Rapid Infusion for Biosimilar Rituximab’s

Formulary/ Governance Committee Paper

Title:Options for Introduction ofRapid Infusion for Biosimilar Rituximab’s

Exec Summary:As a biologic, rituximab has been associated with infusion reactions. To minimise risk, the standard haematology administration protocol for rituximab takes approximately three or four hours for the first infusion and two or three hours for subsequent infusions. On first exposure the infusion rate is gradually increased every 30 minutes and patient observations undertaken every 15minutes. On second infusion rates are higher; these longer infusion rates have impact on nursing and chemotherapy day unit/ward capacity.

There is extensive evidence from practice that ‘off label’ rapid administration (over 60 or 90minutes) of rituximab is safe.This evidence was gathered with the originator molecule with various publications over the last 10 years.

When biosimilar rituximab’s are introduced there is a need to use rapid infusion schedule to minimise the capacity impact of biosimilars.

As clinical evidence of efficacy is extrapolated from trials with originator molecules to biosimilar rituximab, it should be acceptable to extrapolate the evidence from published papers for rapid infusion to biosimilars and adopt it into practice.

Biosimilar rituximab’s will have data to support a rapid infusion (120 minutes) schedule in rheumatology as part of their SPC.

Proposal:For new patients give 1st cycle as per spc over3 to 4 hours, then introduce rapid infusion from cycle two onwards

If switching from Mabthera®to biosimilar or from one biosimilar brand to another then there are 3 main options:

1give first infusion as per cycle one over 3-4 hours regardless of current infusion rate. Then increase to standard/rapid infusion from next cycle depending on current rate

2a.if having standard infusion rate (2-3 hours infusion) introduce biosimilar at same rate then move to rapid infusion as appropriate on subsequent cycles

2b.if having standard infusion rate (2-3 hours infusion) and consider rapid infusion is appropriate for patient then introduce biosimilar as rapid infusion (90 minutes)

3if having rapid infusion (90 minutes) then then introduce biosimilar at same rate

Action Required:Decision is needed at appropriate local Trust governance/ clinical group as to which approach when switching(options 1 to 3) should be adopted.

Prepared by:Steve Williamson, Area Team Cancer Pharmacist, North East and Cumbria.

Disclaimers:This paper was prepared independently for members of the North of England Cancer Alliance Chemotherapy and Haematology Groups.

Permission is granted for its contents to be copied and adopted by other NHS hospitals to aid local decision making but responsibility for accuracy of contents and recommendations in this paper thereafterlies with the user(s) and not with the original author.

This document does not represent official NHS England Guidance.

Background

Rituximab is a monoclonal antibody used in a variety of haematology malignancies, including, non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). It forms the backbone of many successful chemotherapy regimens, R-CHOP, RCVP, BR etc. In 2017 biosimilar rituximab became available and will eventually replace use of the originator IV MabThera® rituximab brand following publication of the commissioning position from NHS England1. NHS England have stated biosimilars ‘will drive greater competition to release cost efficiencies to support the treatment of an increasing number of patients and the uptake of new and innovative medicines.’2

Biosimilar MABs are biological medicines that are developed to be highly similar to an existing biological medicine. They undergo comprehensive regulatory approval to demonstrate comparability to an existing licensed biological medicine. Like all biological medicines they are subject to pharmacovigilance monitoring, e.g. batch number tracking and must be prescribed by brand name3.

Clinical Evidence Required for Biosimilars

In their FAQ document published in April 2017 UK Medicines Information has confirmed that there are no differences in the licensed indications and dosing between biosimilar rituximab and the reference product, outlined the clinical trials use in the regulatory process4. A key concept of biosimilarity is that clinical trials are designed to demonstrate similarity in physical attributes and pharmacokinetics and only need to show non-inferiority in efficacy in selected clinical populations.

Biosimilars do not have to repeat the phase II/ III clinical trials in all indications, as they are therapeutically equivalent extrapolation of clinical trials using originator molecule is accepted and allows biosimilars to be used for full range of licensed indications in NHL andCLL is acceptable.

Administration Method

Rituximab is used for a wide range of cancer patients. It is also used in non–haematology illnesses such as rheumatoid arthritis. Rituximab had placed a large capacity burdenon chemotherapy day units due to its prolonged infusion time, leading many NHS hospitalsadopt a rapid infusion schedule.

As a biologic, rituximab has been associated with infusion reactions, which are usually mild to moderate in nature including, fever, rash, and cardiovascular or respiratory insufficiency5,6. Rarely more severe anaphylactic type reactions can occur. To minimise risk, the standard administration protocol for rituximab takes approximately three or four hours for the first infusion and two or three hours for subsequent infusions in the oncology. In addition premedication with paracetamol and an antihistaminic is always given before each administration of rituximab.

