Rituxan Side Effects

Generic Name: rituximab

Please note - some side effects for Rituxan may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Rituxan - for the Consumer

Rituxan

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Rituxan:

Diarrhea; flushing; headache; indigestion; light-headedness; mild fever and chills, especially with the first dose; mild muscle or joint pain; muscle spasms; nausea; night sweats; runny nose; sneezing; throat irritation; trouble sleeping; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Rituxan:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest or throat; swelling of the mouth, face, lips, throat, or tongue; unusual hoarseness); blurred vision or other vision changes; changes in thinking or strength; chest pain; confusion; decreased amount of urine or dark urine; decreased balance or coordination; disorientation; dizziness; drowsiness; fainting; fast or irregular heartbeat; fever, chills, cough, or persistent sore throat; headache; numbness of an arm or leg; painful urination; persistent muscle, back, or joint pain; red, swollen, peeling, or blistered skin; severe or persistent stomach pain; severe weakness or fatigue; shortness of breath; skin or mouth sores or ulcers; sudden leg pain; swelling of the hands, legs, or feet; trouble walking or talking; unusual bleeding or bruising; wheezing; white patches in the mouth or throat.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Rituxan Side Effects - for the Professional

Rituxan

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Infusion reactions [see Warnings and Precautions (5.1)]
• Tumor lysis syndrome [see Warnings and Precautions (5.2)]
• Mucocutaneous reactions [see Warnings and Precautions (5.3)]
• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.4)]
• Hepatitis B reactivation with fulminant hepatitis [see Warnings and Precautions (5.5)]
• Infections [see Warnings and Precautions (5.6)]
• Cardiac arrhythmias[see Warnings and Precautions (5.7)]
• Renal toxicity[see Warnings and Precautions (5.8)]
• Bowel obstruction and perforation [see Warnings and Precautions (5.9)]

The most common adverse reactions of Rituxan (incidence ≥ 25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia.

The most common adverse reactions of Rituxan (incidence ≥ 25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia.

   Clinical Trials Experience in Lymphoid Malignancies

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 another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Rituxan in 2783 patients, with exposures ranging from a single infusion up to 2 years. Rituxan was studied in both single-arm and controlled trials (n = 356 and n = 2427=1926). The population included 1180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, and 676 patients with CLL. Most NHL patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy.

Infusion Reactions

In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions (5.1).]

Infections

Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single‑arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions (5.4), (5.5), (5.6).]

In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low‑grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B‑cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan.

Cytopenias and hypogammaglobulinemia

In patients with NHL receiving rituximab monotherapy, NCI‑CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single‑arm studies.

In studies of monotherapy, Rituxan‑induced B‑cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients.

Relapsed or Refractory, Low-Grade NHL

Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, low‑grade or follicular, CD20‑positive, B‑cell NHL treated in single‑arm studies of Rituxan administered as a single agent [see Clinical Studies (14.1)]. Most patients received Rituxan 375 mg/m2 weekly for 4 doses.

Table 1: Incidence of Adverse Reactions in ≥ 5% of Patients with Relapsed or Refractory, Low‑Grade or Follicular NHL, Receiving Single‑agent Rituxan (N=356)a,b

	All Grades (%)	Grade 3 and 4 (%)
a Adverse reactions observed up to 12 months following Rituxan. b Adverse reactions graded for severity by NCI‑CTC criteria.
Any Adverse Reactions	99	57
Body as a Whole	86	10
Fever	53	1
Chills	33	3
Infection	31	4
Asthenia	26	1
Headache	19	1
Abdominal Pain	14	1
Pain	12	1
Back Pain	10	1
Throat Irritation	9	0
Flushing	5	0
Heme and Lymphatic System	67	48
Lymphopenia	48	40
Leukopenia	14	4
Neutropenia	14	6
Thrombocytopenia	12	2
Anemia	8	3
Skin and Appendages	44	2
Night Sweats	15	1
Rash	15	1
Pruritus	14	1
Urticaria	8	1
Respiratory System	38	4
Increased Cough	13	1
Rhinitis	12	1
Bronchospasm	8	1
Dyspnea	7	1
Sinusitis	6	0
Metabolic and Nutritional Disorders	38	3
Angioedema	11	1
Hyperglycemia	9	1
Peripheral Edema	8	0
LDH Increase	7	0
Digestive System	37	2
Nausea	23	1
Diarrhea	10	1
Vomiting	10	1
Nervous System	32	1
Dizziness	10	1
Anxiety	5	1
Musculoskeletal System	26	3
Myalgia	10	1
Arthralgia	10	1
Cardiovascular System	25	3
Hypotension	10	1
Hypertension	6	1

