■
`
`RITUXAN"'
`Rituximab
`
`DESCRIPTION
`The RITUXAN (Rituximab) antibody is a genetically engineered chimeric murine/human mono(cid:173)
`clonal antibody directed against the CD20 antigen found on the surface of nonnal and malignant
`B lymphocytes. The antibody is an IgG, kappa immunoglobulin containing murine light- and
`heavy-chain variable region sequences and human constant region sequences. Rituximab is com(cid:173)
`posed of two heavy chains of 451 amino acids and two light chains of 213 amino acids (based on
`cDNA analysis) and has an approximate molecular weight of 145 kD. Rituximab has a binding
`affinity for the CD20 antigen of approximately 8.0 nM.
`
`The chimeric anti-CD20 antibody is produced by mammalian cell (Chines1.: Ha.mster ovary)
`suspension culture in a nutrient medium containing the antibiotic gentarnicin. Gentamicin is
`not detectable in the final product. The anti-CD20 antibody is purified by affinity and ion
`exchange chromatography. The purification process includes specific viral inactivation and
`removal procedures.
`
`RITUXAN is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV)
`administration. RITUXAN is supplied at a concentration of JO mg/mL in either I 00 mg (IO mL)
`or 500 mg (50 mL) sing1c-use vials. The product is fonnu)ated for intravenous administration in
`9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate. 0.7 mg/mL polysorbate 80. and
`Sterile Water for Injection. The pH is adjusted to 6.5.
`
`CLINICAL PHARMACOLOGY
`General
`Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation
`antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately
`35 kD located on pre-B and mature B lymphocytes.,., The antigen is also expressed on >90% of
`B-cell non-Hodgkin's lymphomas (NHL)' but is not found on hematopoietic stem cells, pro-B
`cells, normal plasma cells or other normal tissues." CD20 regulates an early step(s) in the activa(cid:173)
`tion process for cell cycle initiation and differentiation,• and possibly functions as a calcium ion
`channel.' CD20 is not shed from the cell surface and does not internalize upon antibody binding.'
`Free CD20 antigen is not found in the circulation.2
`
`Pre-clinical Pharmacology and Toxicology
`Mechanism of Action: The Fab domain of Rituximab binds 10 the CD20 antigen on B-lymphocytes
`and the Fe domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible
`mechanisms of cell lysis include complement-dependent cytotoxicity (CDC)' and antibody-depen(cid:173)
`dent cellular cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-
`4 human s-cell lymphoma line.•
`
`Nonna) Tissue Cross-reactivity: Rituximab binding was observed on lymphoid cells in the thymus,
`the white pulp of the spleen, and a majority of B-lymphocytcs in peripheral blood and lymph
`nodes. Little or no binding was observed in non-lymphoid tissues examined.
`
`Human Pharmacokinetics/Phannacodynamics
`In patients given single doses at 10, 50, I 00, 250 or 500 mg/m2 as an IV infusion, serum levels and
`the half-life of Rituximab were proportional to dose. In 9 patients given 375 mg/m 2 as an JV infu.
`sion for four doses, the mean serum half-life was 59.8 hours (range I I.I to 104.6 hours) after the
`first infusion and 174 hours (range 26 to 442 hours) after the fourth infusion. The wide range of
`half-lives may reflect the variable tumor burden among patients and the changes in CD20 positive
`(nonnal and malignant) B-cell populations upon repeated administrations.
`
`Rituximab at a dose of 375 mg/m' was administered as an IV infusion at weekly intervals for four
`doses to 166 patients. The peak and trough serum levels of Rituximab were inversely correlated
`with baseline values for the number of circulating CD20 positive B cells and measures of disease
`burden. Median steady-state serum levels were higher for responders compared to nonresponders;
`however, no difference was found in the rate of elimination as measured by serum half-life. Serum
`levels were higher in patients with International Working Fonnulation (IWF) subtypes B, C, and
`D as compared to those with subtype A. Rituximab was detectable in the serum of patients three
`to six months after completion of treatment.
`
`The pharmacokinetic profile of Rituximab when administered as six infusions of 375 mg/m2 in
`combination wilh six cycles of CHOP chemolherapy was similar m that seen with Rituximab alone.
