Gazyva Dailymed

• Infusion-Related Reactions: Premedicate patients with glucocorticoid, acetaminophen, and anti-histamine. Monitor patients closely during infusions. Interrupt, reduce rate, or discontinue for infusion-related reactions based on severity. (2.1, 5.3)
• Hypersensitivity Reactions Including Serum Sickness: Discontinue GAZYVA permanently. (5.4)
• Tumor Lysis Syndrome: Premedicate with anti-hyperuricemics and adequate hydration, especially for patients with high tumor burden, high circulating lymphocyte count or renal impairment. Correct electrolyte abnormalities, provide supportive care, and monitor renal function and fluid balance. (5.5)
• Infections: 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: In patients with Grade 3 to 4 neutropenia, monitor laboratory tests until resolution and for infection. Consider dose delays and infection prophylaxis, as appropriate. (5.7)
• Thrombocytopenia: Monitor for decreased platelet counts and bleeding. Transfusion may be necessary. (5.8)
• Disseminated Intravascular Coagulation: Evaluate cause and monitor for bleeding, thrombosis, and need for supportive care. (5.9)
• Immunization: Avoid administration of live virus vaccines during GAZYVA treatment and until B-cell recovery. (5.10)
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use effective contraception. (5.11)

5.1Hepatitis 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.

5.2Progressive 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.

5.3Infusion-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, anti-histamine, 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 IRR to GAZYVA. 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.

5.4Hypersensitivity 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 IRRs. 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 GAZYVA use [see Contraindications (4)].

5.5Tumor 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.

5.6Infections

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.

5.7Neutropenia

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.

5.8Thrombocytopenia

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.

5.9Disseminated Intravascular Coagulation (DIC)

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.

5.10Immunization

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.

5.11 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)].

6 Adverse Reactions

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

The most common adverse reactions (incidence ≥ 20% and ≥ 2% greater in the GAZYVA treated arm) were:

• Previously untreated CLL: infusion-related reactions and neutropenia. (6)
• Relapsed or refractory NHL: infusion-related reactions, fatigue, neutropenia, cough, upper respiratory tract infections, and musculoskeletal pain. (6)
• Previously untreated NHL: infusion-related reactions, neutropenia, upper respiratory tract infections, cough, constipation, 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.

6.1 Clinical Trials 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.

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

Body SystemAdverse Reactions	GAZYVA + Chlorambuciln = 336		Rituximab product + Chlorambuciln = 321
	All Grades%	Grades 3 to 4%	All Grades%	Grades 3 to 4%
Injury, Poisoning and Procedural Complications
Infusion-Related Reaction	66	20	38	4
Blood and Lymphatic System DisordersAdverse reactions reported under "Blood and lymphatic system disorders" reflect those reported by investigator as clinically significant.
Neutropenia	38	33	32	28
Thrombocytopenia	14	10	7	3
Gastrointestinal Disorders
Diarrhea	10	2	8	< 1
Constipation	8	0	5	0
General Disorders and Administration Site Conditions
Pyrexia	9	< 1	7	< 1
Infections and Infestations
Nasopharyngitis	6	< 1	3	0
Urinary Tract Infection	5	1	2	< 1

Table 6 Post-Baseline Laboratory Abnormalities (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA Arm) in Patients with CLL (Stage 2)

Laboratory Abnormalities	GAZYVA + Chlorambuciln = 336		Rituximab product + Chlorambuciln = 321
	All Grades %	Grades 3 to 4 %	All Grades %	Grades 3 to 4 %
Hematology
Leukopenia	84	35	62	16
Lymphopenia	80	39	50	16
Neutropenia	76	46	69	41
Thrombocytopenia	48	13	40	8
Anemia	39	10	37	10
Chemistry
Hypocalcemia	37	3	32	< 1
ALT increased	28	2	21	1
AST increased	27	2	21	< 1
Hyponatremia	26	7	18	2
Hypoalbuminemia	23	< 1	16	< 1
Hypokalemia	14	1	10	< 1

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 7 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 7 Adverse Reactions (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA Arm) in Patients with Relapsed or Refractory NHL (GADOLIN)

