Rituximab in renal patients

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Rituximab is a monoclonal antibody, which binds to transmembrane antigen CD20, resulting in B cell depletion.  It is licensed in combination with glucocorticoids, for the treatment of adult patients with severe, active granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA) 1, which are ANCA associated vasculitic diseases.  Off-label renal uses include systemic lupus erythematosus (SLE), membranous nephropathy (MN), and relapsing steroid sensitive minimal change disease (MCD).

Dosing

Dosing and frequency are at the discretion of the prescribing Nephrologist and may vary based on new evidence or patient need.

Vasculitis

Induction: 1000mg repeated after 2 weeks
Maintenance: 500mg to 1000mg every 6 to 12 months1 (patients may receive a reduced dose of 500mg due to age/frailty or very low bodyweight eg below 50kg)

Duration: To be reviewed after 2 years

Membranous nephropathy

Dose: 1000mg repeated after 2 weeks2, then for review

The following off label indications require an NHS Highland unlicensed use of a licensed medicine form to be completed before supply can be made:

  • Systemic lupus erythematosus/Lupus nephritis
  • Membranous nephropathy
  • Minimal change disease
PJP (Pneumocystis jirovecci (prev. Pneumocystis carinii) Pneumonia) Prophylaxis

The following patient groups should receive PJP prophylaxis:

  • Patients prescribed rituximab for vasculitis: Duration: 1 year after last dose of rituximab. 
  • Patients at higher risk of PJP: eg patients on concomitant immunosuppression (eg steroids) or patients with underlying pulmonary disease eg pulmonary fibrosis should be prescribed PJP prophylaxis.

Co-trimoxazole 480mg daily should be prescribed first line.  If not tolerated, contraindicated or patient is allergic, dapsone 100mg daily, or, atovaquone 750mg twice daily, may be considered.  Ensure PJP prophylaxis is prescribed on HERMES and request primary care to continue supply. 

Patients on rituximab only, for indications other than vasculitis, will not routinely receive PJP prophylaxis.

Contraindications and cautions for use

In general, rituximab is safe and well tolerated.  However, the following contraindications should be applied:

  • Hypersensitivity to rituximab or its constituents
  • Allergy to any murine (mouse) products or other severe allergies or hypersensitivities
  • Immunocompromised patients (e.g. neutropenia)
  • Acute or chronic infections (including TB, hepatitis C or active severe infections)
  • Severe heart failure (NYHA class IV) or severe uncontrolled cardiac disease
  • Pregnancy / Breast feeding
  • Recent Live vaccination

a) Infections

Serious infections, including fatalities, can occur during therapy with rituximab.  Rituximab should not be administered to patients with an active and / or severe infection (eg tuberculosis, sepsis and opportunistic infections) or severely immunocompromised patients (eg in hypogammaglobulinaemia).  Caution should be exercised when considering the use of rituximab in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection.

Patients reporting signs and symptoms of infection following rituximab therapy should be promptly evaluated and treated.  Before giving a subsequent course of rituximab treatment, patients should be re‐evaluated for any potential risk for infections.

b) Hepatitis B

Very rare cases of hepatitis B reactivation, including reports of fulminant hepatitis, have been reported in subjects receiving rituximab and patients should be screened prior to commencement of therapy.  Testing should include Hepatitis B surface antibody, Hepatitis B surface antigen and hepatitis B core antibody.  If positive, refer to a hepatologist.

c) Chicken pox

Patients should be advised to avoid coming into close contact with chickenpox.  In the event, that they come into contact with chicken pox or develop chicken pox and immune status is unknown then check for Varicella zoster IgG and refer to the ‘Green book’3 for further advice.  Significant exposure to varicella zoster (VZ) is defined as face to face contact or more than 15 minutes in the same room during infective period (from 48 hours prior to development of rash up until crusting of rash).  If the patient can confirm that they have definitely had chickenpox in the past, then immunoglobulin infusion is not required3.

