1428/GENENTECH
`
`Pulmozyme-Coht.
`
`INHALATION SOLUTION
`Manufactured by
`GENENTECH. Inc.
`I DNA Way
`South San Francisco, CA 94080-4990
`Shown in Product Identification Guide, page 313
`
`RITUXAN®
`Rituximab
`
`WARNINGS
`
`I:l<
`
`Fatal Infusion Reactions: Deaths within 24 hours of
`RITUXAN infusion have been reported. These fatal re(cid:173)
`actions followed an infusion reaction complex which in~
`eluded hypoxia, pulmonary infiltrates, acute respiratory
`distress syndromej myocardial infarction, ventricular fi(cid:173)
`brillation or cardiogenic shock. Approximately 80% of
`fatal infusion reactions occurred in association with the
`first
`infusion.
`(See WARNINGS and ADVERSE
`REACTIONS.)
`Patients who develop severe infusion reactions should
`have RITUXAN infusion discontinued and receive med(cid:173)
`ica] treatment.
`
`Tumor lysis Syndrome {TLS}: Acute renal failure re(cid:173)
`quiring dialysis with instances of fatal outcome has
`been reported in the setting of TL.S following treatment
`with RITUXAN. (See WARNINGS.)
`
`Severe Mucocutaneous Reactions: Severe mucocuta(cid:173)
`neous reactions, some with fatal outcome, have been re(cid:173)
`ported in association with RITUXAN treatment. (See
`WARNINGS and ADVERSE REACTIONS.)
`
`DESCRIPTION
`The RITUXAN® (Rituximab) antibody is a genetically engi(cid:173)
`neered chimeric murine/human monoclonal antibody di(cid:173)
`rected against the CD20 antigen found on the surface of
`normal and malignant B lymphocytes. The antibody is an
`IgG 1 kippa immunoglobulin containing murine light- and
`heavy~chain variable region sequences and human constant
`region sequences. Rituximab is composed of two heavy
`chains of 451 amino acids and two light chains of213 amino
`acids (based on eDNA analysis) and has an approximate mo(cid:173)
`lecular 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 mamma(cid:173)
`lian cell (Chinese Hamster Ovary) suspension culture in a
`nutrient medium containing the antibiotic gentamicin. Gen(cid:173)
`tamicin is not detectable in the final product. The anti(cid:173)
`CD20 antibody is purified by affinity and ion exchange chro(cid:173)
`matography. The purification process includes specific viral
`inactivation and removal procedures. Rituximab drug prod(cid:173)
`uct is manufactured from either bulk drug substance man(cid:173)
`ufactured by Genentech, Inc. (US License No. 1048) or uti(cid:173)
`lizing formulated bulk Rituximab supplied by !DEC Phar(cid:173)
`maceuticals Corporation (US License No. 1235) under a
`shared manufacturing arrangement.
`RITUXAN is a sterile, clear, colorless, preservative-free liq(cid:173)
`intravenous (!V) administration.
`uid concentrate for
`RITUXAN is supplied at a concentration of 10 mg/mL in ei(cid:173)
`ther 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The
`product is formulated for IV 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.
`
`CL~CALP~COLOGY
`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-Band mature
`2 The antigen is also expressed on > 90% of
`B lymphocytes. 1
`•
`B-cell non-Hodgkin's lymphomas _(NHLJ,3 but is not found
`on hematopoietic stem cells, pro-B cells, normal plasma
`cells or other normal tissues. 4 CD20 regulates an early
`step(s) in the activation process for cell cycle initiation and
`differentiation, 4 and possibly functions as a calcium ion
`channel. 5 CD20 is not shed from the cell surface and does
`not internalize upon antibody binding.6 Free CD20 antigen
`is not found in the circulation.2
`Preclinical Pharmacology and Toxicology
`Mechanism of Action: The Fab domain of Rituximab binds
`to the CD20 antigen on B lymphocytas, and the Fe domain
`recruits immune effector functions to mediate B-celllysis in
`vitro. Possible mechanisms of cell lysis include complement(cid:173)
`dependent cytotoxicity (CDCJ7 and antibody-dependent cell
`mediated cytotoxicity (ADCC), The antibody has been
`shown to induce apoptosis in the DHL-4 human 8-celllyro(cid:173)
`phoma line.8
`Normal '!'issue Cross-reactivity: Rituximab binding was ob(cid:173)
`served on lymphoid cells in the thymus, the white pulp of
`the spleen, and a majority of R lymphocytes in peripheral
`blood and lymph nodes. Little or no binding was observed in
`the non-lymphoid tissues examined.