On first exposure the infusion rate is gradually increased every 30 minutes in 50mg/hour increments to a maximum of 400 mg/hour with patient observations undertaken every 15minutes. On second infusion rates are higher increasing at 100mg/hour increments at 30 minutes intervals, to a maximum of 400 mg/hour.

These prolonged infusion rates have impact on nursing and chemotherapy day unit/ward capacity.

Products

Both biosimilar (Truxima®) and originator (Mabthera®) product data sheets5,6 recommend administration in an environment where full resuscitation facilities are immediately available. Another biosimilar version of rituximab is expected to be marketed by Sandoz later in 2017 and will have the exactly the same infusion rate guidance as the originator and Truxima®7.

When rituximab is administered at the standard rate, the patient's infusion time may last up to 6 hours. Longer administration time is inconvenient for the patient as well as nurses.

Exclusions

Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion5,6.

Benefits of Rapid Infusion

  • The time spent giving rituximabat standard varies from patient to patient. There are anumber of reasons for this. At times, a member of staff may not be available to increase the rate in accordance with the protocol, or the rate may be slowed down or even stopped if the patient has a reaction to the drug. In general, however, the normal length of time a chair is occupied at present is approximately three hours, once the infusion starts. Additionally, time will be spent in the chair whilst the drug is prepared and pre-meds given. Chemotherapy is usually then administered, taking the chair time up to five hours.
  • The infusion time will reduce to 60 or 90 minutes with rapid infusion, plus the time taken for preparation and administration of chemotherapy. This is approximately ninety minutes less.
  • From a practical point of view, use of rapid infusion meansmost chemotherapy units can use the same chair for two rituximab patients in one day instead of just one patient, potentially doubling capacity.

Evidence

The only available data available for rapid infusion for biosimilars both Napp and Sandoz brand rituximab biosimilars is for rheumatologyinfusion6,, there is no new data for rapid infusion of biosimilar rituximab(s) with either brand.

There are many published papers which show that rapid infusion is safe8-16. The majority of papers are small case study type reports or conference abstracts. Most of these papers are summarised in two review papers 17,18.

  • There are two main alternate rapid-infusion schedules described inthe haematology setting, either infusion over 60minutes or over 90minutes.
  • The 60 minute protocols involved administration of rituximab at either a constantrate or rate escalation after the first 15 minutes for completion of the total dose within 60 minutes17.
  • The 90 minute protocolswere developed with 20% of the rituximab dose administered in the first 30 minutes, with the remaining 80% over the following 60 minutes17

It must be noted that all rapid-infusion protocols are only used after the patient has had standard administration rate of at least the first dose to ensure patients tolerate the drug.

A systematic review found that both the 60 minute and 90 minute schedule appear safe with low incidences of reactions18, noting that in the 60 minute schedule additional steroids were given as a premedication. The review recommended the 90 minute schedules as the preferred option.

Recommendations

The 90 minute rapid infusion protocol is already in place in North of England Cancer Alliance and should be adopted for biosimilar rituximab. There is greater safety evidence of than for the 60 minute schedule.

For new patients it is recommended to give the first cycle as per spc over 3 to 4 hours, then introduce rapid infusion from cycle two onwards.

Options

If switching from Mabthera®to biosimilar or from one biosimilar brand to another then there are3 main options.

  1. Give first infusion as per cycle one over 3-4 hours regardless of current infusion rate. Then increase to standard/rapid infusion from next cycle depending on current rate.

2a.If having standard infusion rate (2-3 hours infusion) introduce biosimilar at same rate then move to rapid infusion as appropriate on subsequent cycles.

2b.If having standard infusion rate (2-3 hours infusion) and consider rapid infusion is appropriate for patient then introduce biosimilar as rapid infusion (90 minutes)

3If having rapid infusion (90 minutes) then then introduce biosimilar at same rate.

Hospitalschemo teams need to make a decision on which of options 1, 2 or 3 to adopt

Practical Considerations

  • Patients will be locally assessed as to whether they are considered suitable, for example, they need to be performance status 0 or 1; have shown no signs of adverse reaction during previous infusions; and is contra-indicated in patients with high tumour bulk/burden or with high circulating lymphocyte counts. This needs to be agreed in each hospital.
  • Patients should be excluded if they have co-morbidities, such as cardiac impairment.
  • Rapid rituximab infusion is unlicensed (off label) and chemotherapy teams wishing to follow this practice must ensure they gain appropriate governance approval within their own hospital prior to adopting this practice. The unlicensed nature of the infusion rate should be explained to patients at the time of consent
  • Patients should beconsented for rapid infusion when consenting for rituximab treatment, with full explanation from consultant haematologist.Note there is no need to consent for biosimilar rituximab if already consented for originator rituximab.
  • Patients need to have had at least one infusion administered over the standard time(s) without any reaction
  • The 90 minute rapid infusion schedulefor Rituximab presented in a 250ml volume bag is 20% of the dose over 30 minutes (100ml/hour), followed by the remaining 80% over 60minutes (200ml/hour).
  • Patients receiving oral steroids should be given them the day before treatment and asked to take them, along with chlorphenamine (or appropriate local formulary antihistamine) and paracetamol, one hour before the infusion is due to start. Patients on regimes not using oral steroids can be given iv steroids and antihistamines once cannulated, but asked to take paracetamol at home.

