Label: GAZYVA- obinutuzumab injection, solution, concentrate

  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Biologic Licensing Application

Drug Label Information

Updated 12/14

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  • BOXED WARNING(What is this?)

    WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

    • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)].
    • Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)].
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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use GAZYVA safely and effectively. See full prescribing information for GAZYVA.

    GAZYVA ® (obinutuzumab)
    Injection, for intravenous infusion
    Initial U.S. Approval: 2013

    WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

    See full prescribing information for complete boxed warning.

    • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death. (5.1)
    • Progressive Multifocal Leukoencephalopathy (PML) resulting in death. (5.2)

    RECENT MAJOR CHANGES

    Dosage and Administration, Recommended Dosage Regimen (2.1) 12/2014
    Warnings and Precautions (5.3, 5.5, 5.6, 5.7) 12/2014
    Warnings and Precautions, Thrombocytopenia (5.7) 6/2014

    INDICATIONS AND USAGE

    GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia. (1, 14)

    DOSAGE AND ADMINISTRATION

    • Premedicate with glucocorticoid, acetaminophen, and anti-histamine. (2.2)
    • Dilute and administer as intravenous infusion. Do not administer as an intravenous push or bolus. (2.1)
    • Recommended dose for 6 cycles (28-day cycles):
      • 100 mg on day 1 Cycle 1
      • 900 mg on day 2 Cycle 1
      • 1000 mg on day 8 and 15 of Cycle 1
      • 1000 mg on day 1 of Cycles 2–6 (2.1)

    DOSAGE FORMS AND STRENGTHS

    • 1000 mg/40 mL (25 mg/mL) single-use vial. (3)

    CONTRAINDICATIONS

    None. (4)

    WARNINGS AND PRECAUTIONS

    • Infusion reactions: Premedicate patients with glucocorticoid, acetaminophen, and anti-histamine. Monitor patients closely during infusions. Interrupt or discontinue infusion for reactions. (2.2, 5.3)
    • Tumor Lysis Syndrome: Anticipate tumor lysis syndrome; premedicate with anti-hyperuricemics and adequate hydration especially for patients with high tumor burden and/or high circulating lymphocyte count. Correct electrolyte abnormalities, provide supportive care, and monitor renal function and fluid balance. (5.4)
    • Neutropenia: Monitor for infection. (5.6)
    • Thrombocytopenia: Monitor platelet counts and for bleeding. Management of hemorrhage may require blood product support. (5.7)
    • Immunization: Do not administer live virus vaccines prior to or during GAZYVA treatment. (5.8)

    ADVERSE REACTIONS

    The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea. (6)

    To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 12/2014

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 1 INDICATIONS AND USAGE

    GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)].

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  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosage Regimen

    • Premedicate before each infusion [see Dosage and Administration (2.2)].
    • Administer only as an intravenous infusion through a dedicated line [see Dosage and Administration (2.5)].
    • Do not administer as an intravenous push or bolus.
    • Monitor blood counts at regular intervals.
    • GAZYVA should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur [see Warnings and Precautions (5.3)].

    Recommended Dose:

    Each dose of GAZYVA is 1000 mg, administered intravenously, with the exception of the first infusions in Cycle 1, which are administered on day 1 (100 mg) and day 2 (900 mg).

    Table 1 Dose of GAZYVA to Be Administered During 6 treatment Cycles Each of 28 days Duration
    Day of treatment cycle Dose of GAZYVA Rate of infusion (in the absence of infusion reactions/hypersensitivity during previous infusions)
    Cycle 1
    (loading doses)
    Day 1 100 mg Administer at 25 mg/hr over 4 hours. Do not increase the infusion rate.
    Day 2 900 mg Administer at 50 mg/hr. The rate of the infusion can be escalated in increments of 50 mg/hr every 30 minutes to a maximum rate of 400 mg/hr.
    Day 8 1000 mg Infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr.
    Day 15 1000 mg
    Cycles 26 Day 1 1000 mg

    If a planned dose of GAZYVA is missed, administer the missed dose as soon as possible and adjust dosing schedule accordingly. If appropriate, patients who do not complete the Day 1 Cycle 1 dose may proceed to the day 2 Cycle 1 dose.

