RITUXAN FOR GPA AND MPA EDUCATION GUIDE FOR NURSES

RITUXAN FOR GPA AND MPA EDUCATION GUIDE FOR NURSES Rituxan + GCC is the first and only FDA-approved therapy for GPA and MPA 1 GCC=glucocorticoids. Indication o Rituxan (rituximab), in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener s Granulomatosis) and Microscopic Polyangiitis (MPA) BOXED WARNINGS o Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Monitor patients closely. Discontinue Rituxan infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions. o Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. o Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with Rituxan, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with Rituxan. Discontinue Rituxan and concomitant medications in the event of HBV reactivation. o Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving Rituxan. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients.

RITUXAN FOR GPA AND MPA EDUCATION GUIDE FOR NURSES This comprehensive resource can help you manage Rituxan treatment for your patients GPA and MPA Overview GPA and MPA Overview 3 Learn about what causes GPA and MPA, and how to identify signs and symptoms. Mechanism of Action RAVE Trial Data 7 11 Find out how Rituxan works to target CD20+ B cells. See the efficacy and safety results from the Phase III RAVE Trial. GPA AND MPA OVERVIEW Dosing and Administration 17 Find out how Rituxan is dosed and administered for patients with GPA and MPA. Common Patient Questions 31 Be prepared for common patient questions with this helpful resource. Coverage and Support 39 See what options are available for coverage for and access to Rituxan. 2 3 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information.

WHAT ARE GPA AND MPA? GPA and MPA are two types of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, or AAV 2 o Both of these conditions affect small- and medium-sized blood vessels 2 o ANCAs are a type of autoantibody. ANCAs lead to inflammation that targets and attacks the blood vessel walls in different tissues and organs in the body 3 o ANCAs are usually present in GPA and MPA, but there are times when this is not the case 3 o In general, GPA and MPA affect the kidneys, lungs, skin, and a number of other organs, but the way the diseases present varies 3 The path to diagnosis Because there is no one simple test to diagnose GPA or MPA, it can be a challenging process for your patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 4 5

WHAT ARE GPA AND MPA? Mechanism of Action Common manifestations of GPA and MPA GPA and MPA are diseases characterized by periods of flare and remission. 2 Below are some of the major organs most commonly affected by GPA and MPA, from the most common to less common. The symptoms of these diseases vary widely, so it s important for patients to talk to a doctor about any symptoms they may be experiencing. 4-6 Organ involvement, arranged from most common to less common GPA: Major organs involved MECHANISM OF ACTION Upper respiratory tract (ears, nose, and throat) Lungs Kidneys Eyes Skin Nervous system MPA: Major organs involved Kidneys Nervous system Skin Gastrointestinal tract Lungs Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. 6 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 7 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information.

PATHOGENESIS OF GPA AND MPA B cells are thought to play a role in GPA and MPA by producing the ANCA antibodies 7 ANCA-induced necrotizing vasculitis in GPA and MPA 8 DIFFERENTIATION CD20 ANCA The autoimmune response in GPA and MPA involves several different cell types, including B cells. The interplay of these cells is not fully understood. B cell Plasma cell ANCA-producing cells release ANCAs that are circulated through the bloodstream. ANCA ICAM ß2 integrin Fc receptor MPO/PR3 Superoxide burst 4 3 TNF receptor Neutrophil 1 2 Proinflammatory cytokines 1 2 3 4 Priming of the neutrophils induces PR3 and MPO to the cell surface, where they interact with ANCA in the bloodstream. This interaction promotes firm adherence of neutrophils to endothelial cells. Further neutrophil priming may also induce the release of proteolytic enzymes and reactive oxygen species. ANCA-activated neutrophils promote the inflammatory process and perpetuate the vasculitis process. Because this process can occur throughout the small-sized blood vessels, widespread damage may occur. This process can be particularly detrimental to highly vascular organs, such as the kidneys and lungs. 3,8 ANCA, antineutrophil cytoplasmic antibody; ICAM, intercellular adhesion molecule; MPO, myeloperoxidase; PR3, proteinase 3; TNF, tumor necrosis factor. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 8 9

ABOUT RITUXAN Rituxan is a targeted B-cell therapy used to treat GPA and MPA Rituxan selectively targets the B cells that are thought to be involved in GPA and MPA. 7 Rituxan binds specifically to the CD20 antigen located on pre-b and mature B lymphocytes. 7,9 * Rituxan selectively targets CD20+ B cells RAVE Trial Data RAVE TRIAL DATA * The mechanism of action of Rituxan has been elucidated primarily in preclinical models. Its clinical significance is unknown. Because they lack CD20, stem cells and plasma cells are not selectively targeted by Rituxan. 9 o The role of stem cells is to regenerate B cells for the immune system 10 o The role of plasma cells is to produce antibodies needed during an immune response 10 BOXED WARNINGS: Infusion Reactions o Rituxan administration can result in serious, including fatal infusion reactions o Deaths within 24 hours of Rituxan infusion have occurred o Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Monitor patients closely o Discontinue Rituxan infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. 10 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 11 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information.

