Potential GAZYVA Side Effects for Chronic Lymphocytic Leukemia

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CLL-11 Stage II: Summary of Investigator-Reported Adverse Reactions¹

Summary of adverse reactions reported in ≥5% of patients with CLL and at least 2% greater in the GAZYVA treated arm (Stage 2)

Body System Adverse Reactions	GAZYVA + chlorambucil (n=336)	rituximab product + chlorambucil (n=321)

	All Grades %	Grades 3 to 4 %	All Grades %	Grades 3 to 4 %
Injury, poisoning, and procedural complications
Infusion-related reactions	66	20	38	4
Blood and lymphatic system disorders^a
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

GAZYVA + chlorambucil (n=336)	rituximab product + chlorambucil (n=321)
Body System Adverse Reactions

Injury, poisoning, and procedural complications

Infusion-related reactions
All Grades %
66	38
Grades 3 to 4 %
20	4
Blood and lymphatic system disorders^a

Neutropenia
All Grades %
38	32
Grades 3 to 4 %
33	28
Thrombocytopenia
All Grades %
14	7
Grades 3 to 4 %
10	3
Gastrointestinal disorders

Diarrhea
All Grades %
10	8
Grades 3 to 4 %
2	<1
Constipation
All Grades %
8	5
Grades 3 to 4 %
0	0
General disorders and administration site conditions

Pyrexia
All Grades %
9	7
Grades 3 to 4 %
<1	<1
Infections and infestations

Nasopharyngitis
All Grades %
6	3
Grades 3 to 4 %
<1	0
Urinary tract infection
All Grades %
5	2
Grades 3 to 4 %
1	<1

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

Withdrawals from treatment due to adverse reactions: 13% of patients receiving GAZYVA + Clb vs 8% of patients receiving rituximab product + Clb¹⁰

Protocol modifications were implemented to help mitigate infusion-related reactions. For more information, click here

CLL-11 Stage II: Summary of Laboratory Abnormalities¹

Post-baseline laboratory abnormalities (incidence ≥10% and ≥2% greater in the GAZYVA arm) in patients with CLL (Stage 2)

Laboratory Abnormalities	GAZYVA + chlorambucil (n=336)	rituximab product + chlorambucil (n=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

GAZYVA + bendamustine followed by GAZYVA monotherapy (n=204)	Bendamustine (n=203)
Laboratory Abnormalities

Hematology

Leukopenia
All Grades %
84	62
Grades 3 to 4 %
35	16
Lymphopenia
All Grades %
80	50
Grades 3 to 4 %
39	16
Neutropenia
All Grades %
76	69
Grades 3 to 4 %
46	41
Thrombocytopenia
All Grades %
48	40
Grades 3 to 4 %
13	8
Anemia
All Grades %
39	37
Grades 3 to 4 %
10	10
Chemistry

Hypocalcemia
All Grades %
37	32
Grades 3 to 4 %
3	<1
ALT increased
All Grades %
28	21
Grades 3 to 4 %
2	1
AST increased
All Grades %
27	21
Grades 3 to 4 %
2	<1
Hyponatremia
All Grades %
26	18
Grades 3 to 4 %
7	2
Hypoalbuminemia
All Grades %
23	16
Grades 3 to 4 %
<1	<1
Hypokalemia
All Grades %
14	10
Grades 3 to 4 %
1	<1

Increased monitoring is recommended in the first cycle of GAZYVA¹

An increased rate of thrombocytopenia was observed in Cycle 1, which decreased with subsequent cycles
- The overall incidence of hemorrhagic events was similar in the GAZYVA and rituximab product treated arms, with 4 and 3 fatal events reported, respectively

The rate of infections was similar between the GAZYVA and rituximab product treated arms¹

The infection rates in the GAZYVA and rituximab product treated arms were comparable (38% vs 37%)
- Grades 3-4: 11% vs 13%, respectively
- Fatal events: 1% of patients in each of the treatment arms

SELECT CLL-11 STAGE II SAFETY INFORMATION

Adverse reactions for GAZYVA + chlorambucil vs rituximab product + chlorambucil

Infusion-Related Reactions: The incidence of infusion-related reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion-related reactions 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 infusion-related reactions were reported beyond the first 1,000 mg infused.