In these single‑arm Rituxan studies, bronchiolitis obliterans occurred during and up to 6 months after Rituxan infusion.

Previously Untreated, Low-Grade or Follicular, NHL

In Study 4, patients in the R‑CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently ( ≥ 5%) in patients receiving R‑CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). [See Clinical Studies (14.2).]

In Study 5, detailed safety data collection was limited to serious adverse reactions, Grade ≥ 2 infections, and Grade ≥ 3 adverse reactions. In patients receiving Rituxan as single-agent maintenance therapy following Rituxan plus chemotherapy, infections were reported more frequently compared to the observation arm (37% vs. 22%). Grade 3-4 adverse reactions occurring at a higher incidence (≥2%) in the Rituxan group were infections (4% vs. 1%) and neutropenia (4% vs. <1%).

In Study 6, the following adverse reactions were reported more frequently ( ≥ 5%) in patients receiving Rituxan following CVP compared to patients 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%), hepato‑biliary 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%). [See Clinical Studies (14.3).]

DLBCL

In Studies 7 and 8, [see Clinical Studies (14.3)], the following adverse reactions, regardless of severity, were reported more frequently ( ≥ 5%) in patients age ≥ 60 years receiving R‑CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions.

In Study 8, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R‑CHOP vs. 1.0% for CHOP).

The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R‑CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R‑CHOP were viral infection (Study 8), neutropenia (Studies 8 and 9), and anemia (Study 9).

CLL

The data below reflect exposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 patients with CLL in Study 10 or Study 11 [see Clinical Studies (14.4)]. The age range was 30-83 years and 71% were men. Detailed safety data collection in Study 10 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions.

Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea.

In Study 10, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%).

In Study 11, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. < 1%). Fifty-nine percent of R-FC-treated patients experienced an infusion reaction of any severity.

   Clinical Trials Experience in Rheumatoid Arthritis

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data presented below reflect the experience in 2578 RA patients treated with Rituxan in controlled and long‑term studies with a total exposure of 5014 patient‑years.

Among all exposed patients, adverse reactions reported in greater than 10% of patients include infusion related reactions, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis.

In placebo‑controlled studies, patients received 2 x 500 mg or 2 x 1000 mg intravenous infusions of Rituxan or placebo, in combination with methotrexate, during a 24‑week period. From these studies, 938 patients treated with Rituxan (2 x 1000 mg) or placebo have been pooled. Adverse reactions reported in ≥ 5% of patients were hypertension, nausea, upper respiratory tract infection, arthralgia, pyrexia and pruritus. The rates and types of adverse reactions in patients who received Rituxan 2 x 500 mg were similar to those observed in patients who received Rituxan 2 x 1000 mg.