`
`Human Pharmacokinetics/Pharmacodynamics
`In patients given single doses at 10, 50, 100, 250 or
`500 mg/m2 as an IV infusion, serum levels and the half-life
`of B.ituximab were proportional to dose. 9 In 14 patients
`given 375 mg/m2 as an IV infusion for 4 weekly doses, the
`mean serum half-life was 76.3 hours (range, 31.5 to !52.6
`hours) after the first infusion and 205.8 hours (range, 83.9
`12 The wide
`to 407.0 hours); after the fourth infusion. 10
`·11 •
`range of half-lives may reflect the variable tumor burden
`among patients and the changes in CD20-positive (normal
`and malignant) B-cell populations upon repeated adminis(cid:173)
`trations.
`RITUXAN at a dose of 375 mg/m2 was administered as an
`IV infusion at weekly intervals for 4 doses to 203 patients
`naive to RITUXAN. The mean CmllX following the fourth in(cid:173)
`fusion was 486 Jlg/mL (range, 77.5 to 996.6 Jlg/mL). The
`peak and trough serum levels of Rituximab were inversely
`correlated with baseline values for the number of circulat(cid:173)
`ing CD20 positive B cells and measures of disease burden.
`Median steady-state serum levels were higher for respond(cid:173)
`ers compared with nonresponders; however, no difference
`was found in the rate of elimination as measured by serum
`half~ life. Serum levels were higher in patients with Interna~
`tional Working Formulation (IWF) subtypes B, C, and D as
`compared with those with subtype A. Rituximab was detect(cid:173)
`able in the serum of patients 3 to 6 months after completion
`of treatment.
`RITUXAN at a dose of 375 mg/m 2 was administered as an
`IV infusion at weekly intervals for 8 doses to 37 patients.
`The mean Cmax after 8 infusions was 550 ).lg/mL (range, 171
`to 1177 pg/mL). 'The mean Croax increased with each succes(cid:173)
`sive infusion through the eighth infusion (Table 1).
`
`Table 1
`Rituximab Cma)l Values
`
`Infusion Number
`
`MeanCmllX
`)lg/mL
`
`Range
`Jlg/mL
`
`1
`2
`3
`4
`5
`6
`7
`8
`
`242.6
`357.5
`381.3
`460.0
`475.3
`515.4
`544.6
`550.0
`
`16.1-581.9
`106.8-948.6
`110.5-731.2
`138.0-835.8
`156.0-929.1
`152.7-865.2
`187.0-936.8
`170.8-1177.0
`
`The pharmacokinetic profile of RITUXAN when adminis·
`tered as 6 infusions of 375 mg/m2 in combination with 6
`cycles of CHOP chemotherapy was similar to that seen with
`RITUXAN alone.
`Administration of RITUXAN resulted in a rapid and sus(cid:173)
`tained depletion of circulating and tissue-based B cells.
`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 Rituximab
`9 Among the 166 patients in the pivotal study,
`~100 mg/m2
`.
`circulating B cells (measured as CD19-positive cells) were
`depleted within the first three doses with sustained deple(cid:173)
`tion for up to 6 to 9 months post-treatment in 83% of pa(cid:173)
`tients. Of the responding patients assessed (n = 80), 1%
`failed to show significant depletion ofCD19-positive cells af(cid:173)
`ter the third infusion of Rituximab as compared to 19% of
`the nonresponding patients. B-cell recovery began at ap(cid:173)
`proximately 6 months following completion of treatment.
`Median B-cell levels returned to normal by 12 months fol(cid:173)
`lowing completion of treatment.
`There were sustained and statistically significant re'duc(cid:173)
`tions in both lgM and IgG serum levels observed from
`5 through 11 months following Rituximab administration.
`However, only 14% of patients had reductions in lgM and/or
`IgG serum levels, resulting in values below the normal
`range.
`CL~CAL STUDIES
`Studies with a collective enrollment of 296 patients having
`relcipsed or refractory low-grade or follicular B-cell NHL are
`d,escribed below (Table 2). RITUXAN regimens tested in(cid:173)
`cfude treatment weekJy for 4 doses and treatment weekly
`for 8 doses. Clinical settings stuclied were initial treatment,
`initial treatment of bulky disease, and retreatment.