RAVE TRIAL DESIGN o The RAVE Trial was a multicenter, randomized, double-blind, double-dummy, noninferiority trial to compare Rituxan (n=99) with CYC (n=98) for the induction of complete remission at 6 months in patients with severe GPA or MPA. Each arm included treatment with GCC 11 The RAVE Trial was conducted by the Immune Tolerance Network and sponsored by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health. Genentech and Biogen also provided funding and study medication 11 o Primary end point of noninferiority was complete remission, which was defined as a BVAS/GPA* of 0 and a complete taper of steroids, at 6 months 7,11 o All patients in the RAVE Trial were eligible for treatment with cyclophosphamide 12 RAVE Trial design: Multicenter, randomized, double blind, double dummy 7,11 Rituxan IV (375 mg/m 2 /wk) x 4 6-MONTH DATA ANALYSIS RITUXAN ARM (n=99) 1-3 IV pulses methylprednisolone (1000 mg each), followed by daily oral prednisone taper (N=197) CROSSOVER PERMITTED IN INDUCTION PHASE Rituxan arm was induction only, whereas control arm was induction + maintenance with AZA CYC FOLLOWED BY AZA ARM (n=98) CYC oral (2 mg/kg daily) followed by AZA at remission daily pills daily pills daily pills daily pills daily pills daily pills AZA daily pills daily pills daily pills daily pills daily pills daily pills daily pills daily pills daily pills daily pills daily pills daily pills 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 MONTHS AZA, azathioprine; BVAS/GPA, Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis; CYC, cyclophosphamide; GCC, glucocorticoids. Adapted from Stone et al N Engl J Med 2010. * The BVAS/GPA is a validated tool that quantifies disease activity based on evidence of active disease in 8 organ systems, an other category, and a physician s global assessment. Disease features are scored only if they are attributed to active vasculitis, as opposed to damage. 13 The crossover design allowed patients who had severe flares during the first 6 months to cross over to the other treatment group in a blinded fashion. CYC dose was adjusted for patients with renal insufficiency. Patients who had a remission between 3 and 6 months were eligible to switch from CYC to AZA. Maintenance therapy continued unless patient experienced relapse. BOXED WARNINGS: Severe Mucocutaneous Reactions o Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan o Discontinue Rituxan in patients who experience a severe mucocutaneous reaction o The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 12 13

RAVE TRIAL DESIGN IN THE RAVE TRIAL, RITUXAN + GCC INDUCED COMPLETE REMISSION FROM GPA AND MPA, WITH STEROID USE TAPERED TO 0 MG RAVE Trial population Key inclusion and exclusion criteria from the RAVE Trial 11,12 Inclusion criteria Diagnosis of GPA or MPA (Chapel Hill criteria) Newly diagnosed or relapsing disease Active disease: BVAS/GPA* 3 Severe disease: 1 major BVAS/GPA item or disease severe enough to require treatment with CYC Positive serum assay for PR3-ANCA or MPO-ANCA Exclusion criteria Limited disease not requiring CYC Mechanical ventilation for alveolar hemorrhage Serum creatinine >4.0 mg/dl CYC use within 4 months before enrollment CYC toxicity Any previous Rituxan use Primary end point of noninferiority was complete remission (defined as BVAS/GPA of 0 and prednisone dose of 0 mg) at 6 months 7,11 o Tertiary end points were complete remission at 12 and 18 months 7 There was no statistically significant difference between the 2 arms 14 No adjustments for multiplicity were made. o Rituxan arm received Rituxan IV (375 mg/m 2 /wk) x 4. CYC followed by AZA arm received CYC oral (2 mg/kg daily) 7 All patients received 1-3 IV pulses methylprednisolone (1000 mg each), followed by daily oral prednisone taper (N=197) Percentage of patients in the RAVE Trial who achieved complete remission CYC, cyclophosphamide; MPO, myeloperoxidase; PR3, proteinase 3. * The Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA). For new or worse disease ranges from 0 to 68, with higher scores indicating more active disease. A BVAS/GPA of 0 indicates remission. 13 Complete remission remission rates rates 6, at 12, 6, 12, and and 18 months 18 months 2,3 7,11,14 Complete Complete remission remission is is defined defined as as BVAS/GPA=0 BVAS/GPA*=0 and and prednisone prednisone dose dose of of 0 0 mg mg 100 PATIENTS REACHING COMPLETE REMISSION, % 80 60 40 20 64 53 44 38 38 Rituxan (n=99) CYC followed by AZA (n=98) 31 0 6 MONTHS 12 MONTHS 18 MONTHS PRIMARY END POINT TERTIARY END POINTS BOXED WARNINGS: Hepatitis B Virus (HBV) Reactivation o HBV reactivation can occur in patients treated with Rituxan, in some cases resulting in fulminant hepatitis, hepatic failure, and death AZA, azathioprine; CYC, cyclophosphamide; GCC, glucocorticoids. * The BVAS/GPA is a validated tool that quantifies disease activity based on evidence of active disease in 8 organ systems, an other category, and a physician s global assessment. Disease features are scored only if they are attributed to active vasculitis, as opposed to damage. 13 o Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with Rituxan o Discontinue Rituxan and concomitant medications in the event of HBV reactivation 14 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. 15

RAVE TRIAL SAFETY DATA No significant difference in overall adverse events occurred between treatment arms at 6 months 11 Incidence of all adverse events occurring in 10% of patients in either treatment arm up to Month 6 7 * Category of adverse events (AEs) Rituxan n=99; n (%) CYC followed by AZA n=98; n (%) Category of AEs Rituxan n=99; n (%) CYC followed by AZA n=98; n (%) Nausea 18 (18) 20 (20) Fatigue 13 (13) 21 (21) Diarrhea 17 (17) 12 (12) Increased ALT 13 (13) 15 (15) Headache 17 (17) 19 (19) Hypertension 12 (12) 5 (5) Muscle spasms 17 (17) 15 (15) Infusion-related reaction 12 (12) 11 (11) Anemia 16 (16) 20 (20) Epistaxis 11 (11) 6 (6) Peripheral edema Insomnia Arthralgia Cough 16 (16) 14 (14) 13 (13) 13 (13) 6 (6) 12 (12) 9 (9) 11 (11) Dyspnea Leukopenia Rash 10 (10) 10 (10) 10 (10) 11 (11) 26 (27) 17 (17) ALT, alanine transaminase; AZA, azathioprine; CYC, cyclophosphamide. * 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. Infusion-related reactions reported in the Rituxan group included cytokine release syndrome, flushing, throat irritation, and tremor. DOSING AND ADMINISTRATION Dosing and Administration BOXED WARNINGS: Progressive Multifocal Leukoencephalopathy (PML) o PML, including fatal PML, can occur in patients receiving Rituxan o Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML 16 Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Please see the Rituxan full Prescribing Information and pages 43-45 17 for BOXED WARNINGS and additional Important Safety Information. 17