Table 2*: Incidence of All Adverse Reactions** Occurring in ≥ 2% and at Least 1% Greater than Placebo Among Rheumatoid Arthritis Patients in Clinical Studies Up to Week 24 (Pooled)

Preferred Term	Placebo + MTX N = 398 n (%)	Rituxan + MTX N = 540 n (%)
*These data are based on 938 patients treated in Phase 2 and 3 studies of Rituxan (2 × 1000 mg) or placebo administered in combination with methotrexate.
**Coded using MedDRA.
Hypertension	21 (5)	43 (8)
Nausea	19 (5)	41 (8)
Upper Respiratory Tract Infection	23 (6)	37 (7)
Arthralgia	14 (4)	31 (6)
Pyrexia	8 (2)	27 (5)
Pruritus	5 (1)	26 (5)
Chills	9 (2)	16 (3)
Dyspepsia	3 (<1)	16 (3)
Rhinitis	6 (2)	14 (3)
Paresthesia	3 (<1)	12 (2)
Urticaria	3 (<1)	12 (2)
Abdominal Pain Upper	4 (1)	11 (2)
Throat Irritation	0 (0)	11 (2)
Anxiety	5 (1)	9 (2)
Migraine	2 (<1)	9 (2)
Asthenia	1 (<1)	9 (2)

Infusion Reactions

In the Rituxan RA pooled placebo‑controlled studies, 32% of Rituxan‑treated patients experienced an adverse reaction during or within 24 hours following their first infusion, compared to 23% of placebo‑treated patients receiving their first infusion. The incidence of adverse reactions during the 24‑hour period following the second infusion, Rituxan or placebo, decreased to 11% and 13%, respectively. Acute infusion reactions (manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasm, with or without associated hypotension or hypertension) were experienced by 27% of Rituxan‑treated patients following their first infusion, compared to 19% of placebo‑treated patients receiving their first placebo infusion. The incidence of these acute infusion reactions following the second infusion of Rituxan or placebo decreased to 9% and 11%, respectively. Serious acute infusion reactions were experienced by < 1% of patients in either treatment group. Acute infusion reactions required dose modification (stopping, slowing, or interruption of the infusion) in 10% and 2% of patients receiving rituximab or placebo, respectively, after the first course. The proportion of patients experiencing acute infusion reactions decreased with subsequent courses of Rituxan. The administration of intravenous glucocorticoids prior to Rituxan infusions reduced the incidence and severity of such reactions, however, there was no clear benefit from the administration of oral glucocorticoids for the prevention of acute infusion reactions. Patients in clinical studies also received antihistamines and acetaminophen prior to Rituxan infusions.

Infections

In the pooled, placebo‑controlled studies, 39% of patients in the Rituxan group experienced an infection of any type compared to 34% of patients in the placebo group. The most common infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, and sinusitis.

The incidence of serious infections was 2% in the Rituxan‑treated patients and 1% in the placebo group.

In the experience with Rituxan in 2578 RA patients, the rate of serious infections was 4.31 per 100 patient years. The most common serious infections (≥0.5%) were pneumonia or lower respiratory tract infections, cellulitis and urinary tract infections. Fatal serious infections included pneumonia, sepsis and colitis. Rates of serious infection remained stable in patients receiving subsequent courses. In 185 Rituxan‑treated RA patients with active disease, subsequent treatment with a biologic DMARD, the majority of which were TNF antagonists, did not appear to increase the rate of serious infection. Thirteen serious infections were observed in 186.1 patient years (6.99 per 100 patient years) prior to exposure and 10 were observed in 182.3 patient years (5.49 per 100 patient years) after exposure.

Cardiac Adverse Reactions

In the pooled, placebo‑controlled studies, the proportion of patients with serious cardiovascular reactions was 1.7% and 1.3% in the Rituxan and placebo treatment groups, respectively. Three cardiovascular deaths occurred during the double‑blind period of the RA studies including all rituximab regimens (3/769 = 0.4%) as compared to none in the placebo treatment group (0/389).

In the experience with Rituxan in 2578 RA patients, the rate of serious cardiac reactions was 1.93 per 100 patient years. The rate of myocardial infarction (MI) was 0.56 per 100 patient years (28 events in 26 patients), which is consistent with MI rates in the general RA population. These rates did not increase over three courses of Rituxan.

Since patients with RA are at increased risk for cardiovascular events compared with the general population, patients with RA should be monitored throughout the infusion and Rituxan should be discontinued in the event of a serious or life‑threatening cardiac event.

