Phenytoin


  Issues for Surgery


Precipitation of rebound seizures or status epilepticus if omitted.


  Advice in the Perioperative period


Elective and Emergency Surgery

Continue.

Patients should be advised to take their regular medications on the day of surgery1, 2, 3.

Abrupt withdrawal of any anticonvulsant drug should be avoided1.

Ensure that the patient is 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-operatively2, 3.

If patients are unable to take their regular oral medication post-operatively, consider using the intravenous route – see Important Information below.


IMPORTANT INFORMATION

Intravenous Phenytoin
Intravenous phenytoin is error-prone throughout the prescribing, preparation, administration and monitoring process; all relevant staff should be made aware of appropriate guidance on the safe use of injectable phenytoin to reduce the risk of error1. Due to its narrow therapeutic index, it is recommended to monitor plasma-phenytoin concentrations. Refer to local guidance and seek specialist advice where necessary.

Dose Equivalence and Conversion
Preparations containing phenytoin sodium are NOT bioequivalent to those containing phenytoin base. If switching between products the difference in phenytoin content may be clincally significant. Care is needed when making these changes and plasma-phenytoin concentration monitoring is recommended1. Seek specialist advice where necessary.


  Interaction(s) with Common Anaesthetic Agents


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

Phenytoin metabolism is saturable: toxic concentrations of phenytoin can develop in patients given drugs that inhibit phenytoin metabolism even to a small degree4, 5. Phenytoin itself is also a potent enzyme inducer, and induces the metabolism of many drugs4, 5. 

Neuromuscular Blocking Drugs (NMBDs)

The recovery time from atracurium, cisatracurium, pancuronium and rocuronium appears to be reduced in those taking phenytoin long-term (more than 1 week) – anticipate the need to use a larger dose of NMBD, and expect an accelerated recovery1, 5, 6, 7. However, acute use of phenytoin can increase the effects of these drugs1.

Phenytoin increases the effects of suxamethonium1, 6, 8. Monitor the outcome with concurrent use – expecting an alteration in recovery time6.

Alfentanil / Fentanyl

Phenytoin is predicted to decrease the exposure to alfentanil/fentanyl1, 6. Monitor concurrent use for alfentanil / fentanyl efficacy and increase the dose of opioid as appropriate6.

Benzodiazepines

Benzodiazepines potentially affect the concentration of phenytoin (toxicity has been seen) – monitor concentration and adjust dose1, 4, 5. Phenytoin (after long-term use) might reduce benzodiazepine concentrations as a result of induction of hepatic drug-metabolising enzymes4, 6. Monitor for reduced efficacy of benzodiazepines and phenytoin toxicity; consider monitoring phenytoin concentrations. Additive central nervous system (CNS) adverse effects (e.g. sedation) might occur6.

Esketamine

Phenytoin is predicted to decrease the exposure to esketamine – monitor and increase the dose of esketamine as appropriate1, 6.

Local Anaesthetics

Phenytoin is predicted to decrease the exposure to IV lidocaine / ropivacaine1, 6. The clinical relevance of reduced lidocaine levels is most likely to be small6. The incidence of central toxic adverse effects may be increased if lidocaine is used concomitantly with phenytoin. Sinoatrial arrest has been reported in one patient – caution is needed when giving two drugs that have cardiac depressant effects4, 6.

The manufacturers suggest that the effects of topical prilocaine and lidocaine may be additive with drugs that can cause methaemoglobinaemia, they name phenytoin. Caution is warranted6.


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


Corticosteroids

Phenytoin greatly reduces the concentrations and effects of dexamethasone and, to a lesser extent hydrocortisone1, 3, 4. Monitor concurrent use, increasing the corticosteroid dose accordingly6. Consider giving an alternative corticosteroid if problems arise6.

Opioids

Phenytoin is predicted to decrease the exposure to buprenorphine and oxycodone – monitor and increase the opioid dose as necessary1, 6.

Phenytoin increases the production of the toxic metabolite of pethidine. Limited evidence suggests that phenytoin induces metabolism of pethidine and could decrease its analgesic efficacy. Bear the possibility of this interaction in mind6.

Antimicrobials

Ciprofloxacin affects the concentration of phenytoin, although the clinical relevance is not thought to be significant1, 5, 6. Bear this interaction in mind in the case of unexpected response to treatment; consider monitoring phenytoin concentrations6. However, quinolones very occasionally cause convulsions and should generally be avoided in patients with epilepsy6.

Phenytoin decreases exposure to doxycyline1, 4, 5, 6. It has been suggested that the doxycycline dose should be doubled6.

Both phenytoin and metronidazole can increase the risk of peripheral neuropathy1. There have been a few anecdotal reports of patients who have developed toxic phenytoin concentrations when given metronidazole. Monitor for signs of phenytoin toxicity (such as blurred vision, nystagmus, ataxia, or drowsiness)6.

Phenytoin serum concentrations can be increased by co-trimoxazole (contains sulfamethoxazole). Monitor phenytoin concentrations and adjust the dose accordingly4, 5, 6.

Whilst single surgical prophylactic doses should not pose a problem, continued post-operative treatment may require close monitoring. Consult current product literature.

Antiemetics

Bear in mind a potential interaction between phenytoin and prochlorperazine – there has been a single report that prochlorperazine has been noted to impair phenytoin metabolism. Monitor for unexpected response to treatment6. However, see Antiepileptics – A General Overview for advice regarding the use of phenothiazine antiemetics in patients with a history of seizures.

Phenytoin is predicted to decrease the exposure to ondansetron1. Be aware that ondansetron might be less effective6.

Paracetamol

Phenytoin decreases the exposure to paracetamol via increased metabolism. Consider an interaction as a possible cause of any reduction in paracetamol efficacy1, 6.


  Further Information


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

Phenytoin is a category 1 antiepileptic and patients should be maintained on a specific manufacturer’s product1. (For more information see Antiepileptics – A General Overview).


  References


  1. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press http://www.medicinescomplete.com [Accessed 30th June 2019]
  2. Perks A, Cheema S, Mohanraj R. Anaesthesia and epilepsy. BJA: British Journal of Anaesthesia. 2012; 108(4):562-571
  3. Carter EL, Adapa RM. Adult epilepsy and anaesthesia. BJA Education. 2015; 15(3):111-117
  4. Phenytoin. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 30th June 2019]
  5. Summary of Product Characteristics – Phenytoin 100mg film-coated tablets. Aurobindo Pharma – Milpharm Ltd. Accessed via www.medicines.org.uk 06/07/2019 [date of revision of the text June 2019]
  6. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 30th June 2019]
  7. Atracurium. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 30th June 2019]
  8. Suxamethonium. In: Brayfield A (Ed), Martindale: The Complete Drug Reference. London: The Royal Pharmaceutical Society of Great Britain. http://www.medicinescomplete.com [Accessed 30th June 2019]