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Ofatumumab

Pronunciation

(oh fa TOOM yoo mab)

Index Terms

  • HuMax-CD20

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Concentrate, Intravenous [preservative free]:

Arzerra: 100 mg/5 mL (5 mL); 1000 mg/50 mL (50 mL) [contains edetate disodium, mouse (murine) and/or hamster protein, polysorbate 80]

Brand Names: U.S.

  • Arzerra

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD20
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Ofatumumab is a monoclonal antibody which binds specifically the extracellular (large and small) loops of the CD20 molecule (which is expressed on normal B lymphocytes and in B-cell CLL) resulting in potent complement-dependent cell lysis and antibody-dependent cell-mediated toxicity in cells that overexpress CD20.

Distribution

Vdss: 5.8 L (following repeated infusions)

Half-Life Elimination

17.1 days (following repeated infusions)

Use: Labeled Indications

Chronic lymphocytic leukemia (CLL), previously untreated: Treatment of previously untreated CLL (in combination with chlorambucil) when fludarabine-based therapy is considered inappropriate

Chronic lymphocytic leukemia (CLL), refractory: Treatment of CLL refractory to fludarabine and alemtuzumab

Chronic lymphocytic leukemia (CLL), extended treatment: Extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL.

Contraindications

U.S. labeling: There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to ofatumumab or any component of the formulation; presence or history of progressive multifocal leukoencephalopathy.

Dosing: Adult

Note: Premedicate with acetaminophen, an antihistamine, and a corticosteroid 30 to 120 minutes prior to treatment (see Premedication below).

Chronic lymphocytic leukemia (CLL), previously untreated: IV: Cycle 1 (cycle is 28 days): 300 mg on day 1, followed by 1,000 mg on day 8; Subsequent cycles: 1,000 mg on day 1 every 28 days; continue for at least 3 cycles until best response or a maximum of 12 cycles (in combination with chlorambucil)

Premedication: Premedicate with oral acetaminophen (1,000 mg) or equivalent, an oral or IV antihistamine (eg, diphenhydramine 50 mg or cetirizine 10 mg orally or equivalent), and an IV corticosteroid (prednisolone 50 mg or equivalent). Full dose corticosteroid is recommended for the first 2 infusions; in the absence of infusion reaction ≥ grade 3, may reduce or omit corticosteroid dose for subsequent infusions.

CLL, refractory: IV: Initial dose: 300 mg on day 1, followed 1 week later by 2000 mg once weekly for 7 doses (doses 2 to 8), followed 4 weeks later by 2,000 mg once every 4 weeks for 4 doses (doses 9 to 12; for a total of 12 doses)

Premedication: Premedicate with oral acetaminophen (1,000 mg) or equivalent, an oral or IV antihistamine (eg, diphenhydramine 50 mg or cetirizine 10 mg orally or equivalent), and an IV corticosteroid (prednisolone 100 mg or equivalent). Full dose corticosteroid is recommended for doses 1, 2, and 9; in the absence of infusion reaction ≥ grade 3, may reduce or omit corticosteroid dose for doses 3 to 8; may administer reduced corticosteroid dose (ranging from half to full dose) with doses 10 to 12 if ≥ grade 3 reaction did not occur with dose 9.

CLL, extended treatment: IV: 300 mg on day 1, followed by 1,000 mg on day 8, followed by 1,000 mg 7 weeks later and then every 8 weeks for up to a maximum of 2 years

Premedication: Premedicate with oral acetaminophen (1,000 mg) or equivalent, an oral or IV antihistamine (eg, diphenhydramine 50 mg or cetirizine 10 mg orally or equivalent), and an IV corticosteroid (prednisolone 50 mg or equivalent). Full dose corticosteroid is recommended for the first 2 infusions; in the absence of infusion reaction ≥ grade 3, may reduce or omit corticosteroid dose for subsequent infusions.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the US manufacturer’s labeling; however, there were no clinically relevant pharmacokinetic effects observed in patients with baseline CrCl ≥30 mL/minute. The Canadian labeling recommends that no dosage adjustment is necessary for CrCl >30 mL/minute.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Adjustment for Toxicity

Infusion reaction: Interrupt infusion for infusion reaction (any severity). If the reaction resolves or remains at ≤ grade 2, resume with the following modifications (based on the grade of the initial reaction):

Grade 1 or 2 infusion reaction:

U.S. labeling: Resume at one-half of the previous rate; may increase (see Administration) based on patient tolerance.