    If a patient experiences an infusion reaction of any grade during infusion, adjust the infusion as follows [see Warnings and Precautions (5.3)]:

    • Grade 4 (life-threatening): Stop infusion immediately and permanently discontinue GAZYVA therapy.
    • Grade 3 (severe): Interrupt infusion and manage symptoms. Upon resolution of symptoms, consider restarting GAZYVA infusion at no more than half the previous rate (the rate being used at the time that the infusion reaction occurred) and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further. Permanently discontinue treatment if patients experience a Grade 3 infusion-related symptom at rechallenge.
    • Grade 1–2 (mild to moderate): Reduce infusion rate or interrupt infusion and treat symptoms. Upon resolution of symptoms, continue or resume infusion and, if patient does not experience any further infusion reaction symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour but not increased further.

    2.2 Recommended Premedication

    Premedication is recommended to reduce the risk of infusion reactions as outlined in Table 2 [see Warnings and Precautions (5.3)].

    Hypotension may occur during GAZYVA intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each GAZYVA infusion and for the first hour after administration [see Warnings and Precautions (5.3)].

    For patients with high tumor burden and/or high circulating absolute lymphocyte counts (greater than 25 × 109/L), premedicate with anti-hyperuricemics (e.g., allopurinol) beginning 12–24 hours prior to start of therapy and ensure adequate hydration for prophylaxis of tumor lysis syndrome [see Warnings and Precautions (5.4)].

    Table 2 Premedication for GAZYVA Infusion to Reduce Infusion-Related Reactions
    Day of Treatment Cycle Patients requiring premedication Premedication Administration
    *
    Hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion reactions.
    Cycle 1:
    Day 1,
    Day 2
    All patients Intravenous glucocorticoid:
    20 mg dexamethasone or 80 mg methylprednisolone*
    Completed at least 1 hour prior to GAZYVA infusion.
    650–1000 mg acetaminophen At least 30 minutes before GAZYVA infusion.
    anti-histamine
    (e.g., 50 mg diphenhydramine)
    Cycle 1:
    Day 8,
    Day 15


    Cycles 26:
    Day 1
    All patients 650–1000 mg acetaminophen At least 30 minutes before GAZYVA infusion.
    Patients with an IRR (≥ Grade 1) with the previous infusion anti-histamine
    (e.g., 50 mg diphenhydramine)
    At least 30 minutes before GAZYVA infusion.

    Patients with a Grade 3 IRR with the previous infusion OR with a lymphocyte count > 25 × 109/L prior to next treatment
    Intravenous glucocorticoid:
    20 mg dexamethasone or 80 mg methylprednisolone1
    Completed at least 1 hour prior to GAZYVA infusion.

    2.3 Premedication for Antimicrobial Prophylaxis

    Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

    2.4 Treatment Interruption for Toxicity

    Consider treatment interruption if patients experience an infection, Grade 3 or 4 cytopenia, or a ≥ Grade 2 non-hematologic toxicity.

    2.5 Preparation and Administration

    Preparation

    Prepare the solution for infusion, using aseptic technique, as follows:

    • Inspect visually for any particulate matter and discoloration prior to administration.
    • Dilute into a 0.9% sodium chloride PVC or non-PVC polyolefin infusion bag. Do not use other diluents such as dextrose (5%).
    • Preparation of solution for infusion on day 1 (100 mg) and day 2 (900 mg) of Cycle 1:
      • Withdraw 40 mL of GAZYVA solution from the vial.
      • Dilute 4 mL (100 mg) of GAZYVA into a 100 mL 0.9% sodium chloride infusion bag for immediate administration.
      • Dilute the remaining 36 mL (900 mg) into a 250 mL 0.9% sodium chloride infusion bag at the same time for use on day 2 and store at 2°C to 8°C (36°F to 46°F) for up to 24 hours. After allowing the diluted bag to come to room temperature, use immediately.
      • Clearly label each infusion bag.
    • Preparation of solution for infusion on day 8 and 15 of Cycle 1 and day 1 Cycles 2–6:
      • Withdraw 40 mL of GAZYVA solution from the vial.
      • Dilute 40 mL (1000 mg) into a 250 mL 0.9% sodium chloride infusion bag.
    • Mix diluted solution by gentle inversion. Do not shake or freeze.
    • For microbiological stability, the diluted GAZYVA infusion solution should be used immediately. Dilute under appropriate aseptic conditions. If not used immediately, the solution may be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours prior to use.

