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RITUXIMAB

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Rituximab is a genetically engineered chimeric murine/human monoclonal antibody against CD20, used to treat non-Hodgkin's lymphomas or signs and symptoms of moderate to severe rheumatoid arthritis (Prod Info RITUXAN(R) IV injection, 2007).

Specific Substances

    1) Anti-cd20 monoclonal antibodies
    2) IDEC-102
    3) Rituksimab
    4) Rituksimabi
    5) Rituximabum
    6) CAS 174722-31-7
    7) ATC: L01XC02

Available Forms Sources

    A) FORMS
    1) Rituximab is available at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials (Prod Info RITUXAN(R) IV injection, 2007).
    B) USES
    1) Rituximab is used for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin's lymphoma, which may or may not be combined with other chemotherapies. It may also be used in patients with stable disease or who are in partial or complete remission. Rituximab can also be used as a first line therapy for diffuse large B-cell, CD20 positive, non-Hodgkin's lymphoma in combination with other anthracycline-based chemotherapy regimens (Prod Info RITUXAN(R) IV injection, 2007).
    2) Rituximab may also be used in combination with methotrexate to reduce the signs and symptoms of moderate to severe rheumatoid arthritis (Prod Info RITUXAN(R) IV injection, 2007).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Rituximab, a CD20-directed cytolytic antibody, is indicated for the treatment of the following: Non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA) in combination with other agents and granulomatosis with polyangiitis.
    B) PHARMACOLOGY: Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. It binds specifically to the antigen CD20, a hydrophobic transmembrane protein. The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. In RA for example, rituximab induces depletion of peripheral B lymphocytes.
    C) EPIDEMIOLOGY: Exposure is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, diarrhea, and abdominal pain are relatively common with rituximab infusions; symptoms appear to decrease with subsequent infusions. Hypotension, hypertension and conduction disturbances have been reported with therapy. Headache, asthenia, and dizziness are relatively common during infusions and usually are reported less frequently with each subsequent infusion.
    2) OTHER: Several fatal reactions have been associated with rituximab, which have included fatal infusion-related reactions (ie, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock), tumor lysis syndrome which may be associated with severe renal toxicity, and severe mucocutaneous reactions (eg, paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, toxic epidermal necrolysis). Electrolyte disturbances may also occur in patients that develop tumor lysis syndrome. Grade 3/4 cytopenias (ie, lymphopenia, anemia, neutropenia, leukopenia, thrombocytopenia) have also been reported. Other events reported are hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiac dysrhythmias, and renal toxicity. Hypersensitivity reactions (hypotension, bronchospasm, and angioedema) have occurred with rituximab infusions, and typically occur with the first infusion. Some cases have been fatal.
    3) INFREQUENT: Infrequent reports of bronchiolitis obliterans and interstitial pneumonitis have occurred months after the completion of therapy. Conjunctivitis, transient ocular edema and visual changes have been reported infrequently with therapeutic use.
    4) RARE: Intestinal perforation and bowel obstruction have been rarely reported in postmarketing experience. There have also been rare reports of prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia.
    E) WITH POISONING/EXPOSURE
    1) No overdose information available. Symptoms are expected to be an extension of adverse events reported with therapy.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported with rituximab.
    0.2.20) REPRODUCTIVE
    A) Rituximab is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of rituximab in pregnant women. However, postmarketing surveillance of rituximab indicates that B-cell lymphocytopenia that generally lasts less than 6 months can occur in infants exposed to rituximab in-utero. Rituximab has been detected postnatally in the serum of infants who were exposed in-utero. There was no evidence of teratogenicity in offspring of cynomolgus monkeys exposed to rituximab during gestation; however, decreased B-cell counts have been reported postnatally in the offspring of monkeys exposed to rituximab during gestation. It is unknown whether rituximab is excreted in human milk; however, it is excreted in the milk of lactating cynomolgus monkeys. Risks to the infant from gastrointestinal or limited systemic exposure to rituximab are unknown.

Laboratory Monitoring

    A) Monitor respiratory and cardiac function, ECG and cardiac rhythm if patients show signs of an infusion reaction. Airway management and ventilation may be necessary.
    B) Monitor serial CBC with differential and platelet count following acute exposure.
    C) Obtain baseline electrolytes and assess renal function and hepatic enzymes after significant overdose. Monitor fluid balance.
    D) Monitor vital signs including temperature.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) SUMMARY
    1) Rituximab is administered parenterally. Oral exposure is unlikely. See PARENTERAL overview for further information.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Limited overdose data. Treatment is symptomatic and supportive. Monitor vital signs and monitor for signs of infection. Hypotension and/or hypertension may develop. Treat hypotension with IVFs as indicated. Cardiac dysrhythmias have been reported with therapy; cardiac monitoring is indicated. Monitor electrolytes, renal function and fluid balance.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Infusion reactions have been reported. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Monitor serial CBC with differential and platelet counts. For severe neutropenia, administer colony stimulating factor (eg, filgrastim, sargramostim). Thrombocytopenia and anemia have been observed with therapy.
    C) DECONTAMINATION
    1) PREHOSPITAL and/or HOSPITAL: GI decontamination is not indicated because an ingestion is unlikely; rituximab is administered parenterally. For dermal exposures, cleanse skin with soap and water, and for eye exposures, flush with water.
    D) AIRWAY MANAGEMENT
    1) Airway management and ventilation may be necessary in a patient that shows signs of an infusion reaction or evidence of unstable or life threatening cardiac dysrhythmias.
    E) ANTIDOTE
    1) None.
    F) ANAPHYLACTOID REACTION
    1) Monitor airway. MILD/MODERATE: Administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factor to patients with severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours; transfusion for severe thrombocytopenia or bleeding.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) OBSERVATION CRITERIA: Patients with significant overdose should be sent to a health care facility for evaluation and treated until symptoms resolve.
    3) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    4) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
    I) PITFALLS
    1) When managing a suspected rituximab overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Based on a population pharmacokinetic analysis of patients with rheumatoid arthritis that received rituximab, the mean volume of distribution was 3.1 L, the mean terminal elimination half-life was 18 days (range, 5.17 to 77.5 days). In patients with granulomatosis with polyangiitis and microscopic polyangiitis that received rituximab once weekly for 4 weeks, the mean clearance and volume of distribution were 0.312 L/day (range, 0.115 to 0.728 L/day) and 4.5 L (range, 2.21 to 7.52 L), respectively. The median terminal elimination half-life was 23 days (range, 9 to 49 days).
    K) DIFFERENTIAL DIAGNOSIS
    1) Rituximab may be administered to cancer patients in combination with other antineoplastic agents. Includes other agents that may cause myelosuppression (eg, methotrexate).