d) Progressive multifocal leukoencephalopathy (PML)

Very rare cases of PML have occurred with rituximab therapy1.  Patients must be monitored for any new or worsening neurological symptoms or signs that may be suggestive of PML.  If PML is suspected, further dosing must be suspended until PML has been excluded.  Patients must be fully informed of this rare complication.  Patients may not notice some symptoms (eg cognitive, neurological or psychiatric symptoms), therefore should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.  If a patient develops PML, rituximab must be permanently discontinued.  Any suspected or confirmed cases should be reported to the MHRA using the yellow card reporting scheme.

e) Vaccinations

The vaccination status of patients being considered for treatment with rituximab should be reviewed and local/national guidance for adult vaccination followed.  If possible, vaccinations (including influenza and pneumococcal) should be completed at least four weeks prior to the first administration of rituximab or seven months after.   If this is not possible, they should still be given but patients may not receive full benefit.  Live vaccines are not recommended in patients while B cell depleted and should be avoided.

f) Cardiovascular history

Use of rituximab in severe heart failure (NYHA class IV) or severe uncontrolled cardiac disease is contraindicated.  In patients treated with rituximab, the occurrence of pre‐existing ischaemic cardiac conditions becoming symptomatic, such as angina pectoris, has been observed, as well as atrial fibrillation and flutter.  Therefore, in patients with a known cardiac history, the risk of cardiovascular complications resulting from infusion reactions should be considered before treatment with rituximab and patients closely monitored during administration. 

Since hypotension may occur, anti‐hypertensive medications should be withheld 12 hours prior to the rituximab infusion.  The rapid infusion regimen should not be used for patients with clinically significant cardiovascular disease, including arrhythmias.

g) Treatment in patients undergoing surgical procedures

Patients with planned elective procedures should ideally have their procedure completed before treatment with rituximab or timed to allow B-cells to recover.  If this is not possible, the risk/benefit should be discussed between the Consultant Nephrologist and Surgeon.  In the case of emergency surgical procedures, it is important to monitor the patient closely for any signs of post‐operative infection.

Consultant Nephrologist role

Prior to cycle 1 (induction)

  • Ensure prescription of rituximab is appropriate for the patient and that indication and potential side effects have been explained. Provide patient with a patient information leaflet (appendix 2). 
  • Complete the Renal rituximab checklist (appendix 1) at clinic and place in patient notes
  • Determine whether indication is licensed. An ‘NHS Highland unlicensed use of a licensed medicine form’ should be completed for indications outwith the product license and forwarded to renal pharmacist prior to initiation. 
  • Inform Specialist Renal Nurse that patient requires rituximab and provide a timescale for when it should be administered.
  • Complete a template prescription, ensuring that dose is selected, and forward to Specialist Renal Nurse (rituximab should be prescribed by brand and all patients should now be given Rixathon® unless specified by Nephrologist).
  • Prescribe rituximab on HERMES (if exact frequency unknown prescribe as ‘as directed’).

Tests to be requested at clinic prior to cycle 1

Hepatitis B antibody, Hepatitis B surface antigen, Hepatitis B core antigen, Hepatitis C antibody, HIV Antigen/Antibody, VZV

FBC, U&Es, LFTs, CRP, Serum immunoglobulins

If high risk for TB, Quantiferon

Tests to be requested within one month prior to every cycle

FBC (Consider delaying treatment if neutrophils less than 1.5 and platelets less than 75 if normal prior to treatment)

Immunoglobulins (refer to Nephrologist if below reference range) 

Prior to maintenance dose

  • Inform Specialist Renal Nurse that patient requires rituximab and provide a timescale for when it should be administered.
  • Complete a template prescription, ensuring that dose is selected, and forward to Specialist Renal Nurse (rituximab should be prescribed by brand and all patients should now be given Rixathon® unless specified by Nephrologist).

