ARZERRA (Page 3 of 6)

5.3 Hepatitis B Virus Infection

Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis.

5.4 Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation.

5.5 Tumor Lysis Syndrome

Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 109 /L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function.

5.6 Cytopenias

Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA [see Adverse Reactions (6.1)]. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

5.7 Immunizations

The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

6 ADVERSE REACTIONS

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

  • Infusion Reactions [see Warnings and Precautions (5.1)]
  • Hepatitis B Virus Reactivation [see Warnings and Precautions (5.2)]
  • Hepatitis B Virus Infection [see Warnings and Precautions (5.3)]
  • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.4)]
  • Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]
  • Cytopenias [see Warnings and Precautions (5.6)]

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6.

The most common adverse reactions (≥10%) were infusion reactions and neutropenia (Table 4).

The data described in Table 4 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 5 includes relevant hematologic laboratory abnormalities.

Table 4. Adverse Reactions with ≥5% Incidence in Patients Receiving ARZERRA plus Chlorambucil and Also ≥2% More than Patients Receiving Chlorambucil
a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex.

Adverse Reactions

ARZERRA plus Chlorambucil

(N = 217)

Chlorambucil

(N = 227)

All Grades

%

Grade ≥3

%

All Grades

%

Grade ≥3

%

Infusion reactionsa

67

10

0

0

Neutropenia

27

26

18

14

Asthenia

8

<1

5

0

Headache

7

<1

3

0

Leukopenia

6

3

2

<1

Herpes simplexb

6

0

4

<1

Lower respiratory tract infection

5

1

3

<1

Arthralgia

5

<1

3

0

Upper abdominal pain

5

0

3

0

Table 5. Post-baseline Hematologic Laboratory Abnormalities Occurring with ≥5% Incidence in Patients Receiving ARZERRA plus Chlorambucil and Also ≥2% More than Patients Receiving Chlorambucil

Investigations

ARZERRA plus Chlorambucil

(N = 217)

Chlorambucil

(N = 227)

All Grades

%

Grade ≥3

%

All Grades

%

Grade ≥3

%

Leukopenia

67

23

28

4

Neutropenia

66

29

56

24

Lymphopenia

52

29

20

7

Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients.

Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone.

Relapsed CLL: The safety of ARZERRA in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide was evaluated in a randomized, open-label, parallel-arm, multicenter trial (Study 2) in 359 patients with relapsed CLL. Patients were randomized to receive ARZERRA as an intravenous infusion (Cycle 1: 300 mg on Day 1 and 1,000 mg on Day 8; followed by 1,000 mg on Day 1 of subsequent 28-day cycles for a maximum of 6 cycles). Standard fludarabine and cyclophosphamide therapy was administered as a 3-day course starting on the first day of each cycle, with initial dosages of 25 mg/m2 for fludarabine and 250 mg/m2 for cyclophosphamide. Table 6 includes adverse reactions occurring up to 60 days after the last dose of study medication.

The most common adverse reactions (≥10%) were infusion reactions, neutropenia, leukopenia and febrile neutropenia (Table 6).

Table 6. Adverse Reactions with ≥5% Incidence in Patients Receiving ARZERRA plus FC and Also ≥2% More than in Patients in Fludarabine and Cyclophosphamide Arm
a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.

Adverse Reactions

ARZERRA plus Fludarabine and Cyclophosphamide

(N = 181)

Fludarabine and Cyclophosphamide Arm

(N = 178)

All Grades

%

Grade >3

%

All Grades

%

Grade >3

%

Infusion reactionsa

60

9

28

3

Neutropenia

55

49

39

36

Leukopenia

15

12

6

3

Febrile neutropenia

10

10

8

8

Bronchitis

6

1

4

<1

Adverse reactions associated with decreased platelet counts (including but not limited to thrombocytopenia, platelet count decreased and pancytopenia) and decreased hemoglobin (including but not limited to anemia, hemoglobin decreased and pancytopenia) occurred less frequently in the ARZERRA plus fludarabine and cyclophosphamide arm than in the fludarabine and cyclophosphamide arm up to 60 days after the last dose of study treatment: 30% (all grades) and 15% (Grade ≥3) vs 38% (all grades) and 28% (Grade ≥3), respectively for decreased platelet counts; and 23% (all grades) and 10% (Grade ≥3) vs 33% (all grades) and 16% (Grade ≥3), respectively for decreased hemoglobin.

Infusion Reactions: On Day 1 of infusion, infusion reactions occurred in 49% (7% were >Grade 3) of patients treated with ARZERRA plus fludarabine and cyclophosphamide, compared to 16% (1% were >Grade 3) of patients treated with fludarabine and cyclophosphamide and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients in the ARZERRA plus fludarabine and cyclophosphamide. Serious adverse events of infusion reactions occurred in 2% of patients in the ARZERRA plus fludarabine and cyclophosphamide compared to <1% of patients treated with fludarabine and cyclophosphamide.