`[See table 2 below]
`
`PHYSICIANS' DESK REFERENCE®
`
`Initial Treatment, Weekly for 4 doses
`A multicenter, open-label, single-arm study was conducted
`in 166 patients with relapsed or refractory low-grade or fol(cid:173)
`licular B-cell NHL who received 375 mg/m2 of RITUXAN
`given as an IV infusion weekly for 4 doses. 13 Patients with
`tumor-masses > 10 em or with >5,000 lymphocytes/pL in
`the peripheral blood were excluded from the study. The
`overall response rate (ORR) was 48% with 6% complete re(cid:173)
`sponse (CRJ and 42% partial response (PRJ rates. The me(cid:173)
`dian time to onset of response was 50 days and the median
`duration of response was 11.2 months (range, 1..9 to 42.1+).
`Disease-related signs and symptoms (including B-symp(cid:173)
`toms) were present in 23% (39/166) of patients at study en(cid:173)
`try and resolved in 64% (25/39) of those patients.
`In a multivariate analysis, the ORR was higher in patients
`with IWF B, C, and D histologic subtypes as compared to
`IWF subtype A (58% vs. 12%), higher in patients whose larg(cid:173)
`est lesion was <5 em vs. >7 em (maximum, 21 em) in great(cid:173)
`est diameter (53% vs. 38%), and higher in patients with che(cid:173)
`mosensitive relapse as compared with chemoresistant (de(cid:173)
`fined as duration of response <3 months) relapse (53% vs.
`36%). ORR in patients previously treated with autologous
`bone marrow transplant was 78% (18/23). The following ad(cid:173)
`verse prognostic factors were not associated with a lower re(cid:173)
`sponse rate: age 2:60 years, extranodal disease, prior an(cid:173)
`thracyclin~ therapy, and bone marrow involvement.
`Initial Treatment, Weekly for 8 Doses
`In a multicenter, single-arm study, 37 patients with re(cid:173)
`lapsed or refractory, low-grade NHL received 375 mg/m2 o
`RITUXAN weekly for 8 doses. The ORR was 57% (CR 14%,
`PR 43%) with a projected median duration of response o
`13.4 months (range, 2.5 to 36.5+ ). 14 (For information on the
`higher incidence of Grade 3 and 4 adverse events, see AD(cid:173)
`VERSE REACTIONS, Risk Factors Associated with In(cid:173)
`creased Rates of Adverse Events.)
`Initial Treatment. Bulky Disease, Weekly for 4 Doses
`In pooled data from multiple studies of RITUXAN, 39 pa
`tients with relapsed or refractory, bulky disease (single le
`sian > 10 em in diameter), low-gTade NHL received
`375 mg/m2 of RITUXA.t" weekly for 4 doses. The ORR was
`36% (CR 3%, PR 33%) with a median duration of response of
`6.9 months (range 2.8 to 25.0+). (For information on th
`higher incidence of Grade 3 and 4 adverse events, see AD
`VERSE REACTIONS, Risk Factors Associated with In
`cr~ased Rates of Adverse Events.)
`Retreatment. Weekly for 4 Doses
`In a multi-center, single-arm study, 60 patients received
`375 mg/m2 of RITUXAN weekly for 4 doses. 15 All patients
`had relapsed or refractory, low-grade or follicular B-cell
`NHL and had achieved an objective clinical response to a
`prior course of RlTUXAN. Of these 60 patients, 55 received
`their second course of RITUXAN, 3 patients received their
`third course and 2 patients received their second and third
`courses ofRITUXAN in this study. The ORR was 38% (10%
`CR and 28% PR) with a projected median duration of re
`sponse of iS months (range, 3.0 to 25.1+ months).
`INDICATIONS AND USAGE
`RITUXAN is indicated for the treatment of patients with
`relapsed or refractory, low-grade or follicular, CD20-posi
`tive, B-cell non-Hodgkin's lymphoma.
`CONTRAINDICATJONS
`RITUXAN is contraindicated in patients with known ana
`phylaxis or IgE-mediated hypersensitivity to murine pro
`teins or to any component of this product. (See WARN
`INGS.)
`WARNINGS (See BOXED WARNINGS.)
`Severe Infusion Reactions (See BOXED WARNINGS, AD
`VERSE REACTIONS and Hypersensitivity Reactions!