Tests to be requested within one month prior to every cycle

FBC (Consider delaying treatment if neutrophils <1.5 and platelets <75 if normal prior to treatment)

Immunoglobulins (refer to Nephrologist if below reference range) 

Patients will be reviewed at renal clinic.  Consultant Nephrologists will be responsible for requesting follow up tests appropriate to the condition being treated.  Most patients will be reviewed 4-6 weeks post infusion, then three monthly, thereafter.

NB all documents are available on PEEL shared in folder named Rituximab

Specialist Renal Nurse role
  • Forward a renal infusion suite referral form (appendix 3) to the relevant infusion suite:

Location of administration

Where to send referral

Raigmore Hospital infusion suite

Email to nhsh.infusionsuite@nhs.scot

Caithness General infusion suite

Email to nhsh.wickmedicalinfusions@nhs.scot

Belford Hospital

Email to Charge Nurse at outpatients (this is currently Mandy Sillars, mandy.sillars@nhs.scot).  The Consultant on duty in Fort William on the day the infusion will be administered should be contacted to confirm they will be available in the event of any issues arising

Western Isles Hospital

Email to wi.nhswidayhospital.nhs.scot

  • Ensure an ITR referral has been submitted requesting blood tests at least one month prior to rituximab administration once date of administration known.
  • Annotate date on rituximab prescription once date of administration known and forward prescription to Renal Pharmacist.
  • Review blood test results prior to rituximab administration and refer to Consultant Nephrologist if any issues.

Email infusion suite to inform them that blood tests have been reviewed and whether it is appropriate for the patient to receive rituximab provided they are well on the day.  The patient’s GP should be cc’d into this email to inform them the patient will be receiving rituximab.

Renal pharmacist role
  • Contact the patient to run through the patient information leaflet and answer any queries.
  • Carry out medicines reconciliation, check for allergies and update HERMES.
  • Check rituximab is prescribed on HERMES.
  • Check blood results and highlight any anomalies to the prescribing Nephrologist.
  • Conduct a pharmacist clinical check of the rituximab prescription and ensure the renal rituximab checklist and ‘unlicensed use of a licensed medicines form’ have been completed, as appropriate.
  • Forward a copy of the rituximab GP information leaflet to the patient’s GP (appendix 4)
  • Forward original prescription to appropriate dispensary ensuring rituximab will be dispensed in time for administration to patient:

Location of administration

Where to send paper prescription for dispensing

Raigmore Hospital infusion suite

Raigmore Hospital pharmacy

Caithness General infusion suite

Caithness General pharmacy

Belford Hospital

Belford Hospital pharmacy

Western Isles Hospital

Western Isles Hospital pharmacy

(Email: WI.pharmacy@nhs.scot)

Nursing staff role

Nursing staff responsible for administering rituximab will:

  • On receiving referral form, book an appointment for patient to receive rituximab within requested timescale and arrange for appointment time to be sent to patient.
  • Ensure rituximab has been dispensed and has arrived in time for administration to patient, and that the original prescription is included with the medication
  • Check an email has been received from the Specialist Renal Nurse confirming that blood tests have been checked and that it is appropriate for patient to receive rituximab provided they are well on the day.
  • Complete the rituximab pre-infusion checklist (appendix 4) and contact a Nephrologist if any issues.
  • Administer pre-medication (chlorphenamine, methylprednisolone and paracetamol) and rituximab as per locally agreed policies.
  • Issue ‘A patient alert card for patients with non oncology diseases’ with every administration of rituximab. Patients should carry this with them in case they are admitted to hospital.
  • Sign rituximab and pre-meds as being administered on the original prescription and sign rituximab as being given on the renal electronic drug administration record (HERMES) if access to HERMES is available.

If being given on the ward nursing staff should liaise with the renal pharmacist and/or ward pharmacist/infusion suite staff to ensure all processes are completed. 

