Version May 2024
Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase.
Hepatitis B virus (HBV) reactivation can occur in patients treated with rituximab-containing products, including rituximab/hyaluronidase, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with rituximab/hyaluronidase. Discontinue rituximab/hyaluronidase and concomitant medications in the event of HBV reactivation.
Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase.
Note: All patients must receive at least 1 full dose of IV rituximab (without experiencing severe adverse reactions) prior to initiating treatment with subcutaneous rituximab/hyaluronidase; patients who do not tolerate a full IV dose should continue to receive IV rituximab in subsequent cycles. May switch to subcutaneous rituximab/hyaluronidase when a full IV dose is successfully administered.
Premedicate with acetaminophen and an antihistamine prior to each dose (consider glucocorticoid premedication if necessary). Antihyperuricemic therapy and aggressive hydration are recommended for patients at risk for tumor lysis syndrome (high tumor burden or lymphocytes >25,000/mm3). In patients with chronic lymphocytic leukemia (CLL), Pneumocystis jirovecii pneumonia (PCP) and antiherpetic viral prophylaxis is recommended during treatment (and for up to 12 months following treatment).
Chronic lymphocytic leukemia: SubQ: Rituximab 1,600 mg/hyaluronidase 26,800 units (fixed dose) on day 1 of a 28-day cycle in cycles 2 through 6 (in combination with fludarabine and cyclophosphamide) (Assouline 2016) (IV rituximab should be administered in cycle 1).
Diffuse large B-cell lymphoma: SubQ: Rituximab 1,400 mg/hyaluronidase 23,400 units (fixed dose) on day 1 of cycles 2 through 8 in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (IV rituximab should be administered in cycle 1). Rituximab/hyaluronidase was administered with either CHOP-14 (14-day cycle) or CHOP-21 (21-day cycle) in the clinical trial (Lugtenburg 2017).
Follicular lymphoma:
Previously untreated: SubQ: Induction: Rituximab 1,400 mg/hyaluronidase 23,400 units (fixed dose) on day 1 of a 21-day cycle in cycles 2 through 8 (in combination with chemotherapy) (Davies 2017); IV rituximab should be administered in cycle 1. In patients with complete or partial response following combination chemotherapy, initiate maintenance treatment (see below).
Maintenance: SubQ: In patients with complete or partial response, initiate rituximab 1,400 mg/hyaluronidase 23,400 units (fixed dose) once every 8 weeks for 12 doses (Davies 2017). Maintenance treatment should be initiated 8 weeks following completion of initial combination chemotherapy treatment.
Non-progressing disease following 6 to 8 cycles of first-line CVP chemotherapy: SubQ: Rituximab 1,400 mg/hyaluronidase 23,400 units (fixed dose) once weekly for 3 weeks (IV rituximab should be administered in week 1 for a total of 4 weeks of therapy) at 6-month intervals to a maximum of 16 doses.
Relapsed or refractory: SubQ: Rituximab 1,400 mg/hyaluronidase 23,400 units (fixed dose) once weekly for 3 or 7 weeks (IV rituximab should be administered in week 1) for a total of 4 or 8 weeks of therapy
Relapsed or refractory (retreatment): SubQ: Rituximab 1,400 mg/hyaluronidase 23,400 units (fixed dose) once weekly for 3 weeks (IV rituximab should be administered in week 1) for a total of 4 weeks of therapy
Relapsed or refractory (maintenance treatment after response to induction treatment) [Canadian labeling]: SubQ: 1,400 mg (fixed dose) once every 3 months until disease progression or maximum duration of 2 years (Rituxan SC Canadian product labeling).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Dosage adjustments for rituximab/hyaluronidase are not recommended; however, adjustments for concomitant chemotherapy may be necessary.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents. All incidences are from combination therapy regimens unless otherwise specified.
