GAZYVA Solution for injection Ref.[10820] Active ingredients: Obinutuzumab

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 healthcare providers 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 healthcare providers 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

John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, occurred 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-Related Reactions

GAZYVA can cause severe and life-threatening infusion-related reactions (IRRs). Sixty-five percent of patients with CLL experienced a reaction to the first 1,000 mg of GAZYVA infused. Thirty-seven percent of patients with relapsed or refractory NHL and 60% of patients with previously untreated NHL experienced a reaction on Day 1 of GAZYVA infusion. IRRs have occurred within 24 hours of receiving GAZYVA. IRRs 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). The most frequently reported symptoms include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

Premedicate patients with acetaminophen, antihistamine, and a glucocorticoid [see Dosage and Administration (2.4)]. Closely monitor patients during the entire infusion. Reduce infusion rate, interrupt infusion or permanently discontinue GAZYVA for IRRs based on severity [see Dosage and Administration (2.5)]. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for IRRs as needed.

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-related 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 Hypersensitivity Reactions Including Serum Sickness

Hypersensitivity reactions have been reported in patients treated with GAZYVA. Signs of immediate-onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria and tachycardia. Late-onset hypersensitivity diagnosed as serum sickness has also been reported, with symptoms that include chest pain, diffuse arthralgia and fever. Hypersensitivity reactions may be difficult to clinically distinguish from infusion-related reactions. However, hypersensitivity very rarely occurs with the first infusion and, when observed, often occurs after previous exposure.

If a hypersensitivity reaction is suspected during or after an infusion, stop the infusion and permanently discontinue treatment. GAZYVA is contraindicated in patients with known hypersensitivity reactions to GAZYVA, including serum sickness with prior obinutuzumab use [see Contraindications (4)].

5.5 Tumor Lysis Syndrome

Tumor lysis syndrome (TLS), including fatal cases, has been reported in patients receiving GAZYVA. Patients with high tumor burden, high circulating lymphocyte count (>25 × 10⁹/L) or renal impairment are at greater risk for TLS.

Administer appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol or rasburicase) and hydration prior to the infusion of GAZYVA for patients at risk for TLS [see Dosage and Administration (2.4)]. During the initial days of GAZYVA treatment, monitor the laboratory parameters of patients considered at risk for TLS. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

5.6 Infections

Fatal and serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. When GAZYVA is administered with chemotherapy followed by GAZYVA monotherapy as in the GALLIUM study, Grade 3 to 5 infections have been reported in up to 8% of patients during combination therapy, up to 13% of patients during monotherapy, and up to 8% of patients after treatment [see Adverse Reactions (6.1)].

In GALLIUM, more Grade 3 to 5 infections were reported in the recipients of GAZYVA and bendamustine (117/410 patients, 29%) as compared to GAZYVA plus CHOP or CVP (43/281 patients, 15%). More fatal infections were reported in patients treated with GAZYVA and bendamustine (3%), as compared to GAZYVA plus CHOP or CVP (< 1%), including during the monotherapy phase and after completion of treatment.

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.

5.7 Neutropenia

Severe and life-threatening neutropenia, including febrile neutropenia, has been reported during treatment with GAZYVA. Monitor patients with Grade 3 to 4 neutropenia frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection. Consider dose delays for Grade 3 or 4 neutropenia. Consider administration of granulocyte colony-stimulating factors (GCSF) in patients with Grade 3 or 4 neutropenia.

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 severe and long lasting (>1 week) neutropenia are strongly recommended to receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Consider antiviral and antifungal prophylaxis.

5.8 Thrombocytopenia

Severe and life-threatening thrombocytopenia has been reported during treatment with GAZYVA in combination with chemotherapy. Fatal hemorrhagic events have been reported in patients with NHL and CLL treated with GAZYVA in combination with chemotherapy, including during Cycle 1.

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 dose delays of GAZYVA and chemotherapy or dose reductions of chemotherapy. 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.

