February 10, 2016
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Arzerra

"The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

 

CLL is a blood and bone ma"...

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Arzerra




Side Effects
Interactions

SIDE EFFECTS

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

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

Extended Treatment in CLL: The most common adverse reactions ( ≥ 10%) were infusion reactions, neutropenia and upper respiratory tract infection (Table 6).

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 7). 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, 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 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

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
aIncludes 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.
bIncludes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex.

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.

Extended Treatment in CLL

The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 2) 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 6 include relevant adverse reactions occurring up to 60 days after the last dose of study medication (last visit for observation arm).

Table 6: Adverse Reactions with ≥ 5% Incidence in Patients Receiving ARZERRA and Also ≥ 2% More than in Patients in Observation Arm

Adverse Reactions ARZERRA
(N = 237)
Observation Arm
(N = 237)
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
aIncludes 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.

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 subjects 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 subjects (5%) treated with ARZERRA and in 5 subjects (2%) in the observation arm. Late-onset neutropenia occurred in 2 subjects ( < 1%) treated with ARZERRA and 1 subject ( < 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 3 [n = 154]) or 3 doses (Study 4 [n = 27]).

The data described in Table 7 and other sections below are derived from 154 patients in Study 3. 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 7: Incidence of All Adverse Reactions Occurring in ≥ 5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset

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
aIncludes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia.
bIncludes rash, rash macular, and rash vesicular.
cIncludes sepsis, neutropenic sepsis, bacteremia, and septic shock.

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.

Immunogenicity

There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 550 patients with CLL were tested during and after treatment for antibodies to ARZERRA. Formation of anti-ofatumumab antibodies was observed in less than 1% of 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.

Postmarketing Experience

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

Mucocutaneous Reactions

Stevens-Johnson syndrome, porphyria cutanea tarda

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

DRUG INTERACTIONS

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

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

Last reviewed on RxList: 1/27/2016

Side Effects
Interactions

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