Drug Safety-related Labeling Changes (SrLC)

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GAZYVA (BLA-125486)

(OBINUTUZUMAB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/17/2025 (SUPPL-40)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Update to Table 13 title; please refer to label for complete information

10/17/2025 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

Extensive changes; please refer to label for complete information.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

Lupus Nephritis

The data below reflects exposure to GAZYVA administered intravenously in patients with ISN/RPS 2003 Class III or IV with or without concomitant Class V lupus nephritis in the REGENCY and NOBILITY studies, up to week 76.

REGENCY (NCT04221477) is a Phase III study which included 136 patients treated with GAZYVA plus standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids [see Clinical Studies (14.3)].

NOBILITY (NCT02550652) is a Phase II study which included 64 patients treated with GAZYVA plus standard therapy consisting of MMF/mycophenolic acid (MPA) and corticosteroids.

The most common adverse reactions (incidence greater than or equal to 5% in the GAZYVA arm) were upper respiratory tract infection, COVID-19, urinary tract infection, bronchitis, pneumonia, infusion related reactions and neutropenia.

The most common serious adverse reactions in the GAZYVA arm were: COVID-19 (11 patients [5.5%]), pneumonia (9 patients [4.5%]), neutropenia (7 patients [3.5%]), urinary tract infections (5 patients [2.5%]) and infusion-related reactions (1 patient [0.5%]). No serious adverse reactions were reported for bronchitis, herpes simplex and upper respiratory tract infections. Two fatal adverse reactions of COVID-19 were reported in the GAZYVA arm.

Adverse reaction rates are presented in Table 13.

Table 13 Adverse Reactions in Adults with Active Lupus Nephritis Treated with GAZYVA Versus Placebo (greater than or equal to 5% Greater in the GAZYVA Arm) in REGENCY and NOBILITY Studies

Newly added table; please refer to label for complete information.

Specific Adverse Reactions

Newly added title to Clinical Trials Experience of subsection 6.1

Infusion-Related Reactions

. . .

Lupus Nephritis

In the pooled REGENCY and NOBILITY studies, infusion-related reactions (IRRs) were reported in 14% of patients in the GAZYVA arm versus 10% of patients in the placebo arm. IRRs in both arms were predominantly Grade 1-2 and occurred during or after the first infusion. Grade 3-4 IRRs were reported in 1.5% of patients in the GAZYVA arm vs 0.5% of patients in the placebo arm. All Grade 3-4 events occurred during or after either the first or second infusion.

The incidence of IRRs in the GAZYVA arm decreased from 11% during the first infusion to 3% during the second infusion, decreasing further with subsequent infusions to 0.5% during the sixth infusion. The severity of IRRs in the GAZYVA arm also decreased with subsequent infusions with 1% patients reporting Grade 3-4 IRRs during the first infusion and 0.5% patients reporting Grade 3-4 IRRs during the second infusion. In subsequent infusions all IRRs were Grade 1-2 in severity. No Grade 5 IRRs were reported [see Warnings and Precautions (5.3)].In the REGENCY study, most common IRR signs or symptoms included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia.

Neutropenia

. . .

Lupus Nephritis

In the pooled REGENCY and NOBILITY studies, neutropenia and related adverse reactions (i.e., leukopenia, lymphopenia, lymphocyte count decreased, febrile neutropenia, and neutrophil count decreased) were reported in 14% of patients in the GAZYVA arm versus 6% of patients in the placebo arm. Grade 3-4 neutropenia was reported in 7% of patients treated with GAZYVA versus 0.5% of patients in the placebo arm. Neutropenia and related adverse reactions resolved/improved spontaneously or with use of granulocyte colony-stimulating factors in 96% of patients [see Warnings and Precautions (5.7)].

Infection

. . .

Lupus Nephritis

In the pooled REGENCY and NOBILITY studies, infections were reported in 72% of patients in the GAZYVA arm versus 62% of patients in the placebo arm. The most frequently reported infections were upper and lower respiratory tract infections. Grade 3-5 infections were reported in 11% of patients in the GAZYVA arm versus 10% of patients in the placebo arm. Fatal infection events were reported in 1% of patients in the GAZYVA arm versus 0.5% of patients in the placebo arm [see Warnings and Precautions (5.6)].

. . .

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

. . .

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Pregnant women with systemic lupus erythematosus (SLE) are at increased risk of adverse pregnancy outcomes, including worsening of the underlying disease, premature birth, miscarriage, and intrauterine growth restriction. Maternal LN increases the risk of hypertension and preeclampsia/eclampsia. Passage of maternal autoantibodies across the placenta may result in adverse neonatal outcomes, including neonatal lupus and congenital heart block.

