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Ofatumumab

Medically reviewed by Drugs.com. Last updated on Mar 5, 2020.

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]

Solution Auto-injector, Subcutaneous [preservative free]:

Kesimpta: 20 mg/0.4 mL (0.4 mL) [contains disodium edta, polysorbate 80]

Brand Names: U.S.

  • Arzerra
  • Kesimpta

Pharmacologic Category

  • Anti-CD20 Monoclonal Antibody
  • Antineoplastic Agent, Anti-CD20
  • Antineoplastic Agent, Monoclonal Antibody
  • 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 (following repeated administrations): IV: 6.1 L; SubQ: 5.4 L.

Metabolism

SubQ: Expected pathway is degradation to small peptides and amino acids by proteolytic enzymes.

Excretion

Eliminated via both target-independent and target-mediated B-cell binding routes.

Half-Life Elimination

Following repeated administrations: IV: 17.6 days; SubQ: ~16 days. Higher baseline B-cell counts at the start of therapy result in a greater component of target-mediated elimination and a shorter ofatumumab half-life at the start of therapy.

Use: Labeled Indications

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

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

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

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

Multiple sclerosis, relapsing: Kesimpta: Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Contraindications

IV (Arzerra): 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.

SubQ (Kesimpta): Active hepatitis B virus infection.

Dosing: Adult

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

Chronic lymphocytic leukemia (CLL), previously untreated: Arzerra: 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: Arzerra: 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: Arzerra: 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: Arzerra: 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.

Multiple sclerosis, relapsing:Kesimpta:

Note: Administer all live or live-attenuated vaccines at least 4 weeks prior and non-live vaccines at least 2 weeks prior to initiation of therapy. Screen for hepatitis B prior to initiation; do not administer to patients with active hepatitis B confirmed by hepatitis B surface antigen (HBsAg) and anti-HBV tests. For patients who are negative for HBsAg and positive for hepatitis B core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment. Obtain quantitative serum immunoglobulins prior to therapy initiation; for patients with low serum immunoglobulins, consult immunology specialists prior to initiation. In high-risk populations or in countries with high burden, screen for latent infections (eg, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease specialists regarding treatment options before initiating therapy (Farez 2019).

SubQ: Initial: 20 mg once weekly for 3 doses (weeks 0, 1, and 2); maintenance: 20 mg once monthly starting at week 4.

Missed dose: Administer as soon as possible without waiting until next scheduled dose; administer subsequent doses at the recommended intervals.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

IV: Arzerra: 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

IV (Arzerra): 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.

SubQ (Kesimpta): Before administration, allow Sensoready pen or prefilled syringe to reach room temperature for about 15 to 30 minutes; do not remove needle cover during this time.

Administration

IV: Arzerra: 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.

SubQ: Kesimpta: Administer only by SubQ injection in the abdomen, thigh, or outer upper arm; avoid moles, scars, stretch marks, or areas where the skin is tender, bruised, red, scaly, or hard. The first injection should be performed under the guidance of a health care professional. Sensoready pens and syringes are for one-time use only; discard after use.

Storage

Store intact vials, Sensoready pens, and prefilled syringes at 2°C to 8°C (36°F to 46°F); do not freeze or shake. 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. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. 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

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

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. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

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

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. 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. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. 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

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Drugs listed as exceptions to this monograph are discussed in separate drug interaction monographs. 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%:

Antineoplastic:

Dermatologic: Skin rash (14%)

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

Hematologic & oncologic: Anemia (16%; grades 3/4: 5%), neutropenia (24%; ≥ grade 3: ≥22%; may be prolonged >2 weeks)

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

Nervous system: Fatigue (15%)

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

Miscellaneous: Fever (20%), infusion related reaction (46%; day 1 reactions: 25% to 44%; subsequent infusions: 2% to 29%)

Multiple sclerosis:

Infection: Infection (52%), serious infection (3%)

Local: Injection site reaction (systemic [chills, fatigue, fever, myalgia]: 21%; local: [erythema, pain, pruritus, swelling]: 11%)

Nervous system: Headache (13%)

Respiratory: Upper respiratory tract infection (39%)

1% to 10%:

Antineoplastic:

Cardiovascular: Hypertension (5%), hypotension (5%), peripheral edema (9%), tachycardia (5%)

Dermatologic: Hyperhidrosis (5%), urticaria (8%)

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

Infection: Herpes zoster infection (5% to 6%), influenza (6%), sepsis (8%)

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

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

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

Multiple sclerosis:

Genitourinary: Urinary tract infection (10%)

Hematologic & oncologic: Decreased serum immunoglobulins (immunoglobulin M: 6% to 8%)

Neuromuscular & skeletal: Back pain (8%)

<1%: Immunologic: Antibody development

Postmarketing:

Dermatologic: Stevens Johnson syndrome

Endocrine & metabolic: Porphyria cutanea tarda

Hematologic & oncologic: Tumor lysis syndrome

Hepatic: Hepatitis B (new-onset or reactivation)

Nervous system: Progressive multifocal leukoencephalopathy

ALERT: U.S. Boxed Warning

Hepatitis B virus infection (Arzerra):

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 (Arzerra):

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:

• Hematologic toxicity (Arzerra): 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 (Arzerra)]: Hepatitis B virus (HBV) reactivation may occur in patients receiving CD20-directed antibody treatment, including ofatumumab for chronic lymphocytic leukemia (CLL); may result in fulminant hepatitis, hepatic failure, and death. Fatal cases of HBV have also occurred in patients not previously infected with HBV. No reports of HBV reactivation have occurred in multiple sclerosis (MS) clinical studies; ofatumumab is used at higher doses and for shorter duration of therapy for CLL. Prior to initiating therapy, screen for HBV in all patients, including hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) measurements, as well as additional markers as necessary according to local guidelines; monitor for clinical and laboratory signs of hepatitis or HBV during and for several months after treatment. Active hepatitis B infection is a contraindication for ofatumumab use in patients with MS. HBV reactivation has been reported up to 12 months after therapy discontinuation. Discontinue ofatumumab (and concomitant chemotherapy/immunosuppressants) 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 (eg, liver disease experts) 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 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.