Neutropenia: The proportion of patients that had Grade 3 or greater neutropenia reported up to 60 days after the last dose of study medication was higher in patients treated with ARZERRA plus fludarabine and cyclophosphamide (51%) compared to the fludarabine and cyclophosphamide arm (37%). Grade 3 or greater neutropenic sepsis occurred in 2 patients (1%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 3 patients (2%) in the fludarabine and cyclophosphamide arm. Prolonged neutropenia occurred in 18 patients (10%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 20 patients (11%) in the fludarabine and cyclophosphamide arm. Late-onset neutropenia occurred in 13 patients (7%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 5 patients (3%) in the fludarabine and cyclophosphamide arm.

During the period between the first dose and 60 days after last dose there were five (3%) patients who died in the ARZERRA plus fludarabine and cyclophosphamide arm and ten (6%) patients who died in the fludarabine and cyclophosphamide arm.

Extended Treatment in CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 3) in 474 patients who had responded to therapy for their recurrent or progressive disease. Patients were randomized to receive ARZERRA as an intravenous infusion every 8 weeks or observation. The infusion schedule for ARZERRA was 300 mg on Day 1 followed 1 week later by 1,000 mg on Day 8 followed 7 weeks later by 1,000 mg and every 8 weeks thereafter for up to a maximum of 2 years. The data described in Table 7 include relevant adverse reactions occurring up to 60 days after the last dose of study medication (last visit for observation arm). The most common adverse reactions (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection (Table 7).

Table 7. Adverse Reactions with ≥5% Incidence in Patients Receiving ARZERRA and Also ≥2% More than in Patients in Observation Arm
a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.
ARZERRA(N = 237) Observation Arm(N = 237)
Adverse Reactions All Grades% Grade ≥3% All Grades% Grade ≥3%
Infusion reactionsa 46 4
Neutropenia 24 22 9 8
Upper respiratory tract infection 19 1 9 0
Bronchitis 9 <1 7 <1
Pneumonia 8 5 5 3
Influenza 6 0 3 0
Herpes zoster 5 <1 3 <1
Insomnia 5 <1 2 0
Back pain 5 0 3 0
Hypogammaglobulinemia 5 <1 <1 <1

Infusion Reactions: Infusion reactions occurred in 25% of patients on the day of Infusion 1 (300 mg) and decreased with subsequent infusions (between 2% to 10%).

Infections: A total of 154 patients (65%) treated with ARZERRA compared with 120 patients (51%) in the observation arm experienced bacterial, viral, or fungal infections. The incidence of serious infections, however, was similar for patients treated with ARZERRA (20%) and the observation arm (18%). The proportions of fatal infections in patients treated with ARZERRA and in the observation arm were 2% and 3% respectively.

Neutropenia: The proportion of patients that had Grade 3 or greater neutropenia reported up to 60 days after the last dose of study medication was higher in patients treated with ARZERRA (22%) compared with the observation arm (8%). There were no cases of neutropenic sepsis reported with ARZERRA. Prolonged neutropenia occurred in 13 patients (5%) treated with ARZERRA and in 5 patients (2%) in the observation arm. Late-onset neutropenia occurred in 2 patients (<1%) treated with ARZERRA and 1 patient (<1%) in the observation arm.

During the period between the first dose and 60 days after last dose there were two (1%) patients in the ofatumumab group who died due to adverse events and five (2%) patients in the observation group.

Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 4 [n = 154]) or 3 doses (Study 5 [n = 27]).

The data described in Table 8 and other sections below are derived from 154 patients in Study 4. All patients received 2,000 mg weekly from the second dose onward. Ninety percent (90%) of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white.

In refractory CLL, the most common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 8). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation.

Table 8. Incidence of All Adverse Reactions Occurring in ≥5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset
a Includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia.b Includes rash, rash macular, and rash vesicular.c Includes sepsis, neutropenic sepsis, bacteremia, and septic shock.

Adverse Reaction

Total Population

(N = 154)

Fludarabine‑ and Alemtuzumab‑refractory

(N = 59)

All Grades

%

Grade ≥3

%

All Grades

%

Grade ≥3

%

Pneumoniaa

23

14

25

15

Pyrexia

20

3

25

5

Cough

19

0

19

0

Diarrhea

18

0

19

0

Anemia

16

5

17

8

Fatigue

15

0

15

0

Dyspnea

14

2

19

5

Rashb

14

<1

17

2

Bronchitis

11

<1

19

2

Nausea

11

0

12

0

Upper respiratory tract infection

11

0

3

0

Edema peripheral

9

<1

8

2

Back pain

8

1

12

2

Chills

8

0

10

0

Nasopharyngitis

8

0

8

0

Sepsisc

8

8

10

10

Urticaria

8

0

5

0

Insomnia

7

0

10

0

Headache

6

0

7

0

Herpes zoster

6

1

7

2

Hyperhidrosis

5

0

5

0

Hypertension

5

0

8

0

Hypotension

5

0

3

0

Muscle spasms

5

0

3

0

Sinusitis

5

2

3

2

Tachycardia

5

<1

7

2

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions.

Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine‑ and alemtuzumab‑refractory group was 17%.

Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration.

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