What prophylaxis is required for patients on rituximab (Rituxan)?

Prophylaxis Required for Patients on Rituximab

Patients receiving rituximab require Pneumocystis jirovecii pneumonia (PJP) prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) during treatment and for at least 6 months after the last dose, and hepatitis B virus (HBV) screening with prophylaxis for those at risk. 1, 2

PJP Prophylaxis

Mandatory Prophylaxis Indications

All patients receiving rituximab should receive PJP prophylaxis regardless of concomitant steroid dose or underlying condition. 1, 3, 2

• The EULAR 2024 guidelines explicitly recommend TMP-SMX prophylaxis for all patients with ANCA-associated vasculitis receiving rituximab, cyclophosphamide, and/or high-dose glucocorticoids 1
• The FDA label for rituximab mandates PCP prophylaxis for GPA/MPA patients during treatment and for at least 6 months following the last rituximab infusion 2
• The ACR 2021 guidelines conditionally recommend prophylaxis for patients with GPA/MPA receiving rituximab or cyclophosphamide, independent of steroid dose 1
• PCP prophylaxis should be considered for pemphigus vulgaris patients during and following rituximab treatment 2

Prophylactic Regimen

TMP-SMX is the preferred agent, providing a 91% reduction in PJP occurrence and 83% reduction in PJP-related mortality. 3

• Standard dosing options include:
  • 80 mg/400 mg three times weekly (preferred due to lower adverse event rates of 18.2% vs 63.1% with higher dosing) 4
  • 160 mg/800 mg twice weekly 4
  • Single-strength tablet daily 3
• A large retrospective study of 3,524 patients demonstrated that TMP-SMX prophylaxis reduced PJP incidence with an adjusted subdistribution hazard ratio of 0.20 (95% CI, 0.10-0.42) 5
• The number needed to treat to prevent one PJP infection was 32 (24.8-39.4), while the number needed to harm for severe adverse drug reactions was 101 (61.9-261.1) 5

Duration of Prophylaxis

Continue prophylaxis for a minimum of 6 months after the last rituximab dose, with consideration for extended duration in high-risk patients. 1, 3, 2

• HBV reactivation data suggests rituximab's immunosuppressive effects may persist up to 1-2 years after the last dose, supporting consideration of extended prophylaxis 3
• Prolonged prophylaxis should be considered for patients with:
  • Repeated rituximab infusions 3
  • Structural lung disease 3
  • Ongoing immunosuppressive therapy 3
  • Hypogammaglobulinemia (IgG <3 g/L) 1, 3
• The onset of PJP typically occurs between 6 and 16 weeks after chemotherapy initiation 6

Critical Drug Interaction

Monitor carefully when combining TMP-SMX with methotrexate, as there is a potential drug interaction when TMP-SMX is dosed at 800 mg/160 mg twice daily. 1

• The TMP-SMX dose used for Pneumocystis prophylaxis (lower doses) is generally tolerated but requires monitoring when used with methotrexate 1
• This interaction is less problematic with prophylactic dosing compared to therapeutic dosing 1

Risk Without Prophylaxis

Rituximab increases PJP risk 3.65-fold (95% CI 1.65-8.07) compared to non-rituximab regimens, with a mortality rate of 27-30% when PJP develops. 6, 7, 8

• The prevalence of PJP in rituximab-treated NHL patients was 2.95% vs 1.32% in controls 6
• Among 30 patients who developed PJP during rituximab treatment, 88% developed acute hypoxemic respiratory failure, 53% required ICU admission, and 30% died 7
• Patients receiving prophylaxis had significantly better first-year survival rates (73% vs 38%) 6

Hepatitis B Virus Screening and Prophylaxis

Mandatory Screening

Screen all patients for HBV with HBsAg, anti-HBs, and anti-HBc before initiating rituximab. 1

• Rituximab is classified as a high-risk agent for HBV reactivation 1
• HBV reactivation is a common event after rituximab-based chemo-immunotherapy 1

Prophylaxis for HBsAg-Positive Patients

All HBsAg-positive patients require antiviral prophylaxis with lamivudine or entecavir during rituximab treatment and for 2-3 months after completion. 1

• Late reactivations have been observed, requiring careful follow-up 1
• For patients receiving rituximab, antiviral prophylaxis may need to be continued up to 2 years after the last dose 1

Prophylaxis for HBsAg-Negative/Anti-HBc-Positive Patients

Routine prophylaxis is recommended for HBsAg-negative/anti-HBc-positive patients receiving rituximab due to high reactivation risk. 1

• Alternative approach is watchful monitoring with serum ALT and HBsAg every 3 months until 6 months after the last dose 1
• However, given rituximab's classification as high-risk, prophylaxis is preferred over monitoring alone 1

Herpes Virus Prophylaxis

Consider herpes simplex virus (HSV) and varicella-zoster virus (VZV) prophylaxis with acyclovir or valacyclovir when rituximab is combined with other high-risk agents. 1

• Antiviral prophylaxis against HSV/VZV is not routinely required for rituximab monotherapy 1
• When rituximab is combined with purine analogues or alemtuzumab, HSV/VZV prophylaxis should be initiated in the first week of therapy and continued until 2 months after completion 1

Immunoglobulin Monitoring

Measure serum immunoglobulin concentrations (particularly IgG) prior to each rituximab course to detect secondary immunodeficiency. 1

• Check IgG levels at baseline and every 6 months during rituximab treatment 3
• For patients with hypogammaglobulinemia (IgG <3 g/L) and recurrent severe infections, consider immunoglobulin supplementation at replacement doses (400-800 mg/kg/month) 1
• Low IgG at baseline may predict higher risk of secondary immunodeficiency and justify more prolonged prophylaxis 3

Common Pitfalls to Avoid

• Do not wait for high rituximab doses to initiate prophylaxis - even reduced doses cause profound B-cell depletion 3
• Do not discontinue prophylaxis prematurely - continue for minimum 6 months after last dose 3
• Do not rely on ANCA or CD19+ B-cell testing alone - structured clinical assessment should inform treatment decisions 1
• Do not delay HBV screening - must be completed before rituximab initiation 1
• Do not assume rituximab monotherapy is low-risk - prophylaxis is still indicated even without concomitant chemotherapy or high-dose steroids 3, 7