This site is intended for health professionals only

Remodelling delivery of mAbs in rheumatoid arthritis



Tocilizumab, a monoclonal antibody targeted at the interleukin-6 receptor, is now available as a subcutaneous formulation for the management of moderate to severe rheumatoid arthritis
Tina Hawkins MRPharm
Independent Pharmacist prescriber
Rheumatology Pharmacist, Leeds Teaching Hospital NHS Trust, UK
In May 2014, Chugai and Roche launched a subcutaneous formulation of tocilizumab (RoActemra®) for the management of moderate to severe rheumatoid arthritis (RA). The new formulation offers patients the flexibility of injecting tocilizumab at home rather than having to attend hospital on a regular basis for intravenous administration. Unlike the intravenous formulation, the licence for the subcutaneous formulation is currently limited to RA and allows use as a monotherapy where there is a contraindication or intolerance to methotrexate.1 Trials involving the use of the subcutaneous formulation in the management of systemic juvenile idiopathic arthritis (sJIA) are currently underway, but results from these are not expected until 2017.
Mode of action
Tocilizumab is a humanised/IgG1 monoclonal antibody directed against the interleukin-6 (IL-6)receptor in its soluble and transmembrane form. IL-6 is a multifunction cytokine that has a wide range of biological activities in various target cells and regulates immune responses, acute phase reactions, haematopoiesis and bone metabolism.2 Because IL-6 is involved in a number of important physiological roles, deregulated overproduction of IL-6 causes various pathologic conditions, including autoimmune, inflammatory and lymphoproliferative disorders.2 In RA, elevated production of IL-6 is observed in the synovial fluid and blood with levels correlating with disease activity.3 Some of the clinical aspects of RA, such as overproduction of acute phase proteins, raised platelet counts, anaemia, induction of osteoclasts, production of autoantibodies and decreased albumin can be explained by activities of IL-6.2,3
Clinical efficacy
The intravenous formulation of tocilizumab was the first biologic agent to demonstrate superiority over methotrexate monotherapy in early RA.4,5 The key global studies involving subcutaneous tocilizumab were BREVACTA and SUMMACTA, in addition to these there were two studies involving Japanese patients only (MATSURI and MUSASHI).6–10 MATSURI was a Phase I/II study that aimed to determine the appropriate dose of tocilizumab in Japanese patients.10 In the MUSASHI study, the effectiveness and safety of subcutaneous tocilizumab 162mg every other week monotherapy was shown to be of comparable efficacy to intravenous tocilizumab 8mg/kg every four weeks monotherapy.9 None of the studies were designed to evaluate the outcome of switching patients stabilised on intravenous tocilizumab to the subcutaneous formulation.
BREVACTA was a two-year, Phase III, randomised, multicentre, parallel-group study with a 24 week double-blind placebo-controlled period followed by an open label period of 72 weeks. The primary end point of the study was to demonstrate superiority of subcutaneous tocilizumab over placebo for the American College of Rheumatology (ACR) 20 response at week 24, with the key secondary end point being radiographic data. In the active treatment arm, patients were administered 162mg subcutaneous tocilizumab every other week.8 All patients were required to be on a stable dose of disease-modifying antirheumatic drugs (DMARDs) prior to entrance in the study. Up to 20% of patients in the study were permitted to have failed with a previous tumour necrosis factor inhibitor (TNFi). The study population consisted of 656 patients (active group n=437, placebo n=219) with a mean disease duration of 11 years and severe disease activity (DAS28 active arm 6.7 versus placebo 6.6).8 The primary end point of an ACR20 at week 24 reached statistical significance (60.9% versus 31.5%, p<0.0001).8 Statistically significant differences were also achieved for the ACR50 (39.8% versus 12.3% p<0.0001), ACR70 (19.7% versus 5.0% p<0.0001), DAS28 and HAQ-DI scores.8 Superiority was also demonstrated with regards to inhibition of joint damage in terms of change in the mTSS from baseline (p=0.0149).8 The adverse event profile with subcutaneous tocilizumab was comparable to previous studies involving intravenous tocilizumab.8
SUMMACTA was a placebo-controlled study comparing the efficacy and safety of subcutaneous tocilizumab 162mg weekly to intravenous tocilizumab 8mg/kg given every four weeks in adult patients with RA.6 Patients must have received one or more traditional DMARDs at a stable dose for eight weeks or longer. In addition to this, they were required to have a previous inadequate response to at least one DMARD. Prior exposure to biologic medicines was permitted, with the exception of tocilizumab. Concomitant oral glucocorticoids (≤10mg/day prednisolone or equivalent) and non-steroidal inflammatory drugs (up to maximum recommended dose) were allowed provided the patient had been on a stable dose for at least four weeks prior to the initial baseline assessment. The primary outcome of the study was to demonstrate the non-inferiority of subcutaneous tocilizumab to intravenous tocilizumab with regard to the proportion of patients in each group achieving an ACR20 response using a 12% non-inferiority margin. Secondary outcomes were the disease activity score using 28 joints (DAS28), ACR responses, health assessment questionnaire scores and safety assessments. Of the 1262 patients assigned to treatment in the study, 1095 patients were included in the final analysis (subcutaneous tocilizumab n=558, intravenous tocilizumab n=537).6 The most common protocol violation leading to exclusion was non-stable dose of DMARD in both groups.6 The study met its primary endpoint by demonstrating the non-inferiority of subcutaneous tocilizumab 162mg weekly to IV tocilizumab 8mg/kg four weekly (ACR20 week 24 69.4%, IV (95% CI 65.5–73.2) versus 73.4% subcutaneous (95% CI 69.6–77.1).6 In addition, ACR50 response, ACR70 response, DAS28 remission and decrease in HAQ-DI score were similar between the groups.6 Subcutaneous tocilizumab had a comparable safety profile, with the exception of injection site reactions. No injection site reaction resulted in dose interruption or withdrawal from the study.6