Range Of Toxicity

    A) TOXICITY: No lethal dose has been established. Single doses of up to 500 mg/m(2) have been administered in clinical trials. There have been rare reports of fatal- and near-fatal infusion reactions after a single dose of rituximab.
    B) THERAPEUTIC DOSE: ADULT: Recommended dose for non-Hodgkin's lymphoma is 375 mg/m(2) via an IV infusion once weekly for 4 or 8 doses. Recommended dose for rheumatoid arthritis is two 1000 mg IV infusions separated by 2 weeks. It should not be administered by intravenous push or bolus; the initial rate of infusion should not exceed 50 mg/hr. If tolerated, the infusion may gradually be increased by 50 mg/hr increments every 30 minutes, up to a maximum of 400 mg/hr. PEDIATRIC: The safety and efficacy of rituximab has not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Rituximab, a CD20-directed cytolytic antibody, is indicated for the treatment of the following: Non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis (RA) in combination with other agents and granulomatosis with polyangiitis.
    B) PHARMACOLOGY: Rituximab is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. It binds specifically to the antigen CD20, a hydrophobic transmembrane protein. The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. In RA for example, rituximab induces depletion of peripheral B lymphocytes.
    C) EPIDEMIOLOGY: Exposure is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Nausea, vomiting, diarrhea, and abdominal pain are relatively common with rituximab infusions; symptoms appear to decrease with subsequent infusions. Hypotension, hypertension and conduction disturbances have been reported with therapy. Headache, asthenia, and dizziness are relatively common during infusions and usually are reported less frequently with each subsequent infusion.
    2) OTHER: Several fatal reactions have been associated with rituximab, which have included fatal infusion-related reactions (ie, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock), tumor lysis syndrome which may be associated with severe renal toxicity, and severe mucocutaneous reactions (eg, paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, toxic epidermal necrolysis). Electrolyte disturbances may also occur in patients that develop tumor lysis syndrome. Grade 3/4 cytopenias (ie, lymphopenia, anemia, neutropenia, leukopenia, thrombocytopenia) have also been reported. Other events reported are hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiac dysrhythmias, and renal toxicity. Hypersensitivity reactions (hypotension, bronchospasm, and angioedema) have occurred with rituximab infusions, and typically occur with the first infusion. Some cases have been fatal.
    3) INFREQUENT: Infrequent reports of bronchiolitis obliterans and interstitial pneumonitis have occurred months after the completion of therapy. Conjunctivitis, transient ocular edema and visual changes have been reported infrequently with therapeutic use.
    4) RARE: Intestinal perforation and bowel obstruction have been rarely reported in postmarketing experience. There have also been rare reports of prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia.
    E) WITH POISONING/EXPOSURE
    1) No overdose information available. Symptoms are expected to be an extension of adverse events reported with therapy.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported with rituximab.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in 53% of patients treated with rituximab; chills have occurred in 33% of patients (Prod Info Rituxan(R) intravenous injection, 2013).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) Hypotension and hypertension have been reported with use (Prod Info Rituxan(R) intravenous injection, 2013).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) In a phase II study (n=131) of patients with mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma, conjunctivitis (n=4), transient ocular edema (n=2), burning (n=1), transient visual changes (n=1), and loss of visual acuity (n=1) were reported. Permanent and severe loss of visual acuity occurred 1 month after rituximab in a patient with previously treated mantle-cell lymphoma and underlying well-controlled glaucoma (Foran et al, 2000).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension (all grades) has been reported in 10% of patients during therapeutic infusions (Prod Info Rituxan(R) intravenous injection, 2013).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension (all grades) has been reported in 6% of patients during therapeutic infusions (Prod Info Rituxan(R) intravenous injection, 2013).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Dysrhythmias (ventricular tachycardia/supraventricular tachycardia, trigeminy, irregular pulse) have been reported during therapeutic infusion. Symptoms usually occur more frequently during the first infusion (8%) and are less frequent during subsequent infusions (4%) (Prod Info Rituxan(R) intravenous injection, 2013; Maloney et al, 1994a; Anon, 1997; Anon, 1997a). Patients with a history of cardiac events may have a recurrence of these clinical events during rituximab therapy; cardiac monitoring throughout the infusion period and immediately post-infusion is recommended (Prod Info Rituxan(R) intravenous injection, 2013).
    b) In 3 randomized, active-controlled trials, evaluating the use of rituximab in combination with chemotherapy in the treatment of diffuse, large, B-cell lymphoma, of whom 396 (43%) patients were age 65 or greater and 123 (13%) were age 75 or greater, elderly patients experienced more cardiac adverse events, mostly supraventricular dysrhythmias, than younger subjects (Prod Info Rituxan(R) intravenous injection, 2013).
