Rituximab Side Effects and Management Protocol
Infusion-Related Reactions
Up to 77% of patients experience infusion reactions during the first rituximab infusion, with severe reactions occurring in approximately 10% of cases, making premedication and careful monitoring essential for all patients. 1
Common Reaction Manifestations
- Mild to moderate reactions include rash, urticaria, fever, myalgia, headache, transient hypertension, rigors, and chills, occurring in approximately 20-32% of patients 2, 3
- Severe reactions are characterized by hypoxia, pulmonary infiltrates, respiratory distress, bronchospasm, hypotension, myocardial infarction, ventricular fibrillation, and cardiogenic shock, with fatal outcomes reported 1, 4
- Gastrointestinal symptoms including nausea, vomiting, diarrhea, and abdominal pain frequently occur during infusion reactions 4
Reaction Grading and Management Algorithm
For Grade 1 reactions (primarily cutaneous symptoms): 4
- Stop or slow the infusion rate immediately 1
- Provide symptomatic treatment 1
- Resume infusion at 50% of the previous rate after symptom resolution 1
- Same-day rechallenge at reduced infusion rate is safe and appropriate 4, 5
For Grade 2 reactions (urticaria, nausea, vomiting, dyspnea, or asymptomatic bronchospasm): 4
- Stop the infusion immediately 1
- Administer methylprednisolone 40 mg IV 6
- Provide symptomatic treatment 1
- Resume at 50% rate once symptoms resolve 1
- Most patients (84%) tolerate same-day rechallenge, though 16% may experience recurrent grade 1-2 reactions 5
For Grade 3 reactions (symptomatic bronchospasm, dyspnea, hypoxia, wheezing): 4
- Stop the infusion immediately 1
- Provide aggressive symptomatic treatment 1
- Administer methylprednisolone 40 mg IV 6
- Consult allergy specialist before attempting rechallenge 4, 6
- Desensitization protocols under specialized care are necessary for future infusions 4, 6
- All patients with grade 3 reactions experienced recurrent reactions with same-day rechallenge 5
For Grade 4 reactions (anaphylaxis or severe hypotension): 4
- Stop the infusion immediately 1
- Provide aggressive symptomatic treatment 1
- Permanently discontinue rituximab 1
- Desensitization is the only option if rituximab remains necessary 4
Mandatory Premedication Protocol
All patients must receive premedication before each rituximab infusion: 1, 4
- Antihistamine (diphenhydramine 25-50 mg) administered 30 minutes before infusion 1, 6
- Acetaminophen 650-1000 mg administered 30 minutes before infusion 4, 6
- For patients with previous grade 2-4 reactions: add methylprednisolone 40 mg IV 20-30 minutes before infusion 6
Intravenous Infusion Protocol
First Infusion - Standard Protocol 7
- Initiate at 50 mg/hr 7
- In absence of infusion toxicity, increase by 50 mg/hr increments every 30 minutes 7
- Maximum rate: 400 mg/hr 7
- Typical dose: 375 mg/m² for first cycle 3
Subsequent Infusions - Standard Protocol 7
- Initiate at 100 mg/hr 7
- In absence of infusion toxicity, increase by 100 mg/hr increments every 30 minutes 7
- Maximum rate: 400 mg/hr 7
- Typical dose: 500 mg/m² for subsequent cycles 3
Rapid Infusion Protocol (Selected Patients Only) 7
- Only for previously untreated follicular NHL and DLBCL patients who did not experience grade 3-4 reactions in Cycle 1 7
- Administer 20% of total dose in first 30 minutes, remaining 80% over next 60 minutes 7
- Contraindications: patients with clinically significant cardiovascular disease or circulating lymphocyte count ≥5,000/mm³ 7
Supportive Measures During Infusion 3
- Intravenous hydration: 2000 mL daily on days 0 and 1 of each cycle 3
- Allopurinol 300-600 mg daily for tumor lysis syndrome prevention 3
- Continuous monitoring of vital signs during infusion 6
Serious Delayed Adverse Effects
Hepatitis B Reactivation 4, 7
- Mandatory screening: measure HBsAg and anti-HBc before initiating treatment 7
- Can result in fulminant hepatitis, hepatic failure, and death 4, 7
- Discontinue rituximab and all concomitant medications if reactivation occurs 7
- Initiate preemptive antiviral therapy if HBV positive 4
Progressive Multifocal Leukoencephalopathy (PML) 4, 7
- Fatal encephalitis caused by JC polyomavirus 4
- Presents with new or changing neurological symptoms: confusion, dizziness, loss of balance, difficulty talking or walking, decreased strength, vision problems 7
- Requires immediate discontinuation of rituximab 7
Severe Mucocutaneous Reactions 4, 7
- DRESS, AGEP, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported 4
- These reactions are not amenable to desensitization and require permanent drug avoidance 4, 6
- Patients should report painful sores, ulcers, blisters, peeling skin, rash, or pustules immediately 7
Immunologic Complications 2, 4
- Hypogammaglobulinemia risk increases with multiple courses, particularly in patients receiving repeated treatments 2
- Monitor serum immunoglobulin levels before and periodically after rituximab 2
- Increased infection risk due to B-cell depletion, with median antibody recovery time of 9 months (range 5.9-14.4 months) 4
- Consider Pneumocystis pneumonia prophylaxis with concomitant immunosuppression 4
Tumor Lysis Syndrome 4
- Develops within 12-24 hours of first infusion 4
- Manifests as increased serum creatinine, potassium, phosphate, lactate dehydrogenase, and uric acid 4
- Patients at highest risk: those with high tumor burden 4
- Patients should report nausea, vomiting, diarrhea, and lethargy immediately 7
Cardiovascular Complications 4, 7
- Myocardial infarction, ventricular fibrillation, cardiogenic shock, and hypotension reported 1, 4
- Patients should report chest pain and irregular heartbeats immediately 7
Critical Monitoring Requirements
Before initiating rituximab: 4, 7
- Screen for HBV infection (HBsAg and anti-HBc) 7
- Obtain baseline CBC with differential and platelet count 7
- Measure baseline immunoglobulin levels 4
- Screen for latent tuberculosis 4
During rituximab therapy: 7
- CBC with differential and platelet counts at 2-4 month intervals 7
- Monitor for cytopenias after final dose until resolution 7
- Observe patients during and after infusion for infusion-related reactions 1
- Monitor kidney and liver function periodically 4
Important Clinical Caveats
- Infusion reactions decrease in frequency with subsequent infusions, with 63% occurring during first exposure 5
- Patients with higher absolute lymphocyte counts are at increased risk for infusion toxicity 3
- Rituximab-induced serum sickness occurs more commonly in patients with autoimmune diseases (78-85% of cases) and typically presents 7-21 days after infusion 4, 6
- The death rate in uncontrolled rituximab trials for ITP was 3%, though causality was unclear 2
- Fractionated infusion protocol (100 mg over 2 hours, then escalating rate) reduces severe reactions 3