`
`Administration of RITUXAN resulted in a rapid and sustained depletion of circulating and tis(cid:173)
`sue-ba:scU B cell:,. Lymph node biopsies performed 14 days after therapy showed a decrease in
`the percentage of B-cells in seven of eight patients who had received single doses of Rituxirnab
`~100 mg/m2• 9 Among the 166 patients in the pivotal study, circulating B-cells (measured as
`CDJ9+ cells) were depleted within the first three doses with sustained depletion for up to 6 to 9
`months post-treatment in 83% of patients. One of the responding patients (I%), failed to show
`significant depletion of CDJ9+ cells after the third infusion of Rituximab as compared to 19% of
`the nonresponding patients. B-cell recovery began at approximately six months foJlowing com(cid:173)
`pletion of treatment. Median B-cell levels returned to normal by twelve months follov.·ing com(cid:173)
`pletion of treatment.
`
`There were sustained and statistically significant reductions in both lgM and IgG serum levels
`observed from 5 through 11 months following Rituximab administration. However, only 14% of
`patients had reductions in IgG and/or IgM serum levels, resulting in values below the normal range.
`
`CLINICAL STUDIES
`A multicenter. open-label. singlc-ann study was conducted in 166 patients with relapsed or refrac(cid:173)
`tory low-grade or follicular B-cell NHL who received 37~ mg/m' of RITUXAN given as an IV
`infusion weekly for four doses. Patients wilh tumor masses >IO cm or with >5,000 lympho•
`cytes/µL in the peripheral blood were excluded from the study. The overall response rate (ORR)
`was 48% (80/166) with a 6% (10/166) complete response (CR) and a 42% (70/166) partial
`response (PR) rate. Disease-related signs and symptoms (including B-symptoms) were present in
`23% (39/166) of patients at study entry and resolved in 64% (25/39) of those patients. The medi(cid:173)
`an time to onset of response was 50 days and the median duration of response is projected to be
`IO to 12 months.
`
`In a multivariate analysis, the ORR was higher in patients with IWF B, C, and D histologic sub·
`types as compared to IWF A subtype (58% vs. 12% ), higher in patients whose largest lesion was
`<5 cm vs. > 7 cm in greatest diameter (55% vs. 38% ), and higher in patients with chemosensitive
`relapse as compared to chemoresistant (defined as duration of response <3 months) relapse (53%
`vs. 36% ). ORR in patients previously treated with auto1ogous bone marrow transplant was 78%
`( I 8/23). The following factors were not associated with a lower response rate: age ~ 60 years.
`extranodal disease, prior anthracycline therapy, and bone marrow involvement.
`
`In a second multicenter, multiple-dose study, 37 patients with relapsed or refractory B-cell NHL
`received 375 mg/m' of RITUXAN as an IV infusion once weekly for fourdoses. 1• 11 The ORR was
`46% with a median duration of response of 8 .6 months (range 2.6 to 26.2+ ). Single doses of up to
`500 mg/m 2 were well-tolerated.'
`
`Twenty patients have received two courses and one patient has received three courses of RITUX.
`AN as 4 weekly infusions of 375 mg/m~ per infusion. The percentage of patients repor1ing adverse
`
`events upon retreatment was similar to that reported following the first course, although the inci(cid:173)
`dence of specific adverse events differed (sec ADVERSE EVENTS). All patients had obtained an
`objective clinical response (CR or PR) to the first course of RITUXAN™ (Rituximab): upon
`retreatment, 6 of 12 patients evaluable for response obtained a complete or partial remission.
`
`Twenty-nine patients with relapsed or refractory, bulky (single lesion of> IO cm in diameter). low
`grade NHL received 375 mg/m' of RITUXAN as four weekly infusions. The overall incidence of
`adverse events and the incidence of Grade 3 and 4 adverse events was higher in patients with bulky
`disease than in patients with non-bulky disease (see ADVERSE EVENTS). Ten of 21 patients
`evaluable for response have obtained a complete or partial remission.
`
`INDICATIONS AND USAGE
`RITUXAN is indicated for the treatment of patients with relapsed or refractory low-grade or fol(cid:173)
`licular, CD20 positive, B-cell non-Hodgkin's lymphoma.
