Class: Antineoplastic Agents
VA Class: AN900
[Posted 09/25/2013] ISSUE: FDA approved changes to the prescribing information of the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab) to add new Boxed Warning information about the risk of reactivation of hepatitis B virus (HBV) infection. The revised labels also will include additional recommendations for screening, monitoring, and managing patients on these drugs to decrease this risk.
In patients with prior HBV infection, HBV reactivation may occur when the body’s immune system is impaired. HBV reactivation has occurred in patients with prior HBV exposure who are later treated with drugs classified as CD20-directed cytolytic antibodies, including Arzerra (ofatumumab) and Rituxan (rituximab). Some cases have resulted in fulminant hepatitis, hepatic failure, and death.
See the FDA Drug Safety Communication for additional information, including a Data Summary.
BACKGROUND: Arzerra is used to treat chronic lymphocytic leukemia (CLL) in patients who have further disease after treatment with the anti-cancer drugs fludarabine and alemtuzumab. Rituxan is used to treat non-Hodgkin’s lymphoma and CLL. It is also used to treat other medical conditions, including rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
RECOMMENDATION: To decrease the risk of HBV reactivation, FDA recommends that health care professionals:
Screen all patients for HBV infection before starting treatment with Arzerra or Rituxan by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc)
Consult with hepatitis experts regarding monitoring and use of HBV antiviral therapy when screening identifies patients at risk of HBV reactivation due to evidence of prior HBV infection
Monitor patients with evidence of prior HBV infection for clinical and laboratory signs of hepatitis B or HBV reactivation during Arzerra or Rituxan therapy and for several months thereafter, since reactivations have occurred several months following completion of therapy with these drugs
In patients who develop reactivation of HBV while on Arzerra or Rituxan, immediately discontinue the drug and start appropriate treatment for HBV. Also discontinue any chemotherapy the patient is receiving until the HBV infection is controlled or resolved. Because of insufficient data, no recommendation can be made regarding the resumption of Arzerra or Rituxan in patients who develop HBV reactivation hepatitis
- For Patients:
Before receiving Arzerra or Rituxan, tell your health care professional if you have or have had any severe infections, including HBV
If you have had HBV infection, your health care professional should monitor you for HBV infection during treatment and for several months after you stop treatment with Arzerra or Rituxan
For more information visit the FDA website at: and .
Uses for Ofatumumab
Chronic Lymphocytic Leukemia (CLL)
Designated an orphan drug by FDA for the treatment of B-CLL.2
Ofatumumab Dosage and Administration
To minimize risk of infusion-related reactions, administer oral acetaminophen 1 g (or equivalent), an oral or IV antihistamine (cetirizine hydrochloride 10 mg or equivalent), and an IV corticosteroid (prednisolone 100 mg [IV formulation not commercially available in US] or equivalent [e.g., methylprednisolone 80 mg])14 30 minutes to 2 hours prior to each ofatumumab infusion.1
Depending on patient tolerance of the infusions, reduction of corticosteroid dose administered prior to ofatumumab doses 3–8 and 10–12 may be feasible; however, do not reduce corticosteroid dose administered prior to ofatumumab doses 1, 2, and 9.1
Over the course of doses 3–8, corticosteroid dose may be gradually reduced with successive infusions if the previous infusion did not result in an infusion reaction of grade 3 or greater.1
If dose 9 of ofatumumab does not result in an infusion reaction of grade 3 or greater, a prednisolone dose of 50–100 mg (or equivalent) may be administered prior to doses 10–12.1
For solution compatibility information, see Compatibility under Stability.