Canadian labeling: Resume at one-half of the previous rate; may increase (see Administration) based on patient tolerance. If the infusion rate had not been increased above 12 mL/hour prior to interrupting therapy, resume infusion at 12 mL/hour; may then increase based on patient tolerance.

Grade 3 or 4 infusion reaction: Resume infusion at 12 mL/hour; may increase (see Administration) based on patient tolerance.

If reaction severity does not resolve to ≤ grade 2 despite management: Consider permanent discontinuation

Anaphylactic reaction: Discontinue permanently

Reconstitution

Prepare all doses in 1000 mL NS. Begin infusion within 12 hours of preparation.

300 mg dose: Withdraw 15 mL from a 1000 mL NS bag. Add contents of 3 ofatumumab 100 mg vials to NS bag. Gently invert to mix; do not shake.

1000 mg dose: Withdraw 50 mL from a 1000 mL NS bag. Add contents of 1 ofatumumab 1000 mg vial. Gently invert to mix; do not shake.

2000 mg dose: Withdraw 100 mL from a 1000 mL NS bag. Add contents of 2 ofatumumab 1000 mg vials to NS bag. Gently invert to mix; do not shake.

Administration

Do not administer IV push, IV bolus, or as a subcutaneous injection. Premedicate with acetaminophen, an antihistamine, and a corticosteroid 30 to 120 minutes prior to administration (see Dosing). Infuse in an environment equipped to monitor for and manage infusion reactions. Administer with infusion pump and administration set. Do not exceed infusion rates below. Do not mix with or infuse with other medications. Flush line before and after infusion with NS. Begin infusion within 12 hours of preparation. Interrupt infusion for any severity of infusion reaction; if the reaction resolves or remains at ≤ grade 2, may resume infusion (see Dosage Adjustment for Toxicity).

Previously untreated chronic lymphocytic leukemia (CLL) and extended treatment of CLL:

Initial 300 mg dose: Initiate infusion at 12 mL/hour for 30 minutes, if tolerated (no infusion reaction) increase to 25 mL/hour for 30 minutes, if tolerated, increase to 50 mL/hour for 30 minutes, if tolerated, increase to 100 mL/hour for 30 minutes, if tolerated, increase to 200 mL/hour for 30 minutes, if tolerated increase to 300 mL/hour for 30 minutes, if tolerated, increase to 400 mL/hour for remainder of infusion. Median duration of infusion: 4.8 to 5.2 hours.

Subsequent 1,000 mg infusions (if no reaction to previous infusion): Initiate infusion at 25 mL/hour for 30 minutes, if tolerated (no infusion reaction) increase to 50 mL/hour for 30 minutes, if tolerated, increase to 100 mL/hour for 30 minutes, if tolerated, increase to 200 mL/hour for 30 minutes, if tolerated, increase to 400 mL/hour for remainder of infusion. Median duration of infusion: 4.2 to 4.4 hours.

Refractory CLL:

Doses 1 and 2: Initiate infusion at 12 mL/hour for 30 minutes, if tolerated (no infusion reaction) increase to 25 mL/hour for 30 minutes, if tolerated, increase to 50 mL/hour for 30 minutes, if tolerated, increase to 100 mL/hour for 30 minutes, if tolerated, increase to 200 mL/hour for remainder of infusion. Median duration of infusion: 6.8 hours.

Doses 3 to 12: Initiate infusion at 25 mL/hour for 30 minutes, if tolerated (no infusion reaction) increase to 50 mL/hour for 30 minutes, if tolerated, increase to 100 mL/hour for 30 minutes, if tolerated, increase to 200 mL/hour for 30 minutes, if tolerated, increase to 400 mL/hour for remainder of infusion. Median duration of infusion: 4.2 to 4.4 hours.

Compatibility

Stable in NS.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Diluted solutions for infusion must be started within 12 hours of preparation (may store at 2°C to 8°C [36°F to 46°F] if not used immediately); discard any remaining solution 24 hours after preparation.

