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Rituximab

Pronunciation

Pronunciation: ri-TUX-i-mab
Class: Monoclonal antibody

Trade Names

Rituxan
- Injection, solution, concentrate 10 mg/mL

Pharmacology

Rituximab is a monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes.

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Pharmacokinetics

Absorption

C max increases with each successive infusion. The mean C max after the first and second infusion for the 2 × 500 mg dose were 157 and 183 mcg/mL, respectively. The mean C max after the first and second infusion for the 2 × 1,000 mg dose were 318 and 381 mcg/mL, respectively.

Distribution

Binds to lymphoid cells in thymus, white pulp of spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. In patients with rheumatoid arthritis (RA), the Vd was 3.1 L; in patients with Wegener granulomatosis or microscopic polyangiitis, the Vd was 4.5 L.

Elimination

The wide range of half-lives reflect the variable tumor burden and changes in CD19-positive, B-cell populations. In patients with RA, the Cl was 0.335 L/day and the mean half-life was 18 days. In patients with Wegener granulomatosis and microscopic polyangiitis, the Cl was 0.312 L/day and the half-life was 23 days. In patients with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL), the half-life was 22 and 32 days, respectively.

Special Populations

Renal Function Impairment

No formal pharmacokinetic studies have been conducted.

Hepatic Function Impairment

No formal pharmacokinetic studies have been conducted.

Elderly

Age had no effect on rituximab pharmacokinetics.

Children

The pharmacokinetics of rituximab have not been studied in children and adolescents.

Gender

Gender had no effect on rituximab pharmacokinetics.

Weight

Weight had no effect on rituximab pharmacokinetics.

Indications and Usage

Treatment of relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; treatment of previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy, and in patients achieving a complete or partial response to rituximab in combination with chemotherapy as a single-agent maintenance therapy; treatment of nonprogressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line cyclophosphamide, vincristine, and prednisone chemotherapy; treatment of previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone, or other anthracycline-based chemotherapy regimens; in combination with methotrexate for the treatment of adult patients with moderately to severely active RA who have had an inadequate response to 1 or more tumor necrosis factor (TNF)–antagonist therapies; in combination with fludarabine and cyclophosphamide for the treatment of patients with previously untreated and previously treated CD20-positive CLL; in combination with glucocorticoids for the treatment of adults with Wegener granulomatosis or microscopic polyangiitis.

Unlabeled Uses

Neuropathy/polyneuropathy; peripheral ulcerative keratitis; Waldenström macroglobulinemia; idiopathic thrombocytopenic purpura; juvenile idiopathic arthritis.

Contraindications

None well documented.

Dosage and Administration

CLL
Adults

IV 375 mg/m 2 the day prior to the initiation of fludarabine and cyclophosphamide chemotherapy, then 500 mg/m 2 on day 1 of cycles 2 to 6 (every 28 days). Pneumocystis jiroveci pneumonia (PCP) and antiherpetic viral prophylaxis is recommended during treatment and for up to 12 mo following treatment as appropriate.

Diffuse Large B-Cell NHL
Adults

IV 375 mg/m 2 on day 1 of each chemotherapy cycle for up to 8 infusions.

Microscopic Polyangiitis or Wegener Granulomatosis
Adults

IV 375 mg/m 2 once weekly for 4 wk. Fourteen days prior to initiation of rituximab therapy, begin treatment with glucocorticoids (methylprednisolone 1,000 mg/day IV for 1 to 3 days followed by oral prednisone 1 mg/kg/day [max, 80 mg/day]). PCP prophylaxis is recommended during treatment and for up to 6 mo following the last rituximab dose.

Nonprogressing, Low-Grade, CD20-Positive, B-Cell NHL
Adults

IV Following completion of 6 to 8 cycles of cyclophosphamide, vincristine, and prednisone chemotherapy, 375 mg/m 2 infused once weekly for 4 doses at 6-mo intervals to a max of 16 doses.

Previously Untreated, Follicular, CD20-Positive, B-Cell NHL
Adults

IV 375 mg/m 2 infusion, given on day 1 of each cycle of cyclophosphamide, vincristine, and prednisone chemotherapy for up to 8 doses. In patients with complete or partial response, initiate rituximab maintenance 8 wk following completion of rituximab in combination with chemotherapy as a single agent at a dose of 375 mg/m 2 once every 8 weeks for 12 doses.

Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
Adults

IV 375 mg/m 2 once weekly for 4 or 8 doses.

Retreatment of Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

IV 375 mg/m 2 once weekly for 4 doses.

RA
Adults

IV 2 infusions of 1,000 mg separated by 2 wk in combination with methotrexate. Subsequent doses should be administered every 24 wk, but no sooner than every 16 wk.

Concomitant Therapy With Ibritumomab Tiuxetan
Adults

IV 250 mg/m 2 within 4 h prior to administration of indium-111 (In-111) ibritumomab tiuxetan and within 4 h prior to administration of yttrium-90 (Y-90) ibritumomab tiuxetan. Rituximab and In-111 ibritumomab tiuxetan should precede rituximab and Y-90 ibritumomab tiuxetan by 7 to 9 days.

Premedication
Adults

Premedicate before each infusion with acetaminophen and an antihistamine. For patients with RA, methylprednisolone 100 mg IV or its equivalent is recommended 30 min prior to each infusion.

General Advice

  • Administer only as IV infusion. Do not administer as an IV push or bolus.
  • Dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing sodium chloride 0.9% or dextrose 5% in water. Gently invert bag to mix the solution. Do not shake.
  • For the first infusion, infuse rituximab solution at an initial rate of 50 mg/h. If infusion reactions do not occur, escalate infusion rate in 50 mg/h increments every 30 min, to a max of 400 mg/h.
  • Subsequent infusions: Initiate infusion at a rate of 100 mg/h. In the absence of infusion toxicity, increase rate by 100 mg/h increments at 30-min intervals, to a max of 400 mg/h as tolerated.
  • If an infusion reaction develops, the infusion should be temporarily slowed or interrupted. The infusion can continue at half the previous rate upon improvement of patient symptoms.
  • Do not mix or dilute with other drugs.

Storage/Stability

Store vials between 36° and 46°F. Protect vials from direct sunlight. Do not freeze. Store diluted infusions between 36° and 46°F for 24 h.

Drug Interactions

Biological agents or disease-modifying antirheumatic drugs

Limited data are available on the safety of the use of biologic agents or disease-modifying antirheumatic drugs (DMARDs) other than methotrexate in patients exhibiting peripheral B-cell depletion following treatment with rituximab. Risk of infection may be increased. Closely observe patients for signs of infection if biologic agents and/or DMARDs are coadministered with rituximab.

Cisplatin

Renal toxicity has occurred in patients coadministered rituximab and cisplatin in clinical trials. Coadministration of these agents is not an approved treatment regimen.

Tocilizumab

Coadministration may increase the risk of serious infection. Avoid concurrent use.

Vaccines

The safety of immunization with live viral vaccines following rituximab has not been studied, and vaccination with live virus vaccines is not recommended. If a non-live vaccine is administered, give at least 4 wk prior to a course of rituximab.

Adverse Reactions

Cardiovascular

Hypertension (12%); hypotension (10%); fatal cardiac failure, systemic vasculitis (postmarketing).

CNS

Chills (33%); asthenia (26%); headache (19%); insomnia (14%); fatigue (13%); dizziness (10%); anxiety (5%).

Dermatologic

Night sweats, rash (15%); pruritus (14%); urticaria (8%); flushing (5%); severe mucocutaneous reactions, vasculitis with rash (postmarketing).

EENT

Throat irritation (9%); optic neuritis, uveitis (postmarketing).

GI

Nausea (23%); diarrhea (17%); abdominal pain (14%); vomiting (10%); upper abdominal pain (2%); bowel obstruction and perforation (postmarketing).

Hematologic-Lymphatic

B-cell depletion (80%); lymphopenia (48%); anemia (16%); decreased immunoglobulin M and immunoglobulin G serum levels, leukopenia, neutropenia (14%); thrombocytopenia (12%); hyperviscosity syndrome in Waldenström macroglobulinemia, late-onset neutropenia, marrow hypoplasia, prolonged pancytopenia (postmarketing).

Hepatic

Increased ALT (13%).