>10%:
Dermatologic: Alopecia (14% to 24%), dermatological reaction (16%), erythema of skin (9% to 15%), skin rash (10% to 12%; including severe mucocutaneous reactions)
Gastrointestinal: Abdominal pain (7% to 14%), constipation (8% to 25%), diarrhea (14% to 18%), nausea (22% to 38%), vomiting (11% to 21%)
Hematologic & oncologic: Anemia (13% to 23%; grades 3/4: 5%), febrile neutropenia (8% to 14%; grades 3/4: 7% to 14%), leukopenia (6% to 19%; grades 3/4: 3% to 14%), neutropenia (31% to 65%; grades 3/4: 25% to 56%), thrombocytopenia (24%; grades 3/4: 6%)
Immunologic: Antibody development (anti-hyaluronidase antibodies: 11% to 15%; anti-rituximab antibodies: 2% to 12%)
Infection: Serious infection (46% to 56%)
Local: Erythema at injection site (13% to 26%), pain at injection site (8% to 16%)
Nervous system: Chills (8% to 13%), fatigue (11% to 20%), headache (6% to 13%), paresthesia (9% to 16%), peripheral neuropathy (12%; grades 3/4: ≤2%)
Neuromuscular & skeletal: Arthralgia (9% to 13%), asthenia (8% to 17%)
Respiratory: Cough (11% to 23%), dyspnea (4% to 11%), pneumonia (2% to 11%), upper respiratory tract infection (13% to 15%)
Miscellaneous: Fever (13% to 32%)
1% to 10%:
Cardiovascular: Chest pain (6%), hypertension (6%), hypotension (1%), peripheral edema (5% to 8%)
Dermatologic: Pruritus (8% to 10%)
Endocrine & metabolic: Weight loss (8%)
Gastrointestinal: Decreased appetite (8%), dyspepsia (5% to 8%), stomatitis (5% to 8%; grades 3/4: ≤1%), upper abdominal pain (5%)
Genitourinary: Urinary tract infection (2% to 8%)
Hematologic & oncologic: Lymphocytopenia (5%; grades 3/4: 1%)
Infection: Influenza (4%)
Local: Infusion site reaction (≤7%; monotherapy in maintenance setting; higher with combination therapy and initial infusions)
Nervous system: Dizziness (7%), insomnia (1% to 9%)
Neuromuscular & skeletal: Back pain (9%), limb pain (7% to 10%), muscle spasm (8%), myalgia (8%), ostealgia (6% to 10%)
Ophthalmic: Conjunctivitis (5%)
Respiratory: Bronchitis (7% to 8%), flu-like symptoms (3%), nasopharyngitis (10%), oropharyngeal pain (6% to 9%), respiratory tract infection (8%), sinusitis (7%)
Frequency not defined:
Hepatic: Fulminant hepatitis, hepatic failure
Hypersensitivity: Hypersensitivity reaction
Infection: JC virus infection, reactivation of HBV
<1%, postmarketing, and/or case reports: Bone marrow depression, bronchiolitis obliterans, hypogammaglobulinemia (prolonged), inflammatory polyarthropathy, interstitial pulmonary disease, intestinal obstruction, intestinal perforation, Kaposi sarcoma (disease progression), lichenoid dermatitis, lupus-like syndrome, optic neuritis, pancytopenia (prolonged), pemphigoid reaction, pleurisy, progressive multifocal leukoencephalopathy, pyoderma gangrenosum (including genital presentation), serum sickness, severe dermatological reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, uveitis, vasculitis (systemic; with rash), vesiculobullous dermatitis, viral infection
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Known type 1 hypersensitivity or anaphylactic reaction to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation; patients who have or have had progressive multifocal leukoencephalopathy (PML); patients with severe, active infections
Concerns related to adverse effects:
• Bowel obstruction/perforation: Abdominal pain, bowel obstruction, and perforation have been reported (rarely fatal) in patients receiving rituximab-containing products, with an average onset of symptoms of ~6 days (range: 1 to 77 days); evaluate abdominal pain or repeated vomiting.
• Cardiovascular effects: Cardiac events (eg, ventricular fibrillation, myocardial infarction, and cardiogenic shock) may occur with rituximab-containing products. Discontinue rituximab/hyaluronidase for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after administration in patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina.
• Cytopenias: Rituximab is associated with lymphopenia, leukopenia, neutropenia, thrombocytopenia, and anemia; the duration of cytopenias may be prolonged and may extend months beyond treatment. Monitor blood counts.
• Hepatitis B virus reactivation: Hepatitis B virus (HBV) reactivation may occur with rituximab-containing products, including rituximab/hyaluronidase, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection prior to treatment initiation, and monitor patients during and for several months after rituximab/hyaluronidase treatment; also monitor for clinical signs/symptoms of hepatitis or HBV reactivation. Discontinue rituximab/hyaluronidase and concomitant medications if HBV reactivation occurs. If viral hepatitis develops, initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. HBV reactivation has been reported up to 24 months after rituximab discontinuation. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAG negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during rituximab treatment. The safety of resuming rituximab-containing treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with providers experienced in HBV management.