    The product can be administered at a final concentration of 0.4 mg/mL to 4 mg/mL.

    Administration

    • Administer as an intravenous infusion only.
    • Do not administer as an intravenous push or bolus.
    • Do not mix GAZYVA with other drugs.
    • No incompatibilities between GAZYVA and polyvinylchloride (PVC) or non-PVC polyolefin bags and administration sets have been observed [see How Supplied/Storage and Handling (16.1)].
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  • 3 DOSAGE FORMS AND STRENGTHS

    1000 mg/40 mL (25 mg/mL) single-use vial.

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  • 4 CONTRAINDICATIONS

    None.

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Hepatitis B Virus Reactivation

    Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has 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 has also 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 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, i.e., 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 GAZYVA. 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 GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

    In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy and institute appropriate treatment. Resumption of GAZYVA 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 GAZYVA in patients who develop HBV reactivation.

    5.2 Progressive Multifocal Leukoencephalopathy

    JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

    5.3 Infusion Reactions

    GAZYVA can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

    Premedicate patients with acetaminophen, antihistamine, and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

    For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy.

    For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)].

    For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication as is suggested here.

    5.4 Tumor Lysis Syndrome

    Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 × 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

    5.5 Infections

    Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.

    5.6 Neutropenia

    GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

    Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

    Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

    5.7 Thrombocytopenia

    GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

    Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

    5.8 Immunization

    The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.

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  • 6 ADVERSE REACTIONS

    The following adverse reactions are discussed in greater detail in other sections of the label:

    The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.

    6.1 Clinical Trial Experience

    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 practice.

    The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

    Table 3 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1)
    Adverse Reactions
    (MedDRA*)
    System Organ Class
    GAZYVA + Chlorambucil
    n = 241
    Chlorambucil
    n = 116
    All Grades % Grades 3–4 % All Grades % Grades 3–4 %
    *
    MedDRA coded adverse reactions as reported by investigators.
    Adverse events reported under "Blood and lymphatic system disorders" reflect those reported by investigator as clinically significant.
    Injury, poisoning, and procedural complications
    Infusion reactions 69 21 0 0
    Blood and lymphatic system disorders
    Neutropenia 41 35 18 16
    Thrombocytopenia 15 11 8 4
    Anemia 12 5 10 4
    Leukopenia 7 5 0 0
    General disorders and administration site conditions
    Pyrexia 10 < 1 7 0
    Respiratory, thoracic, and mediastinal disorders
    Cough 10 0 7 < 1
    Infections and infestations
    Urinary tract infection 6 2 3 < 1
    Musculoskeletal and connective tissue disorder
    Back pain 5 < 1 2 0
    Table 4 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2)
    Adverse Reactions
    (MedDRA*)
    System Organ Class
    GAZYVA + Chlorambucil
    n = 336
    Rituximab + Chlorambucil
    n = 321
    All Grades % Grades 3–4 % All Grades % Grades 3–4 %
    *
    MedDRA coded adverse reactions as reported by investigators.
    Adverse events reported under "Blood and lymphatic system disorders" reflect those reported by investigator as clinically significant.
    Injury, poisoning and procedural complications
    Infusion reactions 66 20 38 4
    Blood and lymphatic system disorders
    Neutropenia 38 33 32 28
    Thrombocytopenia 14 10 7 3
    Leukopenia 6 4 2 < 1
    General disorders and administration site conditions
    Pyrexia 9 < 1 7 < 1
    Gastrointestinal disorders
    Diarrhea 10 2 8 < 1
    Constipation 8 0 5 0
    Infections and infestations
    Nasopharyngitis 6 < 1 3 0
    Urinary tract infection 5 1 2 < 1
    Table 5 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1)
    Investigations GAZYVA + Chlorambucil
    n = 241
    Chlorambucil
    n = 116
    All Grades % Grades 3–4 % All Grades % Grades 3–4 %
    Hematology
      Neutropenia 78 48 53 27
      Lymphopenia 80 40 9 3
      Leukopenia 84 37 12 < 1
    Chemistry
      Hypocalcemia 38 3 33 2
      Hyperkalemia 33 5 18 3
      Hyponatremia 30 8 12 3
      AST (SGOT increased) 29 1 16 0
      Creatinine increased 30 <1 20 2
      ALT (SGPT increased) 27 2 16 0
      Hypoalbuminemia 23 <1 15 <1
      Alkaline phosphatase increased 18 0 11 0
      Hypokalemia 15 1 5 <1
    Table 6 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2)
    Investigations GAZYVA + Chlorambucil
    n = 336
    Rituximab + Chlorambucil
    n = 321
    All Grades % Grades 3–4 % All Grades % Grades 3–4 %
    Hematology
      Neutropenia 76 46 69 41
      Lymphopenia 80 39 50 16
      Leukopenia 84 35 62 16
      Thrombocytopenia 48 13 40 8
      Anemia 39 10 37 10
    Chemistry
      Hypocalcemia 37 3 32 <1
      Hyperkalemia 14 1 10 <1
      Hyponatremia 26 7 18 2
      AST (SGOT increased) 27 2 21 <1
      ALT (SGPT increased) 28 2 21 1
      Hypoalbuminemia 23 <1 16 <1

