, 7. The MHRA advises that given the rapid and substantial decrease in valproate concentrations, neither monitoring of sodium valproate concentrations nor making dose adjustment is likely to be of benefit6, 9. Therefore, the use of carbapenems with valproic acid or sodium valproate should be avoided1, 2, 3, 6, 7.

Clarithromycin
Clarithromycin might increase the exposure to valproate – the UK manufacturer of clarithromycin advises monitoring the plasma concentration of valproate on concurrent use7.

Hepatotoxicity
Concomitant use of valproate with clavulanic acid (found in co-amoxiclav), doxycycline, flucloxacillin or tigecycline can increase the risk of hepatotoxicity1.

With the exception of carbapenems (see above), whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring. Consult current product literature.

Analgesics

Salicylates (e.g. aspirin) should not be used concomitantly with valproate since they use the same metabolic pathway2, 3.

Concomitant use of valproate and paracetamol may increase the risk of hepatotoxicity1.


  Further Information


MHRA/CHM Advice: Antiepileptic Drugs: updated advice on switching between different manufacturer’s products (November 2017)1

Epilepsy 
Valproate is a category 2 antiepileptic, hence the need for continued supply of a particular manufacturer’s product should be based on clinical judgement and consultation with the patient and / or carer taking into account factors such as seizure frequency and treatment history. (For more information see Antiepileptics – A General Overview).

Other Indications
NICE has advised that generic switching of valproate preparations is not normally recommended due to the clinical implications of possible variations in plasma concentrations1.

Prescribing 

To ensure the correct medication is prescribed for the patient's condition, care must be taken not to confuse Depakote® with Epilim® or sodium valproate. Patients with bipolar disorder and epilepsy are distinct populations. These differences are reflected in the patient information leaflets, which clearly indicate specific indications for these differing medications1.

Monitoring

Plasma-valproate concentrations are not a useful index of efficacy; therefore, routine monitoring is unhelpful and not recommended1.

Liver Toxicity

Liver dysfunction (including fatal hepatic failure) has occurred in association with valproate, usually within the first 6 months of treatment and usually involving multiple antiepileptic therapy. Raised liver enzymes are common and usually transient but patients should be reassessed clinically and liver function (including prothrombin time) monitored until return to normal. Discontinue if abnormally prolonged prothrombin time (particularly in association with other relevant abnormalities e.g. significant decrease in fibrinogen and coagulation factors; increased bilirubin level and raised transaminases)1, 2, 3 – seek advice from Neurologist / Psychiatrist on alternative treatment plan.

Musculoskeletal Disorders

Rarely, valproate treatment has been associated with a decrease in bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy. The mechanism by which valproate affects bone metabolism has not been identified1, 2, 3.

 

  References


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed on 7th July 2019]
  2. Summary of Product Characteristics – Epilim Chrono® (valproic acid, sodium valproate) 500mg. SANOFI. Accessed via www.medicines.org.uk 07/07/2019 [date of revision of the text December 2018]
  3. Summary of Product Characteristics – Depakote® (valproate semisodium) 500mg Tablets. SANOFI. Accessed via www.medicines.org.uk 07/07/2019 [date of revision of the text December 2018]
  4. Perks A, Cheema S, Mohanraj R. Anaesthesia and epilepsy. 2012; 108(4):562-571
  5. Carter EL, Adapa RM. Adult epilepsy and anaesthesia. BJA Education. 2015; 15(3):111-117
  6. Valproate. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 7th July 2019]
  7. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 7th July 2019]
  8. Diazepam. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 7th July 2019]
  9. MHRA Drug Safety Update. Carbapenems: concomitant use with valproic acid not recommended. Volume 3, Issue 10, May 2010. Accessed via www.gov.uk 07/07/2019