. . .

8.5 Geriatric Use

Additions and/or revisions underlined:

. . .

Lupus Nephritis

Clinical studies of GAZYVA in patients with active LN did not include sufficient numbers of patients aged 65 years and older (1 patient) to determine whether they respond differently from younger adult patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Infusion-related Reactions

Advise patients to seek immediate medical attention if signs and symptoms of infusion-related reactions occur [see Warnings and Precautions (5.3) and Adverse Reactions (6.1 and 6.2)].

Tumor Lysis Syndrome

Advise patients to seek immediate medical attention if symptoms of tumor lysis syndrome occur [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

Infections

Advise patients to seek immediate medical attention if signs of an infection occur [see Warnings and Precautions (5.6) and Adverse Reactions (6.1 and 6.2)].

Hepatitis B Virus Reactivation

Advise patients to seek immediate medical attention if symptoms of hepatitis occur [see Warnings and Precautions (5.1)]. Advise patients of the need for hepatitis B virus screening and monitoring during treatment with GAZYVA.

Progressive Multifocal Leukoencephalopathy

Advise patients to seek immediate medical attention if new or changes in neurological symptoms occur [see Warnings and Precautions (5.2)].

Neutropenia, Thrombocytopenia and Disseminated Intravascular Coagulation

Advise patients to seek immediate medical attention if signs and symptoms of bleeding or thrombosis occur. Advise patients of the need for periodic monitoring of blood counts [see Warnings and Precautions (5.7, 5.8 and 5.9) and Adverse Reactions (6.1 and 6.2)].

Immunization

Advise patients to avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.10)].

Embryo-Fetal Toxicity

Advise pregnant women of potential fetal B-cell depletion. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

Contraception

Advise females of reproductive potential to use effective contraception during treatment with GAZYVA and for 6 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with GAZYVA and for 6 months after the last dose [see Use in Specific Populations (8.2)].

10/17/2025 (SUPPL-38)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Infusion-Related Reactions

Additions and/or revisions underlined:

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. In patients with CLL and NHL , 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 IRR symptoms in patients with CLL and NHL include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)].

In patients with LN, IRRs occurred predominantly during infusion of the first 1,000 mg. IRRs were generally mild to moderate and could be managed by the slowing or temporarily halting the infusion [see Dosage and Administration (2.6)]. Severe and life-threatening IRRs requiring symptomatic treatment were also reported. The most common IRR signs or symptoms reported in the REGENCY study included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia [see Adverse Reactions (6.2)].

. . .

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

. . .

Lupus Nephritis

The data below reflects exposure to GAZYVA administered intravenously in patients with ISN/RPS 2003 Class III or IV with or without concomitant Class V lupus nephritis in the REGENCY and NOBILITY studies, up to week 76.

REGENCY (NCT04221477) is a Phase III study which included 136 patients treated with GAZYVA plus standard therapy consisting of mycophenolate mofetil (MMF) and corticosteroids [see Clinical Studies (14.3)].

NOBILITY (NCT02550652) is a Phase II study which included 64 patients treated with GAZYVA plus standard therapy consisting of MMF/mycophenolic acid (MPA) and corticosteroids.

. . .

Specific Adverse Reactions

Newly added title to Clinical Trials Experience of subsection 6.1

Infusion-Related Reactions

. . .

Lupus Nephritis

In the pooled REGENCY and NOBILITY studies, infusion-related reactions (IRRs) were reported in 14% of patients in the GAZYVA arm versus 10% of patients in the placebo arm. IRRs in both arms were predominantly Grade 1-2 and occurred during or after the first infusion. Grade 3-4 IRRs were reported in 1.5% of patients in the GAZYVA arm vs 0.5% of patients in the placebo arm. All Grade 3-4 events occurred during or after either the first or second infusion.

The incidence of IRRs in the GAZYVA arm decreased from 11% during the first infusion to 3% during the second infusion, decreasing further with subsequent infusions to 0.5% during the sixth infusion. The severity of IRRs in the GAZYVA arm also decreased with subsequent infusions with 1% patients reporting Grade 3-4 IRRs during the first infusion and 0.5% patients reporting Grade 3-4 IRRs during the second infusion. In subsequent infusions all IRRs were Grade 1-2 in severity. No Grade 5 IRRs were reported [see Warnings and Precautions (5.3)].In the REGENCY study, most common IRR signs or symptoms included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia.