RITUXAN DOSING AND ADMINISTRATION Overview o It is recommended that patients be treated with glucocorticoids administered as methylprednisolone prior to their Rituxan infusion to treat severe vasculitis symptoms 7 o The amount of Rituxan infused for patients with GPA and MPA depends on body surface area (BSA) o Rituxan should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur Prior to initiating Rituxan Glucocorticoids administered as methylprednisolone 1000 mg/day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to, or with the initiation of, Rituxan and may continue during and after the 4-week course of Rituxan treatment. 7 Dosing information Rituxan is administered by IV infusion at a dose of 375 mg/m 2 (ie, BSA dosing) once weekly for 4 weeks. 7 Dosing information 7 RITUXAN IV (375 mg/m 2 ) + daily oral prednisone 1 2 3 4 WEEKS Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Select Important Safety Information: Tumor Lysis Syndrome (TLS) o Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12 to 24 hours after the first infusion of Rituxan in patients with Non Hodgkin s Lymphoma (NHL) o Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS o Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 18 19

INFUSION STEPS Rituxan should only be administered by a healthcare professional with appropriate medical support to manage serious infusion-related reactions that can be fatal if they occur. Step 1: Obtain supplies Recommended infusion supplies are listed below. Please follow your office protocol. These items must be purchased separately and may be ordered through your distributor of choice. Please note that vials of Rituxan* must be purchased separately. Step 2: Provide Medication Guide and review with patient MEDICATION GUIDE Rituxan (ri-tuk-san) (rituximab) injection Read this Medication Guide before you start Rituxan and before each Rituxan infusion. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or your treatment. What is the most important information I should know about Rituxan? Rituxan can cause serious side effects that can lead to death, including: Standard IV setups including: Optional equipment: Infusion reactions. Infusion reactions are the most common side effect of Rituxan treatment. Serious infusion reactions can happen during your infusion or within 24 hours after your infusion of Rituxan. Your doctor should give you medicines before your infusion of Rituxan to decrease your chance of having a severe infusion reaction. Tell your doctor or get medical help right away if you get any of these symptoms during or after an infusion of Rituxan: o IV tubing (with roller clamps and a Y-access port) o Tourniquet o Normal saline or 5% dextrose in water (D5W) o Adhesive tape o Syringes and needles o IV start supplies o Clamps o Catheter o Alcohol wipes o IV pump hives (red itchy welts) or rash itching swelling of your lips, tongue, throat or face sudden cough shortness of breath, difficulty breathing, or wheezing weakness dizziness or feel faint palpitations (feel like your heart is racing or fluttering) chest pain Severe skin and mouth reactions. Tell your doctor or get medical help right away if you get any of these symptoms at anytime during your treatment with Rituxan: painful sores or ulcers on your skin, lips or in your mouth blisters peeling skin rash pustules Hepatitis B virus (HBV) reactivation. Before Rituxan treatment, your doctor will do blood tests to check for HBV infection. If you have had hepatitis B or are a carrier of hepatitis B virus, receiving Rituxan could cause the virus to become an active infection again. Hepatitis B reactivation may cause serious liver problems including liver failure, and death. You should not receive Rituxan if you have active hepatitis B liver disease. Your doctor will monitor you for hepatitis B infection during and for several months after you stop receiving Rituxan. Infusion-related reactions are a possibility with the administration of Rituxan. Medications and supportive care measures should always be available during an infusion, including but not limited to: Progressive Multifocal Leukoencephalopathy (PML). PML is a rare, serious brain infection caused by a virus. People with weakened immune systems can get PML. Your chance of getting PML may be higher if you are treated with Rituxan alone or with other medicines that weaken your immune system. PML can result in o IV fluids o Glucocorticoids o Oxygen o Epinephrine o Bronchodilators o Acetaminophen Step 3: o Antihistamines Perform Baseline assessment Infusion training and support is available. Contact your Rheumatology Clinical Coordinator to learn more. * Rituxan vials are stable at 2 C to 8 C (36 F to 46 F). Do not use beyond expiration date stamped on carton. Rituxan vials should be protected from direct sunlight. Do not freeze or shake. Note: One additional item appropriate for Rituxan is a medicine-storage refrigerator. Rituxan solutions for infusion may be stored at 2 C to 8 C (36 F to 46 F) for 24 hours. Rituxan solutions for infusion have been shown to be stable for an additional 24 hours at room temperature; however, since Rituxan solutions do not contain a preservative, diluted solutions should be refrigerated at 2 C to 8 C. Select Important Safety Information: Infections o Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Rituxan-based therapy o Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after Rituxan exposure) o Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy o Rituxan is not recommended for use in patients with severe, active infections Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. Check patient s vitals and record patient Baseline assessment. 20 For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 21