5.9 Immunization

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

5.10 Embryo-Fetal Toxicity

Based on its mechanism of action and findings in animals, GAZYVA can cause B-cell depletion in infants exposed to obinutuzumab in-utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving GAZYVA and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Hepatitis B virus reactivation [see Warnings and Precautions (5.1)]
• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)]
• Infusion-related reactions [see Warnings and Precautions (5.3)]
• Hypersensitivity reactions including serum sickness [see Warnings and Precautions (5.4)]
• Tumor lysis syndrome [see Warnings and Precautions (5.5)]
• Infections [see Warnings and Precautions (5.6)]
• Neutropenia [see Warnings and Precautions (5.7)]
• Thrombocytopenia [see Warnings and Precautions (5.8)]

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.

Chronic Lymphocytic Leukemia

The data below are based on a safety population of 773 previously untreated patients with CLL in the CLL11 study. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab product 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 product in combination with chlorambucil. Adverse reactions rates and laboratory abnormalities from the Stage 2 phase are presented below and are consistent with the rates in Stage 1. In addition to the adverse reactions observed in Stage 2, in Stage 1, back pain (5% vs. 2%), anemia (12% vs. 10%) and cough (10% vs. 7%) were observed at a higher incidence in the obinutuzumab treated patients. The incidence of Grade 3 to 4 back pain (<1% vs. 0%), cough (0% vs. <1%) and anemia (5% vs. 4%) was similar in both treatment arms. With regard to laboratory abnormalities, in Stage 1 hyperkalemia (33% vs. 18%), creatinine increased (30% vs. 20%) and alkaline phosphatase increased (18% vs. 11%) were observed at a higher incidence in patients treated with obinutuzumab with similar incidences of Grade 3 to 4 abnormalities between the two arms.

Patients received three 1,000 mg doses of GAZYVA on the first cycle and a single dose of 1,000 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 (2.2)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

Adverse reactions in ≥ 10% of patients in the GAZYVA containing arm were infusion-related reactions, neutropenia, thrombocytopenia, and diarrhea. The most common Grade 3 to 4 adverse reactions (incidence ≥10%) in the GAZYVA containing arm were neutropenia, infusion-related reactions, and thrombocytopenia.

Table 4. Adverse Reactions (Incidence ≥5% and ≥2% Greater in the GAZYVA Arm) in Patients with CLL (Stage 2):

^* Adverse reactions reported under “Blood and lymphatic system disorders” reflect those reported by investigator as clinically significant.

Table 5. Post-Baseline Laboratory Abnormalities (Incidence ≥10% and ≥2% Greater in the GAZYVA Arm) in Patients with CLL (Stage 2):

Non-Hodgkin Lymphoma

GADOLIN

The GADOLIN study evaluated safety in 407 patients with relapsed or refractory NHL, including FL (81%), small lymphocytic lymphoma and marginal zone lymphoma (a disease for which GAZYVA is not indicated), who did not respond to or progressed within 6 months of treatment with rituximab product or a rituximab product-containing regimen. In the population of patients with FL, the profile of adverse reactions was consistent with the overall NHL population. Patients received either GAZYVA in combination with bendamustine (204 patients), followed by GAZYVA monotherapy in patients that had not progressed, or bendamustine alone (203 patients).

Patients randomized to the GAZYVA + bendamustine arm received three weekly 1,000 mg doses of GAZYVA in the first cycle and a single dose of 1,000 mg once every 28 days for 5 additional cycles, in combination with bendamustine 90 mg/m² intravenously on Days 1 and 2 in all 6 cycles. Patients who did not progress on the combination received a single 1,000 mg dose of GAZYVA monotherapy every two months until progression or for a maximum of two years. The control arm received bendamustine 120 mg/m² on Days 1 and 2 of each cycle for 6 cycles, with a cycle length of 28 days. In the GAZYVA arm, 78% of patients received 6 cycles of bendamustine and 82% received their full 6 cycles of GAZYVA; 72 (46%) of the 158 patients who began GAZYVA monotherapy received all planned doses. In the control arm, 72% of patients received 6 cycles of bendamustine.

