Amphotericin B products available

Amphotericin B is available as a liposomal formulation (i.e. lipid-based), with the original brand called AmBisome Liposomal amphotericin B and the generic called Amphotericin B Tillomed Liposomal. It is also available as the conventional, non-liposomal formulation (i.e. non-lipid-based), known as the brand Fungizone.

Liposomal amphotericin B

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.

Brand Ambisome Liposomal amphotericin B

• AmBisome Liposomal amphotericin B 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 AmBisome Liposomal amphotericin B or Amphotericin B Tillomed Liposomal).  Safety mitigation strategies must be implemented to prevent this risk.

Interchangeability between formulations

Interchangeability of liposomal amphotericin B

AmBisome Liposomal amphotericin B and Amphotericin B Tillomed Liposomal can be used interchangeably.  Take into account some of the key differences in licensed doses, including recommendation for a test dose, and 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 product, 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. AmBisome Liposomal amphotericin B 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.

Key differences between brand and generic liposomal formulations

Licensed indications for the brand and generic liposomal formulations are the same, however there are other key differences.

Dosing schedules

There are some key differences in the doses provided for the treatment regimens of the licensed indications: mycoses, mucormycosis and empirical treatment of febrile neutropenia.

Mycoses

• AmBisome Liposomal amphotericin B: 3 to 5mg/kg/day for a minimum of 14 days.
• Amphotericin B Tillomed Liposomal: 1mg/kg/day, increasing stepwise to 3mg/kg/day, usually for 3 to 4 weeks.

Mucormycosis

• AmBisome Liposomal amphotericin B: 5 to 10mg/kg/day. In patients with brain involvement or solid-organ transplant, dose at 10mg/kg/day. Avoid slow escalation of doses.
• Amphotericin B Tillomed Liposomal: 5mg/kg/day starting dose.

For both products the duration of therapy should be determined on an individual basis.

Empirical treatment of febrile neutropenia

• AmBisome Liposomal amphotericin B: 3 to 5 mg/kg/day
• Amphotericin B Tillomed Liposomal: 3mg/kg/day

For both products, treatment is continued until temperature normalised for 3 consecutive days (up to a maximum of 42 days).

HIV associated cryptococcal meningitis

Both products have successfully treated cryptococcal meningitis but only AmBisome Liposomal amphotericin B provides a dosing regimen for cryptococcal meningitis associated with HIV.

AmBisome Liposomal amphotericin B: Single dose 10mg/kg on day one only, in combination with daily flucytosine 100mg/kg and daily fluconazole 1200mg for 14 days. Then fluconazole 800mg daily for 8 weeks, then 200mg daily thereafter for as long as clinically needed.

Visceral Leishmaniasis

Both products have the same recommended dose

Method of administration

Both liposomal products have the same recommendations for the method of administration including the use of a filter.  The only difference is the recommendation for a test dose with Amphotericin B Tillomed Liposomal.  The NPSA product risk assessment report shows Amphotericin B is a high risk product for safety of administration.

Test dose

Liposomal amphotericin B can cause anaphylaxis and anaphylactoid reactions which can occur at any point of treatment.

Amphotericin B Tillomed Liposomal currently recommend a test dose is given before a new course of treatment.  A small amount of the infusion (e.g. 1mg) can be administered for about 10 minutes and then stopped and the patient observed carefully for the next 30 minutes.  The infusion is continued if there have been no severe allergic reactions.

As these reactions can occur at any time, AmBisome Liposomal amphotericin B does not have a recommendation for a test dose and advises the patient is monitored closely.

Excipients

The brand and generic liposomal formulations contain the same list of excipients:

• Hydrogenated soy phosphatidylcholine
• Cholesterol
• Distearoylphosphatidylglycerol
• Alpha tocopherol
• Sucrose (900mg per vial)
• Disodium succinate hexahydrate
• Sodium hydroxide (for pH adjustment)
• Hydrochloric acid (for pH adjustment)

Shelf life and storage

AmBisome Liposomal amphotericin B: 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:

• Liposomal amphotericin B (AmBisome) or AmBisome Liposomal amphotericin B
• 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).