The incidence of Grade 3 to 4 infections in the GAZYVA and rituximab product treated arms was lower in patients receiving GCSF prophylaxis ( 14 %; 16 %) compared with patients not receiving GCSF prophylaxis ( 24 %; 18 %). The incidence of fatal infections in patients receiving GCSF prophylaxis in the GAZYVA and rituximab product treated arms was 2 % and 0 %, respectively , and was 2 % and < 1 % in patients not receiving GCSF prophylaxis . Thrombocytopenia : Chronic Lymphocytic Leukemia The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm ( 14 %) compared to the rituximab product treated arm ( 7 %), with the incidence of Grade 3 to 4 events being 10 % and 3 %, respectively ( Table 4 ). The difference in incidences between the treatment arms is driven by events occurring during the first cycle . The incidence of thrombocytopenia ( all grades ) in the first cycle was 11 % in the GAZYVA and 3 % in the rituximab product treated arms , with Grade 3 to 4 rates being 8 % and 2 %, respectively . Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia ( occurring within 24 hours after the GAZYVA infusion ). The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms , with 3 in the rituximab product and 4 in the GAZYVA treated arms . However , all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1 . Non-Hodgkin Lymphoma The incidence of thrombocytopenia in GADOLIN was lower in the GAZYVA plus bendamustine arm ( 15 %) compared to the arm treated with bendamustine alone ( 24 %). The incidence of hemorrhagic events in GAZYVA plus bendamustine treated patients compared to bendamustine alone was 11 % and 10 %, respectively . Grade 3 to 4 hemorrhagic events were similar in both treatment arms ( 5 % in the GAZYVA plus bendamustine arm and 3 % 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 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 the GAZYVA plus bendamustine treated arm with higher incidence than in the bendamustine alone arm ( 41 % vs . 29 %). In GALLIUM , musculoskeletal disorders were reported in 54 % of patients in the GAZYVA treated arm and 49 % of patients in the rituximab product treated arm . Liver Enzyme Elevations : Hepatic enzyme elevations have occurred in CLL patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels ( AST , ALT and ALP ). The events occurred most frequently within 24 – 48 hours of the first infusion . In some patients , elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome . In the CLL11 study , there was no clinically meaningful difference in overall hepatotoxicity adverse reactions between all arms ( 4 % of patients in the GAZYVA treated arm ). Medications commonly used to prevent infusion reactions ( e . g ., acetaminophen ) may also be implicated in these events . Monitor liver function tests during treatment , especially during the first cycle . Consider treatment interruption or discontinuation for hepatotoxicity . Gastrointestinal Perforation : Cases of gastrointestinal perforation have been reported in patients receiving GAZYVA , mainly in NHL . Worsening of Pre-existing Cardiac Conditions : Fatal cardiac events have been reported in patients treated with GAZYVA .

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 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 . 6.3 Postmarketing Safety Information The following adverse reactions have been identified during post-approval use of GAZYVA .