Serious adverse reactions occurred in 45% of the GAZYVA arm and 37% of the bendamustine-only arm. Fatal adverse reactions within 90 days of treatment occurred in 3.4% and 2.5%, respectively. During treatment and follow-up combined, fatal adverse reactions occurred in 10% of GAZYVA recipients and in 7.4% of recipients of bendamustine alone, with infection and second primary malignancies being the leading causes.

Dose modification due to adverse reactions occurred in 50% of the GAZYVA arm and 42% of the control arm, and discontinuation of any study drug due to adverse reactions occurred in 20% and 17%, respectively.

Table 6 presents selected adverse reactions in GADOLIN. The most common adverse reactions (incidence ≥ 20%) in GAZYVA recipients included infusion-related reactions, fatigue, neutropenia, cough, upper respiratory tract infections, and musculoskeletal pain.

Table 6. Adverse Reactions (Incidence ≥10% and ≥2% Greater in the GAZYVA Arm) in Patients with Relapsed or Refractory NHL (GADOLIN):

^* Includes adverse reactions reported throughout study treatment and follow-up.
^† Includes grouped terms.
^‡ Except where noted, individual events that meet the definition of “infusion-related reaction” are excluded from Table 6 above, as they are included in the grouped term “Infusion-Related Reaction”.
^§ Includes 1 fatal event.

Infusion-related reactions are defined as any related adverse reaction that occurred during or within 24 hours of infusion.

Fatigue includes fatigue, lethargy, asthenia.

Pyrexia includes pyrexia, hyperthermia, body temperature increased.

Cough includes cough, productive cough, upper-airway cough syndrome.

Neutropenia includes neutropenia, agranulocytosis, granulocytopenia, neutrophil count decreased.

Upper respiratory tract infection includes upper respiratory tract congestion, upper respiratory tract inflammation, upper respiratory fungal infection, rhinovirus infection, and all terms containing: upper respiratory tract infection, laryngitis, nasopharyngitis, pharyngitis, rhinitis, tonsillitis, and sinusitis with the exception of sinobronchitis.

Respiratory tract infection unspecified includes respiratory tract infection, respiratory tract infection viral, influenza, influenza-like illness, sinobronchitis, respiratory syncytial virus infection.

Urinary tract infection includes all terms containing: urinary tract infection, cystitis, pyelonephritis.

Musculoskeletal pain includes non-cardiac chest pain, bone pain, spinal pain, myalgia, back pain, neck pain, musculoskeletal discomfort, pain in extremity, and all terms containing “musculoskeletal pain”.

Rash includes drug eruption, skin reaction, all terms containing “rash”, urticaria, and selected terms containing “dermatitis”.

Pruritus includes pruritus, pruritus generalized.

Other clinically relevant adverse reactions (incidence <10% and ≥2% greater in the GAZYVA arm) included:

• Blood and lymphatic system disorders: febrile neutropenia (6%)
• Infection: sepsis (7%)

During GAZYVA monotherapy (158 patients), adverse reactions in ≥10% of patients included upper and lower respiratory tract infections, cough, neutropenia, musculoskeletal pain, fatigue, diarrhea, rash, and urinary tract infection.

Table 7 presents selected new or worsening laboratory abnormalities in the GADOLIN trial.

Table 7. New or Worsening Laboratory Abnormalities (Incidence ≥10% and ≥2% Greater in the GAZYVA Arm?footnote?) in Patients with Relapsed or Refractory NHL (GADOLIN):

^* Two percent difference in either any-grade or Grade 3 to 4 laboratory abnormalities.

In the GAZYVA monotherapy phase, new or worsening grade 3 or 4 abnormalities included neutropenia in 25% of patients (Grade 4, 10%) and lymphopenia in 23% (Grade 4, 5%).

GALLIUM

A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of GAZYVA as compared to rituximab product in 1385 patients with previously untreated follicular lymphoma (86%) or marginal zone lymphoma (14%). Patients received chemotherapy (bendamustine, CHOP, or CVP) combined with either GAZYVA (691 patients) or rituximab product (694 patients), followed in responding patients by GAZYVA or rituximab product monotherapy every two months until disease progression or for a maximum of two years. The study excluded patients having an absolute neutrophil count (ANC) <1500/µL, platelets <75,000/µL, CLcr <40 mL/min and, unless attributable to lymphoma, hepatic transaminases >2.5 × upper limit of normal.