`RITUXAN has caused severe infusion reactions. In som
`cases, these reactions were fatal. These severe reaction
`typically occurred during the first infusion with time to on
`set of 30 to 120 minutes. Signs and symptoms of severe in
`fusion reactions may include hypotension, angioedema, hyp
`oxia or bronchospasm, and may require interruption o
`RITUXAN administration. The most severe manifestation
`and sequelae include pulmonary infiltrates, acute respira
`tory distress syndrome, myocardial infarction, ventricula
`fibrillation, and cardiogenic shock. In the reported cases,
`the following factors were more frequently associated with
`fatal outcomes: female gender, pulmonary infiltrates, and
`chrmlic lymphocytic leukemia or inantle cell lymphoma.
`Management of severe infusion reactions: The RITUXAN
`infusion should be interrupted for severe reactions and sup(cid:173)
`portive care measures instituted as medically indicated
`(e.g., intravenous fluids, vasopressors, oxygen, bronchodila-
`
`Table 2
`Summary of RITUXAN Efficacy Data by Schedule and Clinical Setting (See ADvERSE REACTIONS for Risk Factors
`Associated with Increased Rates of Adverse Events.!
`
`Initial,
`Weeklyx 4
`N = 166
`
`Initial.
`Weekly X 8
`N = 37
`
`Initial, Bulky.
`WeeklyX 4
`N = 391
`
`Retreatment.
`Weeklyx 4
`N = 60
`
`48%
`
`6%
`
`57%
`
`14%
`
`Overall Response Rate
`Complete Response
`Rate
`Median Duration of
`11.2
`13.4
`6.9
`15.0
`Response'·'·' (Months)
`[1.9 to 42.1+]
`[2.5 to 36.5+1
`12.8 to 25.0+1
`[3.0 to 25.1+]
`[Range]
`1Six ofthese patients are included in the first ~~umn. Thus, data from 296 intent to treat patients are provided in .this table.
`2Kaplan-Meier projected with observed range.
`3«+" indicates an ongoing response.
`4Duration of response: interval from the onset of response to disease progression.
`
`36%
`
`3%
`
`38%
`
`10%
`
`Information will be superseded by supplements and subsequent editions
`
`Ex. 2023-0001
`
`

`
`PRODUCT INFORMATION
`
`tors, diphenhydramine, and acetaminophen). In most cases,
`the infusion can be resumed at a 50% reduction in rate (e.g.,
`from 100 mglhr to 50 mg/hr) when symptoms have com~
`pletely resolved. Patients Tequiring close monitoring during
`first and all subsequent infusions include those with pre(cid:173)
`existing cardiac and pulmonary conditions, those with prior
`clinically significant cardiopulmonary adverse events and
`those with hi~h numbers of circulating malignant cells
`(~ 25,000/mm ) with or without evidence of high tumor bur(cid:173)
`den.
`Tumor Lysis Syndrome [TLSl (See BOXED WABNINGS
`and ADVERSE REACTIONS!:
`Rapid reduction in tumor volume followed by acute renal
`failure, hyperkalemia, hypocalcemia, hyperuricemia, or hy(cid:173)
`perphosphatasemia, have been reported within 12 to
`24 hours after the first RITUXAN infusion. Rare instances
`of fatal outcome have been reported in the setting of TLS
`following treatment with RITUXAN. The risks of TLS ap(cid:173)
`pear to be greater in patients with high numbers of circu(cid:173)
`lating malignant cells (~25,000/mm 3) or high tumor bur(cid:173)
`den. Prophylaxis for TLS should he considered for patients
`at high risk. Correction of electrolyte abnormalities, moni(cid:173)
`toring of renal function and fluid balance, and administra(cid:173)
`tion of supportive care, including dialysis, should be initi(cid:173)
`ated as indicated. Following complete resolution ·of the com(cid:173)
`plications of TLS, RITUXAN has been tolerated when re~
`administered in conjunction with prophylactic therapy for
`TLS in a limited number of cases.