    c) In a phase II study of patients with mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma (n=131), dysrhythmias developed in 10 patients (8%) and included bradycardia (n=3), atrial fibrillation (n=2), and nonspecific dysrhythmias or tachycardia (n=5) (Foran et al, 2000).
    D) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) Cutaneous leukocytoclastic VASCULITIS of small vessels developed in a 44-year-old man with conventional B-cell chronic lymphoid leukemia who was treated with rituximab for reduction of tumor burden prior to autologous bone marrow transplantation. The patient developed lower limb pain, fever and shivers 2 days after the first infusion of rituximab (700 milligrams). Inflammatory skin lesions on the ankles, legs, and knees soon developed, spread to thighs and abdomen, became purpuric, and then evolved to postinflammatory pigmentation. The skin lesions did not recur after discontinuation of rituximab. Histology showed small-vessel leukocytoclastic vasculitis without vessel obstruction (Dereure et al, 2001).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions (i.e., bronchospasm (8%), angioedema, and hypotension), cough (13%), rhinitis (12%), dyspnea (7%), and sinusitis (6%) have all occurred with rituximab infusions (Prod Info Rituxan(R) intravenous injection, 2013; Maloney et al, 1994a; Anon, 1997; Anon, 1997a). Upper respiratory infections, bronchitis, and nasopharyngitis have also been reported in some patients treated with rituximab (Prod Info Rituxan(R) intravenous injection, 2013).
    B) OBLITERATIVE BRONCHIOLITIS
    1) WITH THERAPEUTIC USE
    a) Rare, and sometimes fatal cases of bronchiolitis obliterans and pneumonitis have been reported post marketing, up to 6 months after receiving rituximab; the safety of continuation or rechallenge in these patients has not been established (Prod Info Rituxan(R) intravenous injection, 2013; Biehn et al, 2006).
    b) CASE REPORT: A 61-year-old man with mucosal-associated lymphoid tissue nonlymphocytic leukemia was treated with 4 weekly intravenous doses of rituximab alone at 375 mg/m2 only for 2 months. The patient developed symptoms of a productive cough and dyspnea. Histologic evidence of bronchiolitis obliterans with organizing pneumonia (BOOP) was present on biopsy. The patient improved following a course of steroid therapy; 7 months later the patient's pulmonary function tests had normalized. The authors also reported 2 other cases of BOOP at their institution related to rituximab therapy (Biehn et al, 2006).
    C) INTERSTITIAL PNEUMONIA
    1) WITH THERAPEUTIC USE
    a) Rare, and sometimes fatal cases of pneumonitis have been reported post marketing, up to 6 months after receiving rituximab; the safety of continuation or rechallenge in these patients has not been established (Prod Info Rituxan(R) intravenous injection, 2013; Biehn et al, 2006).
    b) CASE REPORTS: Two men (73 and 66 years old) with B-cell lymphoma developed interstitial pneumonitis after being treated with rituximab and standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone). Both patients had been in previously good health. Symptoms included exertional dyspnea, cough, restrictive pattern on pulmonary function testing along with ground-glass opacities (GGO) and multiple infiltrates on chest CT. The patients recovered following cessation of rituximab and a course of steroid therapy (Lee et al, 2006).
    1) The authors noted that 5 other cases have been reported in the literature and the pathogenesis may be related to the release of cytokines; all patients improved with steroid therapy except one that died. Postmortem findings suggested a thrombotic event was the primary injury to the lung in that patient (Lee et al, 2006).
    c) CASE REPORTS: Severe pulmonary reactions were also reported in 3 patients with intravascular large B-cell lymphoma (IVL) with an Asian variant of IVL. Symptoms of dyspnea and hypoxia started within 24 hours of the rituximab infusion. Two patients required mechanical ventilation. Its suggested that an elevation of cytokines and a damaged vascular barrier may result in severe systemic inflammatory response and acute respiratory distress (Wu et al, 2007).
    D) ADULT RESPIRATORY DISTRESS SYNDROME
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: 43-year-old man with idiopathic thrombocytopenic purpura (ITP) who was refractory to therapy with steroids and intravenous immunoglobulin, developed acute respiratory distress syndrome (met consensus criteria: acute onset of bilateral pulmonary infiltrates; PaO2/FIO2 less than 200; normal cardiac function) after one dose of rituximab. Symptoms progressed and the patient required mechanical ventilation one week after rituximab administration. The patient died 3 weeks after receiving rituximab (Montero et al, 2005). The authors concluded that the exact mechanism by which rituximab or other monoclonal antibodies produces ARDS is unknown, but the effects may be due to cytokine release and complement activation with a first-time infusion.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported in 19% of patients during infusions. Symptoms usually occur more frequently during the first infusion (8%) and are less frequent during subsequent infusions (4%) (Prod Info Rituxan(R) intravenous injection, 2013; Anon, 1997a; Maloney et al, 1994a).
