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Rituximab and Hyaluronidase

Pronunciation

(ri TUK si mab & hye al yoor ON i dase)

Index Terms

  • Anti-CD20 Monoclonal Antibody
  • Hyaluronidase and Rituximab
  • Rituximab Subcutaneous

Dosage Forms

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]

Brand Names: U.S.

  • Rituxan Hycela

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD20
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

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.

Distribution

Vdss: SubQ: 8.52 L (CLL); 8.09 L (FL)

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)

Half-Life Elimination

Terminal: 32 days (CLL); 34.1 days (FL)

Use: Labeled Indications

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.

Contraindications

There are no contraindications listed in the manufacturer's 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

Dosing: Adult

Note: All patients must receive at least one full dose of intravenous 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 SubQ 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).

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 2016)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

Dosage adjustments for rituximab/hyaluronidase are not recommended; however, adjustments for concomitant chemotherapy may be necessary.

Reconstitution

Withdraw dose from the vial and transfer to a syringe; label with the peel-off sticker. To avoid clogging the needle, attach the injection needle to the syringe immediately prior to administration; rituximab/hyaluronidase is compatible with polypropylene and polycarbonate syringes and stainless steel transfer and injection needles.

Administration

For SubQ administration only. Inject subcutaneously into the abdomen over approximately 5 minutes (rituximab 1,400 mg/hyaluronidase 23,400 units) to 7 minutes (rituximab 1,600 mg/hyaluronidase 26,800 units). Do not inject 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). Monitor patients for 15 minutes following administration. To avoid clogging the needle, attach the injection needle to the syringe immediately prior to administration; 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.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Store in original packaging to protect from light. Following transfer from vial to syringe, the manufacturer recommends immediate use. If not used immediately, syringes may be stored for 48 hours at 2°C to 8°C (36°F to 46°F) and subsequently for 8 hours at 30°C (86°F) in diffused daylight.

Drug Interactions

Abatacept: RiTUXimab may enhance the adverse/toxic effect of Abatacept. Avoid combination

Alpha-/Beta-Agonists: Hyaluronidase may enhance the vasoconstricting effect of Alpha-/Beta-Agonists. Management: Avoid the use of hyaluronidase to enhance 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. Exceptions: Dipivefrin; EPINEPHrine (Nasal); EPINEPHrine (Oral Inhalation); Isometheptene; Pseudoephedrine. Consider therapy modification

Antihistamines: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving antihistamines (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Certolizumab Pegol: RiTUXimab may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Corticosteroids: 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. Exceptions: Beclomethasone (Nasal); Budesonide (Nasal); Ciclesonide (Nasal); Desonide; Dexamethasone (Ophthalmic); Difluprednate; Flunisolide (Nasal); Fluocinolone (Ophthalmic); Fluticasone (Nasal); Hydrocortisone (Ophthalmic); Loteprednol; Mometasone (Nasal); PrednisoLONE (Ophthalmic); Triamcinolone (Nasal); Triamcinolone (Ophthalmic). Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

DOPamine: Hyaluronidase may enhance the adverse/toxic effect of DOPamine. Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of dopamine. Use of hyaluronidase for other purposes in patients receiving dopamine may be considered as clinically indicated. Consider therapy modification

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Estrogen Derivatives: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Local Anesthetics: Hyaluronidase may enhance the adverse/toxic effect of Local Anesthetics. Exceptions: Benzocaine; Benzydamine; Cocaine; Dibucaine; Dyclonine; Ethyl Chloride; Hexylresorcinol; Lidocaine (Ophthalmic); Lidocaine (Topical); Pramoxine; Proparacaine; Tetracaine (Ophthalmic); Tetracaine (Topical). Monitor therapy

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Phenylephrine (Systemic): Hyaluronidase may enhance the vasoconstricting effect of Phenylephrine (Systemic). Management: Avoid the use of hyaluronidase to enhance dispersion or absorption of phenylephrine. Use of hyaluronidase for other purposes in patients receiving phenylephrine may be considered as clinically indicated. Avoid combination

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Salicylates: May diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving salicylates (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: RiTUXimab may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Also see individual agents. All incidences are from combination therapy regimens.

