3 Regime Prescription Practical considerations 4 Pre-infusion Assessment 4 Administration. 5 Checklist. 5 Administering the infusion

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1 Guidelines for the use and administration of Rituximab in Rheumatoid Arthritis (RA) (To be used in conjunction with local policies for intravenous infusions) Contents Page Introduction 1 Licensed Indication 1 Pre-treatment screening 2 Contraindications 2 Evaluation of response 2 Definition of response 2 Repeated treatment 2 Treatment Dose and Co-medication 3 Regime Prescription Practical considerations 4 Pre-infusion Assessment 4 Administration 5 Checklist 5 Administering the infusion 5 Clinical observations 6 Infusion reactions 6 Post-infusion care 6 Adverse events 7 Patient information 7 References 8 Appendix 1 Documentation for Pre-infusion Assessment (example) 9 Appendix 2 Documentation for Administration of Infusion (example) 11 INTRODUCTION Rituximab is a genetically engineered chimeric mouse / human antibody. It acts by depleting antibody producing B cells. Rituximab has been licensed in the UK since 1998 for the treatment of non- Hodgkins lymphoma and in 2006 it was licensed for use in severe active RA following clinical trials 1, 2. A consensus statement on the use of Rituximab in rheumatoid arthritis (RA) was published in , the British Society for Rheumatology (BSR) have endorsed its use 4 and it is currently being evaluated by NICE.(NICE TA126 issued August 2007). LICENSED INDICATION Severe active RA* in combination with Methotrexate in adult patients who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs, including one or more tumour necrosis factor (TNF) inhibitor therapies

2 *Currently there is no disease activity score (DAS) requirement to qualify for treatment with Rituximab although Smolen et al 3 suggest >3.2. In the UK, if the patient has previously qualified for Anti-TNF a DAS of >5.2 has been required. PRE-TREATMENT SCREENING 3 Detailed history - including o chronic or recent co-morbidity such as cardiovascular and pulmonary disease o recurrent infections o allergies Physical examination to exclude contraindications CXR Routine blood tests Hepatitis B screen Immunoglobulin levels Baseline DAS28 (to monitor response) CD19 There may be some value in baseline CD19 levels, but measuring CD19 posttreatment is not necessary to determine when to repeat treatment, as this decision should be based on the individual patient s signs and symptoms (DAS28) NB: If patients need inactivated vaccinations e.g. Flu, the course should be completed 1 month prior to commencing Rituximab or given at least 7 months after treatment to ensure efficacy of immunisation. CONTRAINDICATIONS Hypersensitivity to Rituximab or other murine proteins Active acute or chronic infection Severe heart failure NYHA Class IV Pregnancy Use in children (safety not yet established) EVALUATION OF RESPONSE Rituximab may take up to 16 weeks from the first infusion to reach a response 3. Although the patient may have been seen prior to this time, any evaluation of response should wait until at least 16 weeks. It is worth noting that the IV glucocorticoid pre-medication may produce an early (usually temporary) effect for up to 8 weeks. DEFINITION OF RESPONSE Smolen et al 3 make some recommendations on defining a response including a minimum improvement of DAS28 of 1.2. REPEATED TREATMENT