`Hypersensitivity Reactions:
`RITUXAN has been associated with hypersensitivity reac·
`tions (non-lgE·mediated reactions) which may respond to
`adjustments in the infusion rate and in mediCal manage(cid:173)
`ment. Hypotension, bronchospasm, and angioedema have
`occurred in association with RITUXAN infusion (see Severe
`Infusion Reactions). RITUXAN infusion should be inter·
`rupted for severe hypersensitivity reactions and can be re·
`sumed at a 50% reduction in rate (e.g., from 100 mglhr to
`50 mg/hr) when symptoms have completely resolved. Treat~
`ment of these symptoms with diphenhydrami"ne and acet(cid:173)
`aminophen is recommended; additional treatment with
`bronchodilators or IV saline may be indicated. In most
`cases, patients who have experienced non-life-threatening
`hypersensitivity reactions have been able to complete the
`full course of therapy. (See DOSAGE and ADMINlSTRA(cid:173)
`TION .) Medications for the treatment of hypersensitivity
`reactions, e.g., epinephrine, antihistamines and corticoster(cid:173)
`oids, should be available for immediate use in the event of a
`reaction during administrB.tion.
`Cardiovascular:
`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
`RITUXAN. Patients with pre-existing cardiac conditions in(cid:173)
`cluding arrhythmias and angina have had recurrences of
`these events during RITUXAN therapy and should be mon(cid:173)
`itored throughout the infusion and immediate post·infusion
`period.
`Renal:
`RITUXAN administration has been associated with severe
`renal toxicity including a-cute renal failure requiring dialy(cid:173)
`sis and m some cases, has led to a fatal outcome. Renal tox(cid:173)
`icity has occurred in patients with high numbers of circulat(cid:173)
`ing malignant cells (>25,000/mm3) or high tumor burden
`who experience tumor lysis syndrome (see Tumor Lysis Syn(cid:173)
`drome) and in patients administered concomitant cisplatin
`therapy during clinical trials. The combination of cisplatin
`and RJTUXAN is not an approved treatment regimen. If
`this combination is used in clinical trials extreme caution
`should be exercised; patients should be monitored closely
`for signs of renal failure. Discontinuation of RITUXAN
`should be considered for those with rising serum creatinine
`or oliguria.
`Severe Mucocutaneous Reactions (See· BOXED WARN(cid:173)
`INGS and ADVERSE REACTIONS.):
`Mucocutaneous reactions, sOme with fatal outcome, have
`been reported· in patients treated with RITUXAN. These re(cid:173)
`pmt..s include paraneoplastic pemphigus (an uncommon dis~
`order which is a manifestation of the patient's underlying
`malignancy), 16 Stevens-Johnson syndrome, lichenoid der(cid:173)
`matitis, vesiculobullous dermatitis, and toxic epidermal
`necrolysis. The onset of the reaction in the reported cases
`has varied from 1 to 13 weeks follOwing RITUXAN expo(cid:173)
`sure. Patients experiencing a severe mucocutaneous reac~
`tion should not receive any further infusions and seek
`prompt medical evaluation. Skin biopsy may help to distin~
`guish among different mucocutaneous reactions and guide
`subsequent treatment. The safety of readministration of
`RITUXAN to patients with any of these mucocutaneous re~
`actions has not been determined.
`
`PRECAUTIONS
`Laboratory Monitoring: Because RITUXAN targets all
`CD20-positive B lymphocytes, malignant and nonmalig(cid:173)
`nant, complete blood counts (CBC) and platelet counts
`should be obtained at regular intervals during RITUXAN
`therapy and more frequently in patients who develop cy~
`topenias (see ADVERSE REACTIONS). The duration of cy(cid:173)
`topenias caused by RITUXAN can extend well beyond the
`treatment period.
`Drug/Laboratory Interactions: There have been no formal
`drug interaction studies performed with RITUXAN. How(cid:173)
`ever, renal toxicity was seen with this drug in combination
`with cisplatin in clinical trials. (See WARNINGS, Renal.)
`
`HACA Formation: Human antichimeric antibody (HACA)
`was detected in 4 of356 patients and 3 had an objective clin~
`ical response. The data reflect the percentage of patients
`whose test results were considered positive for antibodies to
`RITUXAN using an enzyme~linked immunosorbant assay
`(limit of detection = 7 ng/mL). The observed incidence of
`antibody positivity in an assay is highly dependent on the
`sensitivity and specificity of the assay and may be influ(cid:173)
`enced by several factors including sample handling, concom(cid:173)
`itant· medications, and underlying disease. For these re.a(cid:173)
`sons, comparison ofthe incidence of antibodies to RITUXAN
`with the incidence of antibodies to other products may be
`misleading.
`Immunization: The safety Qf immunization with live viral
`vaccines following RITUXAN therapy has not been studied.
