Medication Guide App

Arzerra

Generic Name: Ofatumumab
Class: Antineoplastic Agents
VA Class: AN900

Warning(s)

  • HBV Reactivation
  • Reactivation of HBV infection (including fulminant hepatitis and hepatic failure), sometimes fatal, reported.1 15

  • Screen all patients for HBV infection prior to initiation of therapy.1 15 19 20 21

  • Discontinue ofatumumab and concomitant chemotherapy if HBV reactivation occurs.1 15 (See HBV Reactivation under Cautions.)

  • Progressive Multifocal Leukoencephalopathy (PML)
  • PML, sometimes fatal, can occur.1 (See Progressive Multifocal Leukoencephalopathy under Cautions.)

Introduction

Antineoplastic agent; a recombinant fully human anti-CD20 monoclonal antibody.1 3 5 6 8 9

Uses for Arzerra

Chronic Lymphocytic Leukemia (CLL)

Treatment of B-cell chronic lymphocytic leukemia (B-CLL) that is refractory to both fludarabine and alemtuzumab.1 3 5 Efficacy determined based on overall response rates.1 3 12

Slideshow: Flashback: FDA Drug Approvals 2013

Designated an orphan drug by FDA for the treatment of B-CLL.2

Arzerra Dosage and Administration

General

  • Administer in setting where adequate monitoring can be performed and appropriate medical support for treating infusion-related reactions is available.1

Premedication

  • 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

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.1 Do not administer by rapid IV injection (e.g., IV push or bolus).1

Do not mix with any other drug or administer any other drug simultaneously in the same IV line.1 Flush IV line with 0.9% sodium chloride injection before and after ofatumumab administration.1

Administer diluted ofatumumab solution using an administration set and the inline filter provided by the manufacturer.1 Administer via an infusion pump.1

Dilution

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 an infusion 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 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 an infusion 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 2 vials (each containing 1 g in 50 mL) of the drug and add the drug concentrate to the 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

Interrupt the infusion if an infusion-related reaction of any severity occurs.1 Do not resume the infusion if the reaction is grade 4.1

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

Dosage

Adults

CLL
IV

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
IV

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

Special Populations

Hepatic Impairment

No specific dosage recommendations; not specifically studied in hepatic impairment.1

Renal Impairment

No specific dosage recommendations; not specifically studied in renal impairment.1

Geriatric Patients

No specific dosage recommendations.1

Cautions for Arzerra

Contraindications

  • No known contraindications.1

Warnings/Precautions

Warnings

HBV Reactivation

Reactivation of HBV infection (including fulminant hepatitis, hepatic failure, and death) reported in patients receiving anti-CD20 monoclonal antibodies, including ofatumumab.1 15 16 17 18

Reactivation reported in patients with the following serologic markers: hepatitis B surface antigen-positive [HBsAg-positive]; HBsAg-negative and hepatitis B core antibody-positive [anti-HBc-positive]; or HBsAg-negative, anti-HBc-positive, and hepatitis B surface antibody-positive [anti-HBs-positive].1 15

FDA's review of 109 reports of fatal HBV-related acute liver injury in patients receiving ofatumumab or rituximab revealed highly variable onset of HBV reactivation (from 63 days after initiation of therapy to 12 months after last dose) and recent or concomitant use of other immunosuppressive agents in all 32 patients with documented (by seroconversion or serum HBV DNA) HBV reactivation.15 Longer intervals to HBV reactivation (up to 24 months after completion of rituximab therapy) also reported.16 22

Screen all patients for HBV infection prior to initiation of ofatumumab therapy.1 15 20 21 Consult hepatitis expert regarding monitoring and antiviral prophylaxis for patients with evidence of HBV infection (HBsAg-positive with any antibody status or HBsAg-negative and anti-HBc-positive).1 15 Monitor patients with evidence of current or prior HBV infection for clinical or laboratory manifestations of hepatitis or HBV reactivation during therapy and for several months thereafter.1 15

If HBV reactivation occurs, discontinue ofatumumab and any concomitant chemotherapy immediately and initiate appropriate treatment (e.g., antiviral therapy).1 15 Discontinue concomitant chemotherapy until control or resolution of HBV infection is achieved.15 Consult expert in managing HBV infection regarding resumption of ofatumumab once control of HBV reactivation has been achieved.1 Safety of resuming ofatumumab not known.1 15