INFUSION STEPS Step 4: Prepare primary saline line 1 2 Step 6: Determine the Rituxan dose needed Rituxan is administered by IV infusion at a dose of 375 mg/m 2 (ie, BSA dosing) once weekly for 4 weeks. 7 Dosing information 7 RITUXAN IV (375 mg/m 2 ) + daily oral prednisone Connect and prime a primary IV infusion set with an IV bag of 0.9% sodium chloride, USP. 3 Prepare IV site and insert IV catheter. Attach the IV tubing to IV catheter. Step 5: Premedication Review the physician s order to determine if premedications are to be administered prior to Rituxan infusion. Recommended premedications are acetaminophen and an antihistamine. o Following methylprednisolone infusions, oral prednisone 1 mg/kg/day is recommended (not to exceed 80 mg/day and tapered per clinical need) 1 2 3 4 WEEKS Calculate BSA of the patient using his or her height and weight o The calculation requires the patient s actual body weight and height, measured within 14 days of administering Rituxan o The formula for calculating BSA in the clinical trial was: BSA in m 2 = (weight in kg) 0.425 x (height in cm) 0.725 x 0.007184 Using the patient s BSA, calculate the weekly Rituxan dose The formula for calculating the weekly Rituxan dose was: o Weekly dose = BSA (m 2 ) x 375 mg o Rituxan should be administered each week for 4 weeks Begin IV infusion of 0.9% sodium chloride, USP. Select Important Safety Information: Cardiovascular Adverse Reactions o Discontinue infusions for serious or life-threatening cardiac arrhythmias 22 Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. o Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina 23

INFUSION STEPS Step 7: Prepare Rituxan solution Administration tip Always use aseptic technique. Follow your institution s protocol for preparing medications for IV infusions. The following steps outline a 4-mg/mL final concentration of Rituxan infusion solution using 250 ml 0.9% normal saline, USP, or D5W, USP. For other concentrations, see the drip-rate chart that follows these administration steps. 3 4 5 1 1a 2 Prepare an IV bag of normal saline or D5W containing the appropriate amount needed to dilute Rituxan to the proper concentration as follows: o Using the mixing tables found on the following pages, refer to the table that corresponds with the desired Rituxan concentration (4 mg/ml, 2 mg/ml, or 1 mg/ml) and locate the row with the patient s BSA o Read across to the diluent volume column to identify the amount of normal saline or D5W that should be left in the IV bag Withdraw and discard the unneeded normal saline or D5W. o This amount will vary according to each patient s BSA, the Rituxan dose, and the desired Rituxan concentration Before use, bring Rituxan vials to room temperature. Remove caps and clean rubber stoppers with alcohol wipes. Read across to the Rituxan volume to withdraw column on the mixing tables to identify the Rituxan volume needed based on the BSA-calculated dose. Carefully withdraw that amount of Rituxan. Gentle air injection or the push-pull method can be used to ease the withdrawal of Rituxan. 6 7 Gently add Rituxan to the IV bag. The final IV bag volume should be equal to the Total infusion volume column on the mixing tables. Remove and dispose of needle and syringe in compliance with hospital and/or office protocol. Select Important Safety Information: Renal Toxicity 24 o Monitor closely for signs of renal failure and discontinue Rituxan in patients with a rising serum creatinine or oliguria Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Gently invert IV bag to mix. Do not shake. Label IV bag with patient s name, drug, dose, and date, and then initial it. Connect an infusion set to the IV bag containing Rituxan. Infuse the total volume of the IV bag. See page 26 for full administration instructions. 25

INFUSION STEPS INFUSION SCHEDULE Step 8: Administer Rituxan to patient, and monitor him or her during infusion First infusion (Day 1) o Begin infusion at rate of 50 mg/h 7 o If an infusion reaction does not occur, escalate the infusion rate in 50-mg/h increments every 30 minutes, to a maximum of 400 mg/h 7 Subsequent infusions (Days 8, 15, and 22) o If the patient tolerated the previous infusion well, begin at a rate of 100 mg/h 7 o If an infusion reaction does not occur, continue to escalate the infusion rate in 100-mg/h increments every 30 minutes, to a maximum of 400 mg/h 7 o Infusion times will vary from patient to patient depending upon the dose administered, which is based on the patient s BSA o Interrupt the infusion or slow the infusion rate for infusion reactions (see BOXED WARNINGS). Continue the infusion at one-half the previous rate upon improvement of symptoms 7 CAUTION: DO NOT ADMINISTER RITUXAN AS AN IV PUSH OR BOLUS. o Rituxan should not be infused concomitantly in the same line with other medications o Rituxan can be administered via a drip method or using a pump and a 1- or 2-infusion bag method o Optional 2-bag method: Administer Rituxan using 2 lines as follows: Establish a primary IV line with saline, without medication, to maintain vein patency. This line can also serve as a means of administering additional fluids or medications should it become necessary Prime Rituxan into a second primary IV line and connect to the lowest port (closest to the patient) of the saline line Clamp/interrupt the primary saline line to begin administration of the Rituxan solution PCP prophylaxis Pneumocystis jiroveci pneumonia (PCP) prophylaxis is also recommended for patients with GPA or MPA during treatment and for at least 6 months following the last Rituxan infusion. Select Important Safety Information: Bowel Obstruction and Perforation o Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy 26 Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 27