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab product treated arm, with the incidence of serious adverse events being 1% and <1%, respectively. 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.

Infections: 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.

Thrombocytopenia: The overall incidence of thrombocytopenia reported as an adverse reaction was 14% in the GAZYVA treated arm and 7% in the rituximab product treated arm, with the incidence of Grade 3 to 4 events being 10% and 3%, 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 arm and 4 in the GAZYVA treated arm. However, all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1.

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

Musculoskeletal Disorders: Adverse reactions related to musculoskeletal disorders, including pain, have been reported in the GAZYVA treated arm with higher incidence than in the rituximab product treated arm (18% vs 15%).

Liver Enzyme Elevations: Hepatic enzyme elevations occurred in patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels (AST, ALT, and ALP). The events occurred most frequently within 24-48 hours of the first infusion. There was no clinically meaningful difference in overall hepatotoxicity adverse reactions between all arms (4% of patients in the GAZYVA treated arm).

Gastrointestinal Perforation: Cases of gastrointestinal perforation have been reported in patients receiving GAZYVA.

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

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Side Effect Information for Patients

NEXT: Incidence of IRRs

Indications

GAZYVA^® (obinutuzumab), in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

GAZYVA^® (obinutuzumab), in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma (FL).

GAZYVA^® (obinutuzumab), in combination with bendamustine followed by GAZYVA monotherapy, is indicated for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen.

BOXED WARNINGS: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation
Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA

Contraindications

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

Warnings and Precautions

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 including GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and 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 (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive)
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level, or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, ie, increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death
Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with 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
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

Progressive Multifocal Leukoencephalopathy (PML)

JC virus infection resulting in 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

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, and 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, an 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
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

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 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

Tumor Lysis Syndrome (TLS)

Tumor lysis syndrome, 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 antihyperuricemics (e.g. allopurinol or rasburicase) and hydration prior to the infusion of GAZYVA for patients at risk for TLS. 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

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, 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
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

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

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 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. 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 or anticoagulants), especially during the first cycle

Disseminated 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. 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

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

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. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers. Advise females of reproductive potential to use effective contraception while receiving GAZYVA and for 6 months after the last dose

Lactation

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

Geriatric Use

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
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

Additional Important Safety Information

Previously Untreated CLL

The most common Grade 3 to 4 adverse reactions (incidence ≥10%) observed in patients with CLL in the GAZYVA containing arm were neutropenia, infusion-related reactions, and thrombocytopenia
The most common adverse reactions (incidence ≥10%) observed in patients with CLL in the GAZYVA containing arm were infusion-related reactions, neutropenia, thrombocytopenia, and diarrhea
Adverse reactions rates and laboratory abnormalities from the Stage 2 phase 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

Relapsed/Refractory NHL

The GADOLIN study evaluated safety in 407 patients with relapsed or refractory NHL, including FL (81%), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) (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 patients with follicular lymphoma, the profile of adverse reactions was consistent with the overall NHL population
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. Throughout follow-up, 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
The most common adverse reactions (incidence ≥20%) in GAZYVA recipients included infusion-related reactions, fatigue, neutropenia, cough, upper respiratory tract infections, and musculoskeletal pain
During GAZYVA monotherapy (160 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
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%)

Previously Untreated NHL

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%)
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
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
Throughout treatment and follow-up, the most common adverse reactions (incidence ≥20%) observed at least 2% more in the GAZYVA arm were infusion-related reactions (72%), neutropenia (53%), upper respiratory tract infection (50%), cough (35%), constipation (32%) and diarrhea (30%)
During the monotherapy period, the common adverse reactions (incidence ≥10%) observed at least 2% more with GAZYVA were upper respiratory infection (40%), cough (23%), musculoskeletal pain (20%), neutropenia (19%) and herpesvirus infection (13%)

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch, or calling 1-800-FDA-1088.

Please see the full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.

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