Progressive Multifocal Leukoencephalopathy

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 ofatumumab and initiate diagnostic evaluation (e.g., consultation with neurologist) as clinically indicated.1

Other Warnings and Precautions

Infusion-related Effects

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

Tumor Lysis Syndrome

Tumor lysis syndrome reported.1

Employ appropriate measures (e.g., aggressive IV hydration, antihyperuricemic therapy, correction of blood chemistries, monitoring of renal function) as clinically indicated.1

Hematologic Effects

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

New HBV Infection

Fatal HBV infection reported in patients not previously infected with the virus.1 Monitor for clinical and laboratory evidence of hepatitis.1

Intestinal Obstruction

Small bowel obstruction reported.1 12 Perform diagnostic evaluation if symptoms are suggestive of obstruction (e.g., abdominal pain, repeated vomiting).1

Immunization

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

Therapy Monitoring

Monitor CBCs and platelet counts at regular intervals; more frequent monitoring recommended in patients with grade 3 or 4 cytopenia.1

Infectious Complications

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

Immunogenicity

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

Specific Populations

Pregnancy

Category C.1

Lactation

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

Pediatric Use

Safety and efficacy not established in children.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

Safety and efficacy not established.1

Renal Impairment

Safety and efficacy not established.1

Common Adverse Effects

Neutropenia,1 5 pneumonia,1 pyrexia,1 cough,1 diarrhea,1 anemia,1 5 fatigue,1 dyspnea,1 rash,1 nausea,1 bronchitis,1 upper respiratory infection.1

Interactions for Arzerra

No formal drug interaction studies to date.1

Arzerra Pharmacokinetics

Absorption

Onset

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

Duration

Time required for lymphocytes, including CD19+ B-cells, to recover to normal levels following ofatumumab therapy not fully determined.1

Distribution

Extent

Crosses the placenta in monkeys.1 Not known whether ofatumumab is distributed into milk (see Lactation under Cautions).1

Elimination

Elimination Route

Eliminated through both an antigen CD20-independent route and a B-cell-mediated route.1

Half-life

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

Special Populations

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

Stability

Storage

Parenteral

Injection Concentrate

2–8°C.1 Do not freeze.1 Protect vials from light.1

Following dilution, 2–8°C;1 discard after 24 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

No incompatibilities observed with PVC or polyolefin bags and administration sets.1

Solution Compatibility

Compatible

Sodium chloride 0.9%1

Actions

  • 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

  • Mechanism of cell lysis is thought to involve complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).1 6 7 8 9 10 11

  • 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 15 Importance of informing clinician of presence of HBV carrier state or of any history of HBV infection.15

  • Risk of small bowel obstruction; importance of reporting new or worsening abdominal pain or nausea or a marked increase in feeling unwell.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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ofatumumab (recombinant)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection concentrate, for IV infusion

20 mg/mL

Arzerra

GlaxoSmithKline

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 30, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. GlaxoSmithKline. Arzerra (ofatumumab) for injection prescribing information. Research Triangle Park, NC; 2013 Sep.

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.

15. Food and Drug Administration. Drug safety communication: Boxed warning and new recommendations to decrease risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab) [2013 Sep 25]. From FDA website.

16. Chew E, Thursky K, Seymour JF. Very late onset hepatitis-B virus reactivation following rituximab despite lamivudine prophylaxis: the need for continued vigilance. Leuk Lymphoma. 2013; :. [PubMed 23772645]

17. Oh MJ, Lee HJ. A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience. Clin Mol Hepatol. 2013; 19:51-9. [PubMed 23593610]

18. Yang JD, Girotra M, Vaid A et al. Hepatitis B reactivation in patient with non-Hodgkin's lymphoma receiving rituximab-based chemotherapy: need for education and attention. J Ark Med Soc. 2013; 110:110-2. [PubMed 24367885]

19. Artz AS, Somerfield MR, Feld JJ et al. American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases. J Clin Oncol. 2010; 28:3199-202. [PubMed 20516452]

20. European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012; 57:167-85. [PubMed 22436845]

21. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009; 50:661-2. [PubMed 19714720]

22. Biogen Idec/Genentech. Rituxan (rituximab) prescribing information. South San Francisco, CA; 2013 Sept.

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