Drug Interactions

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Percentages reported as monotherapy and as part of combination chemotherapy regimens.

>10%:

Central nervous system: Fatigue (15%)

Dermatologic: Skin rash (14%)

Gastrointestinal: Diarrhea (18%), nausea (11%)

Hematologic & oncologic: Leukopenia (6% to 67%; grades 3/4: 3% to 23%), neutropenia (24% to 66%; ≥grade 3: 22% to 42%; grade 4: 18%; may be prolonged >2 weeks), lymphocytopenia (52%; grades 3/4: 29%), anemia (16%; grades 3/4: 5%)

Infection: Infection (65% to 70%; includes bacterial, fungal, or viral), serious infection (20%)

Respiratory: Pneumonia (8% to 23%), cough (19%), upper respiratory tract infection (11% to 19%), dyspnea (14%), bronchitis (9% to 11%)

Miscellaneous: Infusion related reaction (46% to 67%; grade ≥3: 4% to 10%; day 1 reactions: 25% to 56%; subsequent infusions: 2% to 29%) ), fever (20%)

1% to 10%:

Cardiovascular: Peripheral edema (9%), hypertension (5%), hypotension (5%), tachycardia (5%)

Central nervous system: Chills (8%), headache (6% to 7%), insomnia (5% to 7%)

Dermatologic: Urticaria (8%), hyperhidrosis (5%)

Gastrointestinal: Upper abdominal pain (5%)

Hematologic & oncologic: Hypogammaglobulinemia (5%; grades 3/4: <1%)

Infection: Sepsis (8%), herpes simplex infection (6%), influenza (6%), herpes zoster (5% to 6%)

Neuromuscular & skeletal: Weakness (8%), back pain (5% to 8%), arthralgia (5%), muscle spasm (5%)

Respiratory: Nasopharyngitis (8%), lower respiratory tract infection (5%), sinusitis (5%)

<1% (Limited to important or life-threatening): Angina pectoris, antibody development, bacteremia, hemolytic anemia, hepatitis B (new onset or reactivation), hepatitis (cytolytic), hypoxia, interstitial pulmonary disease (infectious), intestinal obstruction, peritonitis, porphyria cutanea tarda, progressive multifocal leukoencephalopathy (PML), rigors, sepsis (neutropenic), septic shock, Stevens-Johnson syndrome, thrombocytopenia

ALERT: U.S. Boxed Warning

Hepatitis B virus infection:

Hepatitis B virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab, in some cases resulting in fulminant hepatitis, hepatic failure, and death.

Progressive multifocal leukoencephalopathy:

Progressive multifocal leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Warnings/Precautions

Concerns related to adverse effects:

• Gastrointestinal toxicity: Bowel obstruction and abdominal pain have been reported; patients presenting with abdominal pain should be assessed for presence of obstruction and treated appropriately.

• Hematologic toxicity: Severe and prolonged (≥1 week) cytopenias (neutropenia, thrombocytopenia, and anemia) may occur. Grade 3 or 4 late-onset neutropenia (onset ≥42 days after last treatment dose) and/or prolonged neutropenia (not resolved 24 to 42 days after last dose) has been reported. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred when used in combination with chlorambucil. Monitor blood counts regularly during and after treatment; more frequently if grade 3 or 4 cytopenias develop.

• Hepatitis B virus infection: [US Boxed Warning]: Hepatitis B virus (HBV) reactivation may occur in patients receiving CD20-directed antibody treatment, including ofatumumab; may result in fulminant hepatitis, hepatic failure, and death. Fatal cases of HBV have also occurred in patients not previously infected with HBV. Prior to initiating therapy, obtain hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) measurements in all patients; monitor for clinical and laboratory signs of hepatitis or HBV during and for several months after treatment. HBV reactivation has been reported up to 12 months after therapy discontinuation. Discontinue ofatumumab (and concomitant medications) if viral hepatitis develops and initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAG negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during ofatumumab treatment. The safety of resuming ofatumumab treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with physicians experienced in HBV management.

