NHS Provides Update on Biosimilar Adalimumab With a Focus on ISRs

Biosimilar adalimumab is making its way to patients, some of whom have expressed concerns about the presence of citrate in some of the available biosimilars.
Kelly Davio
January 29, 2019
Biosimilar adalimumab recently entered the European marketplace, and swift adoption by health systems eager to benefit from cost savings means that biosimilar versions are making their way to patients, some of whom have expressed concerns about the presence of citrate in some of the available biosimilars. In the United Kingdom, the National Health Service (NHS) Specialist Pharmacy Service has issued an update on biosimilar adalimumab with a focus on injection site reactions (ISRs) that may be related to the citrate buffer used in some formulations of adalimumab.

The early formulation of the reference adalimumab, Humira, used a citrate buffer to maintain the product within a predefined pH range. Similar systems are also used in products like etanercept and dulaglutide. In pivotal trials, this formulation of the reference Humira was linked with ISRs in 12.9% of patients.

Later, AbbVie, maker of the reference drug, reformulated its product to remove the citrate buffer in an effort to reduce both the product’s injection volume and the incidence of ISRs.

According to the NHS report, there is some weak evidence, derived from 2 small phase 2 studies, to support claims that citrate-free adalimumab, delivered via a 29-gauge needle, may provide some advantage over the original formulation, delivered by 27-gauge needle, in terms of reduced post-injection pain. However, the report’s authors point out, there is no consistent evidence that shows that the difference in discomfort between the 2 options persists longer than 15 minutes.

The report also details the excipients used in the biosimilar adalimumab products available in the NHS system, as well as data on ISRs:
  • Amgevita, made by Amgen, is citrate-free. The European Medicines Agency (EMA) indicates that, in 2 clinical studies comparing the biosimilar to the reference, there was an imbalance in ISRs that favored the biosimilar thorough week 16.
  • Imraldi, made by Samsung Bioepis, contains sodium citrate and citric acid. In a clinical trial, according to the EMA, approximately 3% of patients in the biosimilar arm and 3% of patients in the reference arm had ISRs up to week 24. Up to week 52, the number of patients experiencing ISRs was higher among patients treated with the reference.
  • Hyrimoz, made by Sandoz, contains citric acid. In a clinical trial, according to the EMA, the proportion of patients with ISRs was 6.5% in the biosimilar group and 3.4% in the reference group up to week 17. No imbalance was recorded at later timepoints, however.
  • Hulio, made by Mylan, is citrate-free. The EMA states that, in a clinical trial, ISRs were reported in 1.9% of the biosimilar group versus 3.9% of the reference group.
Notably, among the adalimumab products available in syringe presentations, neither the reference nor any of the biosimilars’ devices contain latex. However, among adalimumab products available as prefilled pens, both Amgevita and Hyrimoz have needle covers that contain a derivative of latex, which could make them unsuitable for patients with latex allergies.


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