3 Repeated infusion courses may be considered between 6-12 months 3, 4 after the initial course. The optimum repeated treatment schedule is being evaluated but currently there is only evidence for retreatment of responders 3. TREATMENT DOSE AND CO-MEDICATION Regime I.V. 1000mg Rituximab on Day 1 and Day 15 Methotrexate given weekly (dose as directed by Rheumatologist) Prescription The Physician should prescribe: - PRE-MEDICATION DRUGS Methylprednisolone 100mg IV (100mgs in 100mls normal saline infused over 30 minutes) to be commenced 60 minutes before Rituximab infusion Paracetamol 1gm orally - 60 minutes prior to infusion Chlorphenamine 10 mg IV - 60 minutes prior to infusion INFUSION THERAPY* The following prescription is based on 2mgs/ml (MabThera 10mg/ml dilution) First infusion - DAY 1 I.V. Rituximab 1000mg in 500mls of normal saline To be infused as follows: o 1 st 30 minutes 50mg/hour (25mls/hour) o 2 nd 30 minutes 100mg/hour (50mls/hour) o Thereafter the rate can be increased by 50mg/hour (25mls/hour) every 30 minutes to a maximum rate of 400mg/hour (200mls/hour) providing no adverse reactions occur Second infusion - DAY 15 (providing DAY 1 infusion was without adverse events) I.V. Rituximab 1000mg in 500mls of normal saline To be infused as follows: o 1 st 30 minutes 100mg/hour (50mls/hour) o 2 nd 30 minutes 200mg/hour (100mls/hour) o Thereafter the rate can be increased by 100mg/hour (50mls/hour) every 30 minutes to a maximum rate of 400mg/hr (200mls/hour) providing no adverse reactions occur AS REQUIRED Chlorphenamine 10 mg IV tds Hydrocortisone 100 mg IV tds Paracetamol 1G orally 4-5 hourly (max 4gm in 24 hours) Metoclopramide 10mg IV tds *NB: Rituximab can be diluted to a concentration of between 1-4mgs/ml normal saline

4 Concentration 1mg/ml 2mgs/ml (Preferred 4mgs/ml concentration above) Volume of fluid 1000mls 500mls 250mls

5 PRACTICAL CONSIDERATIONS Rituximab should only be administered in an area where full resuscitation facilities and close monitoring are available. This is usually done on an out-patient basis. Consideration should be given to the length of infusion time, ensuring that the patient arrives early enough in the day to complete the infusion. The first infusion may take between 6-7 hours to complete (i.e. IV Methylprednisolone 30 minutes; interval 30 minutes; 1 st infusion minimum 4 hours 15 minutes) or longer if the patient has any adverse reactions (see later section). The second infusion can be completed more quickly (Rituximab minimum of 3 hours 15 minutes) if the patient had no adverse effects during the first infusion. PRE-INFUSION ASSESSMENT This may be done 1-2 days prior to both of the infusions. The assessment will be undertaken by a member of the Rheumatology team to assess general health and to check for any sign of infection. Screening tests include: FBC, LFTs and U&Es Urinalysis (MSU, if any sign of infection) The results of blood and urine tests should be reviewed and documented in the patient s notes. Advise the patient to omit any oral anti-hypertensives for 12 hours prior to infusion (Rituximab may cause hypotension during infusion). Patients should bring these medications with them to take in the event of hypertension during the infusion. In hospitals where Pharmacy is preparing the infusion, the prescription should be sent to the Pharmacy Aseptics Facility at least 48 hours before the proposed infusion time. It is the responsibility of the Rheumatology team to then advise the Pharmacy to prepare the drug once all results are found to be satisfactory. If the Rituximab is being prepared by the ward / day unit staff*, the drugs should be ordered from pharmacy once the pre-assessment has been completed. * Rituximab can be classified as a.cytotoxic since it destroys B cells. However, it is different to the small molecules traditionally used as cytotoxic chemotherapy, which generally exert their effect by interfering with DNA replication. These effects are non-specific and can therefore result in adverse events when rapidly dividing healthy cells are also affected. By contrast Rituximab will only destroy CD20 positive B cells. Since the drug product does not contain any anti-microbial preservative or bacteriostatic agents, aseptic technique must be observed during preparation of the infusion solution. Rituximab does not require any special handling precautions beyond those described and is subject to the same considerations as any other preparation for intravenous use, including other monoclonal antibodies See an example of a pre-infusion assessment in Appendix 1