RITUXAN FOR GPA AND MPA: MIXING TABLES 28 These tables are provided for example and are not a substitute for medical judgment 4 2 mg/ml 1 mg/ml TO DELIVER 375 mg/m 2 AT A CONCENTRATION OF 4 mg/ml OF RITUXAN BSA (m 2 ) Rituxan Rituxan Diluent Total dose volume volume infusion (mg) (ml*) + (ml) = volume (ml) 1.3 488 49 74 123 1.4 525 53 80 133 1.5 563 56 84 140 1.6 600 60 90 150 1.7 638 64 96 160 1.8 675 68 102 170 1.9 713 71 107 178 2.0 750 75 113 188 2.1 788 79 119 198 2.2 825 83 125 208 2.3 863 86 130 216 2.4 900 90 135 225 2.5 938 94 141 235 2.6 975 98 147 245 2.7 1013 101 152 253 2.8 1050 105 158 263 2.9 1088 109 164 273 3.0 1125 113 169 282 3.1 1163 116 175 291 3.2 1200 120 180 300 3.3 1238 124 186 310 TO DELIVER 375 mg/m 2 AT A CONCENTRATION OF 1 mg/ml OF RITUXAN BSA (m 2 ) Rituxan dose (mg) Rituxan volume (ml*) Diluent volume (ml) Total infusion volume (ml) 1.3 488 49 441 490 1.4 525 53 477 530 1.5 563 56 504 560 1.6 600 60 540 600 1.7 638 64 576 640 1.8 675 68 612 680 1.9 713 71 639 710 2.0 750 75 675 750 2.1 788 79 711 790 2.2 825 83 747 830 2.3 863 86 777 863 2.4 900 90 810 900 2.5 938 94 844 938 2.6 975 98 877 975 2.7 1013 101 912 1013 2.8 1050 105 945 1050 2.9 1088 109 979 1088 3.0 1125 113 1012 1125 3.1 1163 116 1047 1163 3.2 1200 120 1080 1200 3.3 1238 124 1114 1238 + mg/ml * For ease of reconstitution, some numbers have been rounded. Normal saline or D5W. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. = TO DELIVER 375 mg/m 2 AT A CONCENTRATION OF 2 mg/ml OF RITUXAN BSA (m 2 ) Select Important Safety Information: Immunization o The safety of immunization with live viral vaccines following Rituxan therapy has not been studied, and vaccination with live vaccines is not recommended before or during treatment Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Rituxan dose (mg) Rituxan volume (ml*) Diluent volume (ml) Total infusion volume (ml) 1.3 488 49 196 245 1.4 525 53 212 265 1.5 563 56 224 280 1.6 600 60 240 300 1.7 638 64 256 320 1.8 675 68 272 340 1.9 713 71 284 355 2.0 750 75 300 375 2.1 788 79 316 395 2.2 825 83 332 415 2.3 863 86 346 432 2.4 900 90 360 450 2.5 938 94 375 469 2.6 975 98 390 488 2.7 1013 101 406 507 2.8 1050 105 420 525 2.9 1088 109 435 544 3.0 1125 113 450 563 3.1 1163 116 466 582 3.2 1200 120 480 600 3.3 1238 124 495 619 + = Rituxan for GPA and MPA: infusion drip rates IF YOUR DESIRED mg/h IS: DROPS PER MINUTE BASED ON A TUBE WITH A DELIVERY RATE OF: 10 DROPS/mL 15 DROPS/mL 20 DROPS/mL 60 DROPS/mL FINAL DESIRED RITUXAN CONCENTRATION: 4 mg/ml 50 2 3 4 13 13 100 4 6 8 25 25 150 6 9 13 38 38 200 8 13 17 50 50 250 10 16 21 63 63 300 13 19 25 75 75 350 15 22 29 88 88 400 17 25 33 100 100 FINAL DESIRED RITUXAN CONCENTRATION: 2 mg/ml 50 4 6 8 25 25 100 8 13 17 50 50 150 13 19 25 75 75 200 17 25 33 100 100 250 21 31 42 125 125 300 25 38 50 150 150 350 29 44 58 175 175 400 33 50 67 200 200 FINAL DESIRED RITUXAN CONCENTRATION: 1 mg/ml USING AN INFUSION PUMP, YOUR ml/h SHOULD BE: 50 8 13 17 50 50 100 17 25 33 100 100 150 25 38 50 150 150 200 33 50 67 200 200 250 42 63 83 250 250 300 50 75 100 300 300 350 58 88 117 350 350 400 67 100 133 400 400 29

RITUXAN DOSING AND ADMINISTRATION Summary of how to calculate dosage in GPA and MPA Step 1: Calculate BSA of the patient using his or her height and weight o The calculation requires the patient s actual body weight and height, measured within 14 days before administering Rituxan o The formula for calculating BSA in the clinical trial was: BSA in m 2 = (weight in kg) 0.425 x (height in cm) 0.725 x 0.007184 Step 2: Using the patient s BSA, calculate the weekly Rituxan dose with the following formula o Weekly dose = BSA (m 2 ) x 375 mg Step 3: Rituxan should be administered once each week for 4 weeks o Following methylprednisolone infusions, oral prednisone 1 mg/kg/day is recommended (not to exceed 80 mg/day and tapered per clinical need) 7 PCP prophylaxis is also recommended for patients with GPA or MPA during treatment and for at least 6 months following the last Rituxan infusion. 7 Select Important Safety Information: Embryo-Fetal Toxicity o Rituxan can cause fetal harm due to B-cell lymphocytopenia in infants exposed to Rituxan in-utero o Advise pregnant women of the risk to a fetus o Females of childbearing potential should use effective contraception while receiving Rituxan and for 12 months following the last dose of Rituxan COMMON PATIENT QUESTIONS Common Patient Questions Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. 30 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 31 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information.

TALKING WITH YOUR PATIENTS Talking with your patients about GPA, MPA, and Rituxan The following questions and answers can help you talk about GPA, MPA, and Rituxan with your GPA and MPA patients and help answer any questions or concerns they may have. What are GPA and MPA? GPA and MPA are two types of ANCA-associated vasculitis (AAV). 2 AAV is a form of vasculitis that primarily affects the small- and medium-sized blood vessels in your body. 2 In general, GPA and MPA affect the kidneys, lungs, and skin, but the way the diseases show themselves varies. 3 What causes AAV, which includes GPA and MPA? AAV, which includes GPA and MPA, is caused by a type of inflammation associated with autoantibodies. 2 Regular antibodies exist in the blood and are produced by the immune system to fight germs. An autoantibody is an antibody that acts against the body s own tissues and cells. ANCAs are a type of autoantibody. ANCAs lead to inflammation that targets and attacks the blood vessel walls in different tissues and organs in the body. 3 ANCAs are usually present in these conditions, but there are times when this is not the case. 3 Your doctor or nurse practitioner may perform a blood test to look for ANCAs and a variety of other tests to diagnose GPA and MPA. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. BOXED WARNINGS: Infusion Reactions o Rituxan administration can result in serious, including fatal infusion reactions o Deaths within 24 hours of Rituxan infusion have occurred o Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Monitor patients closely o Discontinue Rituxan infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 32 33