    B) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia (26%) and dizziness (10%) are frequent infusion related reactions. Infusion related symptoms occur more frequently during first infusion (8%) and are less frequent during subsequent infusions (4%) (Prod Info Rituxan(R) intravenous injection, 2013; Anon, 1997a; Maloney et al, 1994a).
    C) CEREBRAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 20-year-old woman with intravascular lymphoma (a rare variant of diffuse large B-cell lymphoma) was treated with R-CHOP (rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisone) and developed a severe headache and became comatose 3 hours into her first rituximab infusion. A CT of the brain showed multifocal intracerebral hemorrhage. The patient recovered completely following supportive care (Ganguly, 2007). The authors suggested that the interaction between rituximab and CD20+ IVL cells might have produced localized tumor lysis and cytokine release leading to rupture of capillary endothelium and multifocal intracerebral hemorrhage; however, no causal relationship could be determined.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea (23%), vomiting (10%), and abdominal pain (14%) usually occur during infusion. Infusion related symptoms occur more frequently during the first infusion (8%) and are less frequent during subsequent infusions (4%) (Prod Info Rituxan(R) intravenous injection, 2013; Anon, 1997a; Anon, 1997; Maloney et al, 1994a).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported in 10% of patients during infusion. Infusion related symptoms occur more frequently during first infusion (8%) and are less frequent during subsequent infusions (4%) (Prod Info Rituxan(R) intravenous injection, 2013; Anon, 1997a; Anon, 1997; Maloney et al, 1994a).
    C) INTESTINAL OBSTRUCTION
    1) WITH THERAPEUTIC USE
    a) Cases of abdominal pain, bowel obstruction and, rarely, perforation, some with fatal outcomes, have been reported in patients receiving rituximab in combination with chemotherapy for diffuse large B-cell non Hodgkin's lymphomas (NHL). In postmarketing reports, the mean time to onset of symptoms was 6 days (range 1 to 77) in patients with documented gastrointestinal perforation, receiving rituximab for low-grade or follicular NHL and diffuse large B-cell NHL (Prod Info Rituxan(R) intravenous injection, 2013).
    D) GASTROINTESTINAL PERFORATION
    1) WITH THERAPEUTIC USE
    a) Cases of abdominal pain, bowel obstruction and, rarely, perforation, some with fatal outcomes, have been reported in patients receiving rituximab in combination with chemotherapy for diffuse large B-cell non Hodgkin's lymphomas (NHL). In postmarketing reports, the mean time to onset of symptoms was 6 days (range 1 to 77) in patients with documented gastrointestinal perforation, receiving rituximab for low-grade or follicular NHL and diffuse large B-cell NHL (Prod Info Rituxan(R) intravenous injection, 2013).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) RELAPSING TYPE B VIRAL HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Reactivation of hepatitis B virus including fulminant hepatitis, hepatic failure, and death has been reported in patients treated with rituximab. The median time to diagnosis of hepatitis was approximately 4 months after initiation of rituximab therapy. Appropriate screening for hepatitis B virus is recommended prior to initiating rituximab therapy (Prod Info Rituxan(R) intravenous injection, 2013).
    1) CASE REPORT: Acute hepatitis B developed in a 69-year-old man 6 months after completing a 4-week course of rituximab monotherapy for follicular lymphoma. The patient had previously completed seven cycles of chemotherapy (cyclophosphamide, etoposide, doxorubicin, prednisone) with interferon alfa-2b, then six cycles of high-dose cytarabine. He continued on prednisone in the interim period between rituximab administration and clinical hepatitis B. Prior to rituximab therapy, antibodies to hepatitis B surface antigen (anti-HBs) were present, with no evidence of hepatitis B surface antigen (HBsAg) itself. With hepatitis B activation, anti-HBs disappeared, but HBsAg, immunoglobulin M to hepatitis B core antigen and serum hepatitis B virus deoxyribonucleic acid (HBV-DNA) were found. After recovery, HBsAg persisted in the absence of anti-HBs (Dervite et al, 2001).
    B) VIRAL HEPATITIS
    1) WITH THERAPEUTIC USE
    a) ADENOVIRAL HEPATITIS
    1) CASE REPORT: A 60-year-old man with a history of Waldenstrom macroglobulinemia, which was quiescent until 18 months prior to death when a new onset of lymphocytic infiltration was observed on bone marrow biopsy. The patient died of multiple organ failure and markedly elevated liver enzymes 3 weeks after finishing his final course of rituximab (a total of 11200 mg of rituximab was given during the entire treatment course). Autopsy findings revealed evidence of pneumonia with no adenoviral infection, or a residual lymphoproliferative process in the bone marrow. The liver was found to be enlarged with numerous hepatocytes with basophilic intranuclear inclusions consistent with adenoviral infections. Other organs were negative for adenoviral infections. The authors suggest that there may be an association between rituximab therapy and fatal viral reactivation (Iyer et al, 2006).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ACUTE RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) Acute renal failure resulting in dialysis or death have been associated with the use of rituximab and the development of tumor lysis syndrome. Patients with greater than 25,000/cubic millimeter of circulating malignant cells, high tumor burden (who experience tumor lysis syndrome), or concomitant administration with cisplatin appear to be at increased risk to develop impaired renal function (Prod Info Rituxan(R) intravenous injection, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) Grade 3/4 lymphopenia (40%), thrombocytopenia (2%), neutropenia (6%), leukopenia (4%) and anemia (3%) have all been reported in patients receiving rituximab therapy (Prod Info Rituxan(R) intravenous injection, 2013).