    Infusion Reactions: The incidence of infusion reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

    Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 140 patients for whom these mitigation measures were implemented, 74 patients (53%) experienced a reaction with the first 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see Dosage and Administration (2)].

    Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (Table 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab treated arm.

    Infection: The incidence of infections was similar between GAZYVA and rituximab treated arms. Thirty-eight percent of patients in the GAZYVA treated arm and 37% in the rituximab treated arm experienced an infection, with Grade 3–4 rates being 11% and 13%, respectively. Fatal events were reported in 1% of patients in both arms.

    Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab treated arm (7%), with the incidence of Grade 3–4 events being 10% and 3%, respectively (Table 4). The difference in incidences between the treatment arms is driven by events occurring during the first cycle. The incidence of thrombocytopenia (all grades) in the first cycle were 11% in the GAZYVA and 3% in the rituximab treated arms, with Grade 3–4 rates being 8% and 2%, respectively. Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion).

    The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms, with 3 in the rituximab and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

    Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the rituximab treated arm.

    Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab treated arm (18% vs. 15%).

    Liver Enzyme Elevations: Hepatic enzyme elevations have occurred in patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. In some patients, elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome. In the pivotal study, there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent infusion reactions (e.g., acetaminophen) may also be implicated in these events. Monitor liver function tests during treatment, especially during the first cycle. Consider treatment interruption or discontinuation for hepatotoxicity.

    6.2 Immunogenicity

    Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Of the GAZYVA treated patients, 7% (18/271) tested positive for anti-GAZYVA antibodies at one or more time points. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

    Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

    6.3 Additional Clinical Trial Experience

    Worsening of Pre-existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA.

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  • 7 DRUG INTERACTIONS

    No formal drug interaction studies have been conducted with GAZYVA.

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category C

    Risk Summary

    There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child's healthcare providers.

    Animal Data

    In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on day 28 postpartum, obinutuzumab was detected in offspring, and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

    8.3 Nursing Mothers

    It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys, and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from obinutuzumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

    8.4 Pediatric Use

    The safety and effectiveness of GAZYVA in pediatric patients has not been established.

    8.5 Geriatric Use

    Of 336 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 273 patients (81%) were ≥ 65 years of age and 156 patients (46%) were ≥ 75 years of age. The median age was 74 years. Of the 156 patients ≥ 75 years of age, 72 (46%) experienced serious adverse events and 11 (7%) experienced adverse events leading to death. For 180 patients < 75 years of age, 59 (33%) experienced a serious adverse event and 4 (2%) an adverse event leading to death. No significant differences in efficacy were observed between patients ≥ 75 years of age and those < 75 years of age [see Clinical Studies (14.1)].

    8.6 Renal Impairment

    Based on population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) ≥ 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min [see Clinical Pharmacology (12.3)].

