Dosing and Administration Guide for ARZERRA Indications ARZERRA (ofatumumab) is indicated: In combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate For the treatment of patients with CLL refractory to fludarabine and alemtuzumab Important Safety Information for ARZERRA WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA. Please see additional Important Safety Information on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, To learn more, please visit http://hcp.novartis.com/products/arzerra.
Welcome Understanding the Difference Between First-Line and FA-Refractory Dosing for ARZERRA (ofatumumab) Table of Contents This guide is designed to be used as a quick reference for the proper dosing of ARZERRA in the treatment of first-line CLL and CLL that is refractory to fludarabine and alemtuzumab (FA). osing for ARZERRA Plus Chlorambucil D for First-Line CLL................... 4 For your convenience, dosing instructions specific to each indication are organized separately: first-line CLL in the first section (page 4) and FA-refractory CLL in the second section (page 8). General information about product handling is covered in the third section (page 14). Premedication........................ 5 Dosing Recommendations............... 4 Infusion Rates........................ 6 osing for ARZERRA for CLL Refractory D to Fludarabine and Alemtuzumab..... 8 Dosing Recommendations............... 8 If you have any questions regarding ARZERRA or would like to schedule an in-service program, please contact Novartis Pharmaceuticals Corporation or visit us at http://hcp.novartis.com/products/arzerra. Premedication........................ 9 Infusion Rates....................... 10 I nfusion Rate Dose Modifications for Infusion Reactions.................. Product Handling.................. 14 Preparation of Solution................ 14 Dilution............................ 14 Administration...................... 15 How Supplied....................... 16 Storage............................ 17 Support and Resources................ 18 Safety ARZERRA can cause serious, including fatal, infusion reactions. Infusion reactions occur more frequently with the first 2 infusions. 2 on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, I ndications and Important Safety Information................ 20 3
Dosing for ARZERRA (ofatumumab) Plus Chlorambucil Treatment should be continued for a minimum of 3 cycles until best response* or a maximum of cycles Cycle 1 Day 1 300 mg Cycles 2 up to Day 8 1000 mg Day 1 of each 28-day cycle 1000 mg Chlorambucil: 10 mg/m2 orally days 1-7 of each 28-day cycle1 Please note: The chlorambucil dosing information seen here was evaluated in the pivotal trial, but is not a recommendation from the Dosage and Administration section of the Prescribing Information2 First-Line CLL Dosing Dosing for ARZERRA Plus Chlorambucil for First-Line CLL1 Premedication1 Patients should receive the following premedication 30 minutes to 2 hours prior to each infusion of ARZERRA Oral acetaminophen 1000 mg (or equivalent) plus Oral or IV antihistamine (diphenhydramine 50 mg or cetirizine 10 mg or equivalent) plus IV corticosteroid (prednisolone 50 mg or equivalent) Corticosteroid may be reduced or omitted for subsequent infusions if a grade 3 or greater infusion-related adverse event did not occur during the first 2 infusions Infusion reactions may occur despite premedication In the pivotal trial1: Median number of cycles completed was 6 Dosing Recommendations1 After Cycle 1, ARZERRA is dosed in 28-day cycles. Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available Dilute according to instructions on page 14 Administer as an intravenous (IV) infusion according to the schedule outlined above Do not administer as an intravenous push or bolus or as a subcutaneous injection Premedicate before each infusion * The pivotal trial defined best response as 2 consecutive response assessments of stable disease, partial response, or complete response.1 4 on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, 5
Dosing for ARZERRA Plus Chlorambucil for First-Line CLL1 Infusion Rates Infusion initiation rates for ARZERRA (ofatumumab) Infusion Initiation Rates Cycle 1, Day 1a (ml/hour) Cycle 1, Day 8b and Cycles 2-c (ml/hour) mg/hour ml/hour Interval After Start of Infusion (min) Cycle 1, Day 1 (300 mg) 3.6 0-30 Cycle 1, Day 8 (1000 mg) 31-60 50 61-90 50 100 Cycles 2 through (1000 mg) Cycle Initiate infusion at a rate of mg/hour if a grade 3 or greater infusion-related adverse event was experienced during the previous infusion In the absence of an infusion-related adverse event, the rate of infusion may be increased every 30 minutes as described in the Infusion Rate Table to the right. Do not exceed the infusion rates in the following Infusion Rate Table Safety Overall, 67% of previously untreated patients experienced one or more symptoms of infusion reactions (10% grade 3, none were fatal). Infusion reactions occurred most frequently during Cycle 1 (56% on Day 1 [6% grade 3] and 23% on Day 8 [3% Grade 3]) and decreased with subsequent infusions. 6 Infusion rates for ARZERRA on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, 91-0 100 200 1-150 200 400 151-180 300 400 >180 400 400 Cycle 1, Day 1=300 mg; median duration of infusion=5.2 hours. a b Cycle 1, Day 8=1000 mg; median duration of infusion=4.4 hours. Cycles 2 through =1000 mg; median durations of infusion= 4.2 to 4.4 hours. c Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/ anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment. 7