    b) A single occurrence of transient aplastic anemia (pure red cell aplasia) and 2 occurrences of hemolytic anemia following therapy were reported (Prod Info Rituxan(R) intravenous injection, 2013; Maloney et al, 1994a; Anon, 1997a).
    c) Rare cases of prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia (40 days after last dose of rituximab) have been reported in patients with hematologic malignancies receiving rituximab (Prod Info Rituxan(R), 2003). Half of the patients recovered; with 50% of those receiving growth factor support. Postmarketing reports indicate a 0.02% rate (Benyunes et al, 2003).
    d) In a phase II study (n=131) of patients with mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma, grade 3/4 hematologic toxicity which represented a new abnormality from baseline included lymphocytopenia (25%), leukopenia (5%), neutropenia (3%), anemia (2%), and thrombocytopenia (6%) (Foran et al, 2000).
    B) CYTOPENIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 71-year-old woman with mantle cell lymphoma developed cytopenia after receiving a second dose of rituximab. Initial symptoms included fever, chills and rigors, followed by vomiting and diarrhea. Approximately, 18 hour after the infusion the leukocyte and platelet count decreased significantly (1 x 10(9)/L and 10 x 10(9)/L, respectively). No active signs of bleeding occurred. Within two days, the platelet count gradually rose and the leukocyte count began to improve within 4 days (Ram et al, 2009). Based on available data, the authors suggest that rituximab-associated cytopenia is self-limited and generally mild, which is likely to occur within a few hours of exposure and reach nadir within 1 day and resolve spontaneously. Cytokine release syndrome may be a risk factor for developing rituximab-associated cytopenia. It has been observed in over 80% of patients developing cytopenia and may be mediated through complement activation.
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Two young children (ages 2 and 3 years, respectively) with autoimmune hemolytic anemia developed severe acute thrombocytopenia and neutropenia after receiving rituximab therapy. In the first patient, laboratory studies one week after finishing a 4-week course of rituximab were as follows: WBC 1.9 x 10(9)/L with neutrophils 0.02 x 10(9)/L and platelets 232 x 10(9)/L. The patient improved following granulocyte-colony stimulating factor and blood transfusions. The second child with acute anemia received 3 weekly infusions of rituximab and 7 days later developed a further drop in the platelet count (165 x 10(9)/L to 74 x 10(9)/L, which further dropped to 22 x 10(9)/L). Following platelet transfusions and supportive care, the patient improved. No further episodes were reported; however, neither child showed any improvement in their underlying autoimmune hemolytic anemia (Larrar et al, 2006).
    D) PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) Progressive multifocal leukoencephalopathy, a fatal viral infection of the central nervous system, has been reported with therapeutic use of rituximab when it was used to treat systemic lupus erythematosus (SLE) (no authors listed, 2007).
    1) CASE REPORTS: Progressive multifocal leukoencephalopathy (PML) was reported in 23 patients being treated for hematologic malignancies with rituximab. Fatal PML caused by reactivation of JC virus occurred in two patients after being treated with rituximab for systemic lupus erythematosus (SLE). The first patient was a 70-year-old female with a history of lupus nephritis and hemolytic anemia previously treated with cyclophosphamide, azathioprine and varying doses of corticosteroids. After 6 infusions of rituximab, the patient developed vertigo, tongue biting and difficulty walking. An MRI revealed multiple brain lesions, and brain biopsy revealed findings of PML. The second patient was a 45-year-old female with a history of SLE previously treated with cyclophosphamide and intravenous methylprednisolone. After 3 infusions of rituximab, the patient developed new neurological signs and symptoms. An MRI revealed multiple brain lesions and cerebral spinal fluid was positive for JC virus confirming the diagnosis of PML (US Food and Drug Administration, 2006).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH THERAPEUTIC USE
    a) Fatal mucocutaneous reactions such as paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis have been reported with rituximab (Prod Info Rituxan(R) intravenous injection, 2013).
    b) Onset of symptoms have varied and may occur on the first day of therapy (Prod Info Rituxan(R) intravenous injection, 2013). A skin biopsy is recommended in patients experiencing dermal events to distinguish between the various mucocutaneous reactions before therapy is continued (Prod Info RITUXAN(R) IV injection, 2007).
