Rituximab in renal patients (Guidelines)

Vasculitis

• Induction: 1000mg repeated after 2 weeks
• Maintenance: 500mg to 1000mg every 6 to 12 months (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 weeks, then for review

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.

Dose:

• First line: Co-trimoxazole 480mg daily. 
• 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. 

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

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.

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.

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’ for further advice. 
• Significant exposure to varicella zoster (VZ) is defined as 'face to face contact for 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 required.

Progressive multifocal leuko‐encephalopathy (PML)

• Very rare cases of PML have occurred with rituximab therapy. 
• 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.

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.

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. 

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.

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.

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 hypotension. 

Cytokine release syndrome

Patients should be closely monitored for onset of cytokine release syndrome.

• 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 rate.

Preparation

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

• 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.

Administration

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 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 15 minutes 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.

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 (see below) 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.

NHS Highland intranet access required for these documents.

• Renal Rituximab checklist for use at clinic prior to first cycle 
• Infusion suite referral form 
• Rituximab pre-infusion checklist

• Rituximab GP information leaflet

• NHS Highland patient information leaflet: Treatment of diseases affecting the kidney using Rituximab

ANCA : Anti-Neutrophil Cytoplasmic Antibodies
FBC : Full Blood Count
GPA : Granulomatosis with Polyangiitis
HBcAb : Hepatitis B Core Antibody
HBsAb : Hepatitis B Surface Antibody
HBsAg : Hepatitis B Surface Antigen
HERMES : NHS Highland’s Prescribing System
HIV : Human Immunodeficiency Virus
IgG : Immunoglobulin G
ITR : Integrated Test Request
MCD : Minimal Change Disease
MHRA : Medicines and Healthcare products Regulatory Agency
MN : Membranous Nephropathy
MPA : Microscopic Polyangiitis
NYHA : New York Heart Association
PEEL : Shared Folder System
PJP : Pneumocystis jirovecii Pneumonia
PML : Progressive Multifocal Leukoencephalopathy
SLE : Systemic Lupus Erythematosus
TB : Tuberculosis
VZV : Varicella Zoster Virus