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Infusion-related Reactions

Advise patients to seek immediate medical attention if signs and symptoms of infusion-related reactions occur [see Warnings and Precautions (5.3) and Adverse Reactions (6.1 and 6.2)].

. . .

07/27/2022 (SUPPL-34)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined

…

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 (5.11) and Clinical Pharmacology (12.2)].

…

07/12/2022 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Thrombocytopenia

Additions and/or revisions underlined:

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 and if clinically indicated, evaluate laboratory coagulation parameters [see Warnings and Precautions (5.9)]. 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 that may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

5.9 Disseminated Intravascular Coagulation (DIC)

Newly added subsection:

Fatal and severe DIC has been reported in patients receiving GAZYVA for treatment of follicular lymphoma and chronic lymphocytic leukemia. The majority of DIC cases have involved changes in platelets and laboratory coagulation parameters following the first infusion, with spontaneous resolution usually occurring by Day 8. In some cases, DIC was associated with IRRs, TLS, or both [see Adverse Reactions (6.1)]. In patients with suspected DIC, evaluate potential causes, and monitor coagulation parameters, platelet counts, and for signs and symptoms of bleeding or thrombosis. Manage according to standard guidelines for DIC. Supportive care, including transfusion of blood products and other medical management, may be necessary.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Disseminated intravascular coagulation [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Disseminated Intravascular Coagulation

In GALLIUM, DIC was reported as an adverse reaction in 0.3% of the GAZYVA treated patients. All events occurred within 1-2 days after the first infusion.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

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

• Signs and symptoms of infusion-related reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].
• Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].
• Signs of infections including fever and cough [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].
• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)].
• New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)].
• Signs and symptoms of bleeding or thrombosis [see Warnings and Precautions (5.8 and 5.9)].

Advise patients of the need for:

• Periodic monitoring of blood counts [see Warnings and Precautions (5.7, 5.8 and 5.9) and Adverse Reactions (6.1)].
• Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.10)].
• Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

Advise pregnant women of potential fetal B-cell depletion. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with GAZYVA and for 6 months after the last dose [see Use in Specific Populations (8.3)].

Advise women not to breastfeed during treatment with GAZYVA and for 6 months after the last dose [see Use in Specific Populations (8.2)].

02/14/2022 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Following Table 10: New or Worsening Laboratory Abnormalities (Incidence greater than or equal to 10% and greater than or equal to 2% greater in the GAZYVA arm) in Patients with Previously Untreated NHL (GALLIUM), additions and/or revisions underlined:

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%).

GAZELLE

GAZELLE (NCT03817853) is a single-arm study designed to characterize the safety of GAZYVA administered as a shortened-duration infusion (approximately 90 minutes) in patients with previously untreated FL. All patients received GAZYVA at the standard infusion rate with premedication during Cycle 1. If no Grade 3 or higher IRR occurred with any infusion during Cycle 1, GAZYVA was administered over approximately 90 minutes in Cycle 2 and subsequent cycles. The primary safety measure was the proportion of patients who experienced Grade 3 or higher IRRs with the 90-minute infusion at Cycle 2. GAZYVA was administered in combination with CHOP, CVP or bendamustine for 6 to 8 cycles (induction), followed by monotherapy for up to 2 years.

Of the 113 patients treated with GAZYVA, 99 (88%) received the 90-minute infusion starting in Cycle 2. In total, 97% of patients who received GAZYVA at either a standard or shorter infusion duration received premedication in Cycle 2. IRRs were observed in 63% of patients throughout induction (including IRRs observed after standard-duration infusion). In cycle 1, 58% of patients developed IRRs with the standard infusion rate (Grade greater than or equal to 3 IRR, 5%). Of the patients who received the 90-minute infusion, 10% had IRRs of any grade in Cycle 2, with 8% and 2% of patients having a Grade 1 IRR or Grade 2 IRR, respectively. Following Cycle 2, one (1%) patient experienced a Grade 3 IRR, which occurred after the 90-minute infusion at Cycle 5.

Infusion-Related Reactions

Chronic Lymphocytic Leukemia

The incidence of IRRs in the CLL11 study was 65% with the first infusion of GAZYVA …

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

In GAZELLE, 10% of patients with FL experienced IRRs of any grade at Cycle 2 when GAZYVA was administered over approximately 90 minutes.

03/27/2020 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Embryo-Fetal Toxicity

(new subsection added)

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.

5.3 Infusion-Related Reactions

(additions and revisions underlined)

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.

