Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
riTUXimab (subcut)
Rituximab is a chimeric mouse-human monoclonal IgG1κ antibody. It binds to the CD20 antigen (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and on > 90% of B cell non-Hodgkin’s lymphomas. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Rituximab is thought to deplete CD20-positive cells via antibody-dependent cell-cytotoxicity and complement-mediated cell lysis. The subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20) to increase dispersion and absorption.
| Bioavailability |
71% (follicular NHL patients) |
Binds to lymphoid tissues with little or no binding to non-lymphoid tissues.
Rituximab subcut fixed dosing results in higher exposure to rituximab than at recommended IV dosing.
The metabolism of rituximab is not fully understood.
| Active metabolites | no |
| Inactive metabolites | no |
| Half-life |
34.1 days (follicular lymphoma) |
-
Non-Hodgkin lymphoma (NHL)
-
Chronic lymphocytic leukemia (CLL)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The adverse effects below are those reported for rituximab IV unless the subcutaneous formulation was associated with a relevant difference in incidence.
(*incidence based on rituximab subcut)
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (1%) | I | |||
| Arterial thromboembolism (1-2%) | E | ||||
| Cardiotoxicity (rare) | E | ||||
| Hypertension (5%) | I E | ||||
| Hypotension (10%) | I | ||||
| Venous thromboembolism (3%) | E | ||||
| Dermatological | Alopecia (1-10%) | E | |||
| Rash (11%) (may be severe) | I E | ||||
| Gastrointestinal | Abdominal pain (7%) | I E | |||
| Anorexia, weight loss (3%) | E | ||||
| Constipation (1%) | I | ||||
| Diarrhea (4%) | I | ||||
| Dyspepsia (3%) | E | ||||
| GI obstruction (<1%) | E D | ||||
| GI perforation (<1%) | E D | ||||
| Mucositis (1%) | E | ||||
| Nausea, vomiting (17%) | I | ||||
| General | Edema (5%) | E | |||
| Fatigue (18%) | I | ||||
| Flu-like symptoms (>10%) | I E | ||||
| Hematological | Hemolysis (<1%) | E | |||
| Hyperviscosity (Waldenstrom's; rare) | I E | ||||
| Immunosuppression | E | ||||
| Myelosuppression ± infection (26%) * (including opportunistic infections, bleeding) | E | ||||
| Hypersensitivity | Administration-related reactions (48%) * (3% severe including hypersensitivity; cutaneous 23%) | I | |||
| Immune | Antibody response (1%) (antichimeric antibodies) | E | |||
| Other - Viral reactivation (including hepatitis B; rare) | D | ||||
| Metabolic / Endocrine | Abnormal electrolyte(s) (2%) | E | |||
| Hyperglycemia (5%) | E | ||||
| Tumor lysis syndrome (<1%) | I | ||||
| Musculoskeletal | Musculoskeletal pain (8%) (or stiffness) | I E | |||
| Neoplastic | Secondary malignancy (5%) (with chemotherapy) | L | |||
| Nervous System | Anxiety (2%) | E | |||
| Dizziness (7%) | E | ||||
| Headache (13%) | I E | ||||
| Leukoencephalopathy (PML - rare) | E | ||||
| Neuropathy (rare, peripheral or cranial) | E D | ||||
| Paresthesia (16%) | E | ||||
| Posterior reversible encephalopathy syndrome (PRES) (rare) | E | ||||
| Sleep disorder (2%) | E | ||||
| Ophthalmic | Conjunctivitis (1%) | E | |||
| Optic nerve disorder (rare) | E | ||||
| Watering eyes (3%) | E | ||||
| Renal | Nephrotoxicity (1-10%) | E | |||
| Respiratory | Cough, dyspnea (8%) | I E | |||
| Pneumonitis (rare) | I E | ||||
| Vascular | Vasculitis (rare) | E D | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
In general, higher incidences of local cutaneous reactions (23% vs 13%) and neutropenia (severe; 26% vs 21%) were observed in patients treated with rituximab subcut as compared to the IV formulation. Anaphylaxis, severe hypersensitivity reactions, cytokine release syndrome or tumour lysis syndrome appeared to be less common, which is expected given the most common time for many acute reactions is in cycle 1, when it is always given as the IV formulation. However, anaphylaxis is the most common with the second cycle.
Adverse effects are more frequent in older patients, and in patients with high bulk disease.
In clinical trials with rituximab IV, there was a higher incidence of severe neutropenia in rituximab-containing arms as compared to the chemotherapy-only arms.