• Hypersensitivity: Rituximab-containing products are associated with hypersensitivity reactions (may be related to cytokine release and/or other chemical mediators). Due to the higher risk of hypersensitivity and other acute reactions, patients must receive at least one full dose of intravenous rituximab prior to receiving subcutaneous rituximab/hyaluronidase. Infusion-related reactions (with the use of intravenous rituximab formulations) usually occur within 30 to 120 minutes and may include hypotension, angioedema, bronchospasm, hypoxia, urticaria, and in more severe cases pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and/or anaphylactoid events. Anaphylactic and other hypersensitivity reactions may occur (typically occur within minutes of infusion initiation); severe cytokine release syndrome may occur within 1 to 2 hours of starting infusion. Patients with a history of pulmonary insufficiency or with pulmonary tumor infiltration may have a poorer outcome. Closely monitor patients with a history of prior cardiopulmonary reactions or with preexisting cardiac or pulmonary conditions and patients with high numbers of circulating malignant cells (>25,000/mm3). Prior to administration, premedicate patients with acetaminophen and an antihistamine (and consider glucocorticoids). Observe patients for at least 15 minutes following subcutaneous administration; increase observation time in patients at higher risk of hypersensitivity reactions. Interrupt rituximab/hyaluronidase administration immediately for signs of a severe reaction; initiate aggressive symptomatic treatment. Medications for the treatment of hypersensitivity reactions (eg, bronchodilators, epinephrine, antihistamines, corticosteroids) should be available for immediate use.
• Infections: Serious and potentially fatal bacterial, fungal, and either new or reactivated viral infections may occur during treatment and after completing therapy with rituximab-containing products. Infections have been observed in patients with prolonged hypogammaglobulinemia, defined as hypogammaglobulinemia >11 months after rituximab exposure. Associated new or reactivated viral infections have included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue rituximab/hyaluronidase in patients who develop serious infections and initiate appropriate anti-infective treatment.
• Mucocutaneous and cutaneous reactions: Severe, including fatal, mucocutaneous reactions may occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase. Paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis have been reported. Discontinue in patients experiencing severe mucocutaneous skin reactions; the safety of reexposure following mucocutaneous reactions has not been evaluated. Subcutaneous rituximab has been associated with localized cutaneous (and injection site) reactions (eg, pain, erythema, swelling, induration, rash, pruritus, hemorrhage); may occur >24 hours after administration. Reactions have been mostly mild to moderate and have resolved without intervention. Local reactions were most common during the first rituximab/hyaluronidase cycle (incidence decreases with subsequent injections).
• Progressive multifocal leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) (including fatalities) may occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase. Promptly evaluate any neurological changes; consider neurology consultation, brain MRI and lumbar puncture for suspected PML. Discontinue rituximab/hyaluronidase in patients who develop PML; consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.
• Renal toxicity: Rituximab-containing products may cause severe or fatal renal toxicity. Patients who received combination therapy with cisplatin and rituximab for NHL experienced renal toxicity (associated with tumor lysis syndrome) during clinical trials; this combination is not an approved treatment regimen. Renal toxicity also occurred due to tumor lysis syndrome. Monitor for signs of renal failure; discontinue rituximab-containing products with increasing serum creatinine or oliguria.
• Tumor lysis syndrome: Tumor lysis syndrome may occur within 12 to 24 hours after administration of a rituximab-containing product. Hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer prophylaxis (antihyperuricemic therapy, hydration) in patients at high risk (high numbers of circulating malignant cells ≥25,000/mm3 or high tumor burden). Correct electrolyte abnormalities; monitor renal function and hydration status, and administer supportive care as indicated.
Concurrent drug therapy issues:
• Immunizations: Live vaccines should not be given concurrently with rituximab; there is no data available concerning secondary transmission of live vaccines with or following rituximab-containing treatment.
