[u]Patients with Non-Hodgkin's Lymphoma and Patients with Chronic Lymphocytic Leukemia[/u] Infusion-Related Reactions Rituximab can cause an infusion reaction, which may be related to the release of cytokines and/or other chemical mediators. Clinically, it may not be possible to distinguish a severe infusion reaction from an anaphylactic reaction or cytokine release syndrome. Fatal serious infusion reactions have been reported in post-marketing use. Serious infusion reactions usually occur within 30 minutes to 2 hours of the start of a rituximab infusion and are characterized by the development of pulmonary events and, in some cases, rapid tumor lysis and signs of tumor lysis syndrome in addition to fever, chills, chills, hypotension, urticaria, angio-arteriovenous edema, and other symptoms (see Adverse Reactions). . Patients with high tumor loads or high peripheral blood malignant cell counts (]25 x 109/L), such as patients with CLL and condylomatous lymphoma, may be at greater risk for severe infusion reactions. These symptoms are generally reversible after discontinuation of the infusion. Treatment of infusion symptoms with diphenhydramine and acetaminophen is recommended. In addition, treatment with bronchodilators or saline under sedation may be indicated. In most cases, infusion therapy can be restarted at a 50% slower rate (e.g., from 100 mg/h to 50 mg/h) after symptoms have completely resolved. Most patients who experience a nonfatal infusion reaction complete the entire course of rituximab therapy. Serious infusion-related reactions rarely recur when patients continue treatment after complete resolution of signs and symptoms. Anaphylactic and other hypersensitivity reactions have been reported following intravenous administration of protein to patients. In the event of a rituximab-associated hypersensitivity reaction, epinephrine, antihistamines, and glucocorticoids should be administered immediately. Patients with high peripheral blood malignancy cell counts (]25 x 109/L) or high tumor loads, such as those with CLL and condylomatous lymphoma, are at relatively high risk for serious infusion-related reactions and should be handled with particular caution. Patients should be closely observed when the first infusion is administered. Consideration should be given to the need to slow down the infusion rate during the first infusion in such patients or to split a single dose over two days during the first treatment cycle. If the lymphocyte count remains greater than 25 x 109/L, the drug should continue to be administered in this manner in subsequent cycles of therapy. Pulmonary Events Pulmonary events include tissue hypoxia, pulmonary infiltrates, and acute respiratory failure. Some of these events may be secondary to severe bronchospasm and dyspnea. In some cases, symptoms may worsen over time, and in others, after initial improvement, a deterioration of the clinical condition ensues. Therefore, patients who experience pulmonary events or other severe infusion symptoms should be closely monitored until their symptoms have completely resolved. Patients with a history of pulmonary insufficiency or tumor infiltration in the lungs are at greater risk of poor healing and should be treated with extra care by the physician. Acute respiratory failure may be associated with interstitial infiltrative lesions or edema of the lungs, as can be observed on chest X-rays. This symptom usually occurs within 1 or 2 hours of the start of the first infusion. Infusions should be discontinued immediately in patients who have experienced a serious pulmonary event (see Dosage and Administration) and they should be treated aggressively with symptomatic therapy. Rapid Tumor Lysis Rituximab mediates rapid lysis of benign and malignant CD20-positive cells. Signs and symptoms consistent with tumor lysis syndrome (TLS) (e.g., hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia, acute renal failure, elevated LDH levels) have been reportedly observed in patients with high peripheral blood malignant lymphocyte counts. TLS prophylaxis should be considered in high-risk patients (e.g., patients with high tumor load or high peripheral blood malignant cell counts (]25 x 109/L), such as patients with CLL and condylomatous lymphoma). Close and appropriate laboratory monitoring of these patients should be performed after the introduction of rituximab. Appropriate medical therapy should be given to patients who develop signs and symptoms of rapid tumor lysis. In some cases, after treatment of signs and symptoms and complete resolution, rituximab may be continued with concomitant TLS prophylaxis. Rituximab infusion should be administered in a setting where resuscitation equipment is available and immediate and under the close supervision of an experienced oncologist/hematologist. Cardiovascular Because hypotension may occur during rituximab infusion, discontinuation of antihypertensive medications should be considered 12 hours prior to and during the rituximab infusion. In patients treated with rituximab, there has been a history of angina or arrhythmic events such as atrial flutter and fibrillation, heart failure, or myocardial infarction. Therefore, patients with a history of heart disease should be closely monitored. Blood Count