Acute reactions:
- Drug-related reactions, which may be related to cytokine release, include fever and chills/rigors, urticaria, bronchospasm, ARDS, angioedema, hypotension and flushing; they usually occur 30 minutes to 2 hours after the start of the first treatment and may be fatal. The majority of serious reactions were observed with the first rituximab dose, in which approximately 80% of fatal reactions were reported. The incidence decreases with subsequent doses. These reactions are more common in patients with high tumour burdens and are fatal in up to 0.07% of patients. Autoimmune diseases or other co-morbidities may have contributed to the fatal outcome.
- Anaphylaxis (including fatalities) may occur, usually with the second or subsequent doses. These may not be clinically distinguishable from drug-related reactions.
- Severe pulmonary reactions with dyspnea, bronchospasm, hypoxia, and pulmonary infiltrates or edema have been reported, and are more common in patients with pulmonary involvement or disease. Acute symptoms appear within 1-2 hours of the initiation of the first dose, while pneumonitis may appear 1-4 weeks after.
- Signs and symptoms of tumour lysis syndrome (TLS) have been reported to occur within 1 to 2 hours after the first treatment. Patients at risk (high tumour burden) should be closely monitored and prophylaxis considered.
- Symptoms of these acute reactions usually resolve with slowing or interruption of the rituximab infusion and aggressive treatment (IV saline, diphenhydramine and acetaminophen ± bronchodilators, IV corticosteroids or epinephrine). However, deterioration may occur after initial improvement of pulmonary or severe symptoms and patients should be carefully monitored until complete symptom resolution. TLS should be excluded.
- Patients with pre-existing cardiac conditions, including arrhythmias and angina, should be carefully monitored throughout the administration and in the immediate post-administration period. Rituximab should be discontinued in serious or life-threatening cardio-pulmonary events.
Administration-related reactions with subcutaneous rituximab:
Most local cutaneous reactions were mild to moderate and resolved without any specific treatment. These included pain, swelling, induration, hemorrhage, erythema, pruritus and rash. Local cold compresses and topical steroids may be helpful.
Other adverse effects:
Arterial thromboembolism, such as stroke, has been described in elderly patients who received rituximab especially in combination. Patients with cardiovascular disease or risk factors should be carefully monitored for signs of cerebral ischemia.
Severe mucocutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, paraneoplastic pemphigus, lichenoid dermatitis or vesiculobullous dermatitis) have been described and may be fatal. The onset of these reactions can vary from days to several months following exposure to rituximab.
Bowel obstruction and perforation (some fatal cases) have been reported. The mean time of onset for these GI symptoms is 6 days.
Infections are common, including opportunistic infections. Reactivation of tuberculosis or hepatitis B virus (HBV) infection may occur during treatment, with fulminant hepatitis, hepatic failure and death, including in patients with normal hepatitis B surface antigen but who are seropositive. The risk is increased in patients receiving steroids and/or chemotherapy. Patients should be screened (hepatitis B surface antigen, HbsAg and hepatitis B core antibody, HbcAb status) prior to treatment. HBsAg positive patients should receive antiviral prophylaxis during and after rituximab. HBsAg negative, but HBcAb positive patients should be considered for antiviral prophylaxis and be closely monitored for viral reactivation by an HBV expert (2015 rituximab guidelines).
Cases of Pneumocystis Jiroveci Pneumonia (PJP) have been reported. Infections have been reported in some patients with prolonged hypogammaglobulinemia (>11 months after rituximab exposure).
There have been isolated reports of JC virus reactivation in NHL patients, resulting in fatal progressive multifocal leukoencephalopathy (PML). Rituximab should be held at first signs or symptoms suggestive of PML, which may progress over days to weeks and can include progressive unilateral weakness, clumsiness of limbs, confusion, cognitive or personality changes. Patients suspected of having PML should be investigated with MRI and lumbar puncture to evaluate JC viral DNA.
Posterior reversible leukoencephalopathy syndrome (PRES) has been reported rarely; brain imaging confirms diagnosis. Risk factors include hypertension and concomitant immunosuppressive therapy.
Other viral infections (including fatal cases), such as CMV, herpes simplex, varicella, hepatitis C, West Nile, etc. have been reported up to one year following rituximab cessation. Patients who are HIV-positive with Kaposi’s sarcoma have been reported to have rapid Kaposi’s sarcoma progression.
Patients who develop human anti-murine antibodies (HAMA) or human anti-chimeric antibodies for rituximab (HACA) may have allergic or hypersensitivity reactions when treated with rituximab or other murine or chimeric monoclonal antibodies.