Hypophosphatemia and hyperuricemia

In the pooled, placebo‑controlled studies, newly occurring hypophosphatemia (<2.0 mg/dl) was observed in 12% (67/540) of patients on Rituxan versus 10% (39/398) of patients on placebo. Hypophosphatemia was more common in patients who received corticosteroids. Newly occurring hyperuricemia (>10 mg/dl) was observed in 1.5% (8/540) of patients on Rituxan versus 0.3% (1/398) of patients on placebo.

In the experience with Rituxan in RA patients, newly occurring hypophosphatemia was observed in 21% (528/2570) of patients and newly occurring hyperuricemia was observed in 2% (56/2570) of patients. The majority of the observed hypophosphatemia occurred at the time of the infusions and was transient.

Retreatment in Patients with RA

In the experience with Rituxan in RA patients, 2578 patients have been exposed to Rituxan and have received up to 10 courses of Rituxan in RA clinical trials, with 1890, 1043, and 425 patients having received at least two, three, and four courses, respectively. Most of the patients who received additional courses did so 24 weeks or more after the previous course and none were retreated sooner than 16 weeks. The rates and types of adverse reactions reported for subsequent courses of Rituxan were similar to rates and types seen for a single course of Rituxan.

In RA Study 2, where all patients initially received Rituxan, the safety profile of patients who were retreated with Rituxan was similar to those who were retreated with placebo [see Clinical Studies (14.5), and Dosage and Administration (2.5).]

   Clinical Trial Experience in Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data presented below reflect the experience in 197 patients with WG and MPA treated with Rituxan or cyclophosphamide in a single controlled study, which was conducted in two phases: a 6 month randomized, double-blind, double-dummy, active-controlled remission induction phase and an additional 12 month remission maintenance phase. In the 6-month remission induction phase, 197 patients with WG and MPA were randomized to either Rituxan 375 mg/ m2 once weekly for 4 weeks plus glucocorticoids, or oral cyclophosphamide 2 mg/kg daily (adjusted for renal function, white blood cell count, and other factors) plus glucocorticoids to induce remission. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituxan group did not receive additional therapy to maintain remission. The primary analysis was at the end of the 6 month remission induction period and the safety results for this period are described below.

Adverse reactions presented below in Table 3 were adverse events which occurred at a rate of greater than or equal to 10% in the Rituxan group. This table reflects experience in 99 WG and MPA patients treated with Rituxan, with a total of 47.6 patient-years of observation and 98 WG and MPA patients treated with cyclophosphamide, with a total of 47.0 patient-years of observation. Infection was the most common category of adverse events reported (47-62%) and is discussed below.

Table 3: Incidence of All Adverse Reactions Occurring in ≥ 10% of Rituxan-treated WG and MPA Patients in the Clinical Study Up to Month 6*

Preferred Term	Rituxan N = 99 n (%)	Cyclophosphamide N = 98 n (%)
*The study design allowed for crossover or treatment by best medical judgment, and 13 patients in each treatment group received a second therapy during the 6 month study period.
Nausea	18 (18%)	20 (20%)
Diarrhea	17 (17%)	12 (12%)
Headache	17 (17%)	19 (19%)
Muscle spasms	17 (17%)	15 (15%)
Anemia	16 (16%)	20 (20%)
Peripheral edema	16 (16%)	6 (6%)
Insomnia	14 (14%)	12 (12%)
Arthralgia	13 (13%)	9 (9%)
Cough	13 (13%)	11 (11%)
Fatigue	13 (13%)	21 (21%)
Increased ALT	13 (13%)	15 (15%)
Hypertension	12 (12%)	5 (5%)
Epistaxis	11 (11%)	6 (6%)
Dyspnea	10 (10%)	11 (11%)
Leukopenia	10 (10%)	26 (27%)
Rash	10 (10%)	17 (17%)

Infusion Reactions

Infusion-related reactions in the active-controlled, double-blind study were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators. Among the 99 patients treated with Rituxan, 12% experienced at least one infusion related reaction, compared with 11% of the 98 patients in the cyclophosphamide group. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the Rituxan group, the proportion of patients experiencing an infusion related reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were pre-medicated with antihistamine and acetaminophen before each Rituxan infusion and were on background oral corticosteroids which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions.

