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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
ARZERRA® (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab.
The effectiveness of ARZERRA is based on the demonstration of durable objective responses [see Clinical Studies (14)]. No data demonstrate an improvement in disease related symptoms or increased survival with ARZERRA.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage Regimen
The recommended dose and schedule is 12 doses administered as follows:
Prepare all doses in 1,000 mL of 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)].
In the absence of infusional toxicity, the rate of infusion may be increased every 30 minutes as described in Table 1. Do not exceed the infusion rates in Table 1.
2.3 Dose Modification
2.5 Preparation and Administration
Preparation of Solution:
5 WARNINGS AND PRECAUTIONS
5.1 Infusion Reactions
ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions [see Adverse Reactions (6.1)].
Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4)]. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3)].
In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion.
Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.
5.3 Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture.
5.4 Hepatitis B Infection and Reactivation
Fulminant and fatal hepatitis B virus (HBV) infection can occur in patients newly exposed to HBV following treatment with ARZERRA. In addition, hepatitis B reactivation, including fulminant hepatitis and death, occurs with other monoclonal antibodies directed against CD20. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis.
5.5 Intestinal Obstruction
Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected.
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:
The most common adverse reactions (≥10%) in Study 1 were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections.
The most common serious adverse reactions in Study 1 were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation in Study 1.
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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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 1 [n = 154]) or 3 doses (Study 2 [n = 27]).
The data described in Table 2 and other sections below are derived from 154 patients in Study 1. 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.
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 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 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 patients with CLL in Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for anti-ofatumumab antibodies during and after the 24-week treatment period. Results were negative in 46 patients after the 8th infusion and in 33 patients after the 12th infusion.
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.
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)].
8.3 Nursing Mothers
It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman.
8.5 Geriatric Use
Clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3)].
8.6 Renal Impairment
No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3)].
ARZERRA (ofatumumab) is an IgG1κ human monoclonal antibody with a molecular weight of approximately 149 kDa. The antibody was generated via transgenic mouse and hybridoma technology and is produced in a recombinant murine cell line (NS0) using standard mammalian cell cultivation and purification technologies.
ARZERRA is a sterile, colorless, preservative-free liquid concentrate for intravenous administration. ARZERRA is supplied at a concentration of 20 mg/mL in single-use vials. Each single-use vial contains 100 mg ofatumumab in 5 mL of solution. Inactive ingredients include: 8.55 mg/mL sodium citrate and 0.195 mg/mL citric acid monohydrate as buffering agents, 5.85 mg/mL sodium chloride as an isotonic agent, and Water for Injection, USP as the solvent. The pH is 6.5.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ofatumumab binds specifically to both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is expressed on normal B lymphocytes (pre-B- to mature B-lymphocyte) and on B-cell CLL. The CD20 molecule is not shed from the cell surface and is not internalized following antibody binding.
The Fab domain of ofatumumab binds to the CD20 molecule and the Fc domain mediates immune effector functions to result in B-cell lysis in vitro. Data suggest that possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity.
In patients with CLL refractory to fludarabine and alemtuzumab, the median decrease in circulating CD19-positive B cells was 91% (n = 50) with the 8th infusion and 85% (n = 32) with the 12th infusion. The time to recovery of lymphocytes, including CD19-positive B cells, to normal levels has not been determined.
Pharmacokinetic data were obtained from 146 patients with refractory CLL who received a 300-mg initial dose followed by 7 weekly and 4 monthly infusions of 2,000 mg. The Cmax and AUC(0-∞) after the 8th infusion in Study 1 were approximately 40% and 60% higher than after the 4th infusion in Study 2. The mean volume of distribution at steady-state (Vss) values ranged from 1.7 to 5.1 L. Ofatumumab is eliminated through both a target-independent route and a B cell-mediated route. Ofatumumab exhibited dose-dependent clearance in the dose range of 100 to 2,000 mg. Due to the depletion of B cells, the clearance of ofatumumab decreased substantially after subsequent infusions compared to the first infusion. The mean clearance between the 4th and 12th infusions was approximately 0.01 L/hr and exhibited large inter-subject variability with CV% greater than 50%. The mean t1/2 between the 4th and 12th infusions was approximately 14 days (range: 2.3 to 61.5 days).