Refer to protocol by which patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
Rituximab (any formulation) should be administered in a setting where full resuscitation facilities are immediately available, and under the close supervision of someone experienced and capable of dealing with severe rituximab-related reactions.
Since transient hypotension has occurred during rituximab treatment, consideration should be given to withhold antihypertensive medication 12 hours prior to and during the rituximab administration.
Pre-medication:
Administer 30 minutes prior to subcut rituximab (prophylaxis for drug-related reactions described above):
- Oral antipyretic (e.g. acetaminophen)
- H1-receptor antagonist (e.g. diphenhydramine)
- Corticosteroid (e.g. methylprednisolone 80 mg IV) in patients with high bulk disease or pulmonary involvement if no corticosteroids are already being given as part of the chemotherapy regimen.
- In patients who experienced adverse effects with pre-medications, the omission of pre-medications can be considered.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
Other supportive care:
- Prophylaxis for tumour lysis (high bulk disease, WBC > 25 x 109/L)
- HBsAg positive patients should receive antiviral prophylaxis during and after rituximab. HBsAg negative, but HBcAb positive patients should be considered for antiviral prophylaxis and be closely monitored for viral reactivation by an HBV expert.
Patients must receive rituximab as IV infusion during the first cycle, so any infusion-related reactions can be managed by slowing or stopping the infusion.
The subcutaneous formulation must only be given at the second or subsequent cycles, and only if the patient has received at least one full rituximab IV dose at the previous cycle. If a patient is unable to receive the full IV rituximab dose, continue subsequent cycles with rituximab IV until a full IV dose can be successfully given.
|
Setting |
Induction Treatment (Cycle 1) |
Induction treatment Fixed dose (subsequent cycles, only if rituximab IV full dose tolerated) |
Maintenance Fixed dose (after response to induction therapy) |
|
|
Low Grade/Follicular |
||||
|
With CVP or CHOP(1)
|
375 mg/m2 IV
|
If IV rituximab is tolerated:
|
Previously untreated:
|
|
|
Setting |
Treatment (Cycle 1) |
Treatment |
|
Diffuse Large B Cell |
||
|
With CHOP(1) |
375 mg/m2 IV |
1400 mg Subcut day 1 q3w for 6 to 8 cycles |
|
CLL |
||
|
With FC |
375 mg/m2 IV |
1600 mg Subcut day 1 q3w for up to 6 cycles (1, 5)
|
|
1 Give rituximab on day 1 POST-steroid (if applicable) and PRE-cytotoxic regimen. 3 Hematology disease site group guideline recommends q3m dosing as a reasonable schedule. NDFP funds up to a maximum of 8 doses (over 2 years). |
||
|
Toxicity
|
Rituximab Dose* / Rate
|
|
Myelosuppression
|
No adjustment required.
|
|
Severe administration-related or pulmonary
|
|
| Other grade 3 toxicity |
Delay treatment until ≤ grade 2
|
|
Other grade 4 toxicity
|
Discontinue
|
|
*Missed or delayed doses may be administered at a later time point, based on physician’s discretion. |
|
No dosage adjustment required; stop if evidence of hepatitis.
No dosage adjustment required.
No dose adjustment required. Exercise caution as older patients are more likely to experience serious adverse events (including cardiac, pulmonary, or other grade 3/4 toxicity).
Safety and effectiveness in children have not been established. Hypogammaglobulinemia has been observed in pediatric patients and may be severe, requiring long-term immunoglobulin substitution therapy.
Rituximab IV and subcutaneous formulations are not interchangeable. The dosing and concentrations of these products are different.
Rituximab subcutaneous dosing:
- 1400 mg subcut fixed dose (non-Hodgkin lymphoma)
- 1600 mg subcut fixed dose (CLL)
Refer to Safety Considerations for the Implementation of Subcutaneous Rituximab Formulation
- Rituximab should be administered in a setting where full resuscitation facilities are immediately available, and under the close supervision of someone experienced and capable of dealing with severe drug-related reactions.
- For details on rituximab IV administration, refer to the "rituximab" drug monograph.
- Rituximab (subcut) must not be self-administered.
- Rituximab (subcut) is given subcutaneously into the abdominal wall only. Do not give in areas where the skin is red, tender, hard, bruised, or where there are moles or scars.
- Non-Hodgkin’s lymphoma: Give subcutaneously over approximately 5 minutes
- CLL: Give subcutaneously approximately over 7 minutes.
- Observe for at least 15 minutes after administration.
- If there are other subcutaneous medications, they should be given at separate sites.
- Compatible with polypropylene or polycarbonate syringes.