Infections

In the active-controlled, double-blind study, 62% (61/99) of patients in the Rituxan group experienced an infection of any type compared to 47% (46/98) patients in the cyclophosphamide group by Month 6. The most common infections in the Rituxan group were upper respiratory tract infections, urinary tract infections, and herpes zoster.

The incidence of serious infections was 11% in the Rituxan-treated patients and 10% in the cyclophosphamide treated patients, with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia.

Retreatment in Patients with WG and MPA

In the active-controlled, double-blind study, subsequent courses of Rituxan were allowed for patients experiencing a relapse of disease. The limited data preclude any conclusions regarding the safety of subsequent courses of Rituxan with WG and MPA [see Dosage and Administration (2.6), and Warnings and Precautions (5.14)].

   Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading.

Using an ELISA assay, anti‑human anti‑chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low‑grade or follicular NHL receiving single‑agent Rituxan. Three of the four patients had an objective clinical response.

A total of 273/2578 (11%) patients with RA tested positive for HACA at any time after receiving Rituxan. HACA positivity was not associated with increased infusion reactions or other adverse reactions. Upon further treatment, the proportions of patients with infusion reactions were similar between HACA positive and negative patients, and most reactions were mild to moderate. Four HACA positive patients had serious infusion reactions, and the temporal relationship between HACA positivity and infusion reaction was variable.

A total of 23/99 (23%) Rituxan-treated patients with WG and MPA tested positive for HACA by 18 months. The clinical relevance of HACA formation in Rituxan‑treated patients is unclear.

   Postmarketing Experience

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 drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan.

• Hematologic: prolonged pancytopenia, marrow hypoplasia, and late‑onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia.
• Cardiac: fatal cardiac failure.
• Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus‑like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash.
• Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV‑associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection.
• Neoplasia: disease progression of Kaposi’s sarcoma.
• Skin: severe mucocutaneous reactions.
• Gastrointestinal: bowel obstruction and perforation.
• Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease.
• Nervous system: Posterior Reversible Encephalopathy Syndrome (PRES) / Reversible Posterior Leukoencephalopathy Syndrome (RPLS).

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Side Effects by Body System - for Healthcare Professionals

General

General side effects have included fever (49%), chills (32%), asthenia (16%), headache (14%), and abdominal pain (6%).

In general, severe side effects from rituximab may be more likely in patients with higher circulating white counts or a greater tumor burden. Severe and life-threatening (Grade 3 and 4) events have been reported in 10% of patients. The Grade 3 and 4 adverse events included neutropenia (1.9%), chills (1.6%), leukopenia (1.3%), thrombocytopenia (1.3%), hypotension (1%), anemia (1%), bronchospasm (1%), urticaria (1%), headache (0.6%), abdominal pain (0.6%), and arrhythmia (0.6%). A fatal case of septicemia has also been reported.

A cytokine-release syndrome consisting mainly of fever, chills, and stiffness during the first infusion has also been reported when the drug has been administered systemically.

Other

In almost all cases, the infusion related event was reported in relation to the first infusion.

Fatal outcomes were most frequently associated with female patients, patients with pulmonary infiltrates, and patients CLL or mantle cell lymphoma.

Other side effects have included death within 24 hours of infusion (0.04% to 0.07%). Death has occurred as part of an infusion related complex which included hypoxia, pulmonary infiltrates, adult respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock.

A case of serum sickness has also been reported.

Immunologic

Immunologic side effects have included B-cell depletion in 70% to 80% of patients. This was associated with decreased serum immunoglobulins in a minority of patients. An increase in fatal infection in HIV-related lymphoma patients has been reported when rituximab was used in combination with CHOP chemotherapy compared to CHOP alone. One fatal case of a reactivation of a cytomegalovirus has been reported.