Administration of rituximab

a) Infusion related adverse effects

Infusion related adverse effects are common (more than 1 in 10) and more likely to occur with the first infusion, usually within the first one to two hours.  Incidence of infusion related adverse effects decreases with subsequent infusions.1

Infusion related reactions: allergic reactions (headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension and pyrexia), angina pectoris, atrial fibrillation and flutter (in patients with prior cardiac history) and hypotension1.  Pre‐medication with methylprednisolone significantly reduces the incidence and severity of these reactions.

Patients should be closely monitored for onset of cytokine release syndrome.  Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia should have the infusion interrupted immediately and should receive aggressive symptomatic treatment.  In all patients, the infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest x-ray findings.  At this time, the infusion can be initially resumed at not more than one-half the previous rate1.

b) Preparation of rituximab

Rituximab should be made up in 0.9% sodium chloride to a concentration of between 1 and 4mg/mL1

  • To prepare 1000mg dose of Rixathon® rituximab add 1000mg to 500ml of sodium chloride 0.9% to make a final concentration of 1000mg in 600ml = 1.67mg/mL.
  • To prepare 500mg dose of Rixathon® rituximab add 500mg to 250mL of sodium chloride 0.9% to make a final concentration of 500mg in 300mL = 1.67mg/mL.

If other doses are being used contact Renal pharmacist for advice.

c) Administration of rituximab

**Full resuscitation equipment must be available**

Route: Intravenously through a dedicated line

First IV infusion  

  • Start the infusion at 50mg/hr for the first half hour.
  • Monitoring: Temperature, blood pressure, pulse, respiratory rate and oxygen saturation every 15 minutes for first hour or until stable, then hourly until infusion discontinued.
  • If no toxicity during first half hour, rate can be escalated by 50mg/hr at 30-minute intervals to a maximum of 400mg/hr.

**If patient has significant toxicity i.e. hypotension, angioedema, bronchospasm, anaphylaxis; stop infusion and call medical staff immediately.  Prepare to give hydrocortisone, IV fluids and adrenaline.**

  • If reaction was mild (e.g. throat irritation, fever, chills) and resolves, the infusion may be re-started at 50% of the rate prior to the reaction and increased as tolerated.

Second IV infusion (subsequent dose)

  • If first dose well tolerated, start at 100mg/hr and increase by 100mg/hr at 30-minute intervals to a maximum rate of 400mg/hr.
  • Monitoring: Temperature, blood pressure, pulse, respiratory rate and oxygen saturation every 15mins for first hour followed by hourly observations until infusion discontinued.
  • If patient had a reaction to previous dose administer and conduct monitoring as per instructions for first dose.

If post infusion observations satisfactory and administration is uncomplicated day case patients can go directly home.

References
  1. Napp Pharmaceuticals Ltd. SPC Truxima 500 mg concentrate for solution for infusion [rituximab].  Accessed via the eMC medicines.org.uk on 16th August 2019.  Last updated on 7th August 2019. 
  2. Fervenza et al, Rituximab or cyclosporine in the treatment of membranous nephropathy. The New England Journal of Medicine 381: 36–46, 2019.
  3. Public Health England. Immunisation against infectious diseases ‘The Green Book’.  Chapter 34 Varicella.  Accessed online via: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/456562/Green_Book_Chapter_34_v3_0.pdf on 11/10/19
Appendix 1 - Renal Rituximab checklist for use at clinic prior to first cycle

See here

Appendix 2 - Patient information leaflet

See here

Appendix 3 - Infusion suite referral form

See here.

Appendix 4 - GP information leaflet

See here.

Appendix 5 - Rituximab pre-infusion checklist

See here.

Editorial Information

Last reviewed: 30 April 2020

Next review: 28 February 2022

Author(s): Renal MDT

Version: 1

Approved By: TAM subgroup of ADTC

Reviewer Name(s): Renal MDT

Document Id: TAM446