Local

Infusion reactions, including angioedema, bronchospasm, chills, cough, cytokine release syndrome, dizziness, fever, flushing, headache, hypertension, hypotension, myalgia, nausea, pruritus, rigors, sneezing, throat irritation, tremor, urticaria/rash, and/or vomiting (77%).

Metabolic-Nutritional

Hypophosphatemia (21%); peripheral edema (16%); hyperglycemia (9%); LDH increase (7%); hyperuricemia (2%).

Musculoskeletal

Muscle spasms (17%); arthralgia (13%); back pain, myalgia (10%); polyarticular arthritis (postmarketing).

Respiratory

Cough (13%); rhinitis (12%); epistaxis (11%); dyspnea (10%); bronchospasm (8%); sinusitis (6%); fatal bronchiolitis obliterans, fatal interstitial lung disease, pleuritis (postmarketing).

Miscellaneous

Infection (62%); fever (53%); pain (12%); angioedema (11%); disease progression of Kaposi sarcoma, fatal infections in HIV-associated lymphoma, grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection, lupus-like syndrome, serum sickness, viral infections (including progressive multifocal leukoencephalopathy [PML], posterior reversible encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome) (postmarketing).

Precautions

Warnings

Fatal infusion reactions

Deaths within 24 h of infusion have been reported. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusion. Discontinue infusion and provide medical treatment for grade 3 or 4 infusion reactions.

Tumor lysis syndrome

Acute renal failure requiring dialysis with instances of fatal outcome have been reported in the setting of tumor lysis syndrome following treatment in patients with NHL.

Severe mucocutaneous reactions

Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab.

Progressive multifocal leukoencephalopathy

Jakob-Creutzfeldt virus infection resulting in PML and death can occur.


Monitor

Obtain CBC and platelet counts at regular intervals and more frequently in patients developing cytopenias. Perform cardiac monitoring during and after all infusions of rituximab for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. Monitor RA patients throughout the infusion. Monitor renal function and fluid balance, and monitor for infusion reactions and infection. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active hepatitis B virus infection during and for up to several months following therapy.


Pregnancy

Category C .

Lactation

Undetermined. Immunoglobulin G is excreted in human milk; therefore, rituximab may also be excreted.

Children

Safety and efficacy not established.

Elderly

Cardiac adverse reactions (eg, supraventricular arrhythmias), serious infections, malignancies, and serious pulmonary adverse reactions (eg, pneumonia, pneumonitis) were more common among elderly patients.

Cardiac arrhythmias

Discontinue infusions in the event of serious or life-threatening cardiac arrhythmias.

GI effects

Abdominal pain, bowel obstruction, and perforation, sometimes leading to death, have been reported in patients concurrently receiving chemotherapy.

Hepatitis B reactivation

Hepatitis B virus reactivation with fulminant hepatitis, hepatic failure, and death can occur with hematologic malignancies treated with rituximab.

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity.

Infections

Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and up to 1 y following completion of therapy. Discontinue therapy for serious infections.

RA patients

Use of rituximab in patients with RA who have not had inadequate response to 1 or more TNF antagonists is not recommended.

Renal toxicity

Severe, including fatal, renal toxicity can occur after rituximab administration in patients with hematologic malignancies. Consider discontinuing rituximab in patients with rising serum creatinine or oliguria.

Overdosage

Symptoms

No experience with overdosage in humans.

Patient Information

  • Advise patients to read the Medication Guide before starting therapy and with each refill.
  • Advise patient, family, or caregiver to immediately report any of the following to health care provider: chest pain; decreased urine output; fever, chills, or other signs of infection; itching; persistent nausea, vomiting, diarrhea, or appetite loss; persistent or worsening general body weakness; rash; unusual bleeding or bruising.
  • Advise women of childbearing potential to use effective contraceptive methods during treatment and for up to 12 mo following therapy.
  • Inform patients to report any symptoms suggestive of severe mucocutaneous reactions, such as blisters, painful sores on the skin or in the mouth, peeling skin, or ulcers.
  • Advise patients of the potential for serious, including fatal, infusion reactions (eg, blurred vision, cough, dizziness, drowsiness, headache, hives, swelling, trouble breathing or wheezing).
  • Counsel patients with NHL about the possible risk of tumor lysis syndrome while receiving rituximab.

Copyright © 2009 Wolters Kluwer Health.

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