A published abstract of the long-term open extension phase of SUMMACTA up to week 97 has included analysis of patients receiving intravenous tocilizumab who were re-randomised after week 24 to open label subcutaneous tocilizumab. Initial response rates from week 24 for ACR20/50/70, DAS28 and HAQ-DI ≥0.3 were sustained up to week 97.7 The safety profile of switchers was reported to be comparable to those who remained on their original randomised treatment.7
Place in the therapeutic pathway
At present, there is no clear evidence supporting the selection of one biologic DMARD over another in the management of RA. Historically the TNFi have been used preferentially first-line owing to their greater body of evidence and safety data. In 2013, the European League Against Rheumatism (EULAR) updated its guidance regarding the use of both synthetic and biological disease modifying antirheumatic drugs in RA. Unlike its previous guidance, no preference was given with regards to selecting the first biologic DMARD in biologic-naïve patients who had responded insufficiently to methotrexate and/or other synthetic DMARD strategies with or without glucocorticoids.16 The guidance strongly supports the use of methotrexate with all biological agents, but that if biologic monotherapy must be initiated first-line then tocilizumab monotherapy had some supportive evidence.5 A head-to-head trial in patients with established RA who stopped methotrexate therapy revealed intravenous tocilizumab monotherapy to be superior to adalimumab monotherapy in the majority of end points in the study.11 Other studies have also shown some superiority in clinical endpoints with regards to intravenous tocilizumab monotherapy when compared to methotrexate alone.12 At present, EULAR makes no preference with regards to selection of a second biologic agent when there is initial treatment failure with the first.5
In England, the National Institute for Health and Care Excellence (NICE) approves the use of tocilizumab in combination with methotrexate in patients with a diagnosis of RA in three clinical situations.13,14 Initially tocilizumab can be used as a first-line biologic DMARD in biologic-naïve patients in accordance with the technology appraisals TA130 and TA247.13,15 It may also be used following treatment failure with a TNFi where treatment with rituximab is contraindicated or rituximab has been withdrawn as a consequence of an adverse event (TA195).14 The third clinical situation is following treatment failure with one or more TNFi and rituximab.13,14 The economic evaluations within the NICE technology appraisals guidance (TAG) were based on the intravenous formulation of tocilizumab only and the TAGs include a proviso that approval for use is given on the basis of a discounted price as part of an agreed patient access scheme.
In July 2014, the Scottish Medicines Consortium (SMC) approved the use of subcutaneous tocilizumab as monotherapy or in combination with methotrexate in adult patients who had either responded inadequately to, or who were intolerant to previous therapy with one or more DMARD or TNFi.16 Use is restricted by the SMC to current eligibility and continuation rules for biologic therapies in rheumatoid arthritis.16
A dose of 162mg is administered as a once-weekly injection for the indication of RA.1 At present there is limited experience with regards to transferring patients from the intravenous formulation to the subcutaneous route. The datasheet recommends that the first subcutaneous dose of tocilizumab should be administered under the supervision of a qualified healthcare professional when the next dose of the intravenous formulation is due for the patient.1 All patients should be issued with a Patient Alert Card and be advised to immediately contact a healthcare professional if they experience symptoms suggestive of an allergic reaction.1 As with intravenous tocilizumab regular blood monitoring is required in terms of liver function tests (ALT and AST), neutrophils and platelets. The licenced datasheet gives specific recommendations regarding interruption of dosing or an increase in the dosage interval when blood results fall below a specified limit.1
Side effects
With the exception of injection site reaction, the side effect profile of subcutaneous tocilizumab is similar to intravenous tocilizumab with no new safety signals.6–10 The most frequent reported adverse effects in patients receiving both monotherapy and combination therapy were upper respiratory tract infection, nasopharyngitis, headache, hypertension and liver enzyme elevation.1 As with intravenous tocilizumab, elevation in lipid parameters may occur. In RA patients, assessment of lipid parameters should be performed four to eight weeks following initiation of RoActemra therapy.1 Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.