The median age was 60 (range: 23-88), 47% were male, 82% were white, and 97% had an ECOG performance status of 0 or 1. The chemotherapy was bendamustine in 59%, CHOP in 31% and CVP in 10% of patients. Following combination therapy, 624 patients (90%) in the GAZYVA arm and 612 patients (88%) in the rituximab product arm received monotherapy.

Serious adverse reactions occurred in 50% of patients on the GAZYVA arm and 43% of patients on the rituximab product arm. Fatal adverse reactions were reported during treatment in 3% in the GAZYVA arm and 2% in the rituximab product arm, most often from infections in the GAZYVA arm. During treatment and follow-up combined, fatal adverse reactions were reported in 5% of the GAZYVA arm and 4% of the rituximab product arm, with infections and second malignancies being leading causes. In the GAZYVA arm, fatal infections occurred in 2% of patients compared to <1% in the rituximab product arm.

During combination therapy, 93% of patients received all treatment cycles in the GAZYVA arm, and 92% received all treatment cycles in the rituximab product arm. Of the responding patients who began monotherapy with GAZYVA or rituximab product, 76% and 73%, respectively, completed the full course. Dose modification due to adverse reactions occurred in 74% of the GAZYVA arm and 63% of the rituximab product arm throughout study treatment, and discontinuation of any study drug due to adverse reactions occurred in 18% and 15%, respectively.

Throughout treatment and follow-up, the most common adverse reactions (incidence ≥20%) observed at least 2% more in the GAZYVA arm included infusion-related reactions, neutropenia, upper respiratory tract infections, constipation and diarrhea (Table 8). Neutropenia, infusion-related reactions, febrile neutropenia and thrombocytopenia were the most common Grade 3 to 5 adverse reactions (incidence ≥5%) observed more frequently in the GAZYVA arm.

Table 8. Adverse Reactions (Incidence ≥10% and ≥2% Greater in the GAZYVA Arm) in Patients with Previously Untreated NHL (GALLIUM):

^* Includes adverse reactions reported throughout study treatment and follow-up.
^† Includes grouped terms.
^‡ Except where noted, individual events that meet the definition of “infusion-related reaction” are excluded from Table 8 above, as they are already included in the grouped term “Infusion-Related Reaction”. The most common individual terms within the grouped term “Infusion-Related Reaction” in decreasing order of frequency are nausea, chills, pyrexia and vomiting.
^§ Includes adverse reactions reported as infusion-related reactions.

Infusion-related reactions are defined as any related adverse reaction that occurred during or within 24 hours of infusion.

Neutropenia includes neutropenia, agranulocytosis, granulocytopenia, and neutrophil count decreased.

Febrile neutropenia includes febrile neutropenia, neutropenic infection, neutropenic sepsis, and febrile bone marrow aplasia.

Thrombocytopenia includes thrombocytopenia and platelet count decreased.

Upper respiratory tract infection includes upper respiratory tract congestion, upper respiratory tract inflammation, upper respiratory tract infection, rhinovirus infection, and all terms containing: laryngitis, nasopharyngitis, pharyngitis, rhinitis, tonsillitis, and sinusitis with the exception of sinobronchitis.

Herpesvirus infection includes all terms containing “herpes” or "varicella."

Pneumonia includes all terms containing “pneumonia,” bacterial, pneumonia haemophilus, pneumonia pneumococcal, pneumonia fungal, pneumocystis jirovecii infection, lung infection, and lung infiltration.

Diarrhea includes diarrhea, defecation urgency, frequent bowel movement, and all terms containing “gastroenteritis”.

Headache includes all terms containing “headache” and migraine.

Insomnia includes all terms containing “insomnia” and sleep disorder.

Pruritus includes pruritus and pruritus generalized.

During the monotherapy period, the common adverse reactions (incidence ≥10%) observed at least 2% more with GAZYVA were upper respiratory tract infection (40%), cough (23%), musculoskeletal pain (20%), neutropenia (19%), and herpesvirus infection (13%).

