Advice

Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in September 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

Rituximab subcutaneous injection (MabThera, Roche Products Limited) was granted a marketing authorisation in March 2014 for treating non-Hodgkin's lymphoma in adults. Rituximab concentrate for solution for intravenous infusion (MabThera, Roche Products Limited) has been available in the UK since June 1998.

Stage 1 of an open-label randomised controlled trial in adults (SABRINA; n=127) with previously untreated follicular lymphoma demonstrated pharmacokinetic non‑inferiority of 3-week cycles of fixed-dose subcutaneous rituximab 1400 mg compared with intravenous rituximab 375 mg/m2 body surface area. Overall response rate was similar in the 2 groups; however, the trial did not have the statistical power to detect differences between the groups. Administration-related reactions were more common with subcutaneous rituximab compared with intravenous rituximab, although most were mild to moderate.

A time and motion study (Rule et al. 2014) found that administration of subcutaneous rituximab was associated with savings in healthcare professional time and costs compared with intravenous rituximab. However, the study had insufficient power to assess differences between the groups statistically.

Effectiveness

Stage 1 of SABRINA (Davies et al. 2014, n=127) found that, compared with intravenous rituximab, fixed dose subcutaneous rituximab:

  • was pharmacokinetically non-inferior for the primary outcome of ratio of observed mean rituximab serum trough concentrations (Ctrough) between the groups at induction cycle 7 (1.62, 90% confidence interval [CI] 1.36 to 1.94).

  • was associated with a similar overall response rate (84% with intravenous rituximab compared with 90% with subcutaneous rituximab); however, the trial was not powered to detect differences between the groups.

Safety

  • In SABRINA, the most common adverse events in the intravenous and subcutaneous rituximab groups were neutropenia (35% in both groups), nausea (23% and 29% respectively) and constipation (26% and 23% respectively).

  • The summary of product characteristics for rituximab subcutaneous injection states that, during the development programme, the safety profile of the subcutaneous injection was comparable to that of the intravenous infusion, with the exception of local injection site reactions.

  • In SABRINA, administration-related reactions were more common with subcutaneous rituximab compared with intravenous rituximab (50% compared with 32% respectively; statistical analysis not reported). More than 90% of these reactions were mild-to-moderate.

Patient factors

  • Administration of rituximab subcutaneous injection takes approximately 5 minutes, whereas administration of the intravenous infusion can take several hours.

  • In a time and motion study by Rule et al. 2014, subcutaneous rituximab was associated with a reduction in mean participant time spent in the treatment chair or bed, treatment room and hospital compared with intravenous rituximab. The majority of the time saved was time spent in the treatment chair or bed (mean 45.7 minutes and 238.8 minutes respectively: study not powered to analyse differences).

  • Some patients may prefer a subcutaneous injection to an intravenous infusion.

Resource implications

  • The cost per cycle of intravenous rituximab 375 mg/m2 body surface area is estimated to be £1222.40 (based on a body surface area of 1.86 m2 and assuming wastage: MIMS, August 2014).

  • The cost per cycle of subcutaneous rituximab at a fixed dose of 1400 mg is higher at £1344.65 (MIMS, August 2014). However, a commercial pricing agreement is currently in place with NHS England to supply subcutaneous rituximab at a price which provides drug cost savings to NHS England (Roche Products Limited, personal communication, August 2014).

  • In the time and motion study, administration of subcutaneous rituximab was associated with savings in healthcare professional time (mean 30.9−174.8 minutes) and costs (mean £15.22−£115.17) per patient compared with intravenous rituximab.

Introduction and current guidance

Non-Hodgkin's lymphomas are a diverse group of lymphoproliferative malignancies that are categorised according to the cell type affected (B-cell or T-cell), as well as the clinical features and rate of progression of the disease. Most people with a diagnosis of non‑Hodgkin's lymphoma have a B-cell lymphoma. The most common B-cell lymphomas are diffuse large B-cell and follicular lymphoma (NICE clinical guideline final scope on Non-Hodgkin's lymphoma).