Local and National Audit

Consideration may be made to undertaking an audit of infusion reactions for all patients started on biosimilar rituximab to build evidence base that this practice is safe.

An audit collection tool has been developed for optional use in hospitals in North of England Cancer Alliance see Appendix One.

There is an accompanying excel spread sheet to collate audit answers, this is available from or . NHS hospitals undertaking the audit are asked to share their spreadsheet data and be part of national audit.

Further details regarding the audit and further resources (e.g. draft audit registration form template that can be adapted to local use) will be posted on the BOPA website at

Summary

Most chemotherapy day units are experiencing capacity problems. Research shows that rapid infusion is safe and the 90 minute infusion schedule appears to have the strongest evidence.

NHS hospitalsare encouraged to adopt rapid infusion schedule with biosimilars choosing one of the three options id switching patients.

Consideration should be made to audit infusion reactions with biosimilar rituximab to improve the evidence base and support sate practice. An example audit form is provided in appendix one.

References

  1. NHS England, SSC1734 Biosimilar Rituximab - Provider Letter. Issue 11 April 2017. Available from NHS E local commissioning teams on request. See for local contacts.
  2. NHS England. What is a Biosimilar Medicine? 24 Sept 2015. Available at last accessed 28 April 2017
  3. British Oncology Pharmacy Association (2017). Guidelines on implementation of monoclonal antibodies. Implementation of biosimilar monoclonal antibodies. Available at last accessed 28 April 2017
  4. UK Medicines Information (UKMi). Answers to commonly asked questions about biosimilar versions April 2017. Available at last accessed 28 Apr 2017
  5. Roche Products Ltd. Summary of Product Characteristics for MabThera 100mg and 500mg concentrate for solution for infusion. Available at Last accessed 28 April 2017
  6. Napp Ltd. Summary of Product Characteristics for Truxima 500 mg concentrate for solution for infusion. Available at Last accessed 28 April 2017
  7. Personal communication Sandoz Pharmaceuticals (May 2017)
  8. Middleton H, Mollee P, Bird R, et al: Accelerated delivery of rituximab is safe on an out-patient basis. Blood 106, 2005 (abstr 4777)
  9. Salar A, Casao D, Cervera M, et al: Rapid infusion of rituximab with or without steroid-containing chemotherapy: 1-yr experience in a single institution. Eur J Haematol 77:338-340, 2006
  10. Sehn LH, Donaldson J, Filewich A, et al: Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting. Blood 109: 4171-4173, 2007
  11. Milone J, Prates V, Zoppegno L, et al: Rapid infusion of rituximab (RIR) is well tolerated and can safely be delivered in patients with lymphoproliferative diseases. Blood 110, 2007 (abstr 4503)
  12. Corey P, Go R, Schaper A: A nurse can safely deliver rituximab over 90 minutes. Oncology Nursing Society 32nd Annual Congress. April 24-27, 2007, Las Vegas, NV (abstr 2010)
  13. Gibbs S, Pout G, Wimperis J: Rapid infusion rituximab is as clinically effective and safe as conventional infusion regimes in the treatment of diffuse large B-cell lymphoma: A 2-year prospective study. Haematologica 92, 2007 (suppl 2; abstr 0708)
  14. Tuthill M1, Crook T, Corbet T, King J, Webb A Rapid infusion of rituximab over 60 min. Eur J Haematol. 2009 Apr;82(4):322-5..
  15. A rapid rituximabinfusion schedule, safety, and tolerability: A local experience. Abdulmasood, A. a. ; Al Bahrani, B. J. ; Mehdi, I. ; Nada, A. M. M. Journal of Clinical Oncology, 05/20/2011, Vol.29(15_suppl)
  16. Patel J, Ho M, Ho V, Bello C, Djulbegovic B, Sokol L, Wetzstein G. Rapid Infusion Rituximab for Maintenance Therapy: Is It Feasible? 1 Leuk Res Treatment. 2013; 2013: 629283.
  17. Atmar J. Review of the safety and feasibility of rapid infusion of rituximab. J Oncol Pract 2010;6:91–93.
  18. Lang D, Hagger C, Pearson A. Safety of rapid rituximab infusion in adult cancer patients: A systematic review International Journal of Nursing Practice, August 2011, Vol.17(4), pp.357-369


Appendix One

Biosimilar rituximab rapid infusion D&T paper V1.1 open access versionPage 1 of 7May 2017