Table 9 summarizes treatment-emergent laboratory abnormalities during treatment and follow-up. The Grade 3 to 4 abnormalities reported at least 2% more in the GAZYVA arm were lymphopenia, leukopenia, neutropenia, thrombocytopenia, and hyperuricemia. Patients in the GAZYVA arm, as compared to the rituximab product arm, had higher incidences of Grade 4 neutropenia (38% vs. 30%, respectively), Grade 4 lymphopenia (33% vs. 22%), and Grade 4 leukopenia (17% vs. 12%).

Table 9. New or Worsening Laboratory Abnormalities (Incidence ≥10% and ≥2% Greater in the GAZYVA Arm) in Patients with Previously Untreated NHL (GALLIUM):

^* Includes lab abnormalities, reported throughout treatment and follow-up, that were new or worsening, or worsening from baseline unknown.

In the monotherapy phase, new-onset Grade 3 or 4 neutropenia was reported in 21% of patients in the GAZYVA arm (Grade 4, 10%) and 17% of patients in the rituximab product arm (Grade 4, 9%).

Infusion-Related Reactions

Chronic Lymphocytic Leukemia

The incidence of infusion-related reactions (IRRs) in the CLL11 study was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 IRRs was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1,000 mg and <1% thereafter. No Grade 3 or 4 IRRs were reported beyond the first 1,000 mg infused.

Of the first 53 patients receiving GAZYVA in CLL11, 47 (89%) experienced an IRR. 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 1,000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and <3% thereafter [see Dosage and Administration (2.2)].

Non-Hodgkin Lymphoma

Overall, 67% of patients in the GADOLIN study experienced an IRR (all grades) during treatment with GAZYVA in combination with bendamustine. The incidence of Grade 3 to 4 IRRs in GADOLIN was 11%. In Cycle 1, the incidence of IRRs (all grades) was 53% in patients receiving GAZYVA in combination with bendamustine of which 34 (9%) were Grade 3 to 4 in severity. In patients receiving GAZYVA in combination with bendamustine, the incidence of IRRs was highest on Day 1 (37%), and gradually decreased on Days 2, 8 and 15 (23%, 6% and 4%, respectively).

During Cycle 2, the incidence of IRRs was 24% in patients receiving GAZYVA in combination with bendamustine and decreased with subsequent cycles.

During GAZYVA monotherapy in GADOLIN, IRRs (all grades) were observed in 8% of patients. One Grade 3 and no Grade 4 IRRs were reported during GAZYVA monotherapy.

Overall, 2% of patients in GADOLIN experienced an IRR leading to discontinuation of GAZYVA.

In GALLIUM, 72% of patients in the GAZYVA treated arm experienced an IRR (all grades). The incidence of Grade 3 to 4 IRRs for these patients was 12%. In Cycle 1, the incidence of IRRs (all grades) was 62% in the GAZYVA treated arm with Grade 3 to 4 IRRs reported in 10%. The incidence of IRRs (all grades) was highest on Day 1 (60%) and decreased on Days 8 and 15 (9% and 6%, respectively).

During Cycle 2, the incidence of IRRs (all grades) in the GAZYVA treated arm was 13% and decreased with subsequent cycles.

During GAZYVA monotherapy treatment in GALLIUM, IRRs (all grades) were observed in 9% of patients.

Overall, 1% of patients in GALLIUM experienced an IRR leading to discontinuation of GAZYVA.

Neutropenia

Chronic Lymphocytic Leukemia

The incidence of neutropenia reported as an adverse reaction in CLL11 was 38% in the GAZYVA treated arm and 32% in the rituximab product treated arm, with the incidence of serious adverse reactions 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 product treated arm.

Non-Hodgkin Lymphoma

The incidence of neutropenia in GADOLIN was higher in the GAZYVA plus bendamustine arm (37%) compared to the arm treated with bendamustine alone (30%). Cases of prolonged neutropenia (3%) and late onset neutropenia (8%) were also reported in the GAZYVA plus bendamustine arm. The incidence of neutropenia was higher during treatment with GAZYVA in combination with bendamustine (30%) compared to the GAZYVA monotherapy treatment phase (13%).