FREQUENTLY ASKED QUESTIONS What is Rituxan? Rituxan, in combination with glucocorticoids, is the only FDA-approved therapy to treat adults with GPA (Wegener s granulomatosis) and MPA. 1 It is not known if Rituxan is safe or effective in children. 7 Rituxan only targets a specific type of white blood cell found in the immune system. These cells are known as CD20+ B cells and are thought to be involved in GPA and MPA. Rituxan targets these cells and reduces their levels in the body. 7 How is Rituxan thought to work? Rituxan selectively targets a specific type of white blood cell in the immune system. These cells are called B cells, and they are thought to be involved in GPA and MPA. It is important to note that Rituxan targets only certain B cells that have a marker on their surface called CD20. 7,9 Here is more information for you to refer to when explaining to your patients that Rituxan targets only certain B cells.* How can Rituxan help people with GPA or MPA? The RAVE Trial was conducted by the National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network with support from Genentech and Biogen. The goal of the trial was to see if Rituxan, in combination with glucocorticoids, worked as well as cyclophosphamide (CYC) with azathioprine (AZA) (the control group) in bringing on complete remission at 6 months in adults with GPA and MPA. 11 The goal was met at 6 months (64% of Rituxan group, 53% of control group). 11 Also in the study, there was no significant difference in the rates of remission at 6, 12, or 18 months for patients treated with Rituxan compared to patients who received CYC followed by AZA (38% for Rituxan group and 31% for the control group). 7 The study also showed that there were no major differences between the overall side effects experienced by each group. 11 In this clinical trial, complete remission was defined as no disease activity and being able to stop steroids by 6 months. Individual results may vary for each patient. 11 How is Rituxan given? Rituxan is given as an IV infusion once weekly for 4 weeks. 7 An IV infusion is given to you through a needle that s placed in a vein. *The mechanism of action of Rituxan has been elucidated primarily in preclinical models. Its clinical significance is unknown. Important safety considerations When considering any treatment, it s important for patients to understand the potential risks and benefits, and to weigh them with their healthcare providers. More information about the risks associated with Rituxan can be found in the Medication Guide. What can I expect with Rituxan infusions? Your first Rituxan infusion may take 3 to 5 hours. The exact duration varies for each patient based on the Rituxan dose you receive. The first Rituxan infusion is given at a slower rate than following infusions in order to closely monitor for the occurrence of any infusion reactions. Rituxan can cause serious, including fatal, infusion reactions. If symptoms do occur, they are more likely to happen during the first infusion than during following infusions. To help manage reactions, the infusion is slowed or stopped. It is important that you inform your nurse or doctor if you experience any side effects after your Rituxan infusion. BOXED WARNINGS: Severe Mucocutaneous Reactions o Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan o Discontinue Rituxan in patients who experience a severe mucocutaneous reaction o The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined 34 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. 35

FREQUENTLY ASKED QUESTIONS What is the most important information I should know about Rituxan? When starting a treatment, there are many important factors to understand, consider, and discuss with your doctor or nurse practitioner, including the potential risks and benefits. The FDA-approved Rituxan safety information includes the risk of some potentially serious and life-threatening side effects. With Rituxan, they include the following: o Infusion reactions are very common side effects of Rituxan treatment. Serious infusion reactions can happen during your infusion or within 24 hours after your infusion of Rituxan. Your healthcare provider should give you medicines before your infusion of Rituxan to decrease your chance of having a severe infusion reaction o Severe skin and mouth reactions: Tell your healthcare provider or get medical help right away if you get any of these symptoms at any time during your treatment with Rituxan: painful sores or ulcers on your skin, lips, or in your mouth; blisters; peeling skin; rash; or pustules o Hepatitis B virus (HBV) reactivation: If you have had hepatitis B or are a carrier of hepatitis B virus, receiving Rituxan could cause the virus to become an active infection again. Hepatitis B reactivation may cause serious liver problems, including liver failure and death. You should not receive Rituxan if you have active hepatitis B liver disease. Your healthcare provider will monitor you for hepatitis B infection during and for several months after you stop receiving Rituxan o Progressive multifocal leukoencephalopathy (PML): PML is a rare, serious brain infection caused by a virus that can happen in people who receive Rituxan. People with weakened immune systems can get PML. PML can result in death or severe disability. There is no known treatment, prevention, or cure for PML What are common side effects during treatment with Rituxan? o infusion-related reactions o infections (may include fever, chills) o body aches o tiredness o nausea In patients with GPA or MPA, the most common side effects of Rituxan also include: o low white and red blood cells o swelling o diarrhea o muscle spasms Other side effects include: o Aching joints during or within hours of receiving an infusion o More frequent upper respiratory tract infections 36 What are the possible side effects of Rituxan? Rituxan can cause serious life-threatening side effects, including: o Tumor lysis syndrome (TLS): TLS is caused by the fast breakdown of cancer cells. TLS can cause you to have kidney failure and the need for dialysis treatment or an abnormal heart rhythm. TLS can happen within 12-24 hours after an infusion of Rituxan. Tell your healthcare provider right away if you have any of the following signs or symptoms of TLS: nausea, vomiting, diarrhea, or lack of energy o Serious infections: Serious infections can happen during and after treatment with Rituxan and can lead to death. Rituxan can increase your risk of getting infections and can lower the ability of your immune system to fight infections. People with serious infections should not receive Rituxan o Heart problems: Rituxan may cause chest pain, irregular heartbeats, and heart attack. Your healthcare provider may monitor your heart during and after treatment with Rituxan if you have symptoms of heart problems or have a history of heart problems. Tell your healthcare provider right away if you have chest pain or irregular heartbeats during treatment with Rituxan o Kidney problems: especially if you are receiving Rituxan for non Hodgkin s lymphoma (NHL). Rituxan can cause severe kidney problems that lead to death. Your healthcare provider should do blood tests to check how well your kidneys are working o Stomach and serious bowel problems that can sometimes lead to death: Bowel problems, including blockage or tears in the bowel, can happen if you receive Rituxan with chemotherapy medicines. Tell your healthcare provider right away if you have any stomach-area pain during treatment with Rituxan Rituxan HCP Web site Find clinical data, safety information, and downloadable patient information at this comprehensive Web site for healthcare professionals: RituxanForGPAMPA-HCP.com. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. When may I see results and how long could they last? The RAVE Trial was conducted by the National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network with support from Genentech and Biogen. The goal of the trial was to see if Rituxan, in combination with glucocorticoids, worked as well as cyclophosphamide (CYC) with azathioprine (AZA) (the control group) in bringing on complete remission at 6 months in adults with GPA and MPA. 11 In this clinical trial, complete remission was defined as no disease activity and being able to stop steroids by 6 months. 11 In the RAVE Study, 64% of people taking Rituxan and glucocorticoids achieved complete remission at 6 months compared with 53% of people taking CYC + AZA. 11,14 Also in the study, there was no significant difference in the rates of remission at 6, 12, or 18 months for patients treated with Rituxan compared to patients who received CYC followed by AZA (38% for Rituxan group and 31% for the control group). 7 Talk with your doctor or nurse practitioner about how long results may last and to see if Rituxan may be right for you. Keep in mind, individual results may vary. Can I be treated with Rituxan again? Limited data are available on the safety and efficacy of subsequent courses of Rituxan in patients with GPA and MPA. The safety and efficacy of retreatment with Rituxan have not been established. 7 BOXED WARNINGS: Hepatitis B Virus (HBV) Reactivation o HBV reactivation can occur in patients treated with Rituxan, in some cases resulting in fulminant hepatitis, hepatic failure, and death o Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with Rituxan o Discontinue Rituxan and concomitant medications in the event of HBV reactivation Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. 37