`
`CONTRAINDICATIONS
`RITUXAN is contraindicated in patients witJ1 known Type I hypersensitivity ur anaphylactic reac(cid:173)
`tions to murine proteins or to any component of this product. (See WARNINGS.)
`
`WARNINGS
`RITUXAN is associated with hypersensitivity reactions which may respond to adjustments in the
`infusion rate. Hypotension. bronchospasm, and angioedema have occurred in association with
`RITUXAN infusion as part of an infusion-related symptom complex. RITUXAN infusion should be
`interrupted for severe reactions and can be resumed at a50% reduction in rate (e.g., from 100 mg/hr
`to 50 mg/hr) when .<:ymptnm~ have completely re:!<.nlved. Treatment of these '-ymprom~ wirh
`diphenhydramine and acetaminophen is recommended; additional treatment with bronchodilators
`or IV saline may be indicated. In most cases, patients who have experienced non-life-threatening
`reactions have been able 10 complete the full course of therapy. (See DOSAGE and ADMINIS(cid:173)
`TRATION.) Medications for the treatment of hypersensitivity reactions, e.g., epinephrine, anti(cid:173)
`histamines and corticosteroids should be available for immediate use in the event of a reaction dur(cid:173)
`ing administration.
`
`Infusions should be discontinued in the event of serious or life-threatening cardiac arrhythmias.
`Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during
`and after subsequent infusions of RlTUXAN. Patients with preexisting cardiac conditions includ(cid:173)
`ing arrhythmias and angina have had recurrences of these events during RITUXAN therapy and
`should be monitored throughout the infusion and immediate post-infusion period.
`
`PRECAUTIONS
`Luboralory Muniluring: Complete blood counts (CBC) and platelet counts should be obtained ar
`regular intervals during RITUXAN therapy and more frequently in patients who develop cytope(cid:173)
`nias (see ADVERSE EVENTS).
`
`Drug/Laboratory Interactions: There have been no formal drug interaction studies perfonned
`with RITUXAN.
`
`HAMA/HACA Formation: Human anti-murine antibody (HAMA) was not detected in 67
`patients evaluated. Less than 1.0% (3/355) of patients evaluated for human anti-chimeric antibody
`(HACA) were positive. Patients who develop HAMA/HACA titers may have allergic or hyper(cid:173)
`sensitivity reactions when treated with this or other murine or chimeric monoclonal antibodies.
`
`Immunization: The safety of immunization with any vaccine, particularly live viral vaccines, fol(cid:173)
`lowing RITUXAN therapy has not been studied. The ability to generate a primary or anamnestic
`humoral response to any vaccine has also not been studied.
`
`Carcinogenesis, Mutagenesis, lmpairmenl of Fertility: No long-tenn animal studies have been
`perfonned to establish the carcinogenic or mutagemc potenllal of RITUXAN, or to determine its
`effects on fertility in males or females. Individuals of childbearing potential should use effective
`contraceptive methods during treatment and for up to 12 months following RITUXAN therapy.
`
`Pregnancy Category C: Animal reproduction studies have not been conducted with RITUXAN.
`It is not known whether RITUXAN can cause fetal harm when administered lo a pregnant woman
`or whether it can affect reproductive capacity. Human IgG is known to pass the placenta\ barrier,
`and thus may potentially cause fetal B-cell depletion; therefore, RITUXAN should be given to a
`pregnant woman only if clearly needed.
`
`Nursing Mothers: It is not known whether RITUXAN is excreted in human milk. Recause human
`IgG is excreted in human milk and the potential for absorption and immunosuppression in the
`infant is unknown. women should be advised to discontinue nursing until circulating drug levels
`are no longer detectable. (See CLINICAL PHARMACOLOGY.)
`
`Pediatric Use: The safety and effectiveness of RITUXAN in children have not been established.
`
`ADVERSE REACTIONS
`Safety data arc based on 315 patients treated in five single-agent studies of RITUXAN. This
`includes patients with bulky disease (lesions >IO cm), those who have received more than one
`course of RITl IXAN. und pati~:1t.s recC'"iving 375 rng/m~ for eight do5;,e:s.
