May 31, 2016
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Gazyva

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Gazyva

Side Effects
Interactions

SIDE EFFECTS

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

Clinical Trial 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.

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

Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 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]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy.

The most common adverse reactions (incidence ≥ 10%) observed in patients with CLL in the GAZYVA containing arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea.

The most common Grade 3-4 adverse reactions (incidence ≥ 10%) observed in patients with CLL in the GAZYVA containing arm were neutropenia, infusion reactions, and thrombocytopenia.

Table 4 : Summary of Adverse Reactions Reported in ≥ 5% of Patients with CLL and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2)

Adverse Reactions
System Organ Class
GAZYVA + Chlorambucil
n = 336
Rituximab + Chlorambucil
n = 321
All Grades % Grades 3-4 % All Grades % Grades 3-4 %
Injury, poisoning and procedural complications
Infusion reactions 66 20 38 4
Blood and lymphatic system disordersa
Neutropenia 38 33 32 28
Thrombocytopenia 14 10 7 3
Leukopenia 6 4 2 < 1
General disorders and administration site conditions
Pyrexia 9 < 1 7 < 1
Gastrointestinal disorders
Diarrhea 10 2 8 < 1
Constipation 8 0 5 0
Infections and infestations
Nasopharyngitis 6 < 1 3 0
Urinary tract infection 5 1 2 < 1
aAdverse reactions reported under “Blood and lymphatic system disorders” reflect those reported by investigator as clinically significant.

Table 5 : Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients with CLL and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2)

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

Summary Of Clinical Trial Experience In Non-Hodgkin Lymphoma

The safety of GAZYVA was evaluated based on a safety population of 392 patients with indolent NHL, of whom 81% had FL. In the population of patients with FL, the profile of adverse reactions was consistent with the overall indolent NHL population. Patients were treated with either GAZYVA in combination with bendamustine, followed by GAZYVA monotherapy in patients that have not progressed, or with bendamustine alone.

Patients randomized to the GAZYVA + bendamustine arm received three weekly 1000 mg doses of GAZYVA in the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with bendamustine 90 mg/m² on Days 1 and 2 in all 6 cycles. Patient randomized to the bendamustine alone arm received 120 mg/m² on Days 1 and 2. This regimen continued for 6 cycles of 28 days in duration. For patients who did not progress on GAZYVA in combination with bendamustine, a single dose of 1000 mg GAZYVA monotherapy was given every two months until progression or for a maximum of two years. During combination therapy with GAZYVA and bendamustine, 79% of patients received all 6 treatment cycles of GAZYVA and 76% received all 6 treatment cycles of bendamustine compared to 67% of patients in the bendamustine alone arm.

The most common adverse reactions (incidence ≥ 10%) observed in patients with iNHL in the GAZYVA containing arm were infusion reactions, neutropenia, nausea, fatigue, cough, diarrhea, constipation, pyrexia, thrombocytopenia, vomiting, upper respiratory tract infection, decreased appetite, arthralgia, sinusitis, anemia, asthenia and urinary tract infection.

The most common Grade 3-4 adverse reactions (incidence ≥ 10%) observed in patients with iNHL in the GAZYVA containing arm were neutropenia, thrombocytopenia and infusion reactions.

Table 6 :Summary of Adverse Reactions Reported in ≥ 5% of Patients with Indolent NHL and at Least 2% Greater in the GAZYVA plus Bendamustine Followed by GAZYVA Monotherapy Treated Arm

Adverse Reactions
System Organ Class
GAZYVA + Bendamustine followed by GAZYVA monotherapy
n = 194
Bendamustine
n = 198
All Grades % Grades 3-4 % All Grades % Grades 3-4 %
Injury, Poisoning and Procedural Complications
Infusion related reactionsa 69 11 63 6
Blood and Lymphatic System Disorders
Neutropenia 35 33 28 26
Gastrointestinal Disorders
Constipation 19 0 16 0
Dyspepsia 5 0 3 0
General Disorders and Administration Site Conditions
Pyrexia 18 1 14 0
Asthenia 11 1 8 0
Infections and Infestations
Upper Respiratory Tract Infection 13 2 8 1
Sinusitis 12 1 5 0
Urinary Tract Infection 10 3 6 0
Nasopharyngitis 9 0 4 0
Musculoskeletal and Connective Tissue Disorders
Arthralgia 12 0 5 0
Pain in Extremity 9 1 4 0
Respiratory, Thoracic and Mediastinal Disorders
Cough 26 0 17 0
Nasal Congestion 7 0 2 0
Skin and Subcutaneous Tissue Disorders
Pruritus 9 0 6 0
aDefined as any related adverse reaction that occurred during or within 24 hours of infusion.

During the monotherapy period with GAZYVA, the most common adverse reactions in patients with iNHL were cough (15%), upper respiratory tract infections (12%), neutropenia (11%), sinusitis (10%), diarrhea (8%), infusion related reactions (8%), nausea (8%), fatigue (8%), bronchitis (7%), arthralgia (7%), pyrexia (6%), nasopharyngitis (6%), and urinary tract infections (6%). The most common Grade 3-4 adverse reactions during the monotherapy period were neutropenia (10%), and anemia, febrile neutropenia, thrombocytopenia, sepsis, upper respiratory tract infection, and urinary tract infection (all at 1%).

