Phenobarbital (phenobarbitone)

Phenobarbital sodium 200mg/ml injection: 1ml ampoules. Excipients include propylene glycol 90%.

This formulation is classified as Controlled Drug Schedule 3.

Licensed indications - all forms of epilepsy except typical absence seizures and status epilepticus.

In palliative care phenobarbital may be considered by specialist palliative care practitioners for the following:

1. Controlling seizures in patients who are unable to swallow and for whom a benzodiazepine (midazolam/clonazepam) is either ineffective or inappropriate. Unlicensed use when administered by continuous subcutaneous infusion (CSCI)†.
2. Patients with terminal agitation who have not responded to the combined use of a benzodiazepine (midazolam/ clonazepam) and an anti-psychotic (QTlevomepromazine/ QThaloperidol). Unlicensed use.

• Avoid subcutaneous bolus injections; the solution has a high pH 10 to pH 11 that can cause tissue necrosis. 
• For intravenous (IV) administration, dilute with 10 times own volume with water for injection (WFI).  
• Avoid sudden withdrawal.
• In mild/moderate renal and hepatic impairment, use lowest effective dose and monitor for adverse effects.
• Use with caution in elderly patients.

Contra-indications

• Severe hepatic and renal impairment
• Acute intermittent porphyria
• Severe respiratory depression

These are not absolute contra-indications if the patient is in the last days of life. Careful titration is however necessary.

Important drug interactions

Phenobarbital is metabolised by CYP2C19. CYP2C19 Inhibitors may enhance the effect of phenobarbital.

Examples of CYP2C19 inhibitors:

• Fluconazole
• Fluoxetine
• Omperazole
• Lansoprazole.

Phenobarbital induces various cytochrome P450 enzymes (CYP1A2, CYP2B6, CYP2C8/9, CYP2C19 and CYP3A4) that can cause many clinically significant drug interactions.  As enzyme induction may take up to two weeks to develop, dose adjustments of concurrently administered drugs, that are predominantly metabolised by the cytochrome pathway or undergo glucuronidation, may be necessary.

Phenobarbital may decrease the effect of the following (the list is not exhaustive):

Corticosteroids - (dexamethasone, methylprednisolone, prednisolone):

• QTHaloperidol
• Fentanyl
• QTMethadone
• Metronidazole
• Mirtazepine
• Oxycodone
• Phenytoin
• Tricyclics
• Valproate
• Paracetamol
• Clonazepam

Be aware of the potential for interactions: doses may need to be adjusted

Side effects

• Drowsiness, lethargy, ataxia, confusion, respiratory depression, paradoxical excitement, irritability, restlessness, delirium.
• Skin reactions - common if given by CSCI; undiluted Phenobarbital injection is very alkaline.

Terminal refractory agitation: generally third line with specialist palliative care input.

• Initial dose 200mg intramuscular (IM) (undiluted) or  intravenous (IV) (diluted with 10 times own volume) injection. If patient remains unsettled, give 1 or 2 further doses as required of 200mg IM/IV 30 minutes apart.
• Continue treatment with 400mg to 1200mg via CSCI over 24hours. Refer to Practice points below for administration guidance.
• Refer to guideline for treating agitation.

Epilepsy: Refer to guideline for treating seizures.

• Initial dose (If necessary) 100mg by IV injection, dilute 0.5ml phenobarbital 200mg/ml with 5ml WFI.
• Continue treatment with 200mg to 400mg via CSCI over 24 hours. Refer to practice points below for administration guidance.

Status epilepticus: Refer to local guidance.

• 10mg/kg by IV injection at a rate of not more than 100mg/min. Ensure dilution with 10 times own volume of WFI. Maximum dose: 1 gram.

• Specialist palliative care input essential.
• Dilute each 200mg (1ml) phenobarbital ampoule with at least 10ml WFI to minimise irritation when administering dose by subcutaneous infusion or IV injection. However doses of 1600mg or less/24 hours have been administered via CSCI diluted to 17ml with WFI or NaCl 0.9%.
• Diluent, WFI, but sodium chloride 0.9% may also be used.
• May be given undiluted by the IM route.
• Avoid SC bolus injections; CSCI usually well tolerated if diluted appropriately.
• Phenobarbital is incompatible with most drugs when mixed in CSCI. Generally best to administer via a separate CSCI or seek specialist pharmacy advice.
• This formulation is classified as Controlled Drug Schedule 3. Phenobarbital does not legally require safe custody in a locked cabinet or a record to be kept in the Controlled Drug (CD) register.
• CD prescription requirements apply. 

Patient and carer advice point

Report any signs of skin reactions.