Special Populations: Cross-study analyses were performed on data from patients with a variety of conditions, including 162 patients with CLL, who received multiple infusions of ARZERRA as a single agent at doses ranging from 100 to 2,000 mg. The effects of various covariates (e.g., body size [weight, height, body surface area], age, gender, baseline creatinine clearance) on ofatumumab pharmacokinetics were assessed in a population pharmacokinetic analysis.
Body Weight: Volume of distribution and clearance increased with body weight. However, this increase was not clinically significant. No dosage adjustment is recommended based on body weight.
Age: Age did not significantly influence ofatumumab pharmacokinetics in patients ranging from 21 to 86 years of age. No pharmacokinetic data are available in pediatric patients.
Gender: Gender had a modest effect on ofatumumab pharmacokinetics (14% to 25% lower clearance and volume of distribution in female patients compared to male patients) in a cross-study population analysis (41% of the patients in this analysis were male and 59% were female). These effects are not considered clinically important, and no dosage adjustment is recommended.
Renal Impairment: Creatinine clearance at baseline did not have a clinically important effect on ofatumumab pharmacokinetics in patients with calculated creatinine clearance values ranging from 33 to 287 mL/min.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies.
13.3 Reproductive and Developmental Toxicology
Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values). Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown.
The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals.
14 CLINICAL STUDIES
Study 1 was a single-arm, multicenter study in 154 patients with relapsed or refractory CLL. ARZERRA was administered by intravenous infusion according to the following schedule: 300 mg (Week 0), 2,000 mg weekly for 7 infusions (Weeks 1 through 7), and 2,000 mg every 4 weeks for 4 infusions (Weeks 12 through 24). Patients with CLL refractory to fludarabine and alemtuzumab (n = 59) comprised the efficacy population. Drug refractoriness was defined as failure to achieve at least a partial response to, or disease progression within 6 months of, the last dose of fludarabine or alemtuzumab. The main efficacy outcome was durable objective tumor response rate. Objective tumor responses were determined using the 1996 National Cancer Institute Working Group (NCIWG) Guidelines for CLL.
In patients with CLL refractory to fludarabine and alemtuzumab, the median age was 64 years (range: 41 to 86 years), 75% were male, and 95% were White. The median number of prior therapies was 5; 93% received prior alkylating agents, 59% received prior rituximab, and all received prior fludarabine and alemtuzumab. Eighty-eight percent of patients received at least 8 infusions of ARZERRA and 54% received 12 infusions.
The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) with a median duration of response of 6.5 months (95% CI: 5.8, 8.3). There were no complete responses. Anti-tumor activity was also observed in additional patients in Study 1 and in a multicenter, open-label, dose-escalation study (Study 2) conducted in patients with relapsed or refractory CLL.
16 HOW SUPPLIED/STORAGE AND HANDLING
ARZERRA (ofatumumab) is a sterile, colorless, preservative-free liquid concentrate (20 mg/mL) for dilution and intravenous administration provided in single-use glass vials with a latex-free rubber stopper and an aluminum overseal. Each vial contains 100 mg ofatumumab in 5 mL of solution.
ARZERRA is available as follows:
Store ARZERRA refrigerated between 2° to 8°C (36° to 46°F). Do not freeze. Vials should be protected from light.
17 PATIENT COUNSELING INFORMATION
Advise patients to contact a healthcare professional for any of the following:
Advise patients of the need for:
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Principal Display Panel
Injection, for Intravenous Infusion
100 mg/5 mL
For Intravenous Infusion Only.
Must Be Diluted Prior To Administration.
Contains 10 vials
Contains 2 in-line filter sets
Single-Use Vials – Discard Unused Portion
Revised: 09/2010 GlaxoSmithKline LLC
Reproduced with permission of U.S. National Library of Medicine
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