Reason for request
Favourable opinion for reimbursement of two new subcutaneous formulations of infliximab, in combination with methotrexate (MTX) in the treatment of rheumatoid arthritis only in adult patients with active disease when the response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, has been inadequate.
Unfavourable opinion for reimbursement in patients not previously treated with methotrexate or other DMARDs.
No clinical added value compared to infliximab given intravenously (REMICADE and its biosimilars, including REMSIMA 100 mg powder for concentrate for solution for infusion).
According to French and European guidelines, the treatment of rheumatoid arthritis (RA) is based on the early prescription of a disease-modifying anti-rheumatic drug (DMARD) in order to induce clinical and biological remission. Pending the efficacy of a DMARD, corticosteroid therapy may be proposed, which will be reduced and stopped as soon as possible. Close monitoring and frequent treatment adjustments are necessary until the objective is achieved.
In first-line treatment, MTX is the reference conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) for rheumatoid arthritis. In case of a contraindication or intolerance to MTX, leflunomide or sulfasalazine can be used. The Committee considers that the prescription of a biologic therapy (in combination or as monotherapy) is not justified as first-line treatment, unless all csDMARDs are contraindicated.
In second or later-lines therapy, in patients who have responded inadequately or who are intolerant to MTX, treatment should be optimised as follows:
- In the absence of poor prognostic factors, a combination of synthetic disease-modifying anti-rheumatic drugs (MTX/sulfasalazine/hydroxycholoroquine) or a rotation for another synthetic disease-modifying anti-rheumatic drug (leflunomide, sulfasalazine) may be proposed. In case of failure (or contraindication), targeted therapy should be considered. Possible targeted therapies in this situation are: targeted biologic therapies (biologics or bDMARDs) represented by TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), interleukin 6 receptor antagonists (tocilizumab and sarilumab), T lymphocyte co-stimulation modulator (abatacept), or rituximab in certain circumstances only, as well as synthetic targeted therapies (tsDMARDs) represented by JAK inhibitors (baricitinib and tofacitinib), although the Committee recommends their use following the failure of a biologic (third or later lines),
- In the presence of poor prognostic factors, the addition of a targeted therapy to MTX may be proposed.
It should be noted that the use of targeted therapy should be preferentially implemented in combination with MTX. However, if it is necessary to use targeted therapy as monotherapy, an IL6 inhibitor or a JAK inhibitor should be preferred given their demonstrated superiority as monotherapy compared to MTX alone.
It is not possible to establish a preferential hierarchy within the targeted therapies due to the absence of comparative data and given the absence of predictive factors for treatment response. According to the guidelines, bDMARDs can be preferred as second-line therapy given the greater experience with their use and long-term safety data from registries.
The Committee recommends that new chemical agents targeting janus kinases should preferably be used as third or later-lines treatment (i.e., after the failure of at least one biologic therapy).
Role of the medicinal product in the care pathway
REMSIMA 120 mg solution for injection in pre-filled syringe and pen, in combination with methotrexate, is a second-line therapy in the treatment of adult patients with active RA, in case of failure (inadequate response, intolerance or contraindication) of one or more disease-modifying anti-rheumatic drugs (DMARDs), including MTX.
Given the current therapeutic strategy, the prescription of a biologic therapy (in combination with MTX or as monotherapy), irrespective of the product, is not justified in the first-line treatment of RA in adult patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs (first treatment line). Consequently, like other TNF inhibitors, infliximab has no role in the first-line treatment of RA.
These two presentations are the first suitable for subcutaneous administration of infliximab; they therefore represent a new therapeutic option in the management of patients with RA requiring treatment with a biologic therapy. The non-inferiority of the subcutaneous form compared to the intravenous form has been demonstrated, in combination with MTX, in patients with active RA receiving treatment with MTX for at least 3 months and at a stable dose for at least 4 weeks. In the absence of direct comparison, its role compared to the other biologic therapies available cannot be specified.
Subcutaneous treatment should be initiated 4 weeks after the last administration of two intravenous infusions of infliximab 3 mg/kg given 2 weeks apart. The recommended dose is 120 mg once every 2 weeks.
Given the risk of hypersensitivity reactions with subcutaneous infliximab (see paragraph 4.4 of the SmPC), but also with other biologic disease-modifying drugs, the Transparency Committee recommends that the first subcutaneous injection of this drug be given in an appropriate care structure.
The Committee highlights the fact that subcutaneous REMSIMA 120 mg has only demonstrated its efficacy in one of the indications for IV infliximab (REMICADE and biosimilars), the treatment of rheumatoid arthritis. Indication extensions for Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis are expected for the third quarter of 2020 (MA procedure ongoing). Consequently, pending granting of the MA for these new indications, this proprietary medicinal product may only be prescribed in the indication approved by the MA, excluding all the other diseases where infliximab can be used.
The usual dosage of IV REMSIMA is 3 mg/kg. However, according to the SmPC, in the absence of a response or an inadequate response after the first 12 weeks of treatment, the dosage can be optimised, either by increasing the dose up to 7.5 mg/kg, or by increasing the injection frequency. As indicated in the SmPC, the Committee draws prescribers’ attention to the fact that there is insufficient information regarding the switching of patients having received intravenous infusions of infliximab higher than 3 mg/kg every 8 weeks as maintenance treatment to the subcutaneous formulation of infliximab (REMSIMA).
The clinical benefit of REMSIMA 120 mg (infliximab) solution for injection in pre-filled syringe and pen, in the treatment of rheumatoid arthritis is:
Clinical Added Value
|no clinical added value||
the REMSIMA 120 mg (infliximab) solution for injection in pre-filled syringe and pen products provide no clinical added value (CAV V) compared to infliximab given intravenously (REMICADE and its biosimilars, including REMSIMA 100 mg) in the second-line treatment of active rheumatoid arthritis in adults.