Ofatumumab

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]

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 6.1 L (following repeated infusions)

Half-Life Elimination

17.6 days (following repeated infusions)

Use: Labeled Indications

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

Chronic lymphocytic leukemia, relapsed: Treatment of relapsed CLL (in combination with fludarabine and cyclophosphamide).

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

Chronic lymphocytic leukemia, 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

There are no contraindications listed in the manufacturer's US labeling.

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

Dosage and Administration

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) (Hillmen 2015)

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, relapsed: 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 a maximum of 6 cycles (in combination with fludarabine and cyclophosphamide) (Robak 2017)

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 2,000 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) (Wierda 2010)

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 (van Oers 2015)

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: 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:

Resume at one-half of the previous rate; may increase (see Administration) 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 1,000 mL NS. Begin infusion within 12 hours of preparation.

300 mg dose: Withdraw 15 mL from a 1,000 mL NS bag. Add contents of 3 ofatumumab 100 mg vials to NS bag. Gently invert to mix; do not shake.

1,000 mg dose: Withdraw 50 mL from a 1,000 mL NS bag. Add contents of 1 ofatumumab 1,000 mg vial. Gently invert to mix; do not shake.

2,000 mg dose: Withdraw 100 mL from a 1,000 mL NS bag. Add contents of 2 ofatumumab 1,000 mg vials to NS bag. Gently invert to mix; do not shake.

Administration

IV Infusion: 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), relapsed 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.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect from light. Solutions diluted in NS 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

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

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

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. 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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Consider therapy modification

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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

>10%:

Central nervous system: Fatigue (15%)

Dermatologic: Skin rash (14%)

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

Hematologic & oncologic: Neutropenia (24%; ≥grade 3: ≥22%; may be prolonged >2 weeks), 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%; day 1 reactions: 25% to 44%; 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%), insomnia (5% to 7%), headache (6%)

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

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

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

Neuromuscular & skeletal: Back pain (5% to 8%), muscle spasm (5%)

Respiratory: Nasopharyngitis (8%), sinusitis (5%)

<1%, postmarketing, and/or case reports: Antibody development, hepatitis B (new-onset or reactivation), porphyria cutanea tarda, progressive multifocal leukoencephalopathy, Stevens Johnson syndrome, tumor lysis syndrome

Warnings/Precautions

Concerns related to adverse effects:

• 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 resolved 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.
• 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).

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

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 resolved 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

Pregnancy Considerations

Ofatumumab is a humanized monoclonal antibody (IgG₁). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

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.

Patient Education

What is this drug used for?

• It is used to treat a type of leukemia.

Frequently reported side effects of this drug

• Common cold symptoms
• Nausea
• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, trouble speaking, change in balance, or vision changes
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; not able to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Infusion reaction
• Severe loss of strength and energy
• Bruising
• Bleeding
• Swelling of arms or legs
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.