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

…

5.5 Tumor Lysis Syndrome

(additions underlined)

Tumor lysis syndrome (TLS), including fatal cases, has been reported in patients receiving GAZYVA. Patients with high tumor burden, high circulating lymphocyte count (> 25 x 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.

…

5.6 Infections

(additions underlined)

…

Patients with a history of recurring or chronic infections may be at increased risk of infection.

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive additions and revisions, please refer to label for complete information)

6.3 Postmarketing Experience

(additions underlined)

 

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

8 Use in Specific Populations

8.2 Lactation

(subsection revised, additions underlined)

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. 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.

8.3 Females and Males of Reproductive Potential

(new subsection added)

Contraception

GAZYVA can cause fetal harm when administered to a pregnant woman.

Females

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

8.5 Geriatric Use

(revisions underlined)

…

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.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Advise pregnant women of potential fetal B-cell depletion. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

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

Advise women not to breastfeed during treatment with GAZYVA and for at least 6 months after the last dose.

11/16/2017 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Infusion Reactions

(Additions and/or revisions are underlined)

…Thirty-eight 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… The most frequently reported symptoms include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills.

5.6 Infections

(Additions and/or revisions are underlined)

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, 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…

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.

5.8 Thrombocytopenia

(Additions and/or revisions are underlined)

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.

6 Adverse Reactions

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)

Summary of Clinical Trial Experience in Chronic Lymphocytic Leukemia

The data described in Tables 4-5 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…

Table 4 Summary of Adverse Reactions Reported in Greater than or Equal to 5% of Patients with CLL and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) (Table has been revised; please refer to label)

Table 5 Post-Baseline Laboratory Abnormalities by CTCAE Grade in Greater than or Equal to 5% of Patients with CLL and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) (Table has been revised; please refer to label)

 

Summary of Clinical Trial Experience in Non-Hodgkin Lymphoma

GADOLIN

The GADOLIN study evaluated safety in 392 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…

The most common adverse reactions (incidence greater than or equal to 10%) observed in GADOLIN in the GAZYVA containing arm were…

The most common Grade 3 to 4 adverse reactions (incidence ? 10%) observed in GADOLIN in the GAZYVA containing arm were neutropenia, thrombocytopenia and infusion reactions.

Table 6 Summary of Adverse Reactions Reported in Greater than or Equal to 5% of Patients with Relapsed or Refractory NHL and at Least 2% Greater in the GAZYVA plus Bendamustine Followed by GAZYVA Monotherapy Treated Arm (GADOLIN)

During the monotherapy period with GAZYVA, the most common adverse reactions (incidence greater than or equal to 5%) in GADOLIN were…

Table 7 Post-Baseline Laboratory Abnormalities by CTCAE Grade in Greater than or Equal to 5% of Patients with Relapsed or Refractory NHL and at Least 2% Greater in the GAZYVA plus Bendamustine Followed by GAZYVA Monotherapy Treated Arma (GADOLIN)

In the monotherapy phase of treatment with GAZYVA, the most frequently reported hematological laboratory abnormalities (incidence grater than or equal to 20%) were lymphopenia (80%), leukopenia (63%), low hemoglobin (50%), neutropenia (46%) and thrombocytopenia (35%). The most frequently reported hematological Grade 3 to 4 laboratory abnormalities (incidence ? 1%) during the monotherapy period were lymphopenia (52%), neutropenia (27%), leukopenia (20%) and thrombocytopenia (4%).

In the monotherapy phase of treatment with GAZYVA, the most frequently reported chemistry laboratory abnormalities (incidence ? 20%) were elevated creatinine (69%), decreased creatinine clearance (CrCl; 43%), hypophosphatemia (25%), AST/SGOT increased (24%) and ALT/SGPT increased (21%). The most frequently reported chemistry Grade 3 to 4 laboratory abnormalities (incidence ? 1%) during the monotherapy period were hypophosphatemia (5%), hyponatremia (3%) and decreased CrCl (1%).

 

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, CrCl < 40 mL/min and, unless attributable to lymphoma, hepatic transaminases > 2.5 x 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 greater than or equal to 20%) observed at least 2% more in the GAZYVA arm included infusion related reactions, neutropenia, upper respiratory tract infection, cough, constipation and diarrhea (Table 8). Neutropenia, infusion related reactions, febrile neutropenia and thrombocytopenia were the most common Grade 3 to 5 adverse reactions (incidence greater than or equal to 5%) observed more frequently in the GAZYVA arm.