• Immune / Autoimmune Events : Serum sickness 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary GAZYVA is likely to cause fetal B-cell depletion based on findings from animal studies and the drug ’ s mechanism of action [ see Clinical Pharmacology ( 12.1 )]. There are no data with GAZYVA use in pregnant women to inform a drug-associated risk . Monoclonal antibodies are transferred across the placenta . In animal reproduction studies , weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1000 mg monthly produced opportunistic infections and immune complex mediated hypersensitivity reactions . No embryo-toxic or teratogenic effects were observed in the monkeys ( see Data ). Consider the potential risk to the fetus when prescribing GAZYVA to a pregnant woman . The background risk of major birth defects and miscarriage for the indicated population is unknown ; Print-only however , the estimated content background risk in the U . S . general population of major birth defects is 2 % to 4 % and of miscarriage is 15 % to 20 % of clinically recognized pregnancies . Clinical Considerations Fetal / Neonatal Adverse Reactions GAZYVA is likely to cause fetal B-cell depletion ( see Data ). Avoid administering live vaccines to neonates and infants exposed to GAZYVA in utero until B-cell recovery occurs [ see Warnings and Precautions ( 5.8 ) and Clinical Pharmacology ( 12.2 )]. Data Animal Data In a pre- and post-natal development study , pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg / kg obinutuzumab from day 20 of pregnancy until parturition , which includes the period of organogenesis . The high dose results in an exposure ( AUC ) that is 2.4 times the exposure in patients with CLL at the recommended label dose . There were no embryotoxic or teratogenic effects in animals . Secondary opportunistic infections , immune complex mediated hypersensitivity reactions , or a combination of both were observed in exposed dams . When first measured on day 28 postpartum , obinutuzumab was detected in offspring at levels in the range of maternal serum levels on the same day , and B-cells were completely depleted . The B-cell counts returned to normal levels , and immunologic function was restored within 6 months after birth . Obinutuzumab was measured in the milk of lactating cynomolgus monkeys on day 28 postpartum after weekly intravenous administration from day 20 of pregnancy until parturition . Concentrations in milk were approximately 0.04 % and 0.13 % of concentrations in maternal serum in the 25 and 50 mg / kg groups , respectively . 8.2 Lactation Risk Summary There is no information regarding the presence of GAZYVA in human milk , the effects on the breastfed child , or the effects on milk production . However , low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [ see Use in Specific Populations ( 8.1 )]. Human IgG is known to be present in human milk . Published data suggest that antibodies in breast milk do not enter the neonatal and child circulations in substantial amounts . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for GAZYVA and any potential adverse effects on the breastfed child from GAZYVA or from the underlying maternal condition . 8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients have not been established . 8.5 Geriatric Use Chronic Lymphocytic Leukemia Of 336 patients with previously untreated CLL who received GAZYVA in combination with chlorambucil , 81 % were 65 years and older , while 46 % were 75 and older . Of the patients 75 years and older , 46 % experienced serious adverse reactions and 7 % experienced adverse reactions leading to death . Of the patients younger than 75 , 33 % experienced a serious adverse reaction and 2 % an adverse reaction leading to death . No significant differences in efficacy were observed between younger and older patients [ see Clinical Studies ( 14.1 )]. Non-Hodgkin Lymphoma Of 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 . In patients 65 and over , 52 % of patients experienced serious adverse reactions and 26 % experienced adverse reactions leading to treatment withdrawal while in patients under 65 , 28 % and 12 % experienced serious adverse reactions and adverse reactions leading to treatment withdrawal , respectively . No clinically meaningful differences in efficacy were observed between these patients and younger patients in GADOLIN . Of the 691 patients in GALLIUM treated with GAZYVA plus chemotherapy as first-line therapy , 33 % were 65 and over , while 7 % were 75 and over . Of patients 65 and over , 63 % experienced serious adverse reactions and 26 % experienced adverse reactions leading to treatment withdrawal , while in patients under 65 , 43 % experienced serious adverse reactions and 13 % had an adverse reaction leading to treatment withdrawal . No clinically meaningful differences in efficacy were observed between these patients and younger patients in GALLIUM . 10 OVERDOSAGE There has been no experience with overdose in human clinical trials . For patients who experience overdose , treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy . 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following :

• Signs and symptoms of infusion 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 )].

Advise patients of the need for :

• Periodic monitoring of blood counts [ see Warnings and Precautions ( 5.7 and 5.8 ) and Adverse Reactions ( 6.1 )].

• Avoid vaccinations with live viral vaccines [ see Warnings and Precautions ( 5.9 )].

• 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 [ see Use in Specific Populations ( 8.1 )].

GAZYVA ® ( obinutuzumab )

Manufactured by : Genentech , Inc . A Member of the Roche Group South San Francisco , CA 94080-4990

U . S . License No . 1048 Initial US Approval : 2013 Code Revision Date : November 2017 GAZYVA is a registered trademark of Genentech , Inc . GAZ / 010816 / 0009 ( 2 ) 11 / 17 © 2017 Genentech , Inc .

Adding the proteasome inhibitor bortezomib to standard R-CHOP ( rituximab , cyclophosphamide , doxorubicin , vincristine , prednisone ) did not significantly improve outcomes , compared with R-CHOP alone in patients with non – germinal center B-cell – like ( GCB ) diffuse large B-cell lymphoma ( DLBCL ). John P . Leonard , MD , of Weill Cornell Medicine and New York Presbyterian Hospital , and co-authors published the findings in the Journal of Clinical Oncology .

The open-label , multicenter , prospective , randomized , phase II PYRAMID ( Personalized Lymphoma Therapy : Randomized Study of Proteasome Inhibition in Non-GCB DLBCL ) trial enrolled 206 patients from 69 U . S . sites between October 2009 and July 2013 . Adult patients with untreated DLBCL with one or more measurable tumor masses and no central nervous system lymphoma were included . People were excluded from the trial if they had any other malignancy within two years of first dose , grade ≥2 peripheral neuropathy , and heart disease or uncontrolled cardiovascular conditions .

Patients were stratified by International Prognostic Index ( IPI ) risk

February 2018