Serious viral infections, either new, reactivated or exacerbated, have been identified. The majority of patients received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included JC virus [progressive multifocal leukoencephalopathy (PML)], cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, hepatitis B, and hepatitis C. In some cases, the viral infections occurred up to one year following discontinuation of rituximab and have resulted in death.

An increased incidence of grade 3 and 4 infections has been reported in patients with previously treated lymphoma without known HIV infection.

In general, the incidence of infection was not increased.

The signs of PML include confusion, dizziness or loss of balance, difficulty talking or walking, and vision problems. Recognition of these warning signs of PML may be obscured by the fact that these warning signs are also associated with the underlying diseases for which rituximab may be prescribed. Reactivation or exacerbation of viral infections including JC virus leading to PML may occur when patients receive rituximab for any reason. Physicians should maintain a high degree of suspicion for the development of PML in patients under treatment with rituximab. Patients who have been treated with rituximab and present or develop new neurological signs or symptoms should be evaluated for PML.

Hepatic

The majority of the patients received rituximab in combination with chemotherapy. Median time to the diagnosis of hepatitis was approximately four months after the initiation of rituximab and approximately one month after the last dose.

Patients at high risk of hepatitis B virus infection should be screened before initiation of rituximab. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active hepatitis B virus infection and for signs of hepatitis during and for up to several months following rituximab therapy.

In patients who develop viral hepatitis, rituximab and any concomitant chemotherapy should be discontinued and appropriate treatment including antiviral therapy should be initiated. There are insufficient data regarding the safety of resuming rituximab therapy in patients who develop hepatitis subsequent to hepatitis B virus reactivation.

Hepatic side effects including hepatitis B virus reactivation with fulminant hepatitis, hepatic failure, and death have been reported in some patients with hematologic malignancies treated with rituximab.

Cardiovascular

Cardiovascular side effects have included myocardial infarction, ventricular fibrillation, and cardiogenic shock (as parts of an infusion related reaction). Hypotension (10%) has also been reported.

Respiratory

Respiratory side effects have included rhinitis (8%), bronchospasm (8%), throat irritation (6%), hypoxia, pulmonary infiltrates, fatal bronchiolitis obliterans, pneumonitis (including interstitial pneumonitis), and adult respiratory distress syndrome (as parts of an infusion related reaction).

Gastrointestinal

Gastrointestinal side effects have included nausea (18%) and vomiting (7%).

Hematologic

Hematological side effects have included leukopenia (11%), thrombocytopenia (8%), and neutropenia (7%). Severe cytopenias include neutropenia (1.9%), thrombocytopenia (1.3%), and anemia (1.0%).

Metabolic

Metabolic side effects have included angioedema (13%).

Musculoskeletal

Musculoskeletal side effects have included myalgia (7%).

Nervous system

Nervous system side effects have included dizziness (7%).

Dermatologic

The major clinical features of the cutaneous cytokine-release syndrome are pain in the nodules and/or urticarial reaction at the tumor sites.

Dermatologic side effects have included pruritus (10%), rash (10%), and urticaria (8%). Several cases of psoriasis have been reported. A cutaneous cytokine-release syndrome has been reported when the drug was administered locally for cutaneous B-cell lymphoma.

Renal

The risk of TLS has been higher in patients with high numbers of circulating malignant cells.

Renal side effects have included tumor lysis syndrome (TLS) (0.04% to 0.05%) within the first 12 to 24 hours following the first rituximab infusion. TLS is characterized by a rapid reduction in tumor volume and includes renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia.

Oncologic

Oncologic side effects have included disease progression of Kaposi's sarcoma. A case of eccrine squamous syringometaplasia has also been reported.

Ocular

Ocular side effects including a case of bilateral conjunctivitis have been reported.

Genitourinary

Genitourinary side effects including a case of pyelonephritis have been reported.

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