Testing Although rituximab is not myelosuppressive in monotherapy, caution should be exercised when considering the use of rituximab for the treatment of patients with neutrophil counts [1.5 x 109/L and/or platelet counts [75 x 109/L, as limited clinical experience has been accumulated in such patients. Rituximab has been used without myelotoxicity in autologous bone marrow transplantation and other populations that may be at risk for bone marrow decompensation. The need for periodic checking of complete blood counts, including platelet counts, should be considered in the adoption of rituximab as monotherapy. When combining rituximab with CHOP or CVP chemotherapy, periodic complete blood count checks should be performed as a matter of routine medical practice. Infections Rituximab should not be used to treat patients who also have a serious active infection. Hepatitis B Virus Infection Hepatitis B virus (HBV) reactivation, including fulminant hepatitis, has been reported in a number of cases (in some cases fatally) in study subjects taking rituximab, although the majority of the study subjects were also exposed to cytotoxic chemotherapy. Underlying disease states and cytotoxic chemotherapy were confounded with the reported events. For patients at high risk for hepatitis B, hepatitis B virus (HBV) screening should be considered prior to initiating rituximab therapy. Hepatitis B virus carriers and patients with a history of hepatitis B should be closely monitored for clinical signs and laboratory markers of active HBV infection during and for several months after treatment with rituximab. Progressive Multiple LeukoencephalopathyProgressive multiple leukoencephalopathy (PML) has occurred in clinical use of rituximab in the treatment of patients with non-Hodgkin's lymphoma and patients with chronic lymphocytic leukemia (see Adverse Reactions). Most patients are treated with rituximab in combination with chemotherapeutic agents or as a treatment during hematopoietic stem cell transplantation. Therefore, physicians treating patients with non-Hodgkin's lymphoma and patients with chronic lymphocytic leukemia should consider PML in the differential diagnosis of patients reporting seminomics symptoms, and consult with a seminomics physician as clinically indicated. Immunization The safety of immunization with live virus vaccines following treatment with rituximab has not been studied. Immunization with live virus vaccines is not recommended. Patients treated with rituximab may receive non-live vaccines, but response rates to non-live vaccines may be decreased. In a non-randomized clinical study, patients with relapsed low-grade malignant NHL treated with rituximab monotherapy had a lower response rate to immunization with tetanus recall antigen and keyhole chikungunya hemocyanin (KLH) neoantigen compared to untreated control healthy volunteers, 16% vs 81% and 4% vs 69%, respectively (evaluated as a 2-fold or greater increase in antibody titer). Mean values of antibody titers produced by patients before treatment against multiple antigens (Streptococcus pneumoniae, influenza A, mumps, rubella, and varicella) were maintained for at least 6 months after treatment with rituximab. [u]Patients with Rheumatoid Arthritis (RA) and ANCA-Associated Vasculitis (AAV)[/u] With the exception of rheumatoid arthritis and ANCA-associated vasculitis, the efficacy and safety of melphalan/rituximab for the treatment of autoimmune diseases has not been defined. Infusion-Related Reactions Rituximab/Merova-related infusion reactions may be related to the release of cytokines and/or other chemical mediators. Antipyretics and antihistamines should be premedicated prior to each rituximab infusion. In patients with RA, glucocorticoids should be premedicated before each infusion of rituximab in order to reduce the frequency and severity of infusion-related reactions. In patients with RA, most infusion-related reactions reported in clinical trials have been mild to moderate. Fatal serious infusion-related reactions have been reported in postmarketing use (see Adverse Reactions). Patients with prior cardiac disease and prior cardiopulmonary adverse reactions are closely monitored. The most common symptoms include headache, pruritus, throat irritation, flushing, rash, urticaria, hypertension, and fever. In general, the incidence of infusion-related reactions is higher with the first infusion than with the second infusion in any treatment cycle. Subsequent administration of melphalan/rituximab was better tolerated by patients than the first infusion. Serious infusion-related reactions occurred in less than 1% of patients, most of which occurred during the first infusion of the first treatment cycle (see Adverse Reactions). Reactions reported when rituximab infusion is slowed or interrupted, or when antipyretics or antihistamines are administered, generally subside, and in individual cases, e.g., oxygen, intravenous saline solution, or bronchodilators and corticosteroids may be given as needed. Depending on the severity of the infusion-related reaction and the intervention required, treatment with rituximab may be temporarily or permanently discontinued. In most cases, the infusion can be continued by reducing the infusion rate by 50% (e.g., from 100 