COVERAGE AND SUPPORT 38 39 Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Coverage and Support

COVERAGE AND ACCESS More than 95% of plans covered Rituxan for GPA and MPA after appropriate plan requirements were met* * Based on 100 plans (48% of covered total commercial lives, 50% of covered Managed Medicare lives, 40% of Managed Medicaid lives, and 70% of State Medicaid lives). Includes national and regional plans. Some local plans not included. Please see your representative for additional details. This description is provided for informational purposes only. This does not account for prior authorizations or additional medical criteria. The completion and submission of coverage- or reimbursement-related documentation are the responsibility of the patient and health care provider. Genentech, Inc. and Biogen make no representation or guarantee concerning coverage or reimbursement for any service or item. Multiple programs available to help patients prescribed Rituxan COMMERCIALLY INSURED PATIENTS PUBLICLY INSURED PATIENTS UNINSURED PATIENTS REFERRALS TO PATIENT SUPPORT FOR RITUXAN RITUXAN IMMUNOLOGY CO-PAY CARD PROGRAM GENENTECH RHEUMATOLOGY ACCESS SOLUTIONS REFERRALS TO PATIENT ASSISTANCE INDEPENDENT CO-PAY ASSISTANCE FOUNDATIONS GENENTECH ACCESS TO CARE FOUNDATION (GATCF) To be eligible for the Rituxan Immunology Co-pay Card Program, patients must not have public insurance and must meet other criteria. Genentech does not influence or control the operations or eligibility criteria of any independent co-pay assistance foundation and cannot guarantee co-pay assistance after a referral from Genentech Rheumatology Access Solutions. The foundations to which we refer patients are not exhaustive or indicative of Genentech s endorsement or financial support. There may be other foundations to support the patient s disease state. To be eligible for free medicine from GATCF, insured patients must have exhausted all other forms of patient assistance (including the Rituxan Immunology Co-pay Card Program and support from independent co-pay assistance foundations) and meet additional criteria. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 40 41