A wide range of treatments is used for managing non-Hodgkin's lymphoma. For people with low-grade non-Hodgkin's lymphoma who are asymptomatic, management includes observation. For people who need treatment, there can be several phases: induction therapy, assessment of disease response to treatment, maintenance treatment, treatment at the point of first relapse, consolidation after relapse and palliative treatment (see the final scope for the NICE clinical guideline on Non-Hodgkin's lymphoma).

NICE has published the following technology appraisals making recommendations about intravenous rituximab in non-Hodgkin's lymphoma indications:

This evidence summary looks at a new subcutaneous injection of rituximab.

Full text of Introduction and current guidance.

Product overview

Rituximab (MabThera, Roche Products Limited) is a monoclonal antibody that targets the CD20 surface antigen, expressed on normal B-cells and almost all B-cell lymphomas.

The existing intravenous infusion of rituximab (MabThera, Roche Products Limited) is licensed for treating non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, and granulomatosis with polyangiitis and microscopic polyangiitis.

A new subcutaneous injection of rituximab was granted a marketing authorisation in March 2014. Rituximab subcutaneous injection (MabThera, Roche Products Limited) is licensed for treating non-Hodgkin's lymphoma in adults including those with:

  • previously untreated stage III−IV follicular lymphoma in combination with chemotherapy.

  • follicular lymphoma that responded to induction therapy.

  • CD20-positive diffuse large B-cell non-Hodgkin's lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy.

Full text of Product overview

Evidence review

  • This evidence summary discusses the results of stage 1 of an ongoing phase III open‑label randomised controlled trial (SABRINA), reported by Davies et al. (2014). The SABRINA trial was designed to demonstrate pharmacokinetic non-inferiority of subcutaneous rituximab compared with intravenous rituximab. Also discussed in the evidence summary is a UK time and motion study (Rule et al. 2014), which investigated staff time and costs associated with administration of subcutaneous, compared with intravenous rituximab.

  • The SABRINA trial included 127 adults (mean age 55.5 years) with previously untreated histologically confirmed CD20-positive grade 1, 2 or 3a follicular lymphoma. Participants were randomised to 8 cycles of intravenous rituximab at a dose of 375 mg/m2 body surface area (n=64) or 1 cycle of intravenous rituximab at a dose of 375 mg/m2 body surface area followed by 7 cycles of subcutaneous rituximab at a fixed dose of 1400 mg (n=63). All participants also received induction chemotherapy regimens.

  • The ratio of observed geometric mean serum trough concentrations of rituximab (Ctrough) between the subcutaneous and intravenous rituximab groups (the primary outcome) in the per-protocol population was 1.62 (90% CI 1.36 to 1.94). Because the lower limit of the 90% CI exceeded the pre-specified margin of 0.8, subcutaneous rituximab was shown to be pharmacokinetically non-inferior to intravenous rituximab. However this result was not reported in the intention-to-treat population. The European Medicines Agency guideline on Points to consider on switching between superiority and non-inferiority states that non-inferiority studies should be analysed using both the per‑protocol and the intention-to-treat data sets.

  • Secondary efficacy outcomes included overall response rate (the percentage of people achieving a complete, unconfirmed complete or partial response to treatment) at the end of induction treatment. In the intention-to-treat population the overall response rate was similar in the 2 groups (84% in the intravenous rituximab group compared with 90% in the subcutaneous rituximab group in the investigator assessment); however, the trial did not have the statistical power to detect differences between the groups. No other clinical efficacy results or patient-oriented outcomes such as progression-free survival or overall survival were reported in the stage 1 analysis. Quality of life was not assessed.

  • In SABRINA, treatment-related adverse events were more common in the subcutaneous rituximab plus chemotherapy group compared with the intravenous rituximab plus chemotherapy group (73% [45/62] and 46% [30/65] respectively). However, the proportion of people who experienced a serious adverse event did not differ between the groups. The most common adverse events in the intravenous rituximab and subcutaneous rituximab groups were neutropenia (35% in both groups), nausea (23% and 29% respectively) and constipation (26% and 23% respectively).