- Keep vials refrigerated in the outer carton; do not freeze. Protect from light.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- Patients with known hypersensitivity and anaphylactic reactions to proteins of similar mouse or human origin, to Chinese Hamster Ovary (CHO) cell proteins or to any component of this product.
- Patients who have or have had PML, have active and/or severe infections, active hepatitis B, or severely immunocompromised (e.g. AIDS patients with very low CD4 or CD8 counts).
- Avoid the use of live vaccines.
- Exercise caution in patients with a history of recurring or chronic infections or with underlying conditions which may further predispose patients to serious infection. Patients may have increased risk of infection following rituximab treatment.
- Prior to starting rituximab in HBV seropositive patients, consultation with a liver disease expert is recommended to determine ongoing monitoring of HBV reactivation and its management.
- Exercise caution in patients with neutrophil counts < 1.5 x 109/L and/or platelets < 75 x 109/L due to limited experience in this patient group.
- Use with extreme caution in patients with pre-existing cardiovascular disease or in patients with high tumour burden. Consider steroids ± slow IIV infusions or infusions split over 2 days for patients with bulky disease or > 25 x 109/L circulating malignant cells.
- Use with caution in patients with pulmonary insufficiency or lung tumour infiltration, and in patients with myelosuppression.
- Reduced immunogenicity may occur with use of vaccines.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Teratogenicity:
No
-
Mutagenicity:
Unknown
-
Fetotoxicity:
Unknown
Rituximab is not recommended for use during pregnancy. IgGs are known to pass the placental barrier. There have been reports of infants with transient B-cell depletion and lymphocytopenia. Adequate contraception should be used by patients and their partners during treatment, and for 12 months after the last dose.
-
Breastfeeding:
Not recommended
IgG is excreted into breast milk. Breastfeeding is not recommended during treatment and for 6 months after the last dose.
-
Fertility effects:
Unknown
Formal drug interaction studies have not been performed with rituximab (subcut). The following are based on known interactions with rituximab IV.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Antihypertensive agents | potentiation of hypotension with infusion | Additive effects | consider withholding temporarily (12 hours before and during administration) |
| cisplatin | renal failure | Unknown | use with extreme caution; monitor renal function closely |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
baseline and at each visit |
LFTs |
baseline and at each visit |
Renal functions tests |
baseline and at each visit |
| Administration-related and hypersensitivity reactions | During and for at least 15 minutes after each injection, longer in patients at higher risk of hypersensitivity reactions. |
Clinical assessment of tumour lysis syndrome, infection (including viral, opportunistic), bleeding, GI, pulmonary, skin, CNS, cardiovascular side effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Monitor cardiovascular symptoms in patients who have cardiac conditions or recurrent cardiac events with rituximab |
At each visit |
New Drug Funding Program (NDFP Website )
- Rituximab (Biosimilar IV) and Rituximab SC in Combination with Chemotherapy - Indolent B-cell Lymphoma
- Rituximab (Biosimilar IV) and Rituximab SC - Second Line - Chronic Lymphocytic Leukemia
- Rituximab (Biosimilar IV) and Rituximab SC - Retreatment - Indolent Lymphoma
- Rituximab (Biosimilar IV) and Rituximab SC - Retreatment - Aggressive Histology Lymphoma
- Rituximab (Biosimilar IV) and Rituximab SC - Previously Untreated Chronic Lymphocytic Leukemia
- Rituximab (Biosimilar IV) and Rituximab SC - Maintenance Treatment - Lymphoma
- Rituximab (Biosimilar IV) and Rituximab SC - In Combination with Venetoclax - Relapsed Chronic Lymphocytic Leukemia
- Rituximab (Biosimilar IV) and Rituximab SC - HIV-Related Aggressive Histology B-cell Lymphoma
- Rituximab (Biosimilar IV) and Rituximab SC - Aggressive Histology Lymphoma
Burrows, S. H., Akinbobuyi, O., Rule, S. & Crosbie, N. Subcutaneous rituximab can be safely administered without pre-medication. Br. J. Haematol 2018;181:836-7.
Prescribing information (US): Rituxan Hycela®. Genentech Inc., March 2018.
Product Monograph: Rituxan® (rituximab). Roche Canada, October 2016.
Product Monograph: Rituxan® SC (rituximab). Roche Canada, March 28, 2018 and June 2023.
Personal Communication: Rituxan Hycela Administration-Related Reactions. Roche Canada, June 2018.
CCO Practice Guideline: Rituximab in Lymphoma and Chronic Lymphocytic Leukemia
October 2023 Modified Indications and Pregnancy/lactation sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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