2.1 Recommended Dosage Regimen

• Do not administer as an intravenous push or bolus.
• Premedicate before each infusion [see Dosage and Administration (2.4)].
• Administer with an in-line filter set supplied with product.

The recommended dosage and schedule is 12doses administered as follows:

• 300mg initial dose (Dose1), followed 1week later by
• 2,000mg weekly for 7doses (Doses2 through 8), followed 4weeks later by
• 2,000mg every 4weeks for 4doses (Doses9 through 12)

2.2 Administration

Prepare all doses in 1,000mL of 0.9% Sodium Chloride Injection, USP [see Dosage and Administration (2.5)].

• Dose 1: Initiate infusion at a rate of 3.6mg/hour (12mL/hour).
• Dose 2: Initiate infusion at a rate of 24mg/hour (12mL/hour).
• Doses 3 through 12: Initiate infusion at a rate of 50mg/hour (25mL/hour).

In the absence of infusional toxicity, the rate of infusion may be increased every 30minutes as described in Table1. Do not exceed the infusion rates in Table1.

2.3 Dose Modification

• Interrupt infusion for infusion reactions of any severity [see Warnings and Precautions (5.1)].
• For Grade4 infusion reactions, do not resume the infusion.
• For Grade1, 2, or 3 infusion reaction, if the infusion reaction resolves or remains less than or equal to Grade2, resume infusion with the following modifications according to the initial Grade of the infusion reaction.

   

  Grade1 or 2: Infuse at one-half of the previous infusion rate.

   

  Grade3: Infuse at a rate of 12mL/hour.

• After resuming the infusion, the infusion rate may be increased according to Table1 above, based on patient tolerance.

2.4 Premedication

• Premedicate 30minutes to 2hours prior to each dose with oral acetaminophen 1,000mg (or equivalent), oral or intravenous antihistamine (cetirizine 10mg or equivalent), and intravenous corticosteroid (prednisolone 100mg or equivalent).
• Do not reduce corticosteroid dose for Doses 1, 2, and 9.
• Corticosteroid dose may be reduced as follows for Doses 3 through 8 and 10 through 12:
  • Doses 3 through 8: Gradually reduce corticosteroid dose with successive infusions if a Grade3 or greater infusion reaction did not occur with the preceding dose.
  • Doses 10 through 12: Administer prednisolone 50mg to 100mg or equivalent if a Grade3 or greater infusion reaction did not occur with Dose9.

2.5 Preparation and Administration

• Do not shake product.
• Inspect parenteral drug products visually for particulate matter and discoloration prior to administration. ARZERRA should be a clear to opalescent, colorless solution and may contain a small amount of visible translucent-to-white, amorphous, ofatumumab particles. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present.

Preparation of Solution:

• 300-mg dose: Withdraw and discard 15mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 5mL from each of 3single-use 100mg vials of ARZERRA and add to the bag. Mix diluted solution by gentle inversion.
• 2,000-mg dose: Withdraw and discard 100mL from a 1,000-mL bag of 0.9% Sodium Chloride Injection, USP. Withdraw 50mL from each of 2single-use 1,000mg vials of ARZERRA and add to the bag. Mix diluted solution by gentle inversion.
• Store diluted solution between 2° to 8°C (36° to 46°F).
• No incompatibilities between ARZERRA and polyvinylchloride or polyolefin bags and administration sets have been observed.

Administration Instructions:

• Do not mix ARZERRA with, or administer as an infusion with, other medicinal products.
• Administer using an infusion pump with an administration set and the provided in-line filter set.
• Flush the intravenous line with 0.9% Sodium Chloride Injection, USP before and after each dose.
• Start infusion within 12hours of preparation.
• Discard prepared solution after 24hours.

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 2infusions [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 5patients developed Grade3 bronchospasm during infusion.

5.2 Cytopenias

Prolonged (≥1week) 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 Grade3 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 eva luation for PML including consultation with a neurologist, brain MRI, and lumbar puncture.

5.4 HepatitisB Infection and Reactivation

Fulminant and fatal hepatitisB virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers of hepatitisB for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12months 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 eva luation if obstruction is suspected.

5.6 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.

6.1 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 eva luated in 181patients with relapsed or refractory CLL in 2open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000mg beginning with the second dose for 11doses (Study1 [n=154]) or 3doses (Study2 [n=27]).

The data described in Table2 and other sections below are derived from 154patients in Study1. All patients received 2,000mg weekly from the second dose onward. Ninety percent of patients received at least 8infusions of ARZERRA and 55% received all 12infusions. The median age was 63years (range: 41 to 86years), 72% were male, and 97% were White.

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

Infections: A total of 108patients (70%) experienced bacterial, viral, or fungal infections. A total of 45patients (29%) experienced ≥Grade3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%.

Neutropenia: Of 108patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade3 neutropenia. Nineteen (18%) developed Grade4 neutropenia. Some patients experienced new onset Grade4 neutropenia >2weeks in duration.

6.2 Immunogenicity

There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from patients with CLL in Study1 were tested by enzyme-linked immunosorbent assay (ELISA) for anti-ofatumumab antibodies during and after the 24-week treatment period. Results were negative in 46patients after the 8th infusion and in 33patients 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.

8.1 Pregnancy

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 3.5times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral Bcells 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 Blymphocytes. 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.

8.4 Pediatric Use

Safety and effectiveness of ARZERRA have not been established in children.

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)].

8.7 Hepatic Impairment

No formal studies of ARZERRA in patients with hepatic impairment have been conducted.

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 Blymphocytes (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.

12.2 Pharmacodynamics

In patients with CLL refractory to fludarabine and alemtuzumab, the median decrease in circulating CD19-positive Bcells 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 Bcells, to normal levels has not been determined.

12.3 Pharmacokinetics

Pharmacokinetic data were obtained from 146patients with refractory CLL who received a 300-mg initial dose followed by 7weekly and 4monthly infusions of 2,000mg. The Cmax and AUC(0-∞) after the 8th infusion in Study1 were approximately 40% and 60% higher than after the 4th infusion in Study2. The mean volume of distribution at steady-state (Vss) values ranged from 1.7 to 5.1L. Ofatumumab is eliminated through both a target-independent route and a Bcell-mediated route. Ofatumumab exhibited dose-dependent clearance in the dose range of 100 to 2,000mg. Due to the depletion of Bcells, 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 0.01L/hr and exhibited large inter-subject variability with CV% greater than 50%. The mean t1/2 between the 4th and 12th infusions was approximately 14days (range: 2.3 to 61.5days).

Special Populations: Cross-study analyses were performed on data from patients with a variety of conditions, including 162patients with CLL, who received multiple infusions of ARZERRA as a single agent at doses ranging from 100 to 2,000mg. 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 86years 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 287mL/min.

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 7months with up to 3.5times the human dose of ofatumumab. Effects on male and female fertility have not been eva luated in animal studies.

13.3 Reproductive and Developmental Toxicology

Pregnant cynomolgus monkeys dosed with 0.7 or 3.5times 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 Bcells in the dams, with signs of initial Bcell recovery 50days after the final dose. Following Caesarean section at gestational day100, 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 Bcell 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.