Ofatumumab

L04A - Immunosuppressants ATC L04AA52 Antibody approved 2009 Parenteral Black-box warning

JFDA label: Kesimpta Solution for injection 20 mg/0.4ml PFP

⚠ Black-Box Warning

Hepatitis B virus infection:
Progressive multifocal leukoencephalopathy:

Mechanism of Action

Binding Agent of B-lymphocyte antigen CD20 — B-lymphocyte antigen CD20 binding agent

Target	Action	Gene / class
B-lymphocyte antigen CD20 efficacy	BINDING AGENT	MS4A1

Indications

Approved

Chronic lymphocytic leukemia, extended treatment
Chronic lymphocytic leukemia, previously untreated
Chronic lymphocytic leukemia, refractory
Chronic lymphocytic leukemia, relapsed

Contraindications

Source: Lexicomp

Hypersensitivity to ofatumumab or any component of the formulation Absolute
There are no contraindications listed in the manufacturer's US labeling Absolute
presence or history of progressive multifocal leukoencephalopathy Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (4)

Common hypertension · hypotension · Peripheral edema · tachycardia

Nervous system disorders (4)

Very Common Fatigue

Common Chills · headache · insomnia

Blood and lymphatic system disorders (3)

Very Common anemia · Neutropenia

Common Hypogammaglobulinemia, influenza, herpes zoster

Gastrointestinal disorders (2)

Very Common Diarrhea · nausea

Skin and subcutaneous tissue disorders (3)

Very Common Skin rash

Common hyperhidrosis · Urticaria

Musculoskeletal and connective tissue disorders (2)

Common Back pain · muscle spasm

Infections and infestations (2)

Very Common Infection · serious infection

General disorders and administration site conditions (2)

Very Common fever · Infusion related reaction

Respiratory, thoracic and mediastinal disorders (7)

Very Common bronchitis · cough · dyspnea · Pneumonia · upper respiratory tract infection

Common Nasopharyngitis · sinusitis

Dosing

Source: Lexicomp

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.

Refer to adult dosing.

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. CrCl

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

Warnings & Precautions

Source: Lexicomp

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

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 Onco

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

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).

Pregnancy & Lactation

Pregnancy

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.

Lactation

It is not known if ofatumumab is present in human milk. However, human IgG is excreted in breast milk, and therefore, ofatumumab may also be excreted in milk. Available data suggest antibodies present in breast milk do not significantly enter the neonatal and infant circulation. According to the manufacturer, the decision to breastfeed during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.

Monitoring

Clinical pearl	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).

Clinical pearl

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).

Biology & Pharmacokinetics

Pharmacokinetics

Half-life	17.6 days (following repeated infusions)

Drug–drug interactions (79, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Certolizumab pegol	major
Cladribine	major
Clozapine	major
Deferiprone	major
Etanercept	major
Fingolimod	major
Golimumab	major
Infliximab	major
Leflunomide	major
Measles virus vaccine live attenuated	major
Mumps virus strain B level jeryl lynn live antigen	major
Natalizumab	major
Ozanimod	major
Rotavirus vaccine	major
Rubella virus vaccine	major
Samarium (153Sm) lexidronam	major
Siponimod	major
Smallpox (Vaccinia) Vaccine, Live	major
Talimogene laherparepvec	major
Teriflunomide	major
Tofacitinib	major
Typhoid vaccine (live)	major
Upadacitinib	major
Varicella Zoster Vaccine (Recombinant)	major
Yellow Fever Vaccine	major
Alefacept	moderate
Alemtuzumab	moderate
Anakinra	moderate
Anthrax vaccine	moderate
Azathioprine	moderate
Bifidobacterium longum infantis	moderate
Canakinumab	moderate
Candida albicans	moderate
Chloramphenicol	moderate
Chloramphenicol (ophthalmic)	moderate
Clostridium tetani toxoid antigen (formaldehyde inactivated)	moderate
Coccidioides immitis spherule	moderate

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Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Kesimpta Solution for injection 20 mg/0.4ml PFP	Injection 20 mg/0.4 ml	one PFP	The Jordan Drugstore Co	—