    c) Night sweats (15%), rash (15%), angioedema (11%), pruritus (14%), and urticaria (8%) can occur during an infusion (Prod Info Rituxan(R) intravenous injection, 2013; Anon, 1997a; Maloney et al, 1994a).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Both myalgia and arthralgia have been reported in 10% of patients treated with rituximab (Prod Info Rituxan(R) intravenous injection, 2013).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia (9%) has occurred with rituximab infusions (Prod Info Rituxan(R) intravenous injection, 2013).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Hypersensitivity reactions (hypotension, bronchospasm, and angioedema) have occurred with rituximab infusions. These reactions typically occur with the first infusion with an onset of 30 to 120 minutes. Some cases have been fatal (Prod Info Rituxan(R) intravenous injection, 2013).
    B) COMPLICATION OF INFUSION
    1) WITH THERAPEUTIC USE
    a) SYSTEMIC REACTIONS
    1) Infusion-related reactions (e.g., hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation or cardiogenic shock) have resulted in death in some patients receiving rituximab; most reactions were within 24 hours of rituximab administration and associated with the first dose (Prod Info Rituxan(R) intravenous injection, 2013).
    2) High pretreatment CD20+ cells in peripheral blood (more severe infusion reactions) has been reported as a predictor of toxicity (Maloney et al, 1994a).
    b) SURVIVAL
    1) CASE REPORT: A near-fatal infusion reaction (i.e., severe hemodynamic instability and respiratory insufficiency) developed in a 35-year-old female renal transplant recipient after receiving one dose of rituximab. Symptoms developed within 30 minutes and gradually worsened over the next few days. She received supportive therapy and three consecutive daily plasmapheresis treatments. Symptoms markedly improved with plasmapheresis, and she was successfully extubated after 48 hours of mechanical ventilation. The patient completely recovered and was discharged on day 5 (Hastings et al, 2009).
    2) CASE REPORTS/TUMOR LYSIS SYNDROME: A unique infusion-related reaction was reported in 5 patients with evidence of a rapid decline in the blood tumor cell count. All patients had a marked and rapid decline in the blood tumor cells after rituximab administration with infusion-related side effects during the first infusion (ie, severe rigors, fever, bronchospasm, hypoxemia, and thrombocytopenia). Three patients demonstrated tumor lysis syndrome and others had findings indicative of rapid tumor cell destruction (ie, hypocalcemia and increased lactate dehydrogenase) (Byrd et al, 1999).
    3) CASE SERIES: In a phase I/II trial of patients with chronic lymphocytic leukemia (n=26) or small lymphocytic lymphoma (n=7), rituximab was administered 3 times weekly for 4 weeks. On day one, all patients received rituximab 100 mg IV over 4 hours without dose escalation. Rituximab infusion was interrupted and supportive treatment was administered in 13 patients who experienced transient hypoxemia, hypotension, or dyspnea including 2 patients with grade 3/4 events. Compared with patients who did not have an infusion-related reactions, the 13 patients who had reactions had a significantly higher median age (73 years versus 62 years; p=0.02), and significantly higher inflammatory cytokines: tumor necrosis factor-alfa (p=0.007), interferon-gamma (p=0.11), interleukin-8 (p=0.02), and interleukin-6 (p=0.58). Infusion-related reactions were not related to complement depletion (CH50 and C3), disease type, prior therapy, absolute tumor blood count number, extensive nodal involvement or tumor CD20 expression (Byrd et al, 2001a).
    c) FATALITIES
    1) CASE REPORT: A 14-year-old boy with a relapse of pre-B acute lymphoblastic leukemia (ALL) and anaplastic astrocytoma was treated with rituximab and developed a fatal course of systemic inflammatory response syndrome (SIRS). During the second infusion the patient developed an anaphylactoid reaction (ie, hypotension, tachycardia and hypoxia) and received intensive supportive care. The patient was treated with antibiotics for suspected septicemia with leukocytopenia. The patient died 72 hours after the first dose of rituximab from multiple organ failure (Seifert et al, 2006).
    2) CASE REPORT: CYTOKINE RELEASE SYNDROME: A 71-year-old woman diagnosed with Rai stage I B-cell chronic lymphocytic leukemia 7 years prior, died 9 hours following rituximab administration due to cytokine release syndrome. Her disease progressed despite previous treatment with chlorambucil, fludarabine, and fludarabine with cyclophosphamide. Rituximab was administered cautiously because of high tumor burden, however the patient suffered a cardiopulmonary collapse. The authors reveal that the manufacturer has noted 8 other fatalities possibly related to rituximab-induced cytokine release syndrome (Lim et al, 1999).
    C) SERUM SICKNESS DUE TO DRUG
    1) WITH THERAPEUTIC USE
    a) Serum sickness (described as sudden onset of fever, rash and arthralgias) is a rare event following rituximab therapy, but several cases have been reported in postmarketing experience (Prod Info Rituxan(R) intravenous injection, 2013; Finger & Scheinberg, 2007; Todd & Helfgott, 2007).
    1) CASE REPORT: A 68-year-old man with stage 2A mantle cell lymphoma developed an abrupt onset of severe polyarthralgias and joint swelling, rash and fever 13 days after receiving a single treatment of cyclophosphamide, vincristine, prednisone, and rituximab. Symptoms rapidly improved with corticosteroid therapy; no recurrence was reported. Of note, indomethacin therapy was initially started for symptoms with no clinical or subjective improvement (Todd & Helfgott, 2007).
    2) CASE REPORTS: Two patients with autoimmune diseases and marked hypergammaglobulinemia each received rituximab therapy and developed severe serum-sickness-like reaction. Both recovered following IV corticosteroid therapy (Finger & Scheinberg, 2007).