`
`Infusion-Related Events: An infusion-related symptom complex consisting of fever and
`chills/rigors occurred in the majority of patients during the firsr RITUXAN infusion. Other fre(cid:173)
`quent infusion-related symptoms included nausea, urticaria, fatigue, headache, pruritus, bron(cid:173)
`chospasm, dyspnea, sensation of tongue or throat swelling (angioedema), rhinitis, vomiting,
`hypotension, flushing, and pain at disease sites. These reactions generally occurred within 30 min(cid:173)
`utes to 2 hours of beginning the first infusion, and resolved with slowing or intem.iption of the
`RITUXAN infusion and with supportive care (IV saline, diphenhydramine. and acetaminophen).
`The incidence of infusion-related events decreased from 80% (7% Grade 3/4) during the first infu(cid:173)
`sion to approximately 40% (5% to 10% Grade 3/4) with subsequent infusions. Mild to moderate
`hypotension requiring intenuption of RITUXAN infusion with or without the administration of IV
`saline occurred in 32 (10%) patients. Isolated occurrences of severe reactions requiring
`epinephrine have been reported in patients receiving RITUXAN for other indicarions.
`Angioedema was reported in 41 (13%) patients and was serious in one patient. Bronchospasm
`occurred in 25 (8%) patients; one-quarter of these patients were treated with bronchodilators. A
`single report of bronchiolitis obliterans was noted.
`
`Immunologic Events: RITUXAN induced B-cell depletion in 70 to 80% of patients and was asso(cid:173)
`ciated with decreased serum immunoglobulins in a minority of patients, The incidence of infection
`does not _appear to be increased. During the treatment period, 50 patients in the pivotal trial devel(cid:173)
`oped 68 rnfect1ous events; 6 (9%) were Grade 3 in severity and none were Grade 4 events. Of the
`
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`6 serious infectious events. none were associated with neutropcnia. The serious bacterial event!.
`included sepsis due to Listeria (n=I), Staphylococcal bac1eremia (n=I) and polymicrobial sepsis
`(n=l ). In the post-treatment period (30 days to 11 months following the last dose), bacterial infec(cid:173)
`tions included sepsis (n=I); significant viral infections included herpes simplex infections (n=2)
`and herpes zoster (n=3).
`
`Retreatment Events: Twenty-one patients have received more than one course of RITUXAN™
`(Rituximab), The percentage of patients reporting any adverse event upon retreatment was simi(cid:173)
`lar to the percentage of patients reporting adverse events upon initial exposure. The following
`adverse events were reported more frequently in retreated subjects: asthenia, throat irritation,
`flushing, tachycardia, anorexia, Ieukopenia, thrombocytopenia, anemia, peripheral edema, dizzi(cid:173)
`ness, depression. respiratory symptoms. night sweats. and pruritus.
`
`Hematologic Events: During the treatment period (up to 30 days following last dose) severe
`thrombocytopenia occurred in 1.3% of patients, severe neutropenia occurred in 1.9% of patients,
`and severe anemia occurred in 1.0% of patients. A single occurrence of transient nplastic anemia
`(pure red cell aplasia) and two occurrences of hemolytic anemia following RITUXAN therapy
`were reponcd.
`
`Cardiac Events: Four patients developed arrhythmias during RITUXAN infusion. One of the four
`discontinued treatment because of ventricular tachycardia and supraventricular tachycardias. The
`other three patients experienced trigeminy (I) and irregular pulse (2) and did not require discon(cid:173)
`tinuation of therapy. Angina was reported during infusion and myocardial infarction occurred 4
`days post-infusion in one subject with a prior history of myocardial infarction.
`
`Table J.