Table 7 :Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5% of Patients with iNHL and at Least 2% Greater in the GAZYVA plus Bendamustine Followed by GAZYVA Monotherapy Treated Arma

Laboratory Abnormalities GAZYVA + Bendamustine followed by GAZYVA monotherapy
n = 194
Bendamustine
n = 198
All Grades % Grades 3-4 % All Grades % Grades 3-4 %
Hematology
  Neutropenia 75 52 77 42
  Leukopenia 86 47 88 34
  Lymphopenia 99 93 99 85
Chemistry
  Hypocalcemia 38 2 26 2
  Hypophosphatemia 41 7 38 7
  ALT/SGPT increased 35 1 31 4
  Elevated creatinine 87 4 92 2
  Creatinine Clearance (decreased) 58 6 61 4
aTwo percent different in either the All Grades or Grade 3-4 Lab Abnormalities.

In the monotherapy phase of treatment with GAZYVA, the most frequently reported hematological laboratory abnormalities were lymphopenia (80%), leukopenia (63%), low hemoglobin (50%) and neutropenia (46%). The most frequently reported hematological Grade 3-4 laboratory abnormalities during the monotherapy period were lymphopenia (52%), neutropenia (27%) and leukopenia (20%).

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

Infusion Reactions

Chronic Lymphocytic Leukemia

The incidence of infusion reactions was 65% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 20% with 7% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and < 1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. 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 1000 mg (64 patients on day 1, 3 patients on day 2, and 7 patients on both days) and < 3% thereafter [see DOSAGE AND ADMINISTRATION].

Non-Hodgkin Lymphoma

Overall, 69% of patients experienced an infusion reaction (all grades) during treatment with GAZYVA in combination with bendamustine. The incidence of Grade 3-4 infusion reactions was 11%. In Cycle 1, the incidence of infusion reactions (all grades) was 55% in patients receiving GAZYVA in combination with bendamustine with Grade 3-4 infusion reactions reported in 9%. In patients receiving GAZYVA in combination with bendamustine, the incidence of infusion reactions was highest on Day 1 (38%), and gradually decreased on Days 2, 8 and 15 (25%, 7% and 4%, respectively).

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

During GAZYVA monotherapy, infusion reactions (all grades) were observed in 8% of patients. No grade 3-4 infusion reactions were reported during GAZYVA monotherapy.

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

Neutropenia

Chronic Lymphocytic Leukemia

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

Non-Hodgkin Lymphoma

The incidence of neutropenia was higher in the GAZYVA plus bendamustine arm (38%) compared to the arm treated with bendamustine alone (32%). Cases of prolonged neutropenia (3%) and late onset neutropenia (7%) were also reported in the GAZYVA plus bendamustine arm.

Infection

Chronic Lymphocytic Leukemia

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

Non-Hodgkin Lymphoma

The incidence of infection was 66% in the GAZYVA plus bendamustine arm and 56% in the bendamustine arm, with Grade 3-4 events reported in 16% and 14%, respectively. Fatal events were reported in 3% of patients in the GAZYVA plus bendamustine arm and 4% in the bendamustine arm.

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 treated arm (7%), with the incidence of Grade 3–4 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 were 11% in the GAZYVA and 3% in the rituximab treated arms, with Grade 3–4 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 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 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 3-4 hemorrhagic events were similar in both treatment arms (5% in the GAZYVA plus bendamustine arm and 3% in the bendamustine arm).

Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome in patients with CLL was 2% in the GAZYVA treated arm, and in patients with iNHL was 0.5% in the GAZYVA plus bendamustine treated arm.

Musculoskeletal Disorders

Chronic Lymphocytic Leukemia

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

Non-Hodgkin Lymphoma

Adverse events related to musculoskeletal disorders (all events from the System Organ Class), including pain, have been reported in the GAZYVA plus bendamustine treated arm with higher incidence than in the bendamustine alone arm (41% vs. 29%).

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 pivotal CLL study, there was no clinically meaningful difference in overall hepatotoxicity adverse events 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.

Gastro-Intestinal Perforation: Cases of gastro-intestinal perforation have been reported in patients receiving GAZYVA, mainly in NHL.

Immunogenicity

Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Of the GAZYVA treated patients with CLL, 7% (18/271) tested positive for anti-GAZYVA antibodies at one or more time points. In the pivotal iNHL trial, two out of 194 (1%) patients in the GAZYVA plus bendamustine arm tested positive for anti-GAZYVA antibodies at baseline and experienced infusion reactions. No patients with iNHL developed anti-GAZYVA antibodies during or following GAZYVA treatment. Neutralizing activity of anti-GAZYVA antibodies has not been assessed.

Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known.

Additional Clinical Trial Experience

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

Read the Gazyva (obinutuzumab injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No formal drug interaction studies have been conducted with GAZYVA.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 3/7/2016

Side Effects
Interactions

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