Bioequivalence of salmeterol and fluticasone

A double-blind, randomised, single-dose, replicate, four-way, crossover bioequivalence study to demonstrate the bioequivalence of salmeterol and fluticasone from the test product Salmeterol xinafoate/fluticasone propionate HFA pressurised metered dose inhaler (pMDI) 25/250µg per actuation (Genetic S.p.A) with that from the reference Seretide Evohaler 25/250µg (containing salmeterol xinafoate/ fluticasone propionate 25/250µg per actuation; Allen & Hanburys), administered as 50/500µg (2 actuations) in healthy adult male subjects under fasting conditions.

The test product when administered using a Volumatic spacer was shown to be inequivalent to the reference product. Combisal (salmeterol/fluticasone) should not be administered using the Volumatic spacer.

In-vitro supporting data

In-vitro bioequivalence study for Salmeterol-Fluticasone propionate 25/50, 25/125 & 25/250 µg/actuation (test) versus Seretide 25/50, 25/125 & 25/250 µg/actuation (reference) using the valved holding chamber AeroChamber Plus.

The following tests were performed:

• Uniformity of delivered dose

Uniformity of delivered dose was compliant with European Pharmacopoeial requirements and equivalence was demonstrated between test and reference product.

• Aerodynamic particle size distribution

Aerodynamic particle size distribution showed that deposition of the different impactor groupings was similar between test and reference product.

In-vitro bioequivalence study for Salmeterol-Fluticasone propionate 25/50 µg, 25/125 & 25/250 µg/actuation (test) versus Seretide 25/50, 25/125 & 25/250 µg/actuation (1).

Combisal has the same qualitative and quantitative composition, including the polymorphic form of the active substances as the reference product Seretide.

The following tests were performed on three batches of test and reference product:

• Uniformity of delivered dose

Uniformity of delivered dose was compliant with European Pharmacopoeial requirements and equivalence was demonstrated between test and reference product.

• Aerodynamic particle size distribution with and without the use of AeroChamber Plus and Volumatic spacers

The deposition and fine particle mass of the test and reference were shown to be equivalent, with and without the spacers (with the spacers being used before and after cleaning).

• Spray pattern analysis

Spray patterns of the test and reference product were shown to equivalent for d_max and ovality. The sameness of spray pattern was also evaluated and shown to be similar.

The deposition and fine particle mass of the test and reference were shown to be equivalent, with and without a spacer (with the spacer being used before and after cleaning).

Conclusion

Combisal 25/50 µg, 25/125 µg and 25/250 µg per metered dose pressurised inhalation, suspension are ‘hybrid applications’. This means that they are similar to the ‘reference medicines’ containing the same active substances, already authorised in the EU, called Seretide Evohaler 25/50 µg per metered dose pressurised inhalation suspension (PL 10949/0337; Glaxo Wellcome UK Limited), Serotide Evohaler 25/125 µg per metered dose pressurised inhalation, suspension (PL 10949/0338; Glaxo Wellcome UK Limited) and Seretide Evohaler 25/250 µg per metered dose pressurised inhalation suspension (PL 10949/0339; Glaxo Wellcome UK Limited).

The equivalence of Combisal to the reference Seretide Evohaler has been conclusively demonstrated for the higher strength product (25/250µg), based on the submitted in-vivo PK studies, when used with the AeroChamber Plus spacer or without spacer. A biowaiver has been claimed for the lower strengths (25/50µg and 25/125µg) which is supported by in-vitro data.

Further details of these studies can be found in the Public Assessment Report (PAR)

Reference 1) Data on file 1010422379 v 3.0 April 2021 Combisal bioequivalence