Table 8 Common Adverse Reactions (Greater than or Equal to 10% Incidence and Greater than or Equal to 2% Greater in the GAZYVA Arm) in Patients with Previously Untreated NHL (GALLIUM) (Table has been added; please refer to label)

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

Neutropenia includes neutropenia, agranulocytosis, febrile neutropenia, 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, sinusitis bacterial, upper respiratory tract infection bacterial, pharyngitis streptococcal, sinusitis fungal, upper respiratory fungal infection, acute sinusitis, chronic sinusitis, laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, rhinovirus infection, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection.

Herpesvirus infection includes genital herpes, genital herpes zoster, herpes dermatitis, herpes ophthalmic, herpes simplex, herpes simplex pharyngitis, herpes virus infection, herpes zoster, herpes zoster disseminated, herpes zoster infection neurological, herpes zoster oticus, nasal herpes, ophthalmic herpes simplex, ophthalmic herpes zoster, oral herpes, varicella, varicella zoster virus infection. Pneumonia includes pneumonia bacterial, pneumonia haemophilus, pneumonia pneumococcal, pneumonia fungal, pneumocystis jirovecii infection, pneumocystis jirovecii pneumonia, atypical pneumonia, lung infection, pneumonia, pneumonia aspiration, lung infiltration.

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

Diarrhea includes diarrhea, defecation urgency, frequent bowel movement, gastroenteritis, gastroenteritis viral.

Headache includes cluster headache, headache, sinus headache, tension headache, migraine.

Insomnia includes initial insomnia, insomnia, sleep disorder.

Pruritus includes pruritus and pruritus generalized.

During the monotherapy period, the common adverse reactions (incidence greater than or equal to 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 Common New or Worsening Laboratory Abnormalities (Greater than or Equal to 10% Incidence and Greater than or Equal to 2% Greater in the GAZYVA Arm) in Patients with Previously Untreated NHL (GALLIUM) (Table has been added; please refer to label)

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 Reactions:

Chronic Lymphocytic Leukemia

The incidence of infusion reactions in the CLL11 study was 65% with the first infusion of GAZYVA…

Of the first 53 patients receiving GAZYVA in CLL11, 47 (89%) experienced an infusion reaction…

Non-Hodgkin Lymphoma

Overall, 69% of patients in the GADOLIN study experienced an infusion reaction (all grades) during treatment with GAZYVA in combination with bendamustine. The incidence of Grade 3 to 4 infusion reactions in GADOLIN was 11%...

During GAZYVA monotherapy in GADOLIN, infusion reactions (all grades) were observed in 8% of patients…

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

In GALLIUM, 72% of patients in the GAZYVA treated arm experienced an infusion reaction (all grades). The incidence of Grade 3 to 4 infusion reactions for these patients was 12%. In Cycle 1, the incidence of infusion reactions (all grades) was 62% in the GAZYVA treated arm with Grade 3 to 4 infusion reactions reported in 10%. The incidence of infusion reactions (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 infusion reactions (all grades) in the GAZYVA treated arm was 13% and decreased with subsequent cycles.

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

Overall, 1% of patients in GALLIUM experienced an infusion reaction 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 (38%) compared to the arm treated with bendamustine alone (32%)… The incidence of neutropenia was higher during treatment with GAZYVA in combination with bendamustine (31%) compared to the GAZYVA monotherapy treatment phase (12%).

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,…

Non-Hodgkin Lymphoma

The incidence of infection in GADOLIN was 66% in the GAZYVA plus bendamustine arm and 56% in the bendamustine arm, with Grade 3 to 4 events reported in 16% and 14%, respectively…

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 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…

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…

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 (24%)…

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 were 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 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: …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)…

6.2 Immunogenicity

(Additions and/or revisions are underlined)

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 to GAZYVA 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.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Non-Hodgkin Lymphoma

Of 194 patients in GADOLIN with relapsed or refractory NHL treated with GAZYVA plus bendamustine, 44% were 65 and over, while 14% were 75 and over… 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.

11/16/2017 (SUPPL-18)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

GAZYVA is contraindicated in patients with known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or to any of the excipients, or serum sickness with prior obinutuzumab use.

5 Warnings and Precautions

5.4 Hypersensitivity Reactions Including Serum Sickness

(Newly added subsection)

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, the infusion must be stopped and treatment permanently discontinued. Patients with known hypersensitivity reactions to GAZYVA, including serum sickness, must not be retreated.

 

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

• Hepatitis B virus reactivation
• Hypersensitivity reactions including serum sickness

6.3 Postmarketing Safety Information

(Newly added subsection)

The following adverse reactions have been identified during post-approval use of GAZYVA.

• Immune/Autoimmune Events: Serum sickness