Dosing for ARZERRA for CLL Refractory to Fludarabine and Alemtuzumab1 Premedication ARZERRA is administered as infusions over a 24-week period Patients should receive the following premedication 30 minutes to 2 hours prior to each infusion of ARZERRA Weekly Weeks 1-8 Dose 300 mg 1 Doses 2000 mg 2-8 Every 4 Weeks Oral Acetaminophen Weeks, 16, 20, 24 1000 mg or equivalent plus Doses 2000 mg 9- Dosing Recommendations Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available Dilute according to instructions on page 14 Administer as an IV infusion according to the schedule outlined above Do not administer as an IV push or bolus or as a subcutaneous injection Premedicate before each infusion Oral or IV Antihistamine Diphenhydramine 50 mg or cetirizine 10 mg or equivalent plus FA-Refractory CLL Dosing Dosing for ARZERRA (ofatumumab) IV Corticosteroid Prednisolone 100 mg or equivalenta o not reduce corticosteroid dose for Doses 1, 2, D and 9. Corticosteroid dose may be reduced as follows: a Doses 3 through 8: Corticosteroid may be reduced or omitted with subsequent infusions if a grade 3 or greater infusion reaction did not occur with the preceding dose Doses 10 through : Administer prednisolone 50 mg to 100 mg or equivalent if a grade 3 or greater infusion reaction did not occur with Dose 9 Infusion reactions may occur despite premedication In a study of FA-refractory patients (study 2), 88% of patients received at least 8 infusions of ARZERRA and 54% received infusions. 8 on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, 9
Dosing for ARZERRA for CLL Refractory to Fludarabine and Alemtuzumab1 Infusion Rates Infusion initiation rates for ARZERRA (ofatumumab) Infusion rates for ARZERRA mg/hour ml/hour Interval After Start of Infusion (min) Dose 1 (300 mg) 3.6 0-30 Dose 2 (2000 mg) 31-60 50 24 Dose Doses 3 through (2000 mg) Infusion Initiation Rates 50 Initiate infusion at a rate of mg/hour if a grade 3 or greater infusion-related adverse event was experienced during the previous infusion Dose 1a (ml/hour) Dose 2b (ml/hour) Doses 3-b (ml/hour) 61-90 50 50 100 91-0 100 100 200 >0 200 200 400 Dose 1=300 mg; median duration of infusion=6.8 hours. a Doses 2 and 3 through =2000 mg; median duration of infusion for Dose 2=6.8 hours; median durations of infusion for Doses 3 through =4.2 to 4.4 hours. b In the absence of an infusion-related adverse event, the rate of infusion may be increased every 30 minutes as described in the Infusion Rate Table to the right. Do not exceed the infusion rates in the following Infusion Rate Table Safety In FA-refractory CLL patients, infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2000 mg), and less frequently during subsequent infusions. 10 on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, Infusion Reactions (cont d) Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication. 11
Infusion Rate Dose Modifications for Infusion Reactions1 Infusion Rate Dose Modifications Interrupt infusion for infusion reactions of any severity. Treatment can be resumed at the discretion of the treating physician. The following infusion rate modifications can be used as a guide If the infusion reaction resolves or remains less than or equal to grade 2, resume infusion with the following modifications according to the initial grade of the infusion reaction Infuse at one-half of the previous infusion rate Grade 3 or 4: Infuse at a rate of ml/hour Consider permanent discontinuation of ARZERRA (ofatumumab) if the severity of the infusion reaction does not resolve to less than or equal to grade 3 despite adequate clinical intervention Permanently discontinue therapy for patients who develop an anaphylactic reaction to ARZERRA Infusion reactions occur more frequently with the first 2 infusions. Infusion Rate Dose Modifications Grade 1 or 2: After resuming the infusion, the infusion rate may be increased according to the Infusion Rate Tables on pages 6-7 and 10-11 based on patient tolerance Infusion Reactions (cont d) Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, 13
Product Handling1 Preparation of Solution Administration Do not shake product Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. ARZERRA (ofatumumab) should be a clear to opalescent, colorless solution. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present Dilution 300-mg dose: Withdraw and discard 15 ml from a 1000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 5 ml from each of 3 single-use, 100-mg vials of ARZERRA and add to the bag 1000-mg dose*: Withdraw and discard 50 ml from a 1000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 50 ml from 1 single-use, 1000-mg vial of ARZERRA and add to the bag Do not administer as an IV push or bolus or as a subcutaneous injection Do not mix ARZERRA with, or administer as an infusion with, other medicinal products Administer using an infusion pump and an administration set Flush the IV line with 0.9% Sodium Chloride Injection, USP before and after each dose Start infusion within hours of preparation Discard prepared solution after 24 hours 2000-mg dose : Withdraw and discard 100 ml from a 1000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 50 ml from each of 2 single-use, 1000-mg vials of ARZERRA and add to the bag Product Handling Mix diluted solution by gentle inversion No incompatibilities between ARZERRA and polyvinylchloride or polyolefin bags and administration sets have been observed Not actual size. Prepare all doses in 1000 ml of 0.9% Sodium Chloride Injection, USP. *First-line use only. 14 FA-refractory use only. Please see Important Safety Information on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, 15