    8.7 Hepatic Impairment

    GAZYVA has not been studied in patients with hepatic impairment.

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  • 10 OVERDOSAGE

    There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy.

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  • 11 DESCRIPTION

    GAZYVA (obinutuzumab) is a humanized anti-CD20 monoclonal antibody of the IgG1 subclass. It recognizes a specific epitope of the CD20 molecule found on B cells. The molecular mass of the antibody is approximately 150 kDa.

    GAZYVA is produced by mammalian cell (CHO) suspension culture. GAZYVA was engineered for reduced fucose content as compared to a typical IgG1 produced in CHO cells. GAZYVA is a sterile, clear, colorless to slightly brown, preservative-free liquid concentrate for intravenous administration. GAZYVA is supplied at a concentration of 25 mg/mL in 1000 mg single-use vials. The product is formulated in 20 mM L-histidine/L-histidine hydrochloride, 240 mM trehalose, 0.02% poloxamer 188. The pH is 6.0.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysis through (1) engagement of immune effector cells, (2) by directly activating intracellular death signaling pathways (direct cell death), and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis.

    As an antibody with reduced fucose content, obinutuzumab induces greater ADCC activity than rituximab in vitro using human cancer cell lines. Obinutuzumab also demonstrated an increased ability to induce direct cell death when compared to rituximab. Obinutuzumab binds to FcγRIII using purified proteins with a higher affinity than rituximab. Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.

    12.2 Pharmacodynamics

    In clinical trials in patients with CLL, GAZYVA caused CD19 B-cell depletion (defined as CD19 B-cell counts < 0.07 × 109/L). Initial CD19 B-cell recovery was observed in some patients approximately 9 months after the last GAZYVA dose. At 18 months of follow-up, some patients remain B-cell depleted.

    Although the depletion of B cells in the peripheral blood is a measurable pharmacodynamic effect, it is not directly correlated with the depletion of B cells in solid organs or in malignant deposits. B-cell depletion has not been shown to be directly correlated to clinical response.

    Cardiac Electrophysiology

    The potential effects of GAZYVA on the QTc interval have not been studied.

    12.3 Pharmacokinetics

    Based on a population pharmacokinetic (pop-PK) analysis, the geometric mean (CV%) volume of distribution of obinutuzumab at steady state is approximately 3.9 (21) L.

    The elimination of obinutuzumab is comprised of a linear clearance pathway and a time-dependent non-linear clearance pathway. As GAZYVA treatment progresses, the impact of the time-dependent pathway diminishes in a manner suggesting target-mediated drug disposition (TMDD). Based on a pop-PK analysis, the geometric mean (CV%) terminal obinutuzumab clearance and half-life are approximately 0.09 (37%) L/day and 29.7 (35%) days, respectively.

    Specific Populations:

    Age: Age did not affect the pharmacokinetics of GAZYVA.

    Body Weight: Volume of distribution and steady-state clearance both increased with body weight; however, the expected change in exposure does not warrant a dose modification.

    Renal Impairment: Based on the population pharmacokinetic analysis, a baseline creatinine clearance (CrCl) > 30 mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CrCl < 30 mL/min.

    Hepatic Impairment: GAZYVA has not been studied in patients with hepatic impairment.

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  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    No carcinogenicity or genotoxicity studies have been conducted with obinutuzumab.

    No specific studies have been conducted to evaluate potential effects on fertility; however, no adverse effects on male or female reproductive organs were observed in the 26-week repeat-dose toxicity study in cynomolgus monkeys.

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  • 14 CLINICAL STUDIES

    14.1 Chronic Lymphocytic Leukemia

    GAZYVA was evaluated in a three-arm, open-label, active-controlled, randomized, multicenter trial (Study 1) in 781 patients with previously untreated CD20+ chronic lymphocytic leukemia requiring treatment who had coexisting medical conditions or reduced renal function as measured by creatinine clearance (CrCl) < 70 mL/min. Patients with CrCl < 30 mL/min, active infections, positive hepatitis B (HBsAg or anti-HBc positive; patients positive for anti-HBc could be included if hepatitis B viral DNA was not detectable) and hepatitis C serology, or immunization with live virus vaccine within 28 days prior to randomization were excluded from the trial. Patients were treated with chlorambucil control (Arm 1), GAZYVA in combination with chlorambucil (Arm 2), or rituximab in combination with chlorambucil (Arm 3). The safety and efficacy of GAZYVA was evaluated in a Stage 1 comparison of Arm 1 vs. Arm 2 in 356 patients and a Stage 2 comparison of Arm 2 vs. Arm 3 in 663 patients.