>10%:

Central nervous system: Fatigue (11% to 20%), paresthesia (9% to 16%), headache (6% to 13%), peripheral neuropathy (12%; grades 3/4: ≤2%)

Dermatologic: Alopecia (14% to 24%), allergic skin reaction (16%; pain, swelling, induration, hemorrhage, erythema, pruritus, and rash, as well as injection site reactions), erythema (9% to 15%), skin rash (10% to 12%; including severe mucocutaneous reactions)

Gastrointestinal: Nausea (22% to 38%), constipation (8% to 25%), vomiting (11% to 21%), diarrhea (14% to 18%), abdominal pain (7% to 14%)

Hematologic & oncologic: Neutropenia (31% to 65%; grades 3/4: 25% to 56%), anemia (15% to 23%; grades 3/4: 5%), leukopenia (6% to 19%; grades 3/4: 3% to 4%), febrile neutropenia (8% to 14%; grades 3/4: 7% to 14%)

Immunologic: Antibody development (anti-hyaluronidase antibodies: 11% to 13%; anti-rituximab antibodies: 2%)

Infection: Serious infection (46% to 56%; including reactivation of viral infections)

Local: Erythema at injection site (13% to 26%)

Neuromuscular & skeletal: Weakness (8% to 17%), arthralgia (9% to 13%)

Respiratory: Cough (11% to 23%), upper respiratory tract infection (13% to 15%), dyspnea (4% to 11%), pneumonia (2% to 11%)

Miscellaneous: Fever (13% to 32%)

1% to 10%:

Cardiovascular: Peripheral edema (5% to 8%), chest pain (6%), hypertension (6%), hypotension (1%)

Central nervous system: Chills (8% to 13%), insomnia (1% to 9%), dizziness (7%)

Dermatologic: Pruritus (8% to 10%)

Endocrine & metabolic: Weight loss (8%)

Gastrointestinal: Decreased appetite (8%), dyspepsia (5% to 8%), mucosal inflammation (5% to 8%), stomatitis (6%), upper abdominal pain (5%)

Genitourinary: Urinary tract infection (2% to 8%)

Hematologic & oncologic: Lymphocytopenia (5%; grades 3/4: 1%)

Infection: Influenza (4%)

Local: Pain at injection site (8% to 16%)

Neuromuscular & skeletal: Limb pain (7% to 10%), ostealgia (6% to 10%), back pain (9%), muscle spasm (8%), myalgia (8%)

Ophthalmic: Conjunctivitis (5%)

Respiratory: Nasopharyngitis (10%), oropharyngeal pain (6% to 9%), bronchitis (7% to 8%), sinusitis (7%), flu-like symptoms (3%)

Frequency not defined:

Hypersensitivity: Hypersensitivity reaction

Infection: JC virus infection

Local: Infusion site reaction (≤7% monotherapy in maintenance setting; higher with combination therapy and initial infusions)

<1%, postmarketing, and/or case reports: Bone marrow depression, bronchiolitis obliterans, hypogammaglobulinemia (prolonged), interstitial pulmonary disease, intestinal obstruction, intestinal perforation, Kaposi sarcoma (disease progression), lupus-like syndrome, optic neuritis, pancytopenia (prolonged), pleurisy, polyarthritis, progressive multifocal leukoencephalopathy, serum sickness, uveitis, vasculitis (systemic; with rash), viral infection

ALERT: U.S. Boxed Warning

Mucocutaneous reactions:

Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase.

Hepatitis B virus reactivation:

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:

Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase.

Warnings/Precautions

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: [US Boxed Warning]: 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 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. Screening should include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc); monitor patients for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months after treatment. 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 physicians experienced in HBV management.

- American Society of Clinical Oncology (ASCO) provisional clinical opinion update on hepatitis B virus screening recommendations (Hwang 2015): Patients receiving anti-CD20 antibodies are at high risk for hepatitis B virus (HBV) reactivation. Screen for HBV infection with HBsAG and anti-HBc tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). In addition, patients who have risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV prevalence, household or sexual contact with HBV infected patients, high-risk behaviors [eg, intravenous drug use], and HIV infection) should also be screened prior to beginning therapy. Initiate prophylactic antiviral therapy (utilizing antivirals with low rates of viral resistance) for HBsAg positive/anti-HBc positive patients (without delaying cancer therapy) and continue the antivirals during and for ~6 to 12 months after completing treatment. HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment; antiviral therapy may be initiated prophylactically or begun promptly at the first sign of HBV reactivation.

• 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: [US Boxed Warning]: 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: [US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) (including fatalities) may occur in patients receiving rituximab-containing products, including rituximab/hyaluronidase. Promptly evaluate any patient presenting with 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:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• 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.

Monitoring Parameters

Electrolytes (in patients at risk for TLS), CBC with differential; renal function (in patients at risk for TLS), fluid/hydration status balance; blood pressure, vital signs.

Screen all patients for HBV infection prior to therapy initiation (eg, HBsAG and anti-HBc measurements). 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. Hepatitis B virus (HBV) screening recommendations (ASCO provisional clinical opinion update [Hwang 2015]): Screen for HBV infection with hepatitis B surface antigen (HBsAG) and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or resolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during 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.

Pregnancy Considerations

Rituximab crosses the placenta; B-cell lymphocytopenia lasting <6 months may occur in exposed infants. Effective contraception should be used in women of reproductive potential during therapy and for 12 months following treatment. Refer to individual monographs for additional information.

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