Mabthera-Generic, rituximab, 500mg x 1 vial

Targeted Therapy for Certain Types of Non-Hodgkin's Lymphoma

RITUXAN is approved for non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy.

Study schema from “Results of E1496: A phase III trial of CVP with or without maintenance rituximab in advanced indolent lymphoma (NHL)”^*

• Patients had a tissue diagnosis of low-grade NHL (IWF type A, B, or C). Patients who did not progress after 6-8 cycles of CVP received either 4 weekly doses of RITUXAN every 6 months for up to 2 years (n=162) or observation (n=160)
• Neutropenia was the only Grade 3 or 4 adverse event that occurred more frequently
  (≥2%) in the RITUXAN arm compared with those who received no further therapy (4% vs 1%).

Risk reduction demonstrated in NCI^§-sponsored trial using up to 16 doses of RITUXAN following CVP^||

RITUXAN following CVP reduced risk of progression, relapse, or death by 51%

Hazard ratio 0.49; p<0.05 vs observation.

• In the E1496 trial, a phase III clinical trial of 322 patients with low-grade NHL, up to 16 doses of RITUXAN following CVP reduced risk of progression, relapse, or death by 51% over observation
• Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more
  frequently (≥2%) in the RITUXAN arm compared with those who received no further therapy (4% vs 1%)

Clinical benefit was consistent across diverse patient subgroups

• Primary study endpoint: Progression-free survival (PFS), defined as time from randomization to progression, relapse, or death
• Doubled reduction in risk related to PFS was achieved with RITUXAN vs observation (median 28-months follow-up)
• Risk reduction was observed in a diverse set of patient subgroups studied, including those characteristics associated with a poorer prognosis: baseline age >60 years, and gross residual disease post-CVP therapy
• Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently
  (≥2%) in the RITUXAN arm compared with those who received no further therapy (4% vs 1%)

E1496 dosing strategy for RITUXAN based on proven B-cell depletion and recovery

• E1496 dosing for RITUXAN (375 mg/m² weekly x4 every 6 months for up to 2 years) was based on findings from the original single agent, multicenter, pivotal study of RITUXAN 375 mg/m² weekly x4 in relapsed or refractory, low-grade or follicular NHL (McLaughlin study, N=166)
• B cells were depleted rapidly
• RITUXAN following CVP vs observation: The following common adverse reactions were reported more frequently (≥5%) in patients receiving RITUXAN following CVP compared with those who received no further therapy: fatigue (39% vs 14%), anemia (35% vs 20%), peripheral sensory neuropathy (30% vs 18%), infections (19% vs 9%), pulmonary toxicity (18% vs 10%), hepatobiliary toxicity (17% vs 7%), rash and/or pruritus (17% vs 5%), arthralgia (12% vs 3%), and weight gain (11% vs 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the RITUXAN arm compared with those who received no further therapy (4% vs 1%).

Mabtherea (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

IV absorption is immediate and results in a rapid and sustained depletion of circulating and tissue-based cells.

Distribution

Binds to lymphoid cells in thymus, white pulp of spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes.

Elimination

Mean serum half-life is 59.8 h after first infusion and 174 h after fourth infusion. Wide range of half-lives reflect the variable tumor burden and changes in CD20-positive B-cell populations.

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.

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 non-progressing (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 to reduce signs and symptoms and to slow the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to 1 or more tumor necrosis factor (TNF) antagonist therapies.

Unlabeled Uses

Relapsed or refractory chronic lymphocytic leukemia; relapsed or refractory Waldenström macroglobulinemia; thrombocytopenic purpura.

Contraindications

None.

Dosage and Administration

Diffuse Large B-Cell NHL
Adults

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

Non-Progressing, Low-Grade, CD20-Positive, B-cell NHL, After First-Line CVP Chemotherapy
Adults

IV Following completion of 6 to 8 cycles of CVP chemotherapy, administer 375 mg/m ² 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 CVP chemotherapy, for up to 8 doses.

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

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

Retreatment

375 mg/m ² IV infusion once/wk for 4 doses.

RA
Adults

IV 2 infusions of 1,000 mg separated by 2 wk.

Rituximab as a Component of Ibritumomab Tiuxetan Therapeutic Regimen
Adults

IV As a required component of the ibritumomab tiuxetan therapeutic regimen, infuse 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 infusion reactions may occur, consider premedication with acetaminophen and an antihistamine prior to each rituximab infusion.
• Because transient hypotension may occur during rituximab infusion, consider withholding antihypertensive medications 12 h prior to rituximab infusion.
• First infusion: Infuse rituximab solution at an initial rate of 50 mg/h. Do not mix or dilute with other drugs. If infusion reactions do not occur, escalate infusion rate in 50 mg/h increments every 30 min, to a max of 400 mg/h. If an infusion reaction develops, temporarily slow or interrupt infusion. Upon improvement of patient's symptoms, continue infusion at one-half the previous rate.
• Subsequent infusions: If the first infusion is well tolerated, subsequent rituximab infusions can be given at an initial rate of 100 mg/h, and increased in 100 mg/h increments at 30-min intervals, to a max of 400 mg/h as tolerated. If the first infusion is not tolerated, follow the guidelines for first infusion.

Storage/Stability

Rituximab vials are stable at 36° to 46°F. Do not use beyond expiration date stamped on carton. 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

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.

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

Angioedema (11%); hyperglycemia (9%); peripheral edema (8%); LDH increase (7%).

Musculoskeletal

Arthralgia, back pain, myalgia (10%).

Respiratory

Increased cough (13%); rhinitis (12%); bronchospasm (8%); dyspnea (7%); sinusitis (6%); fatal bronchiolitis obliterans and pneumonitis, including interstitial nephritis (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, lupus-like syndrome, pleuritis, polyarticular arthritis, serum sickness, vasculitis with rash, viral infections, including progressive multifocal leukoencephalopathy (PML) (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Elderly

Diffuse large B-cell NHL

No differences in efficacy were observed between patients who where 65 yr of age and older compared with younger 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.

Hypersensitivity

Rituximab is associated with hypersensitivity reactions, which may respond to adjustments in the infusion rate and in medical management.

Renal Function

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.

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 disease modifying anti-rheumatic drugs (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.

Retreatment in RA patients

Safety and efficacy of retreatment have not been established.

RA 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 to read the patient information leaflet before using product the first time and with each refill.
• 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; sores in mouth; unusual bleeding or bruising.