    The majority of patients received 1000 mg of GAZYVA on days 1, 8, and 15 of the first cycle, followed by treatment on the first day of 5 subsequent cycles (total of 6 cycles, 28 days each). The first dose of GAZYVA was divided between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)], which was implemented in 140 patients. Chlorambucil was given orally at 0.5 mg/kg on day 1 and day 15 of all treatment cycles (1 to 6).

    In Study 1, the median age was 73 years, 62% were male, and 95% were Caucasian. Sixty-five percent had a CrCl < 70 mL/min and 76% had multiple coexisting medical conditions. Twenty-two percent of patients were Binet stage A, 42% were stage B, and 36% were stage C. The median estimated CrCl was 62 mL/min. Eighty-one percent of patients treated with GAZYVA in combination with chlorambucil received all 6 cycles compared to 89% of patients in the rituximab treated arm and 67% in the chlorambucil alone arm.

    In the Stage 1 analysis of Study 1, the median progression-free survival (PFS) in the GAZYVA in combination with chlorambucil arm was 27.2 months and 11.2 months in the chlorambucil alone arm (median observation time 22.8 months) as assessed by independent review and is consistent with investigator-assessed PFS. The median overall survival (OS) was not yet reached with a total of 46 deaths: 22 (9%) in the GAZYVA in combination with chlorambucil arm and 24 (20%) in the chlorambucil arm. The hazard ratio for OS was 0.41 (95% CI: 0.23-0.74).

    In the Stage 2 analysis of Study 1, the median PFS was 26.7 months in the GAZYVA arm and 14.9 months in the rituximab arm with a median observation time of 18.7 months (HR: 0.42, 95% CI: 0.33-0.54, p-value <0.0001). These results were assessed by independent review and are consistent with investigator-assessed PFS. Minimal Residual Disease (MRD) was evaluated using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The cutoff for a negative status was one CLL cell per 104 leukocytes in the sample (i.e., an MRD value of <10-4 was considered negative). Among patients who achieved complete response (CR) and complete response with incomplete marrow recovery (CRi) (94 patients in the GAZYVA arm and 34 patients in the rituximab arm), 18 patients (19%) had negative MRD in the bone marrow in the GAZYVA arm compared to 2 patients (6%) in the rituximab arm. Out of the patients who achieved CR and CRi, 39 patients (41%) in the GAZYVA arm and 4 patients (12%) in the rituximab arm were MRD negative in peripheral blood samples collected at least 3 months after the end of treatment.

    Efficacy results are shown in Table 7, and the Kaplan-Meier curves for Stage 1a Overall Survival and Stage 2 PFS are shown in Figures 1 and 2, respectively.

    Table 7 Efficacy Results for Study 1
    Endpoint Stage 1 of Study 1 Stage 2 of Study 1
    GAZYVA + Chlorambucil* Chlorambucil GAZYVA + Chlorambucil* Rituximab + Chlorambucil
    n = 238 n = 118 n = 333 n = 330
    *
    All Stage 1 GClb patients (n = 238) were included in the Stage 2 GClb population (n = 333).
    As defined by independent review. Investigator-assessed PFS was consistent with data from independent review.
    Defined as best overall response rate (ORR = CR + CRi +PR + nPR).
    Median Progression-Free Survival 27.2 months 11.2 months 26.7 months 14.9 months
    (HR 0.19 [0.14; 0.27], p-value < 0.0001 stratified log-rank test) (HR 0.42 [0.33; 0.54], p-value < 0.0001 stratified log-rank test)
    Overall Response Rate 78.2% 33.1% 79.6% 66.3%
      Complete Response 28.2% 0 26.1% 8.8%
      Complete Response with Incomplete Marrow Recovery 2.5% 1.7% 2.1% 1.5%
      Partial Response 45.0% 30.5% 48.6% 54.1%
      Nodular Partial Response 2.5% 0.8% 2.7% 1.8%
    Median Duration of Response 22.4 months 4.7 months 19.6 months 9.7 months
    Overall Survival HR 0.41 [0.23; 0.74], Not Yet Mature
    Figure 1
    Kaplan-Meier Curve of Overall Survival in Patients with CLL in Study 1 (Stage 1)
    Figure 1
    Figure 2
    Kaplan-Meier Curve of Progression-Free Survival in Patients with CLL in Study 1 (Stage 2)
    Figure 2
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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied/Storage