• Immunoglobulin reduction (Kesimpta): Decrease in immunoglobulin levels may occur with use. Obtain quantitative serum immunoglobulins prior to therapy initiation; consult immunology experts prior to initiation for patients with low serum immunoglobulins. Monitor quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider therapy discontinuation in patients with low immunoglobulins who develop severe opportunistic or recurrent infections, or if prolonged hypogammaglobulinemia requires immunoglobulin treatment.

• Infection: Bacterial, fungal, and new or reactivated viral infections may occur during and/or following therapy; monitor closely for signs/symptoms of infection. In MS patients, ofatumumab is associated with an increased risk for upper respiratory tract and urinary tract infections. In high-risk populations or in countries with high burden, screen for latent infections (eg, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other specialists regarding treatment options before initiating therapy (Farez 2019). Delay administration in patients with active infections until the infection has resolved. When initiating ofatumumab before or after other immunosuppressive therapy, increased immunosuppressive effects may occur.

• Infusion reaction (Arzerra): 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.

• Injection-related reactions (Kesimpta): Systemic and local injection reactions, including fever, headache, myalgia, chills, fatigue, erythema, swelling, itching, and pain, may occur with SubQ use. Premedication with corticosteroids, antihistamines, or acetaminophen is of limited benefit. The first injection should be performed under the guidance of an appropriately trained health care professional; symptomatic treatment is recommended if injection-related reactions occur. Incidence of injection-related reactions may be higher with the first injection, most commonly within 24 hours, and decrease with subsequent injections.

• Progressive multifocal leukoencephalopathy: [US Boxed Warning (Arzerra)]: Progressive multifocal leukoencephalopathy (PML) resulting in death may occur with CD20-directed antibody treatment, including ofatumumab, for CLL. No reports of PML have occurred in MS clinical studies; ofatumumab is used at higher doses and for shorter duration of therapy for CLL. At the first sign or symptom suggestive of PML, withhold therapy immediately and perform a diagnostic evaluation; symptoms progress over days to weeks and may include altered mental status, motor deficits (hemiparesis or monoparesis), limb/gait ataxia, and/or vision disturbances. PML may be detected by MRI before clinical symptoms.

• Tumor lysis syndrome (Arzerra): 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 are no data concerning secondary transmission. The ability to generate an immune response to any vaccine following treatment is unknown. When using for the treatment of MS, administer live and live-attenuated vaccines at least 4 weeks prior to initiation of therapy; administer inactivated vaccines at least 2 weeks prior to initiation of therapy. Live and live-attenuated vaccination is not recommended during treatment and after discontinuation until repletion of B-cells; consider using live-attenuated vaccines for patients with MS only if risk of infection is high and killed vaccines are unavailable (Farez 2019).

Special populations:

• Elderly (Arzerra): Patients ≥65 years of age 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

IV:

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 (American Society of Clinical Oncology 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 (PML) (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits).

SubQ: Quantitative serum immunoglobulins (baseline, throughout treatment as clinically necessary, especially in patients with opportunistic or recurrent infections, after discontinuation of therapy until B-cell repletion); HBsAg, hepatitis B core antibody (HBcAb), and other hepatitis B markers as per local guidelines (baseline and as clinically necessary); latent infection screening (eg, tuberculosis) in high-risk populations or in countries with high burden (baseline); signs/symptoms of PML (eg, altered mental status, motor deficits [hemiparesis or monoparesis], limb/gait ataxia, and/or vision disturbances), MRI (as clinically indicated).

Reproductive Considerations

Females of reproductive potential should use effective contraception during therapy and for 6 months after the last dose of ofatumumab.

In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy except in females at high risk of MS activity (AAN [Rae-Grant 2018]). Consider use of agents other than ofatumumab for females at high risk of disease reactivation who are planning a pregnancy. Delaying pregnancy is recommended for females with persistent high disease activity; when disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).

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 data from animal reproduction studies and human data from other anti-CD20 antibodies, transient peripheral B-cell depletion and lymphocytopenia may occur in newborns exposed to ofatumumab in utero.

Information related to the use of ofatumumab in pregnancy is limited (Quattrocchi 2016). In general, disease-modifying therapies for multiple sclerosis (MS) are not initiated during pregnancy, except in patients at high risk of MS activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).

Patient Education

What is this drug used for?

Injection (subcutaneous):

• It is used to treat MS (multiple sclerosis).

IV infusion:

• It is used to treat a type of leukemia.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

All products:

• Feeling tired or weak

• Signs of a common cold

Injection (subcutaneous):

• Pain, redness, or swelling where the shot was given

• Mild fever

• Headache

• Muscle pain

• Back pain

IV infusion:

• Upset stomach

• Diarrhea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

All products:

• Infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal

• Progressive multifocal leukoencephalopathy like confusion, memory problems, low mood (depression), change in the way you act, change in strength on 1 side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight

• Liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

IV infusion:

• Tumor lysis syndrome like fast or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, diarrhea, or not able to eat; or feel sluggish

• Infusion reaction

• Feeling very tired or weak

• Unexplained bruising or bleeding

• Swelling in the arms or legs

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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.