6 ADMINISTRATION On the day of the Rituximab infusion: The nurse should (see checklist Appendix 2): - Check pre-assessment has been performed Check that the patient has not received analgesics containing paracetamol within the last 4 hours and has omitted their morning dose of any anti-hypertensive medication. Take and record Temperature, Pulse, Blood Pressure and O 2 Saturation levels as baseline Insert venflon Ensure infusion pump is ready and working Administer pre-infusion medications as per drug chart, commencing 60 minutes before Rituximab is given In Units where the staff are preparing the infusion, make up as follows, using an aseptic technique: a. 1 single use vial of Rituximab contains 500mg in 50mls, therefore use 2 vials (1000mg) b. Remove an appropriate equivalent volume i.e. 100mls from the bag of I.V. normal saline c. Add Rituximab d. Gently invert the bag to mix and avoid foaming. Administering the infusion: Rituximab is infused through a peripheral cannula using an IV pump with a primed line. NB: The following regime is based on a concentration of 2mgs/ml i.e. 1000mgs in 500mls. The rate of the infusion will depend on the concentration of the Rituximab and whether it is the 1 st or 2 nd infusion. In the event of a reaction to the first infusion, the second infusion should be administered as per instructions for the first infusion. INFUSION RATE FOR DAY 1 INFUSION Time Mgs/hour Mls/hour 1 st 30 minutes 50mg/hour 25mls/hour 2 nd 30 minutes 100mg/hour 50mls/hour Thereafter the rate can be increased by 50mg/hour (25mls/hour) every 30 minutes to a maximum rate of 400mg/hour (200mls/hour) providing no adverse reactions occur (see page 6) The infusion should continue until completed (providing no adverse reactions occur). INFUSION RATE FOR DAY 15 INFUSION if the patient had no reaction to the first infusion Time Mgs/hour Mls/hour 1 st 30 minutes 100mg/hour 50mls/hour 2 nd 30 minutes 200mg/hour 100mls/hour Thereafter the rate can be increased by 100mg/hour (50mls/hour) every 30 minutes to a maximum rate of 400mg/hour (200mls/hour) providing no adverse reactions occur (see page 6) The infusion should continue until completed providing no adverse reactions occur.

7 Clinical observations on DAY 1 and DAY 15 1 st hour Blood pressure, Pulse, Temperature and O 2 sats every 15 minutes Thereafter, every 30 minutes prior to increasing the rate of infusion and throughout the course of the infusion once maximum rate is reached. Most reactions have been noted during the first few minutes of the infusion, so the patient should be observed carefully during this time and following increases in infusion rates. INFUSION REACTIONS Acute infusion reactions may occur within 1-2 hrs of the first Rituximab infusion. These consist of fever, headache, rigors, flushing, nausea, rash, and URTI symptoms. Transient hypotension and bronchospasm are usually related to the infusion rate If the patient experiences an infusion reaction Mild to moderate reactions e.g. low grade fever; hypotension <30mmHg from baseline o Halve the infusion rate and o Consider giving prn medication Moderate to severe reactions e.g. fever >38.5ºC; chills; mucosal swelling; shortness of breath; hypotension by >30mmHg from baseline o STOP the infusion and treat the symptoms. o Contact the doctor. o The infusion should be restarted at half the previous rate only when the symptoms have resolved. Note: in the case of extravasation, Rituximab is not an irritant and no special action is needed POST INFUSION 1. Remove venflon 2. Advise patient to seek medical help if they have any symptoms that could be due to an infection e.g. fever in the hours or days after the infusion ensure they have appropriate contact numbers for the Rheumatology Department or otherwise to contact GP and / or attend A & E 3. Advise patient to restart any anti-hypertensive drugs the day after infusion 4. Organise infusion 2 or follow up appointment as required 5. Ensure patient is having regular methotrexate monitoring according to BSR and local guidelines 6. Ensure the patient has a follow up assessment at 16 weeks to assess response

8 ADVERSE EVENTS 3, 5 Infusion reactions o Mild to moderate infusion reactions 30-35% at 1 st infusion; less with the 2 nd (see above) o Severe infusion reactions are uncommon frequency is reduced by the concomitant use of IV steroids Infections o Small increase in serious infections (not opportunistic infections e.g. TB) See Summary of Product Characteristics (SPC) for full updated list of adverse events ( PATIENT INFORMATION The Arthritis Research Campaign (arc) have produced a patient information leaflet on the use of Rituximab in RA The National Rheumatoid Arthritis Society (NRAS) has patient information about Rituximab on the website