    GAZYVA 1000 mg/40 mL (25 mg/mL) single-use vials containing preservative-free solution (NDC 50242-070-01) are stable at 2°C to 8°C (36°F to 46°F). Do not use beyond expiration date stamped on carton. GAZYVA vials should be protected from light. DO NOT FREEZE. DO NOT SHAKE.

    For the diluted product, chemical and physical stability have been demonstrated in 0.9% NaCl at concentrations of 0.4 mg/mL to 20 mg/mL for 24 hours at 2°C to 8°C (36°F to 46°F) followed by 48 hours (including infusion time) at room temperature (≤ 30°C/86°F). GAZYVA does not contain antimicrobial preservatives. Therefore, care must be taken to ensure that the solution for infusion is not microbiologically compromised during preparation. The solution for infusion should be used immediately. If not used immediately, the prepared solution may be stored up to 24 hours at 2 to 8°C. No incompatibilities between GAZYVA and polyvinyl chloride or polyolefin infusion materials have been observed in concentration ranges from 0.4 mg/mL to 20.0 mg/mL after dilution of GAZYVA with 0.9% sodium chloride.

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  • 17 PATIENT COUNSELING INFORMATION

    Advise patients to seek immediate medical attention for any of the following:

    Advise patients of the need for:

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  • SPL UNCLASSIFIED SECTION

    GAZYVA® (obinutuzumab)

    Manufactured by:
    Genentech, Inc.
    A Member of the Roche Group
    South San Francisco, CA 94080-4990
    U.S. License No. 1048

    GAZYVA is a registered trademark of Genentech, Inc.
    © 2014 Genentech, Inc.

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  • SPL UNCLASSIFIED SECTION

    Representative sample of labeling (see the HOW SUPPLIED section for complete listing):

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  • PRINCIPAL DISPLAY PANEL - 40 mL Vial Carton

    NDC 50242-070-01

    Gazyva
    (obinutuzumab)
    Injection

    1000 mg/40 mL
    (25 mg/mL)

    For Intravenous Infusion After Dilution.
    Single-Use Vial. Discard Unused Portion.

    No preservative.

    Rx only

    1 vial

    Genentech

    10150233

    Principal Display Panel - 40 mL Vial Carton
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  • INGREDIENTS AND APPEARANCE
    GAZYVA 
    obinutuzumab injection, solution, concentrate
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:50242-070
    Route of Administration INTRAVENOUS DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    OBINUTUZUMAB (OBINUTUZUMAB) OBINUTUZUMAB 1000 mg  in 40 mL
    Inactive Ingredients
    Ingredient Name Strength
    HISTIDINE  
    HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE  
    TREHALOSE DIHYDRATE  
    POLOXAMER 188  
    WATER  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:50242-070-01 1 in 1 CARTON
    1 40 mL in 1 VIAL, SINGLE-USE; Combination Product Type = C112160
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA125486 11/01/2013
    Labeler - Genentech, Inc. (080129000)
    Establishment
    Name Address ID/FEI Business Operations
    Roche Diagnostics GmbH 315028860 MANUFACTURE(50242-070), ANALYSIS(50242-070)
    Establishment
    Name Address ID/FEI Business Operations
    F. Hoffmann-La Roche Ltd 485244961 LABEL(50242-070), PACK(50242-070)
    Establishment
    Name Address ID/FEI Business Operations
    Roche Diagnostics GmbH 323105205 API MANUFACTURE(50242-070)
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