What is the recommended method to reconstitute and dilute rituximab for intravenous infusion, including appropriate diluent, final concentration, and infusion rate?

Rituximab Reconstitution and Dilution Protocol

Preparation and Dilution

Rituximab requires no reconstitution—it is supplied as a ready-to-use liquid at 10 mg/mL concentration that must be diluted in 0.9% sodium chloride or 5% dextrose to a final concentration of 1–4 mg/mL before intravenous infusion. 1

Step-by-Step Dilution Procedure

• Use strict aseptic technique with a sterile needle and syringe to withdraw the required dose from the vial 1
• Calculate the dose based on body surface area (375 mg/m² for most indications, or 250 mg/m² for specific protocols such as ibritumomab tiuxetan regimens) 2, 3, 1
• Dilute in an infusion bag containing either 0.9% sodium chloride or 5% dextrose injection to achieve a final concentration between 1 mg/mL and 4 mg/mL 1
• Gently invert the bag to mix—do not shake vigorously 1
• Never mix rituximab with other drugs in the same infusion bag 1
• Discard any unused portion remaining in the vial after withdrawal 1

Storage of Diluted Solution

• Refrigerate diluted solutions at 2–8°C for up to 24 hours 1
• Diluted rituximab has been shown stable for an additional 24 hours at room temperature, but refrigeration is strongly preferred because the solution contains no preservative 1
• Polyvinylchloride and polyethylene infusion bags are both compatible with rituximab 1

Mandatory Premedication

All patients must receive acetaminophen (650–1000 mg orally) and an antihistamine (diphenhydramine 25–50 mg IV or orally) 30 minutes before every rituximab infusion to reduce the 77% incidence of infusion-related reactions. 3, 4, 1

• For rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris, add methylprednisolone 100 mg IV (or equivalent corticosteroid) 30 minutes before infusion 1, 3
• For pediatric patients with mature B-cell non-Hodgkin lymphoma or acute lymphoblastic leukemia, administer prednisone as part of the chemotherapy regimen prior to rituximab 1

First Infusion Rate Protocol

The first rituximab infusion carries the highest risk—82–95% of all infusion reactions occur during this initial dose—and must be administered slowly with continuous monitoring. 3

Standard First Infusion Schedule

• Start at 50 mg/hour for the first 30 minutes 1, 3
• If no reaction occurs, increase by 50 mg/hour every 30 minutes 1, 3
• Maximum rate: 400 mg/hour 1, 3
• Total infusion time for the first dose is typically 3–4 hours 3

Subsequent Infusion Rates

If the first infusion was well-tolerated without grade 3–4 reactions, subsequent infusions can be safely shortened to 90 minutes. 3, 5, 6

Rapid 90-Minute Infusion Protocol (Second and Subsequent Doses Only)

• Administer 20% of the total dose over the first 30 minutes 5
• Administer the remaining 80% over the next 60 minutes 5
• Deliver the total dose in 500 mL of diluent 5
• This rapid schedule has been validated in multiple studies with no grade 3–4 infusion reactions observed 5, 6

Monitoring During Infusion

• Monitor vital signs continuously for at least 2 hours during the first infusion 4, 3
• Continue monitoring for 1–2 hours after infusion completion, particularly for the first dose 4
• Have emergency equipment immediately available: epinephrine, oxygen, IV fluids, bronchodilators, and corticosteroids 4, 1

Management of Infusion Reactions

Grade 1 Reactions (Mild: Flushing, Rash, Pruritus)

• Stop or slow the infusion to 50% of the current rate 3, 7
• Administer additional diphenhydramine and acetaminophen 3
• Resume infusion at 50% of the reduced rate once symptoms resolve 3

Grade 2 Reactions (Moderate: Urticaria, Nausea, Vomiting, Dyspnea Without Hypoxia)

• Stop the infusion immediately 3, 7
• Give methylprednisolone 40 mg IV if not already administered 3
• After complete symptom resolution, restart at 50% of the previous rate 3

Grade 3 Reactions (Severe: Symptomatic Bronchospasm, Hypoxia, Wheezing, Hypotension)

• Stop the infusion immediately and permanently discontinue for that session 3, 7
• Administer methylprednisolone 40 mg IV (or up to 15 mg/kg for very severe cases) 3
• Provide aggressive supportive care: bronchodilators, oxygen, IV fluids 3
• Do not restart the infusion during the same treatment session 7
• All patients who experienced grade 3 reactions had recurrent reactions when same-day rechallenge was attempted 7

Grade 4 Reactions (Life-Threatening: Anaphylaxis, Severe Hypotension, Respiratory Failure, Myocardial Infarction, Ventricular Fibrillation, Cardiogenic Shock)

• Permanently discontinue rituximab—rechallenge is absolutely contraindicated 3, 7, 1
• Initiate emergency resuscitation with epinephrine, high-dose corticosteroids, vasopressors as needed 3
• Approximately 10% of patients experience grade 3–4 reactions 3, 8

Critical Safety Warnings

• Screen all patients for hepatitis B before initiating rituximab due to risk of fatal viral reactivation 3, 4, 7
• Screen for latent tuberculosis prior to administration 4
• Obtain baseline immunoglobulin levels (IgG, IgM, IgA) 2
• Provide Pneumocystis jirovecii pneumonia prophylaxis during treatment and for at least 6 months following the last infusion in patients with granulomatosis with polyangiitis and microscopic polyangiitis 1
• Consider PCP prophylaxis for patients with pemphigus vulgaris during and following treatment 1

Common Pitfalls to Avoid

• Never attempt same-day rechallenge after a grade 3 reaction—all such attempts resulted in recurrent reactions 7
• Do not use the 90-minute rapid infusion for the first dose—this protocol is validated only for second and subsequent infusions 3, 5, 6
• Do not skip premedication—it reduces severe reactions from 4.7% to 1% 3
• Do not dilute rituximab with other drugs or mix it with medications in the same infusion bag 1
• Do not use rituximab if particulates or discoloration are present upon visual inspection 1