- American Society of Clinical Oncology (ASCO) provisional clinical opinion update on hepatitis B virus screening [Hwang 2015]) recommendations: Patients receiving anti-CD20 antibodies are at high risk for hepatitis B virus (HBV) reactivation. Screen for HBV infection infection with hepatitis B surface antigen (HBsAG) and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or unresolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). In addition, patients who have risk factors for HBV infection (eg, birthplace in a country with ≥2% HBV prevalence, household or sexual contact with HBV infected patients, high-risk behaviors [eg, intravenous drug use], and HIV infection) should also be screened prior to beginning therapy. Initiate prophylactic antiviral therapy (utilizing antivirals with low rates of viral resistance) for HBsAg -positive/anti-HBc -positive patients (without delaying cancer therapy) and continue the antivirals during and for ~6 to 12 months after completing treatment. HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment; antiviral therapy may be initiated prophylactically or begun promptly at the first sign of HBV reactivation.

• Infection: Bacterial, fungal, and new or reactivated viral infections may occur during and/or following therapy; monitor closely for signs/symptoms of infection. Discontinue therapy for serious infections and treat appropriately.

• Infusion reaction: May cause serious infusion reactions (some fatal); reactions may include bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia, back pain, abdominal pain, fever, rash, urticaria, angioedema, cytokine release syndrome, and/or anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions and may occur despite premedication. Premedicate prior to infusion with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for reaction of any severity and institute appropriate treatment; may require subsequent rate modification. Discontinue immediately and permanently if anaphylactic reaction occurs.

• Progressive multifocal leukoencephalopathy: [US Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) resulting in death may occur with CD20-directed antibody treatment, including ofatumumab. Consider PML in any patient with new onset or worsening neurological symptoms and if PML is suspected, discontinue ofatumumab and evaluate promptly.

• Tumor lysis syndrome: Tumor lysis syndrome (TLS) has occurred in patients receiving ofatumumab; patients with a high tumor burden and/or high circulating lymphocyte counts (>25,000/mm3) are at increased risk for TLS. Administer prophylactic antihyperuricemic therapy and aggressive hydration beginning 12 to 24 hours prior to ofatumumab treatment. Correct electrolyte abnormalities; monitor renal function and hydration status.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Immunizations: Live vaccines should not be given to patients who have recently received ofatumumab; there is no data concerning secondary transmission. The ability to generate an immune response to any vaccine following treatment is unknown.

Special populations:

• Elderly: Patients ≥65 years experienced a higher incidence of adverse reactions (compared with younger patients).

Monitoring Parameters

CBC with differential (at regular intervals during and after therapy; more frequently if grades 3 or 4 cytopenias develop), renal function, electrolytes

Hepatitis B virus screening recommendations (ASCO provisional clinical opinion update [Hwang 2015]): Screen for hepatitis B virus (HBV) infection with hepatitis B surface antigen (HBsAG) and hepatitis B core antibody (anti-HBc) tests prior to treatment initiation; either a total anti-HBc (with both IgG and IgM) or anti-HBc IgG test should be used to screen for chronic or unresolved HBV infection (do not use anti-HBc IgM as it may only confirm acute HBV infection). HBsAg negative/anti-HBc positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment.

Signs of active hepatitis B infection (during and for up to 12 months after therapy completion); signs/symptoms of hepatitis; signs or symptoms of infusion reaction; signs of infection; fluid status; signs/symptoms of intestinal obstruction (eg, abdominal pain, repeated vomiting); signs/symptoms of progressive multifocal leukoencephalopathy (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits).

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Based on animal data, prolonged depletion of circulating B cells may occur; avoid administering live vaccines to newborns exposed to ofatumumab in utero until B cell recovery occurs. The Canadian labeling recommends women of childbearing potential avoid pregnancy during and for 6 months after the last treatment.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience muscle spasms or insomnia. Have patient report immediately to prescriber signs of infection, signs of hepatic impairment, severe asthenia, considerable nausea, dyspepsia, intolerable diarrhea, ecchymosis, hemorrhaging, back pain, tachycardia, bradycardia, arrhythmia, severe headache, edema of extremities, injection site irritation, signs of tumor lysis syndrome, chills, flushing, dyspnea, significant dizziness, syncope, or angina (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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