mg/h to 50 mg/h) when signs and symptoms have completely subsided. Anaphylactic and other hypersensitivity reactions have been reported in patients at the beginning, during, and after intravenous administration of protein. Medications used to treat hypersensitivity reactions (e.g., epinephrine, antihistamines, and corticosteroids) should be prepared for prompt use in anaphylactic events that occur during rituximab infusion. Infusion-related reactions in patients with AAV in clinical trials are similar to those observed in patients with RA (see Adverse Reactions). In patients with AAV, rituximab in combination with high-dose glucocorticoid therapy may reduce the incidence and severity of such events. Hypotension may occur during cardiovascular rituximab infusion; therefore, antihypertensive agents should not be used during the 12 hours of rituximab infusion. Administration of rituximab to patients with non-Hodgkin's lymphoma may aggravate pre-existing ischemic heart disease and cause symptoms such as angina pectoris, myocardial infarction, atrial fibrillation, ventricular fibrillation, and atrial flutter. Therefore, the risk of cardiovascular complications due to infusion reactions should be considered before initiating treatment with rituximab in patients with a history of cardiac disease, and such patients should be monitored closely during rituximab administration. InfectionsTreatment with rituximab may increase the risk of infection (see Contraindications). Rituximab should not be used in patients with active infections or severely impaired immune response (e.g., severely decreased CD4 or CD8 cell counts). Rituximab should be used with caution in patients with a history of recurrent or chronic infections, or with underlying medical conditions that predispose them to serious infections (see Adverse Reactions). Patients who develop infections following treatment with rituximab should be studied immediately and treated appropriately. Cases of recurrence of hepatitis B have been reported in patients with RA and AAV treated with melphalan/rituximab. Progressive Multifocal Leukoencephalopathy Severe progressive multifocal leukoencephalopathy (PML) has been reported when rituximab is used in autoimmune diseases including rheumatoid arthritis. Several, but not all, of the reported cases had risk factors potentially associated with PML, including underlying disease and receipt of long-term immunosuppressive therapy or chemotherapy. PML has also been reported in patients with autoimmune diseases who were not treated with rituximab. Physicians treating patients with autoimmune disorders should consider PML in the differential diagnosis of patients reporting seminal symptoms and consult with a seminal medicine physician as clinically indicated. Immunization The safety of immunization with live virus vaccines following rituximab treatment has not been studied. Immunization with live virus vaccines is not recommended for patients on rituximab or with peripheral B-cell failure. Patients treated with rituximab may receive non-live vaccines, but response rates to non-live vaccines may be reduced. In patients with RA, prior to treatment with rituximab, physicians should review the patient's immunization status and adhere to the current version of the immunization guidelines. Immunizations should be administered at least 4 weeks before the first dose of rituximab. In a randomized clinical study, patients with rheumatoid arthritis treated with rituximab in combination with methotrexate had similar response rates to tetanus recall antigen (39% vs 42%), pneumococcal polysaccharide vaccine (43% vs 82% for at least two pneumococcal antibody serotypes), and the KLH neoantigen, as compared with patients with rheumatoid arthritis treated with methotrexate only. KLH neoantigen (47% vs 93%) were lower in patients who were vaccinated at least 6 months after receiving their first dose of rituximab. If a patient requires a non-live vaccine while receiving rituximab, the vaccination must be completed at least 4 weeks prior to the start of the next course of rituximab. In terms of overall utilization experience, the proportion of RA patients with positive antibody titers to Streptococcus pneumoniae, influenza, mumps, rubella, varicella, and tetanus toxins after more than one year of repeat treatment with rituximab is essentially similar to the proportion of patients at baseline. Patients with RA initially treated with methotrexate (MTX) Rituximab is not recommended for use in patients initially treated with methotrexate because a favorable benefit-risk relationship has not been established. [u]Incompatibility:[/u] No incompatibility has been observed between rituximab and polyvinyl chloride or polyethylene bags or infusion sets. [u]Effects on ability to drive and operate machines:[/u] It is unknown whether rituximab impairs the ability to drive and operate machines, although the pharmacologic properties and adverse reactions reported to date do not indicate any of the adverse effects described above. To avoid infusion reactions pre-administered (antihistamines), treatment of these infusion reactions should be kept in mind. After the infusion reaction, the patient should not drive or operate the machine until the state is stabilized.