Must be diluted prior to IV infusion.1
Do not shake vial.1
Vials are for single use only. 1
To prepare a 300-mg dose (dose 1 in the 12-dose regimen): Withdraw 15 mL of solution from a polyolefin bag containing 1 L of 0.9% sodium chloride injection and discard the solution.1 Then withdraw 15 mL of ofatumumab injection concentrate from a total of 3 vials (each containing 100 mg in 5 mL) of the drug and add the drug concentrate to the polyolefin bag to yield a final concentration of 0.3 mg/mL; gently invert bag to mix solution.1
To prepare a 2-g dose (doses 2–12 in the 12-dose regimen): Withdraw 100 mL of solution from a polyolefin bag containing 1 L of 0.9% sodium chloride injection and discard the solution.1 Then withdraw 100 mL of ofatumumab injection concentrate from a total of 20 vials (each containing 100 mg in 5 mL) of the drug and add the drug concentrate to the polyolefin bag to yield a final concentration of 2 mg/mL; gently invert bag to mix solution.1
Begin infusion of the diluted solution within 12 hours of preparation.1
Rate of Administration
Dose 1 (300 mg): Infuse as 0.3-mg/mL solution at initial rate of 3.6 mg/hour (12 mL/hour); if infusion-related events do not occur, the infusion rate may be doubled (from 12 mL/hour to 25, 50, 100, and then 200 mL/hour) every 30 minutes to maximum rate of 60 mg/hour (200 mL/hour).1
Dose 2 (2 g): Infuse as 2-mg/mL solution at initial rate of 24 mg/hour (12 mL/hour); if infusion-related events do not occur, the infusion rate may be doubled (from 12 mL/hour to 25, 50, 100, and then 200 mL/hour) every 30 minutes to maximum rate of 400 mg/hour (200 mL/hour).1
Doses 3–12 (2 g each): Infuse as 2-mg/mL solution at initial rate of 50 mg/hour (25 mL/hour); if infusion-related events do not occur, the infusion rate may be doubled (from 25 mL/hour to 50, 100, 200, and then 400 mL/hour) every 30 minutes to maximum rate of 800 mg/hour (400 mL/hour).1
If the infusion reaction is grade 1–3, the infusion may be restarted once the reaction has resolved completely or if it remains grade 2 or less.1 Resume the infusion at one-half the previous infusion rate (for grade 1 and 2 reactions) or at 12 mL/hour (for grade 3 reactions); increase the infusion rate as tolerated by doubling the rate (as described above) every 30 minutes.1
Regimen consists of 12 doses: Initial dose of 300 mg followed 1 week later by 2 g given once weekly for 7 doses, then 4 weeks later by 2 g given once monthly for 4 doses.1
Therapy Interruptions for Toxicity
Interrupt the infusion if an infusion-related reaction of any severity occurs (see Infusion-related Effects under Cautions).1 If the reaction is grade 4, do not resume the infusion.1 If the reaction is grade 1–3, the infusion may be restarted (see Rate of Administration under Dosage and Administration) once the reaction has resolved completely or if it remains grade 2 or less in severity.1
No specific dosage recommendations; not specifically studied in hepatic impairment.1
No specific dosage recommendations; not specifically studied in renal impairment.1
No specific dosage recommendations.1
Cautions for Ofatumumab
No known contraindications.1
Risk of serious infusion-related reactions (e.g., bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, angioedema). 1 Generally occur more frequently during the first 2 infusions than during subsequent infusions of the drug.1 5
In a clinical trial in patients with moderate to severe COPD, grade 3 bronchospasm occurred in 2 of 5 patients during ofatumumab infusions.1
Premedication (acetaminophen, antihistamine, and corticosteroid) recommended prior to each infusion.1 (See Premedication under Dosage and Administration.)
Monitor patients closely during infusions of the drug for manifestations of infusion-related reactions.1
Interrupt the infusion if an infusion-related reaction of any severity occurs.1 (See Rate of Administration under Dosage and Administration.)
Provide appropriate treatment and supportive care for severe reactions (e.g., angina, other manifestations of myocardial ischemia).1
Risk of severe, prolonged (lasting ≥1 week) neutropenia; risk of thrombocytopenia.1
Monitor CBCs and platelet counts at regular intervals; more frequent monitoring recommended in patients with grade 3 or 4 cytopenia.1
Progressive Multifocal Leukoencephalopathy (PML)
PML (which may be fatal) reported.1 12 Consider PML in any patient with new or worsening neurologic manifestations.1 If PML is suspected, discontinue the drug and initiate diagnostic evaluation (e.g., consultation with neurologist, brain magnetic resonance imaging (MRI) scan, lumbar puncture) as clinically indicated.1
Patients Infected with Hepatitis B Virus (HBV)
Risk of reactivation of HBV infection, including fulminant hepatitis and death, with use of anti-CD20 monoclonal antibodies in chronic carriers of this virus.1 Screen patients at high risk for HBV infection prior to initiation of ofatumumab therapy.1 Closely monitor HBV carriers for active HBV infection during and for 6–12 months after completion of therapy.1
Discontinue ofatumumab and initiate appropriate treatment (e.g., antiviral therapy) if viral hepatitis develops or HBV reactivation occurs.1 12 Safety of ofatumumab in patients with active HBV infection is not known.1
Avoid immunization with live virus vaccines in patients who have recently received ofatumumab (safety not established).1
Ability of patients who have received ofatumumab therapy to generate a primary or anamnestic humoral response to any vaccine has not been studied.1
Monitor CBCs and platelet counts at regular intervals; more frequent monitoring recommended in patients with grade 3 or 4 cytopenia.1
Bacterial, viral, or fungal infections reported with ofatumumab therapy in 70% of patients with relapsed or refractory B-CLL; 29% of patients receiving the drug had grade 3 or 4 infections and 12% had fatal infections.1 12
Potential for immunogenicity with the use of therapeutic proteins such as ofatumumab.1 13 In one study, tests for antibodies to ofatumumab either yielded negative results (in 33 and 39% of patients tested after the eighth and twelfth doses, respectively) or were inconclusive (because of assay interference by high concentrations of circulating ofatumumab).1 13
Not known whether ofatumumab is distributed into milk.1 Human IgG distributes into milk, although systemic absorption of these maternal antibodies in breast-fed infants does not appear to be substantial.1 Use ofatumumab with caution, since effects of local GI and limited systemic exposure to the drug are unknown.1
Safety and efficacy not established in children.1
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1
Safety and efficacy not established.1
Safety and efficacy not established.1
Common Adverse Effects
Interactions for Ofatumumab
No formal drug interaction studies to date.1
Median decrease in circulating CD19+ B-cells after doses 8 and 12 in the 12-dose regimen was 91 and 85%, respectively, in patients with fludarabine- and alemtuzumab-refractory B-CLL.1
Time required for lymphocytes, including CD19+ B-cells, to recover to normal levels following ofatumumab therapy not fully determined.1
Eliminated through both an antigen CD20-independent route and a B-cell-mediated route.1
Approximately 14 days (range: 2–61 days) as determined between fourth and twelfth doses in patients with refractory CLL.1
After sequential doses, clearance is decreased substantially because of B-cell depletion.1
Pharmacokinetics not substantially affected by age (over range of 21–86 years), baseline Clcr (over range of 33–287 mL/minute), sex, or body weight.1
For information on systemic interactions resulting from concomitant use, see Interactions.