`The ability to generate a primary or anamnestic humoral
`response to vaccination is currently being studied.
`Carcil"!ogenesis, Mutagenesis, Impairment of Fertility: No
`long-term animal studies have been performed to establish
`the carcinogenic or mutagenic potential of RITUX.AN, or io
`determine its effects on fertility in inales or females. lndi~
`viduals of childbearing potential should use effective contra(cid:173)
`ceptive 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 js not known
`whether RITUXAN can cause fetal harm when adminis(cid:173)
`tered to a pregnant woman or whether it can aff~ct repro(cid:173)
`ductive capacity. Human IgG is known to pass the placental
`bapier, and thus may-potentially cause fetal B~cell deple(cid:173)
`tion; therefore, RITUXAN should be_given to a pregnant
`woman only if clearly needed.
`Nursing Mothel-s:
`It is not known whether RITUXAN is
`excreted in human milk. Because human lgG is excreted in
`human milk and the potential for absorption and immuno~
`suppression in the infant is unknown, women should be ad(cid:173)
`vised to discontinue nursing until circulating drug levels
`are no longer detectable. (See CLINICAL PHARMACOLO(cid:173)
`GY.)
`Pediatric Use: The safety and effectiveness ofRITUXAN in
`pediatric patients have not been established.
`Geriatric Use: Among the 331 patients enrolled in clinical
`studies of single agent RITUXAN, 24% were 65 to 75 years
`old and 5% were 75 years old and older. The overall re(cid:173)
`sponse rates were higher in older (age ::::. 65 years) vs. youn(cid:173)
`ger (age < 65 years) patients (52% vs. 44%, respectively).
`However, the median duration of response, based on
`Kaplan-Meier estimates, was shorter-in older vs. younger
`patients: 10.1 months (range, 1.9 to 36.5+) vs. 11.4 months
`(range, 2.1 to 42.1+), respectively. This sho.rter duration of
`response was not statistically significant. Adverse reactions,
`including incidence, severity and type of adverse reaction
`were similar between older and younger patients.
`ADVERSE REACTIONS
`The most serious adverse reactions caused by RITUXAN in(cid:173)
`clude infusion reactions, tumor lysis syndrome, mucocuta(cid:173)
`neous reactions, hypersensitivity reactions, cardiac ar·
`rhythmias and angina, and renal failure. Please refer to the
`BOXED WARNINGS and WARNINGS sections for detailed
`descriptions of these reactions. Infusion reactions and lym(cid:173)
`phopenia are the most cQmmonly occurring adverse reac~
`tions.
`Because clinical trials are conducted under widely varying
`conditions, adverse reaction rates observed in the clinical
`trials of a drug cannot be directly compared to rates in the
`clinical trials of ~nother drug and may not reflect the rates
`observed in practice. The adverse reaction information from
`clinical trials does, however, provide a basis for identifying
`the adverse events that appear to be related to drug use and
`for apprOximating rates.
`Additional adv~rse reactions have been identified during
`postmarketing use of RITUXAN. Because these 'reactions
`are reported voluntarily from a population of uncertain size,
`it is not always possible to reliably estimate their frequency
`or establish a causal relationship to RITUXAN exposure.
`Decisions to include these reactions in labeling are typically
`based on one or more ofthe following factors: (1) seriousness
`of the reaction, (2) frequency of reporting, or (3) strength of
`camfal connection to RITUXAN.
`Where specific percentages are noted, these data are based
`on 356 patients treated in nonrandomized, single-arm stud(cid:173)
`ies of RITUXAN administered as a single agent. Most pa(cid:173)
`tients received RITUXAN 375 mg/m2 weekly for 4 doses.
`These inc1ude 39 patients with bulky disease (lesions
`~ 10 em) and 60 patients who received more than 1 course of
`RITUXAN. Thirty-seven patients received 375 mg/m 2 for 8
`than
`doses and 25 patients received doses other
`375 mg/m2 for 4 doses and up to 500 mg/m2 single dose in
`the Phase 1 setting. Adverse events of greater severity are
`referred to as "Grade 3 and 4 events" defined by the com(cid:173)
`monly used National Canter Institute Common Toxicity
`Criteria. 17
`
`Table 3
`Incidence of Adverse Events 0:!: 5% of P8tients in Clinical
`Trials IN = 356) (Adverse Events were followed for a
`period of 12 months following RJTUXAN therapy.)
