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Drugs reference index «Rituximab»

Rituximab


Rituximab

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. The CD20 antigen is also expressed on more than 90% of B-cell non-Hodgkin lymphomas (NHL).

Pharmacokinetics

Absorption

C max increases with each successive infusion and was 486 mcg/mL following the fourth infusion. Peak and trough serum levels are inversely correlated with pretreatment circulating CD19-positive B cells and tumor burden.

Distribution

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

Elimination

The wide range of half-lives reflect the variable tumor burden and changes in CD19-positive B-cell populations. In RA patients, the Cl was 0.335 L/day and the mean half-life was 18 days. In NHL patients, the half-life was 22 days.

Duration

Detectable in serum 3 to 6 mo after completion of treatment. B-cell recovery began at about 6 mo following completion of treatment. Median B-cell levels returned to normal by 12 mo after completion of treatment.

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 cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; treatment of nonprogressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy; treatment of previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) 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.

Unlabeled Uses

Neuropathy/polyneuropathy; peripheral ulcerative keratitis; relapsed or refractory chronic lymphocytic leukemia; relapsed or refractory Waldenström macroglobulinemia; thrombocytopenic purpura.

Contraindications

None well documented.

Dosage and Administration

Diffuse Large B-Cell NHLAdults

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

Nonprogressing, Low-Grade, CD20-Positive, B-cell NHLAdults

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

Premedication

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

Previously Untreated, Follicular, CD20-Positive, B-Cell NHLAdults

IV 375 mg/m 2 infusion, given on day 1 of each cycle of CVP chemotherapy, for up to 8 doses.

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

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

Re-treatment

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

Rheumatoid ArthritisAdults

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

Rituximab as a Component of Ibritumomab Tiuxetan Therapeutic RegimenAdults

IV As a required component of the ibritumomab tiuxetan therapeutic regimen, 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.

General Advice

  • Do not administer as an IV push or bolus.
  • Because transient hypotension may occur during rituximab infusion, consider withholding antihypertensive medications 12 h prior to rituximab infusion.
  • 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.
  • Premedicate before each infusion.
  • Do not mix or dilute with other drugs.
  • 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.

Storage/Stability

Rituximab vials are stable at 36° to 46°F. Protect vials from direct sunlight. Do not freeze or shake. Rituximab solutions for infusion may be stored at 36° to 46°F for 24 h, and are stable at room temperature for an additional 24 h. However, because rituximab solutions do not contain a preservative, store diluted solutions refrigerated, at 36° to 46°F.

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 for 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 receiving rituximab and cisplatin concomitantly in clinical trials. Coadministration of these agents is not an approved treatment regimen. If this non-approved combination is used in clinical trials, administer with extreme caution and closely monitor for signs of renal failure.

Live virus 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.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension (10%); hypertension (6%); fatal cardiac failure, systemic vasculitis (postmarketing).

CNS

Asthenia (26%); headache (19%); dizziness (10%); anxiety (5%).

Dermatologic

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

EENT

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

GI

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

Hematologic-Lymphatic

Lymphopenia (48%); leukopenia, neutropenia (14%); thrombocytopenia (12%); anemia (8%); hyperviscosity syndrome in Waldenström macroglobulinemia, late-onset neutropenia, marrow hypoplasia, prolonged pancytopenia (postmarketing).

Metabolic-Nutritional

Hypophosphatemia (21%); angioedema (11%); hyperglycemia (9%); peripheral edema (8%); LDH increase (7%); hyperuricemia (2%).

Musculoskeletal

Arthralgia, back pain, myalgia (10%); polyarticular arthritis (postmarketing).

Respiratory

Increased cough (13%); rhinitis (12%); bronchospasm (8%); dyspnea (7%); sinusitis (6%); fatal bronchiolitis obliterans and pneumonitis, including interstitial pneumonitis (postmarketing).

Miscellaneous

Fever (53%); chills (33%); infection (31%); infusion reactions, including angioedema, bronchospasm (with or without hypotension or hypertension), chills, cough, fever, pruritus, rigors, sneezing, throat irritation, and urticaria/rash (27%); pain (12%); 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, pleuritis, serum sickness, vasculitis with rash, viral infections, including progressive multifocal leukoencephalopathy (PML) (postmarketing).

Precautions

Warnings

Infusion reaction

Deaths within 24 h of infusion have been reported. Reaction complex consists of acute respiratory distress syndrome, anaphylactoid events, angioedema, bronchospasm, cardiogenic shock, hypotension, hypoxia, MI, pulmonary infiltrates, urticaria, or ventricular fibrillation. Approximately 80% of fatal infusion reactions occur with first infusion. Interrupt the rituximab infusion for severe reactions and institute supportive care measures as medically indicated (eg, acetaminophen, bronchodilators, diphenhydramine, IV fluids, oxygen, vasopressors).

Mucocutaneous reactions (severe)

Reported with fatal outcomes.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death can occur.

Tumor lysis syndrome

Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hyperphophatemia, hyperuricemia, or hypocalcemia has been reported within 12 to 24 h after the first rituximab infusion.

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 patients closely for signs of renal failure, especially when the combination of rituximab and cisplatin is used. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active hepatitis B virus infection and for signs of hepatitis during and for up to several months following therapy.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Diffuse large B-cell NHL

No differences in efficacy were observed between patients 65 yr of age and older compared with younger patients. Cardiac adverse reactions (eg, supraventricular arrhythmias) and serious pulmonary adverse reactions (eg, pneumonia, pneumonitis) were more common among elderly patients.

Low-grade or follicular NHL

Studies did not include sufficient numbers of patients 65 yr of age and older to determine whether they respond differently from younger patients.

Rheumatoid arthritis

Response rates and adverse reactions were similar in patients 65 yr of age and older compared with patients younger than 65 yr of age. The rate of serious adverse reactions (eg, CV events, malignancies, serious infections) were higher in elderly patients.

Bowel obstruction

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

Cardiac arrhythmias

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

Coadministration with biologic agents or DMARDs

There are limited data available on the safety of use of biologic agents or DMARDs, other than methotrexate, in patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe patients closely for signs of infection if biologic agents or DMARDs are coadministered with rituximab.

Hepatitis B reactivation

Hepatitis B reactivation with fulminant hepatitis, hepatic failure, and death has been reported in patients with hematologic malignancies.

Immunization

Vaccination with live virus vaccines is not recommended.

Immunogenicity

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

Infections

Not recommended in patients with severe active infections.

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.

Re-treatment in rheumatoid arthritis patients

Safety and efficacy of re-treatment have not been established.

Rheumatoid arthritis patients

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

Overdosage

Symptoms

No experience with overdosage in humans.

Patient Information

  • Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
  • Review dosing schedule with patient, family, or caregiver.
  • 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; hives; itching; persistent nausea, vomiting, diarrhea, or appetite loss; persistent or worsening general body weakness; rash; shortness of breath or difficulty breathing; 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 that serious stomach and bowel problems have been observed and to report any stomach pain during treatment to health care provider.

Copyright © 2009 Wolters Kluwer Health.

  • Rituximab MedFacts Consumer Leaflet (Wolters Kluwer)
  • rituximab Intravenous Advanced Consumer (Micromedex) - Includes Dosage Information
  • Rituxan Prescribing Information (FDA)
  • Rituxan Consumer Overview

See Also...

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