Problem
Amphotericin B injection is available as two different formulations:
- liposomal, for which several products exist
- Fungizone
Amphotericin B liposomal and Fungizone formulations are NOT interchangeable. Deaths have occurred due to inadvertent administration of Fungizone when the liposomal formulation was intended. Fungizone is significantly more nephrotoxic than amphotericin B liposomal formulations.
Safe doses of the amphotericin B liposomal formulation are equivalent to a fatal dose of Fungizone. For example, a daily dose of 5mg/kg liposomal amphotericin for an 80kg patient is 400mg (8 vials). If 8 vials of Fungizone are administered this this could be fatal.
Risk factors
Name similarity
The approved generic names of the two formulations are similar which may contribute to mis-selection. Furthermore, both formulations are manufactured as 50mg vials.
Some reference sources use the terms ‘originator’ or ‘conventional’ when referring to the first-to-market products of both formulations of amphotericin B. These terms should be avoided to further reduce the risk of confusion.
Historic guidance
The MHRA Drug Safety Update Parenteral amphotericin B: reminder of risk of potentially fatal adverse reaction if formulations confused was published when only three amphotericin B products were available, all with different characteristics and pharmacokinetic profiles. It advises healthcare professionals that both the complete generic name and the proprietary name should be used when prescribing, communicating and dispensing amphotericin B products.
Since the Drug Safety Update was published, a number of new and equivalent liposomal formulation products have been introduced, and the Abelcet product has been discontinued. Liposomal formulation products now use the Marketing Authorisation Holder (MAH) name within the product descriptor. This presents challenges for use in digital systems and there is a risk that using the MAH name may present confusion or distract from the word liposomal.
Healthcare professional familiarity
Because Fungizone is relatively infrequently used, frontline healthcare professionals may be unaware of its existence, or the risks associated with it.
Use of unfamiliar terminology within the product description may contribute to confusion when selecting the correct product e.g using pharmacy terms such as ‘CIVAS’ to describe how the product is prepared and supplied may not be a familiar acronym to all healthcare professionals.
Amphotericin B liposomal
Amphotericin B liposomal injection accounts for most UK use of amphotericin B and it is sometimes stocked in clinical settings to ensure timely access. All amphotericin B liposomal products are interchangeable with one another since they are bioequivalent and have the same clinical efficacy and safety profiles.
The adult daily dose of Amphotericin B liposomal is usually between 1mg/kg and 10mg/kg depending on indication.
Amphotericin B liposomal formulations all have ‘liposomal’ in the name.
Preparation and administration recommendations are product specific. Further information is available in the National Injectable Medicines Guide (NIVG)/Medusa and the summary of product characteristics (SmPCs) accessed online via the electronic medicines compendium.
Fungizone
Fungizone is only used for a small number of indications with a low volume of use overall. Fungizone is often restricted to specialist use and is not considered first line therapy. Supply should be on a named patient basis after a robust clinical verification process, unless an organisational risk assessment supports supply via ward stock.
On the rare occasions intravenous use of Fungizone is indicated, the adult daily dose is usually up to 1mg/kg/day (with a maximum of 1.5mg/kg/day).
Mitigate risks to prevent mis-selection
Put measures in place to reduce the potential for confusion and minimise the potential for accidentally selecting the wrong product. Review these measures regularly.
Stockholding
Review and rationalise stockholding. Where more than one formulation is stocked, such as in hospital pharmacies, minimise the risk of selection errors by using separate locations and visual alerts. Note that Fungizone must be stored in the fridge at 2-8C whereas amphotericin B liposomal products should be stored at room temperature.
Using purchasing for safety principles may support mitigation actions.
Nomenclature
Ensure consistent nomenclature is used in local clinical guidelines and protocols, prescribing and supply systems, and formularies.
- All liposomal products must have ‘”liposomal” within the drug name. Consideration should be given to the exclusion of the MAH name in the descriptor to increase prominence of the term ‘liposomal’
- Fungizone must appear in the drug name when that formulation is intended
Organisations should carry out a local assessment of relative risk and benefit to inform their decision about whether to follow the 2018 MHRA advice.
Digital systems
Use the functionality within digital prescribing, dispensing and supply systems to minimise the risk that users inadvertently select Fungizone. Consider visual alerts and dosing limits where appropriate.
Ensure the term ‘liposomal’ is given prominence in the generic name of liposomal formulation products and prominence to the proprietary name ‘Fungizone’ when this the product concerned. Prominence of these terms may take priority over other information such as the MAH name if that is supported.
Validation
Ensure systems only allow the supply of amphotericin B injection when the intended formulation is known and confirmed. The intended formulation must be clearly documented and communicated at the point of prescribing.
Design robust processes and systems that require additional clinical verification prior to the supply of Fungizone.
Promote awareness
Ensure healthcare professionals responsible for prescribing, supply, and administration are aware of the availability of different formulations of amphotericin B injection and the risks associated with selecting the wrong formulation.
Use pharmacy aseptic services
Consider using named patient ready to administer amphotericin B products made by pharmacy aseptic services to minimise the risk of mis-selection in clinical areas. Where this service is used, the process for prescribing and supply should use all the principles for risk mitigation described above.
Acknowledgements
SPS continues to engage with the MHRA and NHSE to understand the best approach to support these changes in practice and if changes to the nomenclature for amphotericin B injection products are possible.