The incidence of neutropenia in GALLIUM was higher in the GAZYVA treated arm (53%) compared to the rituximab product treated arm (47%). Cases of prolonged neutropenia (1%) and late onset neutropenia (4%) were also reported in the GAZYVA treated arm. The incidence of neutropenia was higher during treatment with GAZYVA in combination with chemotherapy (45%) compared to the GAZYVA monotherapy treatment phase (20%).

Infection

Chronic Lymphocytic Leukemia

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

Non-Hodgkin Lymphoma

The incidence of infection in GADOLIN was 68% in the GAZYVA plus bendamustine arm and 59% in the bendamustine arm, with Grade 3 to 4 events reported in 20% and 16%, respectively. Fatal events were reported in 3% of patients in the GAZYVA plus bendamustine arm and 3% in the bendamustine arm.

The incidence of infections in GALLIUM was 82% in the GAZYVA treated arm and 73% in the rituximab product treated arm, with Grade 3 to 4 events reported in 21% and 17%, respectively. In the GAZYVA arm, fatal infections occurred in 2% of patients compared to <1% in the rituximab product arm.

The incidence of Grade 3 to 4 infections in the GAZYVA and rituximab product treated arms was lower in patients receiving GCSF prophylaxis (14%; 16%) compared with patients not receiving GCSF prophylaxis (24%; 18%). The incidence of fatal infections in patients receiving GCSF prophylaxis in the GAZYVA and rituximab product treated arms was 2% and 0%, respectively, and was 2% and <1% in patients not receiving GCSF prophylaxis.

Thrombocytopenia

Chronic Lymphocytic Leukemia

The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm (14%) compared to the rituximab product treated arm (7%), with the incidence of Grade 3 to 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 was 11% in the GAZYVA and 3% in the rituximab product treated arms, with Grade 3 to 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 product and 4 in the GAZYVA treated arms. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

Non-Hodgkin Lymphoma

The incidence of thrombocytopenia in GADOLIN was lower in the GAZYVA plus bendamustine arm (15%) compared to the arm treated with bendamustine alone (25%). The incidence of hemorrhagic events in GAZYVA plus bendamustine treated patients compared to bendamustine alone was 12% and 11%, respectively. Grade 3 to 4 hemorrhagic events were similar in both treatment arms (4% in the GAZYVA plus bendamustine arm and 2% in the bendamustine arm).

In GALLIUM, thrombocytopenia was reported as an adverse reaction in 14% of the GAZYVA treated arm and 8% of the rituximab product treated arm, with the incidence of Grade 3 to 4 events being 7% and 3%, respectively. 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 was 9% in the GAZYVA and 3% in the rituximab product treated arms, with Grade 3 to 4 rates being 5% and 1%, respectively. In GALLIUM, both treatment arms had a 12% overall incidence of hemorrhagic events and a <1% incidence of fatal hemorrhagic events.

Tumor Lysis Syndrome

The incidence of Grade 3 or 4 tumor lysis syndrome in GAZYVA treated patients was 2% in CLL11, 0.5% in GADOLIN and 0.9% in GALLIUM.

Musculoskeletal Disorders

Chronic Lymphocytic Leukemia

Adverse reactions related to musculoskeletal disorders (all events from the body system), including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab product treated arm (18% vs. 15%).

Non-Hodgkin Lymphoma

In GADOLIN, adverse reactions related to musculoskeletal disorders (all events from the body system), including pain, have been reported in the GAZYVA plus bendamustine treated arm with higher incidence than in the bendamustine alone arm (44% vs. 30%).

In GALLIUM, musculoskeletal disorders were reported in 54% of patients in the GAZYVA treated arm and 49% of patients in the rituximab product treated arm.

Liver Enzyme Elevations

Hepatic enzyme elevations have occurred in CLL 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-related reactions or tumor lysis syndrome. In the CLL11 study, there was no clinically meaningful difference in overall hepatotoxicity adverse reactions between all arms (4% of patients in the GAZYVA treated arm). Medications commonly used to prevent infusion-related 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.