`
`Adverse Events 2:5% of Patients (N=315)
`
`Any Adverse Event
`Bodv As A Whole
`Fever
`Chills
`Asthenia
`Headache
`Throat Irritation
`Abdominal Pain
`Cardiovascular System
`H ypotension
`Digestive System
`Nausea
`Vomiting
`Hem1c and Lymphattc System
`Leukopenia
`Thrombocytopenia
`Neutropenia
`Metabolic and Nutritional Svstem
`Angioedema
`Musculo-Skeletal Svstem
`Myalgia
`Nervous System
`Dizziness
`Respiratory System
`Rhinitis
`Bronchospasm
`Skin and Appendages
`Pruritus
`Rash
`Unicaria
`
`Incidence
`All Grades
`N
`%
`275
`87
`
`154
`102
`49
`43
`19
`18
`
`32
`
`55
`23
`
`33
`25
`21
`
`41
`
`21
`
`23
`
`25
`24
`
`32
`31
`24
`
`49
`32
`16
`14
`6
`6
`
`10
`
`18
`7
`
`II
`8
`7
`
`13
`
`7
`
`7
`
`8
`8
`
`10
`10
`8
`
`Severe and life-threatening (Grade 3 and 4) events were reponed in 10% (32/315) of patients. The
`following Grade 3 and 4 adverse events were reported: neutropenia (1.9%), chills (1.6%), leukope(cid:173)
`nia and thrombocytopenia ( 1.3% for each), hypotension. anemia, bronchospasm, and urticaria
`( 1.0% for each), headache, abdominal pain, arrhythmia (0.6% for each). and asthenia, hypertension,
`nausea, vomiting. coagulation disorder, angioedema, arthralgia, pain. rhinitis, increased cough. dys(cid:173)
`pnea, bronchiolitis obliterans, hypoxia, asthma. pruritus. and rash (one patient each, 0.3%).
`
`The following adverse events occurred in 2: 1.0% but <5.0% of patients. in order of decreasing inci.
`dence: flushing, arthralgia, diarrhea, anemia. cough increase. hypertension, lacrimation disorder,
`pain, hyperglycemia, back pain, peripheral edema. paresthesia, dyspepsia, chest pain, anorexia,
`anxiety, malaise, tachycardia, agitation. insomnia, sinusitis, conjunctivitis. abdominal enlarge(cid:173)
`ment, postural hypotension. LDH increase. hypocalcemia, hypesthesia. respiratory disorder, tumor
`pain, pain at injection site, bradycardia, hypenonia. nervousness, bronchitis, and taste perversion.
`
`The proportion of patients reporting any adverse event was similar in patients with bulky disease
`and those with lesions <10 cm in diameter. However, the incidence of dizziness, neutropenia,
`thrombocytopenia, myalgia, anemia and chest pain was higher in patients with lesions >IO cm.
`The incidence of any Grade 3 and 4 event was higher (31 % vs. 13%) and the incidence of Grade
`3 or 4 neutropenia, anemia. hypotension. and dyspnea was also higher in patients with bulky dis(cid:173)
`ease compared with patients with lesions < l 0 cm.
`
`UVERDOSAGE
`There has been no experience with overdosage in human clinical trials. Single doses higher than
`500 mg/m' have not been tested.
`
`DOSAGE AND ADMINISTRATION
`Usual Dose;
`The recommended dosage of RITUXAN is 375 mg/m 2 given as an IV infusion once weekly for
`four doses (days I, 8, 15, and 22). RITUXAN may be administered in an outpatient setting. DO
`NOT ADMINISTER AS AN INTRA VENOUS PUSH OR ROI.US. (See Administration.)
`
`Instructions for Administration
`
`Preparation for Administration: Use appropriate aseptic technique. Withdraw the necessary
`amount of RITUXAN and dilute to a final concentration of I to 4 mg/mL into an infusion bag con(cid:173)
`taining either 0.9% Sodium Chloride USP or 5% Dextrose in Water USP. Gently inven the bag to
`mix the solution. Discard any unused portion left in the vial. Parenteral dn1g products should be
`inspected visually for particulate matter and discoloration prior to administration.
`
`RITUXAN solutions for infusion are stable at 2• to 8-C (36" to 46"F) for 24 hours and al room
`temperature for an additional 12 hours. No incompatibilities between RITUXAN and
`polyvinyk:hloridc or polyclhylcnc bap ha, i: been ob~crvcd.
`
`Administrntion: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOl.llS.
`Hypersensitivity reactions may occur (see WARNINGS). Prcmedication. consisting of
`acetaminophen and diphenhydramine, should be considered before each infusion of RITUXAN""'
`(Rituximab). Premedication may auenuate infusion-related events. Since transient hypotension
`may occur during RITUXAN infusion, consideration should be given to withholding anti(cid:173)
`hypertensive medications 12 hours prior to RITUXAN infusion.
