The licence and supporting evidence for tocilizumab biosimilar

Licensed indications

Tocilizumab biosimilars, Tyenne and Avtozma, have the same licensed indications, for each formulation, as the reference product RoActemra. Refer to the individual summary of medicinal product characteristics for further information.

If tocilizumab is currently used for an unlicensed or off-label indication, then it will still be unlicensed or off-label if biosimilar tocilizumab is used instead.

Preparing to use tocilizumab biosimilar (SPS page) provides links to commissioning statements for unlicensed uses of tocilizumab. 

Evidence supporting safety and efficacy

The clinical efficacy, safety profile and immunogenicity of tocilizumab biosimilars and the reference product (RoActemra) are similar.

Avtozma (Celltrion)

A published, double blind study of 471 adults with moderately to severely active rheumatoid arthritis (RA) were randomised 1:1 to 8mg/kg Avtozma or reference product intravenously every 4 weeks. The study showed evidence of therapeutic equivalence between Avtozma and RoActemra. All patients received a stable dose of methotrexate throughout the study.

Efficacy

The primary outcome was the absolute mean change of Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at 12 and 24 weeks. The estimated difference in DAS28-ESR at week 12 was –0.01 (95% CI −0.26, 0.24) and at week 24 was −0.10 (90% CI −0.30, 0.10). The estimated treatment differences were contained within the predefined equivalence margins.

At 24 weeks patients who received reference product were randomised 1:1 to continue reference product or switch to Avtozma. Efficacy endpoints were maintained or continued to improve after this switch.

Safety

The overall safety profiles of Avtozma and reference product were similar. Frequency of serious adverse events was 4.3% for Avtozma and 3.8% for the reference product.

Tyenne (Fresenius Kabi)

A published, double-blind, parallel-group study of 604 adults with moderately to severely active rheumatoid arthritis (RA) were randomised 1:1 to 162mg Tyenne or reference product via subcutaneous injection weekly for 24 weeks. The study showed evidence of therapeutic equivalence between Tyenne and RoActemra. All patients previously had an inadequate clinical response to at least one disease modifying antirheumatic drug (DMARD) and were receiving a stable dose of methotrexate.

Efficacy

The primary outcome was the absolute mean change of DAS28-ESR at 24 weeks for tocilizumab biosimilar (Tyenne) -3.53 (95% CI -3.74 to -3.32) and the reference product, -3.54 (95% CI -3.75 to -3.35).

This corresponded to a least square mean difference of 0.01 (95% CI -0.19 to 0.22) which was within the equivalence margin of ± 15% supporting clinical equivalence. The mean change of DAS28-ESR in both treatment groups is considered high and clinically relevant in RA.

Safety

Frequency of severe side effects were similar between Tyenne and the reference product (9.3% vs 9.9%). However, injection site reactions occurred more frequently with Tyenne (11.3%) than the reference product (4.6%) after 24 weeks. This difference was reduced after 63 weeks, the frequency of injection site reactions reported as 12.3% and 8% for Tyenne and the reference product, respectively.

Differences between brands

Comparison of the excipients and shelf life of the tocilizumab biosimilars and the reference product (RoActemra) formulations.

Diluent

• Avtozma (IV formulation) – sodium chloride 0.45% or 0.9%
• RoActemra (IV formulation) – sodium chloride 0.9%
• Tyenne (IV formulation) – sodium chloride 0.45% or 0.9%

Sodium content

Most of the sodium burden will come from the diluent used to prepare the IV formulation.

Undiluted IV formulation

Tyenne contains less sodium per vial than RoActemra. Doses of both products up to 800mg are essentially ‘sodium free’, in other words they contain less than 1mmol sodium per dose.

Avtozma contains no sodium.

Assessing the clinical impact of sodium content in medicines (SPS page) provides further information on sodium in medicines.

Subcutaneous formulation

• Avtozma – sodium free
• RoActemra – sodium free
• Tyenne – essentially ‘sodium free’

Other excipients of interest

Sucrose

RoActemra concentrate for solution for infusion is the only product to contain sucrose.

Sorbitol or citrate

None of the products contain sorbitol or citrate.

Polysorbate 80

All tocilizumab products contain polysorbate 80.

Administration

The first administration of a subcutaneous tocilizumab product should be performed under the supervision of a qualified healthcare professional.

The intravenous infusion time is one hour for all tocilizumab products.

Storage and stability

All tocilizumab products should be stored in a refrigerator (2°C to 8°C).

Undiluted vials

Permitted temperature excursions include:

• Tyenne vials can be stored at temperatures up to a maximum of 25°C for a single period of up to 28 days, the vial must be protected from light and discarded if not used within the 4 week period
• RoActerma and Avtozma – no additional stability data

Following dilution

Following dilution, tocilizumab biosimilar and reference product should be used immediately. Additional stability data is available for tocilizumab if prepared in controlled and validated aseptic conditions: 

• Avtozma can be stored for 48 hours up to 30°C and for 1 month at 2 to 8°C
• Tyenne can be stored for 48 hours up to 30°C followed by 14 days at 2 to 8°C
• RoActemra can be stored for 24 hours up to 30°C and for 14 days at 2 to 8°C

Subcutaneous formulations

Individual pens may be stored at room temperature under the following conditions:

• Avtozma can be stored at temperatures up to 30°C for up to 21 days
• Tyenne can be stored at temperatures up to 30°C for up to 14 days
• RoActemra can be stored at temperatures up to 30°C for up to 14 days

NICE recommendations

Where NICE has already recommended the reference biological medicine, the same guidance will apply to the biosimilar. Biosimilars do not require a separate or additional Technology Appraisal (TA). Preparing to use tocilizumab biosimilar (SPS page) provides links to all NICE TAs relating to tocilizumab.

Update history