Managing the risks of using liquid oral phenobarbital

Patient harm

Safety concerns related to phenobarbital oral liquid formulations are system-wide and errors have the potential to cause harm in all patients who are prescribed phenobarbital, but particularly neonates and children.

Confusion between different concentrations of phenobarbital liquid preparations can result in administration of doses that are either higher or lower than intended.

• Lower doses may result in increased seizure activity
• Higher doses may lead to gastro-intestinal disturbances, sedative effects, and respiratory depression

Failure to consider the ethanol (alcohol) content of phenobarbital oral liquid formulations could lead to excessive ethanol exposure, especially in young children with immature metabolic capacity.

High risk scenarios

Use of phenobarbital oral liquid is associated with higher risk in neonatal and paediatric patients, where there is potential for inadvertent selection of an ethanol-containing formulation during prescribing, dispensing or supply processes.

Electronic prescribing and dispensing systems that have multiple phenobarbital oral liquid formulations and strengths available may increase the risk of product mis-selection.

Supply shortages or stock unavailability may necessitate use of an alternative formulation. Without adequate planning and communication, temporary product changes may be continued unintentionally, after the usual formulation becomes available.

Available formulations

The large number of phenobarbital oral liquid formulations available on the NHS Business Services Authority (NHSBSA) dictionary of medicines and devices (dm+d) increases the risk of accidental selection of the wrong product.

Phenobarbital is also available in tablet and injectable formulations.

Ethanol-free products

Phenobarbital Colonis 50 mg/5 mL oral suspension is the only licensed ethanol-free phenobarbital liquid available in the UK.

It contains 0.5 mg/mL of sodium benzoate. The Neonatal and Paediatric Pharmacists Group (NPPG) position statement ‘Choosing an oral liquid medicine for children’ advises that the acceptable daily intake of benzoates in children is up to 5 mg/kg/day. They advise that additional caution is required in children under 3 years due to a higher risk of accumulation, and in neonates and patients with known unconjugated hyperbilirubinaemia.

There are also unlicensed ethanol-free phenobarbital oral liquid preparations available in different strengths and formulations.

Unlicensed formulations should only be used if there is a special clinical need. The use of unlicensed medicines may increase the likelihood of error and should be limited to situations where no suitable licensed alternative is available.

See the following Specialist Pharmacy Service (SPS) pages for advice relating to understanding, using and purchasing unlicensed medicines:

• Explaining the licensed status of medicines (SPS page)
• Using unlicensed medicines (SPS page)
• Purchasing for safety (SPS page)

Ethanol-containing products

Phenobarbital Elixir BP 15 mg/5 mL contains 32.05% w/v of ethanol. There is potential for accumulation of ethanol when ingested repeatedly, especially in young children.  This product is not suitable for use in children.

Clinical use

Liquid formulations of phenobarbital are used as an anticonvulsant in the treatment of all forms of epilepsy except absence seizures.

Children

The NPPG and the Royal College of Paediatrics and Child Health (RCPCH) recommend phenobarbital (ethanol-free) 50mg/5mL as the standard concentration that should be used in children.

Switching formulations

The Medicines and Healthcare Products Regulatory Agency (MHRA) advises that, as a category 1 antiepileptic medicine, patients prescribed phenobarbital should be maintained on a specific manufacturer’s product.

Historically, only unlicensed formulations of ethanol-free phenobarbital oral liquids were available, which has led to a large patient population established on unlicensed formulations.

Due to potential differences in bioavailability of different products, switching patients to the licensed formulation requires a co-ordinated system-wide approach. It may be beneficial to contact specialists for advice.

Risks

Multiple formulations and strengths within prescribing, stockholding and dispensing systems may lead to inadvertent selection of a different formulation than intended.

Many neonatal and paediatric patients remain established on unlicensed phenobarbital oral liquid preparations. Continued use of these products, despite the availability of a licensed alternative, may increase the risk of medication errors and unintended product switching.

Stockholding a range of preparations, due to the clinical need for patients to be maintained on a consistent formulation, increases the risk of confusion and inadvertent selection of an incorrect formulation.

Failure to adequately communicate information relating to the specific formulation and dose supplied at discharge, and subsequent prescribing requirements following transfer of care, may lead to inadvertent product switches.

Failure to consider that a formulation contains ethanol may result in unintended exposure to ethanol following prescribing, dispensing, or administration of an alternative formulation.

There may be a lack of awareness of potential harms associated with exposure to higher than recommended levels of ethanol, when using products with a high volume of ethanol.

Poor communication and documentation failures at transfer of care may result in unintended switches in formulation or strength.

Mitigation

Opportunities exist to minimise potential harm from an inadvertent formulation switch or supply of a clinically incorrect formulation of phenobarbital oral liquid.

Standardise processes and formularies

Establish a system-wide management plan for the safe switching of formulations for patients established on unlicensed formulations of oral liquid phenobarbital to the licensed version where clinically appropriate.

Review and update local and regional clinical guidelines, protocols and formularies to ensure the licensed phenobarbital 50 mg/5 mL oral liquid (ethanol-free) is the preferred formulation in neonatal and paediatric patients, where clinically appropriate. System-wide alignment will reduce the need for local stockholding of multiple formulations.

Ensure medicines reconciliation processes include documentation of the specific phenobarbital oral liquid formulation an individual takes, including if the formulation contains ethanol or not.

Digital systems

Utilise digital functionality on prescribing systems to support correct product selection.

Configure prescribing and dispensing systems to clearly differentiate ethanol-free and ethanol-containing formulations through specific descriptors, alerts and labelling. This should include highlighting ‘ethanol-containing product’ and ‘unsuitable for children’ when relevant on dispensing labels.

Awareness and knowledge

Ensure healthcare professionals are aware of the risks of selecting the wrong formulation of phenobarbital oral liquid and potential harm of unintentionally selecting an ethanol-containing formulation.

Ensure that healthcare professionals are aware that any ambiguity of the prescription in relation to the intended formulation needs to be escalated and the correct formulation ascertained prior to supply. The patient or caregiver should be consulted where possible to confirm the intended formulation.

Ensure the patient or caregiver is made aware of the specific formulation that is intended for their use. They should also be informed that a switch in formulation is not expected without discussion and direction from a healthcare professional, and the reasons why.

Documentation and communication

Ensure there is clear documentation and communication of the specific phenobarbital oral liquid formulation at prescribing and during all transfers of care.

Handling and storage

Limit local stockholding to the minimum number of formulations necessary to meet clinical need.

Ensure physical segregation of different strengths and ethanol-containing and ethanol-free phenobarbital oral liquids (if available locally) to minimise the risk of selection errors.

Consider applying clear descriptor labels to the physical storage space, for example, ‘ethanol-containing’ and ‘unsuitable for use in children’ to support safe selection.

Review guidance with our series of articles Preventing errors on the medicine journey (SPS page) to identify opportunities to prevent mis-selection.

Further resources

The NHSBSA Children’s Standard Liquid Concentration dashboard can help healthcare professionals working in primary care to determine the extent to which phenobarbital oral liquid products prescribed for patients under the age of 18 follow the nationally recommended concentration. Prescribers, prescribing advisors and other members of the team can identify patients on non-standard concentrations and those prescribed unlicensed formulations and review them. This will help to switch to the most clinically safe product where appropriate.

Acknowledgments

Information on prevalent risks associated with phenobarbital liquid was provided by the Patient Safety Team at NHS England.

Thanks to the Neonatal and Paediatric Pharmacists Group (NPPG) and the Patient Safety team at NHS England for their contributions.

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