Reproductive

    3.20.1) SUMMARY
    A) Rituximab is classified as FDA pregnancy category C. There are no adequate and well-controlled studies of rituximab in pregnant women. However, postmarketing surveillance of rituximab indicates that B-cell lymphocytopenia that generally lasts less than 6 months can occur in infants exposed to rituximab in-utero. Rituximab has been detected postnatally in the serum of infants who were exposed in-utero. There was no evidence of teratogenicity in offspring of cynomolgus monkeys exposed to rituximab during gestation; however, decreased B-cell counts have been reported postnatally in the offspring of monkeys exposed to rituximab during gestation. It is unknown whether rituximab is excreted in human milk; however, it is excreted in the milk of lactating cynomolgus monkeys. Risks to the infant from gastrointestinal or limited systemic exposure to rituximab are unknown.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) Rituximab given shortly before pregnancy did not appear to have serious adverse effects on 2 newborns from a twin pregnancy. A 32-year-old woman with rheumatoid arthritis received rituximab at 6 and 8 weeks before conception. After an uncomplicated pregnancy, healthy female twins were delivered at 37 weeks despite a clubfoot in one infant and transient erythema toxicum neonatorum (ETN) in the second. B-cell counts and immunoglobulin levels were normal at birth and 8 months of age. The infant with ETN had a transient, mild leucocytosis at birth with no clinical signs of infection. All other hematologic tests were normal for both infants. At 8 months, both infants had normal development, but one twin suffered from asthma without serious infectious complications (Ton et al, 2011).
    B) ANIMAL STUDIES
    1) LACK OF EFFECT: Although rituximab has been shown to cross the placenta in monkeys, there was no evidence of teratogenicity in offspring of cynomolgus monkeys following oral maternal administration of rituximab during organogenesis and post-coitum days 20 through 50 at doses up to 80% the human therapeutic dose of 2 grams based on AUC. However, decreased lymphoid tissue B cells were noted (Prod Info RITUXAN(R) intravenous injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified rituximab as FDA pregnancy category C (Prod Info RITUXAN(R) intravenous injection, 2014).
    2) There are no adequate and well-controlled studies of rituximab use in pregnant women (Prod Info RITUXAN(R) intravenous injection, 2014).
    B) B-CELL LYMPHOCYTOPENIA
    1) Postmarketing surveillance of rituximab indicates that B-cell lymphocytopenia, generally lasted less than 6 months, can occur in infants exposed to rituximab in-utero; rituximab has been detected postnatally in the serum of infants who were exposed in-utero (Prod Info RITUXAN(R) intravenous injection, 2014).
    2) A review of 12 case reports indicated 4 of 5 neonates whose B-cell counts were measured at birth had B-cell depletion after being exposed to rituximab in utero. Female patients received 3 to 6 cycles of rituximab, beginning 3 months prior to conception or during pregnancy in comparable cumulative doses, for various conditions that included non-Hodgkin lymphoma, systemic lupus erythematosus, autoimmune hemolytic anemia, B-cell lymphoma, Burkitt lymphoma, thrombotic thrombocytopenic purpura, and idiopathic thrombocytopenic purpura. Among the 12 healthy infants, 5 had B-cell counts and immunoglobulin levels measured at delivery and followup (range, 55 days to 6 months). Four of the 5 had B-cell depletion at birth that recovered to normal without infectious complications, and all of the infants had normal immunoglobulin levels at birth and followup. One infant had a low granulocyte count that normalized at 18 months. A second infant had a transient, short neutrophilia due to a mild infection, and a third infant had neutropenia at birth lasting 24 hours. The mothers of 2 infants with low B-cell counts were given concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with rituximab, and a third mother whose infant had low B-cell counts received a glucocorticoid with rituximab. Four of the 5 infants with B-cell depletion at birth had a normal response to vaccinations. No complications were detected in the 12 infants during followup (range, 4 to 35 months) (Ton et al, 2011).
    C) ANIMAL STUDIES
    1) CYNOMOLGUS MONKEYS: Immunosuppression and B cell decreases occurred in the offspring of cynomolgus monkeys with prenatal and postnatal exposure to rituximab at doses 80% the human therapeutic dose of 2 g based on AUC. Exposure intervals varied from postcoitum day 20 to 132 and postpartum day 28 to 134. B-cell counts returned to normal levels and immunologic function recovered within 6 months postpartum (Prod Info RITUXAN(R) intravenous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Lactation studies with rituximab have not been conducted in humans and it is unknown whether the drug is excreted in human milk. However, immunoglobulin G (IgG) is excreted in human milk. Published data demonstrate that antibodies from breast milk are not detected in significant amounts in neonatal and infant circulations. The risks to the infant from gastrointestinal or limited systemic exposure to rituximab are not known (Prod Info RITUXAN(R) intravenous injection, 2014).
    B) ANIMAL STUDIES
    1) Rituximab is excreted in the milk of lactating cynomolgus monkeys (Prod Info RITUXAN(R) intravenous injection, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Long-term animal studies to assess the effect of rituximab on male or female fertility have not been performed (Prod Info RITUXAN(R) intravenous injection, 2014).

Genotoxicity

    A) There have been no studies to determine the genetic potential of rituximab (Prod Info RITUXAN(R) IV injection, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor respiratory and cardiac function, ECG and cardiac rhythm if patients show signs of an infusion reaction. Airway management and ventilation may be necessary.
    B) Monitor serial CBC with differential and platelet count following acute exposure.
    C) Obtain baseline electrolytes and assess renal function and hepatic enzymes after significant overdose. Monitor fluid balance.
    D) Monitor vital signs including temperature.
    4.1.2) SERUM/BLOOD
    A) Monitor serial CBC with differential and platelet count following an acute exposure.
    B) Obtain baseline electrolytes and assess renal function and hepatic enzymes in patients with evidence or tumor lysis syndrome or after significant overdose. Monitor fluid balance.
    4.1.4) OTHER
    A) OTHER
    1) CARDIAC MONITORING
    a) Continuous cardiac monitoring and pulse oximetry after significant overdose.

Radiographic Studies

    A) CHEST X-RAY
    1) Obtain a chest x-ray in patients with respiratory symptoms or signs.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with overdose.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with significant overdose should be sent to a health care facility for evaluation and treated until symptoms resolve.

Monitoring

    A) Monitor respiratory and cardiac function, ECG and cardiac rhythm if patients show signs of an infusion reaction. Airway management and ventilation may be necessary.
    B) Monitor serial CBC with differential and platelet count following acute exposure.
    C) Obtain baseline electrolytes and assess renal function and hepatic enzymes after significant overdose. Monitor fluid balance.
    D) Monitor vital signs including temperature.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) GI decontamination is not indicated because an ingestion is unlikely; rituximab is administered parenterally.
    6.5.3) TREATMENT
    A) SUPPORT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) ENHANCED ELIMINATION
    1) Hemodialysis may be indicated in patients that develop acute renal failure related to tumor lysis syndrome (Prod Info Rituxan(R) intravenous injection, 2013).