  • Administration-related reactions were more common with subcutaneous rituximab compared with intravenous rituximab occurring in 50% and 32% of participants respectively; however more than 90% of these reactions were mild-to-moderate.

  • Stage 1 of the SABRINA trial had a number of limitations. Clinical efficacy results reported in the trial (such as overall response rate and complete response rate) were secondary, not primary endpoints. The short duration of the study and small size (it included only 127 participants) meant it was not powered sufficiently to assess differences between the treatment groups for these outcomes. In addition, it was an open-label study, which could have introduced bias.

  • In SABRINA, overall exposure to rituximab was higher in people in the subcutaneous than the intravenous group because of the fixed-dose. The EPAR states that, because of this, long-term safety issues which potentially could affect overall survival cannot be excluded for subcutaneous rituximab.

  • In the time and motion study reported by Rule et al. 2014, administration of subcutaneous rituximab was associated with savings in healthcare professional time (time savings: 174.8 minutes, 95% CI 172.5 to 177.1 minutes) and costs (cost savings: £115.17, 95% CI £98.95 to £136.93) per patient compared with intravenous rituximab, assuming that during administration of intravenous rituximab, the healthcare professional was actively treating the participant for the total duration of the infusion time, taking up 100% of their time. In alternative analyses that made different assumptions about the amount of time the healthcare professional spent actively monitoring the participant receiving intravenous rituximab infusion, the mean healthcare professional time and costs saved were less (mean time saved: 30.9−69.4 minutes; mean costs saved: £15.22−£41.94). However, the significance of any differences between the groups could not be assessed in this study because the small number of observations (13−38 depending on treatment group and observation area) meant it had insufficient power.

  • Subcutaneous rituximab was also associated with a reduction in mean participant time spent in the treatment chair or bed, treatment room and hospital overall. The majority of the time saved was time spent in the treatment chair or bed (mean 238.8 minutes with intravenous rituximab, compared with 45.7 minutes with subcutaneous rituximab; difference: 193.1 minutes, 95% CI 177.9 to 206.6 minutes).

Full text of Evidence review.

Context

The subcutaneous injection of rituximab provides an alternative route of administration to the intravenous infusion. The cost per cycle of intravenous rituximab at a dose of 375 mg/m2 body surface area per cycle (based on a body surface area of 1.86 m2 and assuming wastage) is estimated to be £1222.40 (MIMS, August 2014). The cost per cycle of subcutaneous rituximab at a fixed dose of 1400 mg per cycle is higher at £1344.65 (MIMS, August 2014). A commercial pricing agreement is currently in place with NHS England to supply subcutaneous rituximab at a price which provides drug cost savings to NHS England (Roche Products Limited, personal communication, August 2014).

Full text of Context.

Estimated impact for the NHS

Subcutaneous rituximab may provide a potential alternative to intravenous rituximab for treating non-Hodgkin's lymphoma. It offers a quicker, less invasive mode of administration; however, administration-related reactions are more common with the subcutaneous injection compared with the intravenous infusion. Before starting rituximab subcutaneous injections, all patients must have received a full dose of rituximab intravenous infusion to facilitate the management of any administration reactions.

The drug cost of rituximab subcutaneous injection is higher than the intravenous infusion. However a commercial pricing agreement is currently in place with NHS England to supply subcutaneous rituximab at a price which provides drug cost savings to NHS England (Roche Products Limited, personal communication, August 2014). The subcutaneous injection offers benefits in terms of healthcare professional time and associated costs saved compared with administration of the intravenous infusion. However these benefits may not be as great if rituximab is used with other drugs given intravenously.

Local decision makers will need to consider the available evidence when making decisions about using subcutaneous rituximab, in the setting of their local care pathways and usual rituximab-containing treatment schedules. The likely benefits of its use will need to be balanced against the increased risk of administration-related reactions, current lack of longer-term efficacy and safety data, and the absence of direct patient-oriented outcomes such as overall survival and quality of life in non-Hodgkin's lymphoma.

Full text of Estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.