9 REFERENCES 1. Edwards CWE, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-Cell-targeted therapy with Rituximab in patients with rheumatoid arthritis N.Engl J Med 2004;350: Edwards JC, Leandro MJ, Cambridge G. Repeated B Lymphocte depletion therapy in rheumatoid arthritis:5 year follow-up 2005 Arthritis and Rheumatism Volume 52:9(Supplement) 3. Smolen JS, Keystone EC, Emery P et al. Consensus statement on the use of Rituximab in patients with rheumatoid arthritis ARD Online First as /ARD British Society of Rheumatology (BSR) Statement on Rituximab for Refractory Rheumatoid Arthritis Summary of Product Characteristics Rituximab (Mabthera) July These guidelines have been developed by Maggie Carr, Consultant Nurse in Rheumatology, Ashford and St Peter s NHS Hospitals Trust and Diane Home, Consultant Nurse in Rheumatology, West Middlesex University Hospital in consultation with medical and pharmacy colleagues. Acknowledgements Rheumatology Departments at University College London Hospitals, St Georges Hospital NHS Trust, London and Wirral Hospital NHS Trust Drug Information at Roche Products ltd Ashford and St Peter s Hospitals (ASPH) NHS Trust 2007 West Middlesex University Hospital NHS Trust 2007 Copyright and other intellectual rights in this document belong to the ASPH NHS Trust and West Middlesex University Hospitals University NHS Trust. The Trusts authorise healthcare organisations to reproduce this material for educational and non-commercial use. Minor update modification made: 22nd July, 2009 (by Susan Oliver)

10 Appendix 1 RITUXIMAB PRE-TREATMENT ASSESSMENT (1-2 days prior to infusion) Patient details label DATE: ASSESSMENT PERFORMED BY: Temp ºC Pulse bpm Resps rpm BP mm/hg Urinalysis IS THE PATIENT PREGNANT /BREASTFEEDING ANY CURRENT INFECTION E.G. COLD, COUGH, DENTAL ABSCESS, UTI ANY KNOWN RECENT EXPOSURE TO CHICKEN POX /SHINGLES ANY VACCINATIONS IN THE LAST 4 WEEKS YES / NO / NA YES / NO YES / NO YES / NO BLOOD TESTS RESULTS: List FBC, LFTs, U&Es ESR CRP Hep B Screen Igs CD19 Page 10 of 13 Version 13 March 2007

11 CHECKLIST: Does the patient have an information leaflet about Rituximab? Does the patient know details of first infusion Date Time Venue Has the patient arranged transport home? Does the patient know that any anti-hypertensive medication needs to be omitted on the morning of infusion? Does the patient know dates for second infusion second pre-treatment visit Are the necessary medications prescribed ready for the infusion? Has the chart been taken to pharmacy (preferably 48 hours before infusion due) Has pharmacy been told to proceed with making up of Rituximab once preassessment satisfactory? Have notes gone to ward? To be filed in patient notes following infusion Y/N - details Page 1 Version 13 March 2007

12 Appendix 2 WARD: ADMINISTRATION OF RITUXIMAB DATE: Rituximab infusion 1 2 (circle) Affix patient details label Checklist prior to commencing infusion 1. Normal FBC Y / N 2. Pre- assessment review documented in notes Y / N 3. Drug chart completed for Rituximab, pre-infusion and prn Y / N medications 4. Baseline observations on arrival within normal parameters Y / N 5. Patient is wearing a hospital name band Y/N If NO to questions 1-4 please contact the Rheumatology Department Insert relevant contact details If YES proceed with Rituximab infusion as per guidelines Document all observations and infusion rates on the record sheet and any other information on the nursing record sheet. (S) Page 12 of 13 Version 13 March 2007

13 DATE NAME HOPSITAL NUMBER Nursing Observations Record Sheet - Rituximab Infusions Time Duration of infusion hr/mins Rate of infusion mls/hr BP mm/hg Pulse bpm Temp ºC O 2 sats % Any adverse reaction? Initials Page 13 of 13 Version 13 March 2007