1. health and fitness
2. therapy

Guidelines for the use and administration of
Rituximab in Rheumatoid Arthritis (RA)
(To be used in conjunction with local policies for intravenous infusions)
Contents
Introduction
Licensed Indication
Pre-treatment screening
Contraindications
Evaluation of response
Definition of response
Repeated treatment
Treatment Dose and Co-medication
• Regime
• Prescription
Practical considerations
Pre-infusion Assessment
Administration
• Checklist
• Administering the infusion
• Clinical observations
• Infusion reactions
Post-infusion care
Adverse events
Patient information
References
Appendix 1 Documentation for Pre-infusion Assessment (example)
Appendix 2 Documentation for Administration of Infusion (example)
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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 nonHodgkins lymphoma and in 2006 it was licensed for use in severe active RA following clinical trials1, 2.
A consensus statement on the use of Rituximab in rheumatoid arthritis (RA) was published in 20073,
the British Society for Rheumatology (BSR) have endorsed its use4 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
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*Currently there is no disease activity score (DAS) requirement to qualify for treatment with Rituximab
although Smolen et al3 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 SCREENING3
•
•
•
•
•
•
•
•
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 response3. 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 al3 make some recommendations on defining a response including a minimum
improvement of DAS28 of ≥1.2.
REPEATED TREATMENT
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Repeated infusion courses may be considered between 6-12 months3, 4 after the initial course. The
optimum repeated treatment schedule is being evaluated but currently there is only evidence for retreatment of responders3.
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 1st 30 minutes
50mg/hour (25mls/hour)
nd
o 2 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:
100mg/hour (50mls/hour)
o 1st 30 minutes
o 2nd 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
• Hydrocortisone
• Paracetamol
• Metoclopramide
10 mg IV
100 mg IV
1G orally
10mg IV
tds
tds
4-5 hourly (max 4gm in 24 hours)
tds
*NB: Rituximab can be diluted to a concentration of between 1-4mgs/ml normal saline
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Concentration
1mg/ml
Volume of fluid
1000mls
2mgs/ml
(Preferred 4mgs/ml
concentration above)
250mls
500mls
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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; 1st 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
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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 O2 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
1st or 2nd 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
1st 30 minutes
50mg/hour
25mls/hour
2nd 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
1st 30 minutes
100mg/hour
50mls/hour
2nd 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.
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Clinical observations on DAY 1 and DAY 15
1st hour – Blood pressure, Pulse, Temperature and O2 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
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ADVERSE EVENTS3, 5
•
•
Infusion reactions
o Mild to moderate infusion reactions – 30-35% at 1st infusion; less with the 2nd (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
(www.emc.medcines.org.uk)
PATIENT INFORMATION
The Arthritis Research Campaign (arc) have produced a patient information leaflet on the use of
Rituximab in RA www.arc.co.uk
The National Rheumatoid Arthritis Society (NRAS) has patient information about Rituximab on the
website www.rheumatoid.org.uk
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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: 2572-81
2. 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 20.12.2006 as 10.1136/ARD.2006.061002
4. British Society of Rheumatology (BSR) Statement on Rituximab for Refractory Rheumatoid
Arthritis 2006 http://www.rheumatology.org.uk/guidelines/clinicalguidelines
5. Summary of Product Characteristics Rituximab (Mabthera) July 2006
www.emc.medcines.org.uk
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)
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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
IS THE PATIENT PREGNANT /BREASTFEEDING
YES / NO / NA
ANY CURRENT INFECTION E.G. COLD, COUGH, DENTAL ABSCESS, UTI
YES / NO
ANY KNOWN RECENT EXPOSURE TO CHICKEN POX /SHINGLES
YES / NO
ANY VACCINATIONS IN THE LAST 4 WEEKS
YES / NO
Urinalysis
BLOOD TESTS RESULTS: List FBC, LFTs, U&Es ESR CRP Hep B Screen Igs CD19
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CHECKLIST:
Y/N - details
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
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Appendix 2
ADMINISTRATION OF RITUXIMAB
WARD:
DATE:
Rituximab infusion
1
2
(circle)
Affix patient details label
Checklist prior to commencing infusion
1. Normal FBC
2. Pre- assessment review documented in notes
3. Drug chart completed for Rituximab, pre-infusion and prn
medications
4. Baseline observations on arrival within normal parameters
5. Patient is wearing a hospital name band
Y/N
Y/N
Y/N
Y/N
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)
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DATE
NAME
HOPSITAL NUMBER
Nursing Observations Record Sheet - Rituximab Infusions
Time
Duration
Rate
of BP
of infusion infusion
mm/hg
hr/mins
mls/hr
Pulse
bpm
Temp ºC
O2 sats
%
Any adverse reaction?
Initials
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