`
`All Grades
`(%)
`
`Grade 3 and
`4(%)
`
`Any Adverse Events
`Body as a Whole
`
`99
`86
`
`57
`10
`
`GENENTECH/1429
`
`Fever
`Chllls
`Infection
`Asthenia
`Headache
`Abdominal Pain
`Pain
`Back Pain
`Throat Irritation
`Flushing
`Cardiovascular System
`Hypotension
`Hypertension
`Digestive System
`Nausea
`Diarrhea
`Vomiting
`Hemic and lymphatic
`System
`Lymphopenia
`Leukopenia
`Neutropenia
`Thrombocytopenia
`Anemia
`Metabolic and Nutritional
`Disorders
`Angioedema
`Hyperglycemia
`Peripheral Edema
`LDH Increase
`Musculoskeletal System
`Myalgia
`Arthralgia
`Nervous System
`Dizziness
`Anxiety
`Respiratory System
`Increased Cough
`Rhinitis
`Bronchospasm
`Dyspnea
`Sinusitis
`Skin and Appendages
`Night Sweats
`Rash
`Pruritus
`Urticaria
`
`53
`33
`31
`26
`19
`14
`12
`10
`9
`5
`25
`10
`6
`37
`23
`10
`10
`67
`
`48
`14
`14
`12
`8
`38
`
`11
`9
`8
`7
`26
`10
`10
`32
`10
`5
`38
`13
`12
`8
`7
`6
`44
`15
`15
`14
`8
`
`1
`·a
`4
`1
`1
`1
`1
`1
`0
`0
`3
`1
`1
`2
`1
`1
`1
`48
`
`40
`4
`6
`2
`3
`3,
`
`1
`1
`0
`0
`. 3
`1
`1
`1
`1
`1
`4
`1
`1
`1
`1
`0
`2
`1
`1
`1
`1
`
`Risk Factors Associated with Increased Rates. of Adverse
`Events:
`Administration of RITUXAN weekly for 8 doses resulted in
`higher rates of Grade 3 and 4 adverse events17 overall (70%)
`compared with administration weekly for 4 ·doses (57%).
`The incidence of Grade 3 or 4 adverse events was similar in
`patients retreated with RITUXAN compared with initial
`treatment (58% and 57%, respectively). The incidence of the
`following clinically significant adverse events was 1--..igher in
`patients with bulky disease (lesions ~10 em) (N = 39) ver~
`sus patients with lesions < 10 em (N = 195): abdominal
`pain, anemia, dyspnea, hypotension, and neutropenia.
`Infusion Reactions (See BOD:::D WARNINGS and WARN(cid:173)
`INGS): Mild to moderate infusion reactions consisting of
`fever and chills/rigors occurred in the majority of patients
`during the first RITUXAN infusion. Other frequent infusion
`reaction symptoms included nausea, pruritus, angioedema,
`asthenia, hypotension, headache, bronchospasm, throat ir(cid:173)
`ritation, rhinitis, urticaria, rash, vomiting, myalgia, dizzi~
`ness, and hypertension. These reactions generally occurred
`within 30 to 120 minutes of beginning the first inf~sion, and
`resolved with slowing or interruption of the RITUXAN in(cid:173)
`fusion and with supportive care (diphenhydramine, acetam(cid:173)
`inophen, IV saline, and vasopressors). In an analysis of data
`from 356 patients with relapsed or refractory, low-grade
`NHLwhoreceived 4 (N = 319)or8 (N = 37)weeklyinfusions
`of RI'rux.AN, the incidence of infusion reactions was high~
`est during the first infusion (77%) and decreased with each
`subsequent infusion (30% with fourth infusion and 14%
`with eighth infusion).
`Infectious Events: RITUXAN induced B·cell depletion in
`70% to 80% of patients and was associated with decreased
`serum immunoglobuliNs in a minority of patients; the lym(cid:173)
`phopenia lasted a median of 14 days (range, 1 to 588 days).
`Infectious events occurred in 31% of patients: 19% of pa~
`tients had bacterial infections, 10% had viral infections, 1%
`had fungal infections, and 6% were .unknown infections. In(cid:173)
`cidence is not additive because a single patient may have
`had more than one tf,pe of infection. Serious infectious
`events (Grade 3 or 4),
`including sepsis occurred in 2% of
`patients.
`.
