Amphotericin B products available

Amphotericin B is available as a liposomal formulation (i.e. lipid-based).  The original brand was called AmBisome but after a name change, it is now known as Amphotericin B Gilead Liposomal.  The generic liposomal amphotericin B is called Amphotericin B Tillomed Liposomal.

Amphotericin B also remains available as the conventional, non-liposomal formulation (i.e. non-lipid-based), known as the brand Fungizone.

Amphotericin B Liposomal

For both liposomal products, each vial contains 50mg of the active substance amphotericin B (50,000 units) encapsulated in liposomes.  After reconstitution, the concentrate contains 4mg/ml amphotericin B.

Original Amphotericin B Gilead Liposomal, previously known as the brand AmBisome

• Amphotericin B Gilead Liposomal 50mg powder for dispersion for infusion

Generic Amphotericin B Tillomed Liposomal

• Amphotericin B Tillomed Liposomal 50mg powder for dispersion for infusion

Safety considerations for liposomal and non-liposomal formulations

Conventional amphotericin B (Fungizone) has more toxicity (especially nephrotoxicity) than liposomal formulations of amphotericin B. The dosage is significantly different.

Patient harm, including fatalities, have been reported following inadvertent administration of conventional amphotericin B infusion (i.e. Fungizone) instead of an intended liposomal formulation (such as Amphotericin B Gilead Liposomal [previously AmBisome] or Amphotericin B Tillomed Liposomal).  Safety mitigation strategies must be implemented to prevent this risk.

Interchangeability between formulations

Interchangeability of liposomal amphotericin B

Amphotericin B Gilead Liposomal (previously AmBisome) and Amphotericin B Tillomed Liposomal can be used interchangeably.  Note the difference in shelf life.

Bioequivalence between brand and generic liposomal formulations

The clinical efficacy and safety profile of the brand and generic liposomal amphotericin B are the same.  Based on the MHRA’s evaluation of qualitative and quantitative sameness, manufacturing process, physico-chemical comparison, different characterisation studies, non-clinical studies and human pharmacokinetic study, it was concluded that the generic Tillomed product is equivalent to the reference Gilead product (previously AmBisome). There are no differences in the contraindications for use, special warnings and precautions, recommended monitoring, drug interactions or adverse effects.

Bioequivalence study results

An open-label, randomised, crossover, single dose bioequivalence study compared Amphotericin B Tillomed Liposomal (test drug) and AmBisome Liposomal amphotericin B (reference drug) powders for solution for infusion in normal, healthy, adult, human subjects.  Blood samples were taken pre-dose and up to 84 hours post dose. The study had 99.97 to 100% power to detect differences in bioavailability. The test/reference drug ratios for area under the curve and their 90% confidence intervals were within the specified limits of 80% to 125% to demonstrate bioequivalence.

Non-interchangeability of liposomal and non-liposomal amphotericin B

Liposomal (e.g. Amphotericin B Gilead Liposomal, previously AmBisome, and Amphotericin B Tillomed Liposomal) and non-liposomal amphotericin B (e.g. Fungizone) are not interchangeable.  There are differences in pharmacokinetics and dosing which can result in overdose and fatality with inadvertent administration.

Differences between brand and generic liposomal formulations

The Summaries of Product Characteristics for Amphotericin B Gilead Liposomal (previously AmBisome) and Amphotericin B Tillomed Liposomal are the same with the exception of differences between the shelf lives of the products.

There are no differences in the indications, dosing schedules, contraindications and warnings, methods of administration, excipients, adverse effects, interactions or other clinical characteristics.

Shelf life and storage

Amphotericin B Gilead Liposomal (previously AmBisome): 4 years

Amphotericin B Tillomed Liposomal: 3 years

There are also some differences in the shelf life after dilution with Dextrose solution. See the summary of product characteristics for these details.

Both products have the same recommendations for storage.

Mitigating against confusion of products

Due to the risk of serious harm following confusion between liposomal formulations and non-liposomal formulations a clear distinction between products is essential. The MHRA recommend prescribing using the proprietary name and common name and specifically to include ‘liposomal’ within the name.

For example:

• Amphotericin B Gilead Liposomal (previously AmBisome)
• Amphotericin B Tillomed Liposomal

Ensure clear differentiation in prescribing systems and pharmacy stock of liposomal formulations and non-liposomal (conventional, non-lipid) formulations, i.e. Fungizone.

Ensure local clinical guidelines/protocols, prescribing systems and formularies are consistent in the nomenclature used for all amphotericin B products, with both the complete generic name and proprietary name used.

Utilise electronic functionality to ensure electronic prescribing, dispensing and supply systems are set up to support users in choosing the correct product.

Review and rationalise stock-holding of amphotericin B to minimise the potential for selecting the incorrect product.

Promote awareness among healthcare professionals responsible for the prescribing, supply and administration of amphotericin B of the availability of different formulations.  Highlight the risk of confusion between a non-liposomal formulation and liposomal formulations and the differences in dosing between the formulations (the recommended dose for non-liposomal amphotericin B (Fungizone) should not exceed 1.5mg/kg).

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