Range Of Toxicity

Summary

    A) TOXICITY: No lethal dose has been established. Single doses of up to 500 mg/m(2) have been administered in clinical trials. There have been rare reports of fatal- and near-fatal infusion reactions after a single dose of rituximab.
    B) THERAPEUTIC DOSE: ADULT: Recommended dose for non-Hodgkin's lymphoma is 375 mg/m(2) via an IV infusion once weekly for 4 or 8 doses. Recommended dose for rheumatoid arthritis is two 1000 mg IV infusions separated by 2 weeks. It should not be administered by intravenous push or bolus; the initial rate of infusion should not exceed 50 mg/hr. If tolerated, the infusion may gradually be increased by 50 mg/hr increments every 30 minutes, up to a maximum of 400 mg/hr. PEDIATRIC: The safety and efficacy of rituximab has not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    1) Non-Hodgkin's Lymphoma
    a) Recommended dose is 375 mg/m(2) IV infusion once weekly for 4 or 8 doses (Prod Info Rituxan(R) intravenous injection, 2013).
    b) FIRST INFUSION: It should not be administered by intravenous push or bolus; the initial rate of infusion should not exceed 50 mg/hr. If tolerated, the infusion may gradually be increased by 50 mg/hr increments every 30 minutes, up to a maximum of 400 mg/hr (Prod Info Rituxan(R) intravenous injection, 2013).
    c) SECOND INFUSION: If cycle 1 is tolerated without a grade 3 or 4 infusion reaction, use a 90-minute infusion with glucocorticoid pretreatment; infuse 20% of the total dose in the first 30 minutes and the remaining 80% over the next 60 minutes. If tolerated, use the same rate for the remainder of the treatment regimen (Prod Info Rituxan(R) intravenous injection, 2013).
    d) Repeat Therapy
    1) Recommended dose is 375 mg/m(2) IV infusion once weekly for 4 doses in patients that develop progressive disease after previous therapy (Prod Info Rituxan(R) intravenous injection, 2013).
    e) Previously Untreated, Follicular, CD20-Positive, B-Cell NHL
    1) Recommended dose is 375 mg/m(2) IV infusion, given on Day 1 of each cycle of chemotherapy for up to 8 infusions (Prod Info Rituxan(R) intravenous injection, 2013).
    f) Previously Untreated, Low Grade, CD20-Positive, B-Cell NHL
    1) Recommended dose following 6 to 8 cycles of CVP chemotherapy is 375 mg/m(2) IV infusion once weekly for 4 doses every 6 months for up to 16 doses (Prod Info Rituxan(R) intravenous injection, 2013).
    2) Rheumatoid Arthritis
    a) Administer rituximab as two-1000 mg IV infusions separated by 2 weeks. Give methylprednisolone (or its equivalent) 100 mg IV 30 minutes prior to each dose of rituximab to minimize any infusion reactions. Subsequent therapy should be administered every 24 weeks or based on clinical necessity, but not sooner than every 16 weeks. Rituximab is administered in combination with methotrexate (Prod Info Rituxan(R) intravenous injection, 2013).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of rituximab has not been established in children (Prod Info Rituxan(R) intravenous injection, 2013).

Minimum Lethal Exposure

    A) Limited overdose information; a minimum lethal dose has not been established (Prod Info Rituxan(R) intravenous injection, 2013).

Maximum Tolerated Exposure

    A) SUMMARY
    1) Single doses of up to 500 mg/m(2) have been administered during dose escalation trials (Prod Info Rituxan(R) intravenous injection, 2013).
    B) CASE REPORTS
    1) A near-fatal infusion reaction (i.e., severe hemodynamic instability and respiratory insufficiency) developed in a 35-year-old female renal transplant recipient after receiving one dose of rituximab. Symptoms developed within 30 minutes and gradually worsened over the next few days. She received supportive therapy and three consecutive daily plasmapheresis treatments. Symptoms markedly improved with plasmapheresis, and she was successfully extubated after 48 hours of mechanical ventilation. The patient completely recovered and was discharged on day 5 (Hastings et al, 2009).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SYSTEMIC
    1) Rituximab, a murine/human monoclonal antibody, binds to the antigen CD20 (human B-lymphocyte–restricted differentiation antigen, Bp35). This antigen is a hydrophobic transmembrane protein, with a molecular weight of approximately 35,000 daltons, that is located on pre-B and mature B lymphocytes. It is also expressed on more than 90% of B-cell non-Hodgkin's lymphomas but not expressed on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. CD20 regulates an early step or steps in the activation process for cell cycle initiation and differentiation and may also function as a calcium ion channel. It is not shed from the cell surface and does not internalize upon antibody binding. No free CD20 antigen is found in the circulation (Prod Info RITUXAN(R) IV injection, 2007).
    B) ANTINEOPLASTIC ACTIVITY
    1) The mechanism of antineoplastic action may involve mediation of B cell lysis (seen in vitro) by means of binding of the Fab domain of rituximab to the CD20 antigen on B lymphocytes and by recruitment of immune effector functions by the Fc domain. Cell lysis may be the result of complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). In addition, the antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line (Prod Info RITUXAN(R) IV injection, 2007).
    2) Rituximab binds to lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. However, there appears to be little or no binding to non-lymphoid tissues (Prod Info RITUXAN(R) IV injection, 2007).
    C) RHEUMATOID ARTHRITIS ACTIVITY
    1) In patients with rheumatoid arthritis (RA), rituximab induced complete depletion of peripheral B lymphocytes, along with a reduction of total serum immunoglobulin levels, including IgM, IgG, and IgA after 6 months of therapy. There was also a reduction in certain biologic markers of inflammation (ie, interleukin-6, C-reactive protein, serum amyloid protein, S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrulinated peptide, and rheumatoid factor) (Prod Info RITUXAN(R) IV injection, 2007).

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