Dosage form specific issues:
• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous [preservative free]:
Rituxan Hycela: Rituximab 1400 mg and hyaluronidase human 23,400 units per 11.7 mL (11.7 mL); Rituximab 1600 mg and hyaluronidase human 26,800 units per 13.4 mL (13.4 mL) [contains polysorbate 80]
No
Solution (Rituxan Hycela Subcutaneous)
1400-23400 MG-UT/11.7ML (per mL): $674.52
1600-26800 MG-UT/13.4ML (per mL): $673.08
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Subcutaneous:
Rituxan SC: 1400 mg/11.7 mL (11.7 mL); 1600 mg/13.4 mL (13.4 mL) [contains polysorbate 80]
SubQ: For SubQ administration only. Administer subcutaneously into the abdomen over ~5 minutes (rituximab 1.4 g/hyaluronidase 23,400 units) to 7 minutes (rituximab 1.6 g/hyaluronidase 26,800 units). To avoid clogging the needle, change needle to a new 1/2-inch to 5/8-inch long, narrow gauge needle (eg, 25 to 30 gauge) immediately prior to administration. Do not administer into areas where the skin is red, bruised, tender, or hard, or where there are moles or scars. If administration is interrupted, continue administration at the same or at a different site (restricted to the abdomen). Rituximab/hyaluronidase is compatible with polypropylene and polycarbonate syringes and stainless-steel transfer and injection needles. Do not administer other subcutaneous medications at the same sites as rituximab/hyaluronidase. Monitor for 15 minutes following administration.
An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761064s013lbl.pdf#page=28, must be dispensed with this medication.
Chronic lymphocytic leukemia: Treatment of adult patients with previously untreated and previously treated chronic lymphocytic leukemia (CLL) (in combination with fludarabine and cyclophosphamide)
Diffuse large B-cell lymphoma: Treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens
Follicular lymphoma: Treatment of adult patients with:
Relapsed or refractory follicular lymphoma (FL) as a single agent;
Previously untreated FL (in combination with first-line chemotherapy) and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy (as single-agent maintenance therapy);
Non-progressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy
Limitations of use: Initiate treatment with rituximab/hyaluronidase only after patients have received at least 1 full dose of a rituximab product by intravenous infusion; rituximab/hyaluronidase is not indicated for the treatment of non-malignant conditions.
Rituxan Hycela may be confused with Rituxan, Remicade.
RiTUXimab/hyaluronidase may be confused with brentuximab, bevacizumab, daratumumab/hyaluronidase, inFLIXimab, obinutuzumab, ofatumumab, ramucirumab, rituximab, ruxolitinib, trastuzumab/hyaluronidase.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Rituximab/hyaluronidase is for subcutaneous (SubQ) administration only. Do not substitute rituximab (IV) for rituximab/hyaluronidase (SubQ). Use caution during product selection, preparation, and administration.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Alpha-/Beta-Agonists: Hyaluronidase may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Management: Do not use hyaluronidase to enhance the dispersion or absorption of alpha-/beta-agonists. Use of hyaluronidase for other purposes in patients receiving alpha-/beta-agonists may be considered as clinically indicated. Risk D: Consider therapy modification
Anifrolumab: Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) may enhance the immunosuppressive effect of Anifrolumab. Risk X: Avoid combination
Antihistamines: May diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Antithymocyte Globulin (Equine): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Antithymocyte Globulin (Equine): Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of anti-CD20 B-cell depleting therapy is reduced. Anti-CD20 B-Cell Depleting Therapies may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Products: Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid combination
Belimumab: May enhance the immunosuppressive effect of RiTUXimab. Risk X: Avoid combination
Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Risk X: Avoid combination
Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Chikungunya Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chikungunya Vaccine (Live): Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Risk D: Consider therapy modification
COVID-19 Vaccines: Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of COVID-19 Vaccines. Management: Administer COVID-19 vaccine 2 to 4 weeks prior to the next scheduled dose of anti-CD20 therapy, if used chronically for the treatment of autoimmune disease. Revaccinate 6 months after completion of anti-CD20 therapy if used over a limited period. Risk D: Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dengue Tetravalent Vaccine (Live): Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Estrogen Derivatives: May diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Influenza Virus Vaccines: Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines 2 weeks prior to starting anti-CD20 B-cell depleting therapies. Vaccination of patients treated with these agents in the past 6 months is not recommended. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Local Anesthetics: Hyaluronidase may enhance the adverse/toxic effect of Local Anesthetics. Risk C: Monitor therapy
Mumps- Rubella- or Varicella-Containing Live Vaccines: Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Phenylephrine (Systemic): Hyaluronidase may enhance the vasoconstricting effect of Phenylephrine (Systemic). Management: Do not use hyaluronidase to enhance the dispersion or absorption of phenylephrine. Use of hyaluronidase for other purposes in patients receiving phenylephrine may be considered as clinically indicated. Risk D: Consider therapy modification
Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination
Poliovirus Vaccine (Live/Trivalent/Oral): Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Rabies Vaccine: Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
Ritlecitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Salicylates: May diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination
Typhoid Vaccine: Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation or 6 months after anti-CD20 B-cell depleting therapies. If vaccinated prior to B cell recovery, consider assessing immune response to vaccination. Risk D: Consider therapy modification
Vaccines (Live): Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Yellow Fever Vaccine: Anti-CD20 B-Cell Depleting Therapies may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Anti-CD20 B-Cell Depleting Therapies may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Verify pregnancy status prior to treatment initiation in patients who may become pregnant.
