"The U.S. Food and Drug Administration today expanded the approved use of Imbruvica (ibrutinib) for chronic lymphocytic leukemia (CLL) patients who have received at least one previous therapy.
CLL is a rare blood and bone marrow disease"...
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Infusion Reactions [see WARNINGS AND PRECAUTIONS]
- Hepatitis B Virus Reactivation [see WARNINGS AND PRECAUTIONS]
- Hepatitis B Virus Infection [see WARNINGS AND PRECAUTIONS]
- Progressive Multifocal Leukoencephalopathy [see WARNINGS AND PRECAUTIONS]
- Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
- Cytopenias [see WARNINGS AND PRECAUTIONS]
Previously Untreated CLL
The most common adverse reactions ( ≥ 10%) were infusion reactions and neutropenia (Table 3).
The most common adverse reactions ( ≥ 10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 5). 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.
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, parallelarm, 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/m 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 data described in Table 3 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 4 includes relevant hematologic laboratory abnormalities.
Table 3: Adverse Reactions With ≥ 5% Incidence in
Patients Receiving ARZERRA Plus Chlorambucil and Also ≥ 2% More Than
Patients Receiving Chlorambucil
|Adverse Reactions||ARZERRA Plus Chlorambucil (N = 217)||Chlorambucil (N = 227)|
|Grade ≥ 3
|Grade ≥ 3
|Herpes simplexb||6||0||4||< 1|
|Lower respiratory tract infection||5||1||3||< 1|
|Upper abdominal pain||5||0||3||0|
|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.
Table 4: Post-baseline Hematologic Laboratory
Abnormalities Occurring With ≥ 5% Incidence in Patients Receiving ARZERRA
Plus Chlorambucil and Also ≥ 2% More Than Patients Receiving Chlorambucil
|ARZERRA plus Chlorambucil
(N = 217)
(N = 227)
|Grade ≥ 3
|Grade ≥ 3
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 that were either Grade 3 or greater, serious, or led to treatment interruption or discontinuation 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.
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.
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 2 [n = 154]) or 3 doses (Study 3 [n = 27]).
The data described in Table 5 and other sections below are derived from 154 patients in Study 2. All patients received 2,000 mg weekly from the second dose onward. Ninety percent 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.
Table 5: Incidence of All Adverse Reactions Occurring
in ≥ 5% of Patients and in the Fludarabine- and Alemtuzumab-refractory
|Fludarabine- and Alemtuzumab- refractory
|Grade ≥ 3
|Grade ≥ 3
|Upper respiratory tract infection||11||0||3||0|
|Edema peripheral||9||< 1||8||2|
|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.
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.
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%.
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.
There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 300 patients with CLL were tested during and after treatment for antibodies to ARZERRA. There was no formation of anti-ofatumumab antibodies in patients with CLL after treatment with ofatumumab.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading.
The following adverse reactions have been identified during post-approval use of ARZERRA. 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.
Infusion-related Cardiac Events: Cardiac arrest.
Read the Arzerra (ofatumumab injection) Side Effects Center for a complete guide to possible side effects
Coadministration of ARZERRA with chlorambucil did not result in clinically relevant effects on the pharmacokinetics of chlorambucil or its active metabolite, phenylacetic acid mustard.
Read the Arzerra Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 4/30/2014
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