Product Handling1 How Supplied Carton NDC Number 3 single-use 100-mg/5-mL vials 1 single-use 1000-mg/50-mL vial Vial NDC 0078-0669-61 Carton of 3 vials NDC 0078-0669-13 Vial and carton NDC 0078-0669-84 Dosing Requirements 1 carton of 3 single-use vials (total of 3 vials), are needed for each 300-mg dose 1 carton of 1 single-use vial (total of 1 vial) is needed for each 1000-mg dose 2 cartons of 1 single-use vial (total of 2 vials) are needed for each 2000-mg dose ARZERRA J-Code: J9302 16 Please see Important Safety Information on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, ARZERRA (ofatumumab) is a sterile, clear to opalescent, colorless, preservative-free liquid concentrate (20 mg/ml) for dilution and intravenous administration provided in single-use glass vials with a rubber stopper (not made with natural rubber latex) and an aluminum overseal. Each vial contains either 100 mg of ARZERRA in 5 ml of solution or 1000 mg of ARZERRA in 50 ml of solution. Storage Store the vials and diluted solution of ARZERRA refrigerated between 2 to 8 C (36 to 46 F) Do not freeze Vials should be protected from light Discard prepared solution after 24 hours ARZERRA is not considered a hazardous material, so there are no biohazard requirements. Dispose per usual hospital/clinic procedures 17
Support and Resources Novartis Pharmaceuticals Corporation is committed to providing you with direct access to the resources you and your patients need while treating CLL with ARZERRA (ofatumumab). Contact Information 1-888-NOW-NOVA (1-888-669-6682) Monday-Friday, 8:30 am-5:00 pm ET Customer Interaction Center Novartis Pharmaceuticals Corporation One Health Plaza East Hanover, NJ 07936-1080 18 Please see Important Safety Information on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, Customized Medical Support You can request personalized assistance from an ARZERRA Medical Sciences Liaison by contacting Novartis Pharmaceuticals Corporation directly via the contact information provided at left. Available Now! Information about ARZERRA is available for you at http://hcp.novartis.com/products/arzerra and for your patients at www.us.arzerra.com. 19
Indications and Important Safety Information Indications ARZERRA (ofatumumab) is indicated: In combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate For the treatment of patients with CLL refractory to fludarabine and alemtuzumab Important Safety Information for ARZERRA WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA. Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment. 20 on pages 22 and 23 and accompanying full Prescribing Information, including Boxed WARNING, Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia. If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has occurred in patients treated with ARZERRA. 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 (ie, 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 level 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, ie, increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-hbc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-hbc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least months following completion of therapy. 21 Important Safety Information Administer ARZERRA in an environment where facilities to adequately monitor and treat infusion reactions are available. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Infusion reactions may occur despite premedication.
Indications and Important Safety Information (cont d) Hepatitis B Virus Reactivation (cont d) In patients who develop reactivation of HBV while receiving ARZERRA (ofatumumab), immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation. Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (> x 109/L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. 22 on pages 20 and 21 and accompanying full Prescribing Information, including Boxed WARNING, Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the previously untreated CLL clinical trial, the most common adverse reactions ( 10%, all grades) were infusion reactions (67% for ARZERRA plus chlorambucil vs 0% for chlorambucil) and neutropenia (27% vs 18%). In the single-arm refractory CLL clinical trial, the most common adverse reactions ( 10%, all grades) were neutropenia, pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. Laboratory Abnormalities In the previously untreated CLL clinical trial, post-baseline hematologic laboratory abnormalities (all grades) occurring with 5% incidence in patients receiving ARZERRA plus chlorambucil and also 2% more than patients receiving chlorambucil were leukopenia (67% for ARZERRA plus chlorambucil vs 28% for chlorambucil), neutropenia (66% vs 56%), and lymphopenia (52% vs 20%). References: 1. ARZERRA [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation, 2015. 2. Data on file. GlaxoSmithKline. 2014. 23
More information available at: http://hcp.novartis.com/products/arzerra. Safety ARZERRA (ofatumumab) can cause serious, including fatal, infusion reactions. Infusion reactions occur more frequently with the first 2 infusions. on pages 20-23 and accompanying full Prescribing Information, including Boxed WARNING, Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 2015 Novartis 10/15 ARZ-179