Gastrointestinal Perforation

Cases of gastrointestinal perforation have been reported in patients receiving GAZYVA, mainly in NHL.

Worsening of Pre-existing Cardiac Conditions

Fatal cardiac events have been reported in patients treated with GAZYVA.

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Seven percent (18/271) of patients with CLL tested positive for anti-GAZYVA antibodies at one or more time points in CLL11. No patients developed anti-GAZYVA antibodies during or following GAZYVA treatment in GADOLIN, while 1 patient (1/564, 0.2%) developed anti-GAZYVA antibodies in GALLIUM. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

The following adverse reactions have been identified during postapproval use of GAZYVA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune/Autoimmune Events: Serum sickness

Risk Summary

Based on findings from animal studies and its mechanism of action, GAZYVA can cause fetal B-cell depletion [see Clinical Pharmacology (12.1)]. There are no data with GAZYVA use in pregnant women to inform a drug-associated risk. Monoclonal antibodies are transferred across the placenta. In animal reproduction studies, weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1,000 mg monthly produced opportunistic infections and immune complex mediated hypersensitivity reactions. No embryo-toxic or teratogenic effects were observed in the monkeys (see Data). Advise pregnant women of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

GAZYVA is likely to cause fetal B-cell depletion (see Data). Avoid administering live vaccines to neonates and infants exposed to GAZYVA in utero until B-cell recovery occurs [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.2)].

Data

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, which includes the period of organogenesis. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. There were no embryo-toxic or teratogenic effects in animals. Secondary opportunistic infections, immune complex mediated hypersensitivity reactions, or a combination of both were observed in exposed dams. When first measured on day 28 postpartum, obinutuzumab was detected in offspring at levels in the range of maternal serum levels on the same day, and B-cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Obinutuzumab was measured in the milk of lactating cynomolgus monkeys on day 28 postpartum after weekly intravenous administration from day 20 of pregnancy until parturition. Concentrations in milk were approximately 0.04% and 0.13% of concentrations in maternal serum in the 25 and 50 mg/kg groups, respectively.

Risk Summary

There is no information regarding the presence of GAZYVA in human milk, the effects on the breastfed child, or the effects on milk production. However, low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [see Use in Specific Populations (8.1)]. Human IgG is known to be present in human milk. Because of the potential of serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with GAZYVA and for 6 months after the last dose.

Contraception

GAZYVA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with GAZYVA and for 6 months after the last dose.

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

Chronic Lymphocytic Leukemia

Of 336 patients with previously untreated CLL who received GAZYVA in combination with chlorambucil, 81% were 65 years and older, while 46% were 75 and older. Of the patients 75 years and older, 46% experienced serious adverse reactions and 7% experienced adverse reactions leading to death. Of the patients younger than 75, 33% experienced a serious adverse reaction and 2% an adverse reaction leading to death. No significant differences in efficacy were observed between younger and older patients [see Clinical Studies (14.1)].

Non-Hodgkin Lymphoma

Of 204 patients in GADOLIN with relapsed or refractory NHL treated with GAZYVA plus bendamustine, 44% were 65 and over, while 14% were 75 and over. In patients 65 and over, 55% of patients experienced serious adverse reactions and 28% experienced adverse reactions leading to treatment withdrawal while in patients under 65, 37% and 14% experienced serious adverse reactions and adverse reactions leading to treatment withdrawal, respectively. No clinically meaningful differences in efficacy were observed between these patients and younger patients in GADOLIN.

Of the 691 patients in GALLIUM treated with GAZYVA plus chemotherapy as first-line therapy, 33% were 65 and over, while 7% were 75 and over. Of patients 65 and over, 63% experienced serious adverse reactions and 26% experienced adverse reactions leading to treatment withdrawal, while in patients under 65, 43% experienced serious adverse reactions and 13% had an adverse reaction leading to treatment withdrawal. No clinically meaningful differences in efficacy were observed between these patients and younger patients in GALLIUM.