Drug interactions
Pro-inflammatory cytokines, such as IL-6, have been associated with suppression of hepatic cytochrome P450 (CYP450) enzymes. Reduction in these cytokines following the administration of tocilizumab may lead to normalisation of enzyme expression and improved drug metabolism. When starting or stopping therapy with subcutaneous tocilizumab, patients taking medicinal products that are metabolised via CYP450 3A4, 1A2 or 2C9 (for example, atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) should be monitored becuase doses may need to be increased to maintain therapeutic effect.1 Population pharmacokinetic analyses have not detected any effect of methotrexate, non-steroidal anti-inflammatory drugs or corticosteroids on the clearance of tocilizumab.
Prior to the introduction of subcutaneous tocilizumab, only the TNFis adalimumab, certolizumab and etanercept were licenced for the treatment of RA with or without methotrexate. Although combination with methotrexate is recommended with all biologic DMARDs there are a number of patients for whom methotrexate is contraindicated or the patient is unable to tolerate either oral or subcutaneous methotrexate. Subcutaneous tocilizumab monotherapy offers these individuals an effective therapy with the flexibility of self-administration. For those patients currently having to attend hospital regularly for infusions of tocilizumab, subcutaneous tocilizumab will provide greater freedom for patients and ease current pressures on hospital infusion units.
Key points
  • Subcutaneous tocilizumab is licenced for the treatment of moderate to severe rheumatoid arthritis (RA) in patients who have responded inadequately or been intolerant of one or more disease-modifying antirheumatic drug (DMARD) or tumour necrosis factor inhibitor (TNFi).
  • It can be given without methotrexate where there is intolerance/contraindication to methotrexate.
  • Phase III studies have shown comparable efficacy to the intravenous formulation.
  • Current Phase III studies have not directly assessed the clinical efficacy of switching from the intravenous preparation to the subcutaneous preparation in stable RA patients.
  • As with the intravenous preparation, regular blood monitoring is required.
  1. RoActemra 162mg solution for injection in pre-filled syringe. (accessed 12 January 2015).
  2. Adachi Y, Yoshio-Hoshino N, Nishimoto N. The blockade of IL-6 signalling in rational drug design. Curr Pharm Des 2008;14:1217–24.
  3. Nishimoto N et al. Mechanisms and the pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman’s disease. Blood 2008;12(10):3959–64.
  4. Besada E. Potential patient benefit of a subcutaneous formulation of tocilizumab for rheumatoid arthritis: a critical review. Patient Prefer Adherence 2014;8:1051–9.
  5. Smolen JS et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis doi:10.1136/annrheumdis-2013–204573.
  6. Burmester GR et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying anti-rheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis 2014;73:69–74.
  7. Burmester GR et al. The efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA study). Ann Rheum Dis 2014; vol./is. 73/,0003–4967.
  8. Kivitz AJ et al. A randomized, double-blind, parallel group study of the safety and efficacy of tocilizumab subcutaneous versus placebo in combination with traditional DMARDs in patients with moderate to severe rheumatoid arthritis (BREVACTA). Arthritis Rheum, December 2012; vol./is 64/12(4170),0004-3591.
  9. Ogata A. The MUSASHI study: Comparison of subcutaneous tocilizumab monotherapy versus intravenous tocilizumab monotherapy: Results from a double-blind, parallel-group, comparative phase III non-inferiority study. Ann Rheum Dis, June 2013, vol./is.71/,0003–4967.
  10. Ohta S et al. Mechanism based approach using a biomarker response to evaluate tocilizumab subcutaneous injection in patients with rheumatoid arthritis with an inadequate response to synthetic DMARDs (MATSURI study). J Clin Pharmacol, January 2014, vol./is. 54/1(109-119),0091-2700;1552–4604.
  11. Gabay C et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013;381:1541–50.
  12. Dougados M et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis 2013;72:43–50.
  13. NICE technology appraisal guidance 247. Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198) Issued February 2012. (accessed 12 January 2015).
  14. NICE technology appraisal guidance 195. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor Issued: August 2010. (accessed 12 January 2015).
  15. NICE technology appraisal guidance 130. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis Issued: October 2007. (accessed 12 January 2015).
  16. Scottish Medicines Consortium. Tocilizumab, 162mg, solution for injection in pre-filled syringe (RoActemra®) SMC No. (982/14) Published 11 August 2014. (accessed 12 January 2015).

Be in the know
Subscribe to Hospital Pharmacy Europe newsletter and magazine