Body SystemAdverse ReactionsIncludes adverse reactions reported throughout study treatment and follow-up. , Includes grouped terms.	GAZYVA + Bendamustine followed by GAZYVA monotherapyn = 204		Bendamustinen = 203
	All Grades%	Grades 3 to 5%	All Grades%	Grades 3 to 5%
Procedural Complications
Infusion-Related ReactionExcept where noted, individual events that meet the definition of "infusion-related reaction" are excluded from Table 7 above, as they are included in the grouped term "Infusion-Related Reaction".	67	11	63	5
General Disorders
Fatigue	40	3	36	3
Pyrexia	19	1	15	1
Blood and Lymphatic System Disorders
Neutropenia	37	35Includes 1 fatal event.	29	27
Infections and Infestations
Upper Respiratory Tract Infection	36	3	23	1
Respiratory Tract Infection, Unspecified	14	1	8	0
Urinary Tract Infection	13	3	7	0
Respiratory, Thoracic and Mediastinal Disorders
Cough	31	<1	21	0
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal Pain	28	1	20	0
Arthralgia	12	<1	5	0
Skin and Subcutaneous Tissue Disorders
Rash	17	<1	14	<1
Pruritus	11	0	6	0

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

Table 8 New or Worsening Laboratory Abnormalities (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA ArmTwo percent difference in either any-grade or Grade 3 to 4 laboratory abnormalities.) in Patients with Relapsed or Refractory NHL (GADOLIN)

Laboratory Abnormalities	GAZYVA + Bendamustine followed by GAZYVA monotherapyn = 204		Bendamustinen = 203
	All Grades %	Grades 3 to 4 %	All Grades %	Grades 3 to 4 %
Hematology
Lymphopenia	97	92	96	84
Leukopenia	84	47	87	34
Neutropenia	76	53	75	42
Chemistry
Hypophosphatemia	41	8	38	7
Hypocalcemia	39	3	24	1
ALT/SGPT increased	36	2	31	3
Alkaline phosphatase increased	27	0	23	0
Hyperbilirubinemia	21	2	17	2
Hyperkalemia	20	3	18	0

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 9). 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 9 Adverse Reactions (Incidence ≥ 10% and ≥ 2% Greater in the GAZYVA Arm) in Patients with Previously Untreated NHL (GALLIUM)

Body SystemAdverse Reactions Includes adverse reactions reported throughout study treatment and follow-up. , Includes grouped terms.	GAZYVA + chemotherapy followed by GAZYVA monotherapyn = 691		Rituximab product + chemotherapy followed by rituximab product monotherapyn = 694
	All Grades%	Grades 3 to 5%	All Grades%	Grades 3 to 5%
Injury, Poisoning and Procedural Complications
Infusion-Related Reaction Except where noted, individual events that meet the definition of "infusion-related reaction" are excluded from Table 9 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.	72	12	60	8
Blood and Lymphatic System Disorders
Neutropenia Includes adverse reactions reported as infusion-related reactions.	53	49	47	41
Thrombocytopenia	14	7	8	3
Infections and Infestations
Upper Respiratory Tract Infection	50	3	43	1
Herpesvirus Infection	18	3	14	1
Pneumonia	14	7	12	6
Respiratory, Thoracic and Mediastinal Disorders
Cough	35	< 1	28	< 1
Gastrointestinal Disorders
Constipation	32	< 1	29	< 1
Diarrhea	30	3	26	2
Nervous System Disorders
Headache	18	< 1	15	< 1
Musculoskeletal and Connective Tissue Disorders
Arthralgia	16	0	14	< 1
Psychiatric Disorders
Insomnia	15	< 1	12	< 1
Metabolism and Nutrition Disorders
Decreased Appetite	14	< 1	12	< 1
Skin and Subcutaneous Tissue Disorders
Pruritus	11	< 1	9	0

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

Laboratory Abnormalities Includes lab abnormalities, reported throughout treatment and follow-up, that were new or worsening, or worsening from baseline unknown.	GAZYVA+ chemotherapy followed by GAZYVA monotherapyn = 691		Rituximab product + chemotherapy followed by rituximab product monotherapyn = 694
	All Grades %	Grades 3 to 4 %	All Grades %	Grades 3 to 4 %
Hematology
Lymphopenia	97	83	95	67
Leukopenia	92	49	89	39
Neutropenia	84	59	76	50
Thrombocytopenia	68	11	50	4
Chemistry
ALT increased	50	3	43	2
AST increased	44	1	41	1
Hypophosphatemia	36	5	33	5
Hypoalbuminemia	33	1	25	1
Hypoproteinemia	32	0	30	0
Hypocalcemia	32	1	26	1
Hyperuricemia	28	28	22	22
Hyponatremia	26	4	20	3
Hyperkalemia	23	1	17	1
Hypernatremia	16	< 1	13	0

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 ≥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. 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.

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

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 5). 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 5). 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.

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.

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 IRRs 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 IRRs (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.

6.2 Immunogenicity

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.

6.3 Postmarketing Experience

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