ADDITIONAL PATIENT SUPPORT BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION Eligible commercially insured patients pay per drug co-pay $5 under the Rituxan Immunology Co-pay Card Program Eligible commercially insured patients receive up to $15,000 per 12-month period. They pay $5 per drug co-pay until the $15,000 limit is reached. It is not a benefit plan and may only be used to purchase Rituxan when prescribed for an FDA-approved indication. Please visit RACopay.com for complete program terms and conditions. If a patient does not qualify for the Rituxan Immunology Co-pay Card Program, Genentech Rheumatology Access Solutions may be able to help. In order to qualify for the benefits of the Rituxan Immunology Co-pay Card, the patient may be required to pay certain out-of-pocket expenses for each treatment. Patients must also be taking the medication for a Food and Drug Administration (FDA)-approved indication. Patients using Medicare, Medicaid, or any other government-funded program to pay for their medications are not eligible. Patients who start utilizing their government coverage during their enrollment period will no longer be eligible for the program. Once enrolled, this Co-pay Card Program will not honor claims with date of service or medication dispensing that precede program enrollment by more than 120 days. Participating patients, pharmacies, physician offices, and hospitals are responsible for reporting the receipt of all Co-pay Card benefits or reimbursement received to any insurer, health plan, or other third party who pays for or reimburses any part of the prescription filled using the Co-pay Card Program. This card is not health insurance or a benefit plan. The patient or their guardian must be 18 years or older to receive Co-pay Card benefits. This Co-pay Card Program is void if the card is reproduced and where prohibited by law. It is only valid for Genentech products and only valid in the U.S. and Puerto Rico. This program is not valid where prohibited by law, and shall follow state restrictions in relation to AB-rated generic equivalents where applicable (e.g. MA, CA). Program duration is contingent upon patient s ability to meet and maintain all eligibility requirements set forth by the program. Genentech, Inc., reserves the right to rescind, revoke, or amend the program without notice at any time. Patient, guardian, pharmacist, prescriber, and any other person using the Co-pay Card agree not to seek reimbursement for all or any part of the benefit received by the recipient through the offer. Additional terms and conditions apply. Please visit https://racopay.com/rituxan-copay-card-eligibility for the full list of terms and conditions. The Rituxan Prepaid MasterCard is issued by The Bancorp Bank pursuant to license by MasterCard International Incorporated. The Bancorp Bank; Member FDIC. This card may not be used everywhere Debit MasterCard is accepted. No cash or ATM access. MasterCard is a registered trademark of MasterCard International Incorporated. Get reliable and effective support from Genentech Rheumatology Access Solutions Genentech Rheumatology Access Solutions provides reliable, effective access and reimbursement services to assist your patients and practices after Rituxan has been prescribed. Call (866) 681-3261 or visit Genentech-Access.com/Rituxan-GPA-MPA for assistance and additional information. BOXED WARNINGS Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Monitor patients closely. Discontinue Rituxan infusion for severe reactions and provide medical treatment for Grade 3 or 4 infusion reactions. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. Hepatitis B Virus (HBV) Reactivation: HBV reactivation can occur in patients treated with Rituxan, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with Rituxan. Discontinue Rituxan and concomitant medications in the event of HBV reactivation. Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving Rituxan. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. Warnings and Precautions Tumor Lysis Syndrome (TLS): Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of Rituxan in patients with Non Hodgkin s Lymphoma (NHL). Administer aggressive intravenous hydration and antihyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis, as indicated. Infections: Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Rituxan-based therapy. Discontinue Rituxan for serious infections and institute appropriate antiinfective therapy. Rituxan is not recommended for use in patients with severe, active infections. Cardiovascular Adverse Reactions: Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. Renal Toxicity: Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with Non Hodgkin s Lymphoma (NHL). Monitor closely for signs of renal failure and discontinue Rituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation: Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur. Immunization: The safety of immunization with live viral vaccines following Rituxan therapy has not been studied, and vaccination with live vaccines is not recommended before or during treatment. 42 Attention Healthcare Provider: Provide Medication Guide to patient prior to Rituxan infusion. For healthcare professional use only. Not to be distributed to patients. Please see the Rituxan full Prescribing Information and pages 43-45 for BOXED WARNINGS and additional Important Safety Information. 43

BOXED WARNINGS AND ADDITIONAL IMPORTANT SAFETY INFORMATION Warnings and Precautions (Cont d) Embryo-Fetal Toxicity: Rituxan can cause fetal harm due to B-cell lymphocytopenia in infants exposed to Rituxan in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving Rituxan and for 12 months following the last dose of Rituxan. Concomitant Use With Biologic Agents and DMARDs Other Than Methotrexate: Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with Rituxan. Retreatment in Patients with Granulomatosis With Polyangiitis (GPA) and Microscopic Polyangiitis (MPA): Limited data are available on the safety and efficacy of subsequent courses of Rituxan in patients with GPA and MPA. The safety and efficacy of retreatment with Rituxan have not been established. Adverse Reactions Clinical Trials Experience in GPA and MPA Adverse reactions reported in 15% of Rituxantreated patients vs cyclophosphamide-treated patients were infections (62% vs 47%), nausea (18% vs 20%), diarrhea (17% vs 12%), headache (17% vs 19%), muscle spasms (17% vs 15%), anemia (16% vs 20%), and peripheral edema (16% vs 6%), respectively. Infusion Reactions: In the active-controlled, double-blind study, 12% vs 11% (Rituxan-treated vs cyclophosphamide) of patients experienced at least one infusion-related reaction. Infusionrelated 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 premedicated 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, doubleblind study, 62% vs 47% (Rituxan-treated vs cyclophosphamide-treated, respectively) of patients experienced an infection 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% vs 10% (Rituxan-treated vs cyclophosphamide, respectively), with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia. Hypogammaglobulinemia: Hypogammaglobulinemia (IgA, IgG, or IgM below the lower limit of normal) has been observed in patients with GPA and MPA treated with Rituxan. At 6 months, in the Rituxan group, 27%, 58%, and 51% of patients with normal immunoglobulin levels at baseline had low IgA, IgG, and IgM levels, respectively, compared to 25%, 50%, and 46% in cyclophosphamide group. Adverse Reactions (Cont d) Immunogenicity A total of 23/99 (23%) Rituxan-treated patients with GPA or MPA tested positive for antirituximab antibodies by 18 months. The clinical relevance of anti-rituximab antibody formation in Rituxan-treated patients is unclear. You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. For additional Important Safety Information, please see the Rituxan full Prescribing Information, including BOXED WARNINGS. 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Anti-neutrophil cytoplasmic antibody pathogenesis in small-vessel vasculitis: an update. Am J Pathol. 2009;175(5):1790-1798. 9. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders. Arthritis Rheum. 2003;48(6):1484-1492. 10. Wols HAM. Plasma cells. In: Encyclopedia of Life Sciences. Hoboken, NJ: John Wiley & Sons Inc; 2005. 11. Stone JH, Merkel PA, Spiera R, et al; for RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. 12. Stone JH, Merkel PA, Spiera R, et al; for RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis [supplemental appendix]. N Engl J Med. 2010;363(3):221-232. 13. Stone JH, Hoffman GS, Merkel PA, et al; for International Network for the Study of the Systemic Vasculitides (INSSYS). A disease-specific activity index for Wegener s granulomatosis: modification of the Birmingham Vasculitis Activity Score. Arthritis Rheum. 2001;44(4):912-920. 14. 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