Patients who may become pregnant should use effective contraception during therapy and for 12 months following the last rituximab/hyaluronidase dose.
Rituximab/hyaluronidase may be used as monotherapy or in combination with other chemotherapy agents (eg, cyclophosphamide, doxorubicin, fludarabine, vincristine); refer to the rituximab, hyaluronidase, and other individual monographs for additional information.
Rituximab crosses the placenta. Based on human data, rituximab-containing products may cause adverse outcomes in infants following in utero exposure.
Rituximab/hyaluronidase may be used as monotherapy or in combination with other chemotherapy agents (eg, cyclophosphamide, doxorubicin, fludarabine, vincristine); refer to the rituximab, hyaluronidase, and other individual monographs for additional information.
Rituximab is present in breast milk (Bragnes 2017); excretion of hyaluronidase is not known.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy or for 6 months after the last dose of rituximab/hyaluronidase.
Rituximab/hyaluronidase may be used as monotherapy or in combination with other chemotherapy agents (eg, cyclophosphamide, doxorubicin, fludarabine, vincristine); refer to the rituximab, hyaluronidase, and other individual monographs for additional information.
Electrolytes (in patients at risk for tumor lysis syndrome [TLS]), CBC with differential; renal function (in patients at risk for TLS). Monitor fluid/hydration status balance; BP, vital signs. Evaluate pregnancy status prior to treatment in patients who may become pregnant.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up. In addition, carriers and patients with evidence of current infection or recovery from prior hepatitis B infection should be monitored closely for clinical and laboratory signs of HBV reactivation and/or infection during therapy and for up to 2 years following completion of treatment.
Monitor for hypersensitivity reactions (observe for 15 minutes following administration); signs of active hepatitis B infection (during and for up to 12 months after therapy completion); cardiac monitoring during and after infusion (in patients with preexisting cardiac disease or if arrhythmias develop during or after subsequent infusions); monitor for signs/symptoms of bowel obstruction/perforation (abdominal pain, vomiting); signs or symptoms of progressive multifocal leukoencephalopathy (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits); signs/symptoms of TLS and/or mucocutaneous or cutaneous skin reactions.
Rituximab is a monoclonal antibody directed against the CD20 antigen on the surface of pre-B and mature B-lymphocytes. CD20 regulates cell cycle initiation; and, possibly, functions as a calcium channel. Rituximab binds to the antigen on the cell surface, activating complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity.
Hyaluronidase increases the absorption rate of rituximab-containing products by increasing permeability of subcutaneous tissue through temporary depolymerization of hyaluronan; at the recommended doses, hyaluronidase acts locally and the effects are reversible. Permeability of the subcutaneous tissue is restored within 24 to 48 hours.
Onset of action:
CLL: B-cells begin to deplete following the first cycle of rituximab, with 28% of patients B-cell depleted prior to the dose in cycle 2; by cycle 6, 96% of patients were B-cell depleted.
FL: Peripheral B-cell counts decrease to levels below normal following the first cycle of rituximab and are maintained during treatment with rituximab/hyaluronidase.
Duration of action:
CLL: Patients remained B-cell depleted until month 9, where signs of repletion were seen.
FL: After discontinuing rituximab/hyaluronidase, B-cell repletion begins after 6 months (may be longer in some patients)
Distribution: Vdss: SubQ: 8.52 L (CLL); 8.09 L (FL)
Bioavailability (compared to IV rituximab): SubQ: 63.4% (CLL); 64.6% (FL)
Half-life elimination (terminal): 32 days (CLL); 34.1 days (FL)
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