Truxima

1 INDICATIONS AND USAGE TRUXIMA (rituximab-abbs) is a CD20-directed cytolytic antibody indicated for the treatment of adult patients with: Non-Hodgkin's Lymphoma (NHL) ( 1.1 ). Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent. Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens. Chronic Lymphocytic Leukemia (CLL) ( 1.2 ). Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC). Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies ( 1.3 ). Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) in adult patients in combination with glucocorticoids ( 1.4 ). Moderate to severe Pemphigus Vulgaris (PV) in adult patients ( 1.5 ) 1.1 Non–Hodgkin's Lymphoma (NHL) TRUXIMA (rituximab-abbs) is indicated for the treatment of adult patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent. Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. 1.2 Chronic Lymphocytic Leukemia (CLL) TRUXIMA is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL. 1.3 Rheumatoid Arthritis (RA) TRUXIMA, in combination with methotrexate, is indicated for the treatment of adult patients with moderately-to-severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies. 1.4 Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) TRUXIMA, in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA). 1.5 Pemphigus Vulgaris (PV) TRUXIMA is indicated for the treatment of adult patients with moderate to severe pemphigus vulgaris.

2 DOSAGE AND ADMINISTRATION Administer only as an intravenous infusion ( 2.1 ). Do not administer as an intravenous push or bolus ( 2.1 ). TRUXIMA should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur( 2.1 ). The dose for NHL is 375 mg/m 2 ( 2.2 ). The dose for CLL is 375 mg/m 2 in the first cycle and 500 mg/m 2 in cycles 2-6, in combination with FC, administered every 28 days ( 2.3 ). The dose as a component of Zevalin ® (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m 2 ( 2.4 ). The dose for RA in combination with methotrexate is two-1000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion ( 2.5 ). The induction dose for adult patients with active GPA and MPA in combination with glucocorticoids is 375 mg/m2 once weekly for 4 weeks. The follow up dose for adult patients with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation ( 2.6 ). The dose for PV is two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. Dose upon relapse is a 1,000 mg intravenous infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusions may be no sooner than 16 weeks after the previous infusion ( 2.7 ). Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion ( 2.8 ). 2.1 Important Dosing Information Administer only as an Intravenous Infusion [ see Dosage and Administration (2.8) ]. Do not administer as an intravenous push or bolus. TRUXIMA should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur [see Warnings and Precautions (5.1) ] . Premedicate before each infusion [ see Dosage and Administration (2.8) ]. Prior to First Infusion: Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with TRUXIMA [see Warnings and Precautions (5.3) ] . Obtain complete blood counts (CBC) including platelets prior to the first dose. During TRUXIMA Therapy: In patients with lymphoid malignancies, during treatment with TRUXIMA monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each TRUXIMA course. During treatment with TRUXIMA and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias [ see Adverse Reactions (6.1) ] . In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at two to four month intervals during TRUXIMA therapy. Continue to monitor for cytopenias after final dose and until resolution. First Infusion : Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Subsequent Infusions : Standard Infusion: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr. For previously untreated follicular NHL and DLBCL patients : If patients did not experience a Grade 3 or 4 infusion related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen. I…

5 WARNINGS AND PRECAUTIONS Tumor lysis syndrome: Administer aggressive intravenous hydration, anti-hyperuricemic agents, monitor renal function ( 5.5 ). Infections: Withhold TRUXIMA and institute appropriate anti-infective therapy ( 5.6 ). Cardiac adverse reactions: Discontinue infusions in case of serious or life-threatening events ( 5.7 ). Renal toxicity: Discontinue in patients with rising serum creatinine or oliguria ( 5.8 ). Bowel obstruction and perforation: Consider and evaluate for abdominal pain, vomiting, or related symptoms ( 5.9 ). Immunizations: Live virus vaccinations prior to or during TRUXIMA treatment not recommended ( 5.10 ). Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception ( 5.11 ). 5.1 Infusion-Related Reactions Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes. Rituximab product-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA, GPA and MPA, and PV patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue TRUXIMA. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (greater than or equal to 25,000/mm3) [see Warnings and Precautions (5.7) , Adverse Reactions (6.1) ]. 5.2 Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. Discontinue TRUXIMA in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined. 5.3 Hepatitis B Virus Reactivation (HBV) Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatme…

4 CONTRAINDICATIONS None. None ( 4 )

7 DRUG INTERACTIONS Formal drug interaction studies have not been performed with rituximab products. In patients with CLL, rituximab did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab. Renal toxicity when used in combination with cisplatin ( 5.8 ).

8.1 Pregnancy Risk Summary Based on human data, rituximab products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to in-utero [ see Clinical Considerations ] . In animal reproduction studies, intravenous administration of rituximab to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B-cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Advise pregnant women of the risk to a fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated populations is unknown. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies. Clinical Considerations Fetal/Neonatal Adverse Reactions Observe newborns and infants for signs of infection and manage accordingly. Data Human data Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Animal Data An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells. A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero. Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Infusion-related reactions [ see Warnings and Precautions (5.1) ] Severe mucocutaneous reactions [ see Warnings and Precautions (5.2) ] Hepatitis B reactivation with fulminant hepatitis [ see Warnings and Precautions (5.3) ] Progressive multifocal leukoencephalopathy [ see Warnings and Precautions (5.4) ] Tumor lysis syndrome [ see Warnings and Precautions (5.5) ] Infections [ see Warnings and Precautions (5.6) ] Cardiovascular adverse reactions [ see Warnings and Precautions (5.7) ] Renal toxicity [ see Warnings and Precautions (5.8) ] Bowel obstruction and perforation [ see Warnings and Precautions (5.9) ] Most common adverse reactions in clinical trials were: NHL (greater than or equal to 25%): infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia ( 6.1 ). CLL (greater than or equal to 25%): infusion-related reactions and neutropenia ( 6.1 ). RA (greater than or equal to 10%): upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis (other important adverse reactions include infusion-related reactions, serious infections, and cardiovascular events) ( 6.1 ). GPA and MPA (greater than or equal to 15 %): infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, infusion-related reactions ( 6.1 ). PV (greater than or equal to 15%): infusion-related reactions, depression, upper respiratory tract infection/nasopharyngitis, headache (other important adverse reactions include infections) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact TEVA Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 clinical practice. B-Cell Malignancies The data described below reflect exposure to rituximab in 3,092 patients, with exposures ranging from a single infusion up to 2 years. Rituximab was studied in both single-arm and controlled trials (n=356 and n=2,427). The population included 1180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, 676 patients with CLL, and 309 patients with another indication. Most NHL patients received rituximab as an infusion of 375 mg/m 2 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 rituximab 375 mg/m 2 as an initial infusion followed by 500 mg/m 2 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 rituximab-based therapy. The most common adverse reactions of rituximab (incidence ≥25%) observed in clinical trials of patients with NHL were infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia. The most common adverse reactions of rituximab (incidence ≥25%) observed in clinical trials of patients with CLL were: infusion-related reactions and neutropenia. Infusion-Related Reactions In the majority of patients with NHL, infusion-related reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first rituximab infusion. Infusion-related reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the rituximab infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion-related reactions was highest duri…