`
`First Infusion: The RITUXAN solution for infusion should be administered intravenously at an ini•
`tial rate of 50 mg/hr. RITUXAN should not be mixed or diluted with other drugs. If hypersensi(cid:173)
`tivity or infusion-related events do not occur, escalate the infusion rate in 50 mg/hr increments
`every 30 minutes, to a maximum of 400 mg/hr. If hypersensitivity or an infusion-related event devel(cid:173)
`ops, the infusion should be temporarily slowed or interrupted (see WARNINGS). The infusion can
`continue at one-half the previous rate upon improvement of patient symptoms.
`
`Subsequent Infusions: Subsequent RITUXAN infusions can be administered at an initial rate of
`100 mg/hr. and increased by 100 mg/hr increments at 30-minute intervals. to a maximum of
`400 mg/hr as tolerated.
`
`Stability and Storage: RITUXAN vials are stable at r to s·c (36" to 46'F). Do not use beyond
`expiration date stamped on carton. RITUXAN vials should be protected from direct sunlight.
`
`HOW SUPPLIED
`RITUXAN is supplied as 100 mg and 500 mg of sterile, preservative-free, single-use vials.
`Single unit I 00 mg carton: Contains one IO ml vial of RITUXAN (IO mg/ml).
`NDC 50242-051-21
`Single unit 500 mg carton: Contains one 50 mL vial of RITUXAN (IO mg/ml).
`NDC 50242-053-06
`
`REFERENCES
`
`I. Valentine MA, Meier KE, Rossie S, et al. Phosphorylation of the CD20 phosphoprotein in rest(cid:173)
`ing B lymphocytes. J. Biol. Chem. 1989 264(19):11282-11287.
`
`2. Einfeld DA, Brown JP, Valentine MA, et al. Molecular cloning of the human B cell CD20
`receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J.
`1988 7(3):711 -717.
`
`3. Anderson KC, Bates MP, Slaughenhoupt BL, et al. Expression of human B cell-associated
`antigens on leukemias and lymphomas: A model of human B cell differentiation. Blood 1984
`63(6):1424-1433.
`
`4. Tedder TF, Boyd AW, Freedman AS, et al. The B cell surface molecule BI is functionally
`linked with B cell activation and differentiation. J. Immunol. 1985 135(2):973-979.
`
`5. Tedder TF, Zhou LJ, Bell PD, et al. The CD20 surface molecule of B lymphocytes functions
`as a calcium channel. J. Cell. Biochem. 1990 14D:195.
`
`6. Press OW, Applebaum F, Ledbetter JA, Martin PJ, Zarling J, Kidd P, et al. Monoclonal anti(cid:173)
`body 11'5 (anti-CD20) serotherapy of human B-cell lymphomas. Blood 1987 69(2):584-591.
`
`7. Reff ME, Carner C, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells
`in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994 83(2):435-445.
`
`8. Demidem A. Lam T, Alas S, Hariharan K. Hanna N. and Bonavida B. Chimeric anti-CD20
`(IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by
`cytotoxic drugs. Cancer Chemotherapy & Radiopharmaceuticals 1997 12(3):177-186.
`
`9. Maloney DG. Liles TM. C:z-.erwins.ki C. Waldichuk J. Rosenberg J. Grillo-L6pez A. et al. Phase
`I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal anti(cid:173)
`body (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994 84(8):2457-2466.
`
`10. Maloney DG, Grillo-L6pez AJ. Bodkin D, White CA, Liles T-M. Royston I. et al. IDEC(cid:173)
`C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lym(cid:173)
`phoma. J. Clio. Oncol. 1997 15(10):3266-3274.
`
`11. Maloney DG, Grillo-L6pez Al, White CA, Bodkin D, Schilder Rl, Neidhart JA, et al. IDEC(cid:173)
`C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low(cid:173)
`grade non-Hodgkin's lymphoma. Blood 1997 90(6):2188-2195.
`
`Jointly Manuractured by:
`
`IDEC Pharmaceuticals Corporation
`11011 Torreyana Road
`San Diego, CA 92121
`
`Genentech. Inc.
`I DNA Way
`South San Francisco, CA 94080-4990
`
`© 1997 (DEC Pharmaceuticals Corporntion and Gcnentcch, Inc.
`
`G48(l97-R0 (544)
`Nmemhcr 1997
`
`