Sodium chloride 0.9%1
An IgG1 kappa immunoglobulin that binds specifically to antigen CD20 (expressed on the surface of normal and malignant B-cells, including B-CLL cells), triggering a host immune response causing B-cell lysis.1 3 6 7 8 9 10
Compared with rituximab, ofatumumab appears to display more potent CDC activity against B-cell lines in vitro (due to enhanced cytotoxicity against rituximab-resistant and low-CD20-expressing B-CLL cells)7 8 9 11 and may dissociate more slowly from antigen CD20;6 7 clinical importance of these differences remains to be established.12
Advice to Patients
Risk of infusion-related reactions; importance of reporting signs and symptoms of such reactions (e.g., fever, chills, rash, breathing difficulty) that occur within 24 hours of infusion.1
Risk of cytopenias; importance of reporting bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue.1
Risk of infection; importance of reporting signs and symptoms of infection (e.g., cough, fever).1
Risk of PML; importance of reporting new or worsening neurologic manifestations (e.g., confusion, dizziness or loss of balance, difficulty speaking or walking, changes in vision).1
Risk of HBV reactivation; importance of reporting symptoms of hepatitis (e.g., worsening fatigue, icteric changes).1
Risk of small bowel obstruction; importance of reporting new or worsening abdominal pain or nausea.1
Importance of routine monitoring of blood cell counts.1
Advise patients that they should not receive a live virus vaccine if they have recently received ofatumumab.1
Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
For injection concentrate, for IV infusion
AHFS DI Essentials. © Copyright, 2004-2013, Selected Revisions July 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
1. GlaxoSmithKline. Arzerra (ofatumumab) for injection prescribing information. Research Triangle Park, NC; 2009 Oct.
2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website.
3. Osterborg A, Kipps TJ, Mayer J et al. Single-agent ofatumumab, a novel CD20 monoclonal antibody, results in high response rates in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL) also refractory to alemtuzumab or with bulky lymphadenopathy. Paper presented at 14th Congress of the European Hematology Association, Berlin, Germany: 2009 Jun 6. Abstract No. 0494.
4. GlaxoSmithKline, Research Triangle Park, NC: Personal communication.
5. Osterborg A, Kipps T, Mayer J et al. Ofatumumab (HuMax-CD20), a novel CD20 monoclonal antibody, is an active treatment for patients with CLL refractory to both fludarabine and alemtuzumab or bulky fludarabine-refractory disease: results from the planned interim analysis of an international pivotal trial. Blood. 2008; 112 (American Society of Hematology Annual Meeting Abstracts):Abstract No. 328.
6. Teeling JL, French RR, Cragg MS et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004; 104:1793-800. [PubMed 15172969]
7. Coiffier B, Lepretre S, Pedersen LM et al. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008; 111:1094-100. [PubMed 18003886]
8. Maddocks KJ, Lin TS. Update in the management of chronic lymphocytic leukemia. J Hematol Oncol. 2009; 2:29. [PubMed 19619273]
9. Taylor RP, Lindorfer MA. Immunotherapeutic mechanisms of anti-CD20 monoclonal antibodies. Curr Opin Immunol. 2008; 20:444-9. [PubMed 18585457]
10. Teeling JL, Mackus WJ, Wiegman LJ et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20. J Immunol. 2006; 177:362-71. [PubMed 16785532]
11. Pawluczkowycz AW, Beurskens FJ, Beum PV et al. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX. J Immunol. 2009; 183:749-58. [PubMed 19535640]
12. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125326: Medical Review(s). From FDA website.
13. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 125326: Clinical pharmacology and biopharmaceutics review(s). From FDA website.
14. Schimmer BP, Parker KL. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Bunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill; 2006:1587-1612.
More about ofatumumab
- Other brands: Arzerra