`Hematologic Events: Grade 3 and 4 cytopenias17 were re~
`ported in 12% of patients treated with RITUXl).N; these in(cid:173)
`clude: lymphopenia (40%), neutropenia (6%), leukopenia
`(4%), anemia (3%), and thrombocytopenia (2%) .. The median
`duration of lymphopenia was 14 days (range, 1 to 588 days)
`and of neutropenia was 13 days (range, 2 to 116 days). A
`single oc-currertce of transient aplastic anemia (pure red cell
`aplasia) and two occurrences of hemolytic anemia following
`RITUXAN therapy were reported. In addition, there have
`been rare postmarketing reports of prolonged pancytopenia
`and marrow hypoplasia.
`
`Continued on next page
`
`Consult 2 0 0 2 POR® supplements and future editions for revisions
`
`Ex. 2023-0002
`
`

`
`1430/GENENTECH
`
`Rituxan-Cont.
`
`Cardiac Events (See BOXED WARNINGS): Grade 3 or 4
`cardiac-related events include hypotension. Rare, fatal car(cid:173)
`diac failure with symptomatic onset weeks after RITUXAN
`has also been reported. Patients who develop clinically sig(cid:173)
`nificant cardiopulmonary events should have RITUXAN in(cid:173)
`fusion discontinued.
`Pulmonary Events !See BOXED WARNINGS): 135 pa(cid:173)
`tients (38%) experienced pulmonary events. The most com(cid:173)
`mon respiratory system adverse events experienced were
`increased cough, rhinitis, bronchospasm, dyspnea, and si(cid:173)
`nusitis. Three pulmonary events have been reported in tem(cid:173)
`poral association with RITUXAN infusion as a single agent:
`acute bronchospasm, acute pneumonitis presenting
`1-4 weeks post-RITUXAN infusion, and bronchiolitis oblit(cid:173)
`erans. One case of bronchiolitis obliterans was associated
`with progressive pulmonary symptoms and culminated in
`death several months following the last RITUXAN infusion.
`The safety of resumption or continued administration of
`RITUXAN in patients with pneumonitis or bronchiolitis ob·
`literans is unknown.
`Immune/Autoimmune Events:
`Immune/autoimmune
`events have been reported, including uveitis, optic neuritis
`in a patient with systemic vasculitis, pleuritis in a patierit
`with a lupus-like syndrome, serum sickness with polyartic·
`ular arthritis, and vasculitis with rash.
`In clinical trials, < 5%
`Less Commonly Observed Events:
`and > 1% of the patients experienced the following events
`regardless of causality assessment: agitation, anorexia, ar·
`thritis, conjunctivitis, depression, dyspepsia, edema, hyper(cid:173)
`kinesia, hypertonia, hypesthesia, hypoglycemia, injection
`site pain, insomnia, lacrimation disorder, malaise, nervous·
`ness, neuritis, neuropathy, paresthesia, somnolence, ver·
`tigo, weight decrease.
`OVERDOSAGE
`There has been no experience with overdosage in human
`clinical trials. Single doses of up to 500 mg/m2 have been
`given in controlled clinical trials. 10
`DOSAGE AND ADMINISTRATION
`Initial Therapy:
`RITUXAN is given at 375 mg/m2 IV infusion once weekly for
`4 or 8 doses.
`Retreatment Therapy:
`Patients who subsequently develop progressive disease may
`be safely retreated with RITUXAN 375 mg/m2 IV infusion
`once weekly for 4 doses. Currently there are limited data
`concerning more than 2 courses.
`RITUXAN may be administered in an outpatient setting.
`DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR
`BOLUS. (See Administration.)
`Instructions for Administration
`Preparation for Administration: Use appropriate aseptic
`technique. Withdraw the necessary amount of RlTUXAN
`and dilute to a final concentration of 1 to 4 mg/mL into an
`infusion bag containing either 0.9% Sodium Chloride, USP,
`or 5% Dextrose in Water1 USP. Gently invert the bag to mix
`the solution. Discard any unused portion left in the vial.
`Parenteral drug products should be inspected visually for
`particulate matter and 4iscoloration prior to administra~
`tion.
`RITUXAN solutions for infusion may be stored at 2-S"C
`(36-46"F) for 24 hours. RITUXAN solutions for infusion
`have been shown to be stable for an additional 24 hours at
`room temperature. However, since RITUXAN solutions do
`not contain a preservative, diluted so-lutions should be
`stored refrigerated (2-SoC). N