Ofatumumab (Monograph)

Brand name: Kesimpta
Drug class: Immunomodulatory Agents

Medically reviewed by Drugs.com on Aug 19, 2022. Written by ASHP.

Introduction

Immunomodulatory agent; a recombinant human anti-CD20 monoclonal antibody.

Uses for Ofatumumab

Multiple Sclerosis (MS)

Treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Ofatumumab is one of several disease-modifying therapies used in the management of relapsing forms of MS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing-remitting MS who have had recent relapses and/or MRI activity. Clinicians should consider the adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate disease-modifying therapy.

Ofatumumab Dosage and Administration

General

Pretreatment Screening

• Screen for hepatitis B virus (HBV) infection prior to initiating therapy by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) at a minimum. Ofatumumab is contraindicated in patients with active HBV infection.

• Test for quantitative serum immunoglobulins prior to initiating therapy. For patients with low serum immunoglobulins, consult immunology experts before initiating ofatumumab.

• Evaluate for active infections; delay administration until the infection resolves.

Patient Monitoring

• Monitor for quantitative serum immunoglobulins during therapy, especially in patients with opportunistic or recurrent infections, and after discontinuance of therapy until recovery of B-cell counts.

• In patients who are HBsAg-negative and positive for HBcAb, or HBV carriers (i.e., HBsAg-positive), monitor according to local standards to prevent infection or reactivation of infection.

Premedication and Prophylaxis

• Limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen.

Other General Considerations

• Complete any necessary immunizations ≥4 weeks prior to initiation of ofatumumab for live or live-attenuated vaccines, and whenever possible, ≥2 weeks prior to initiation of ofatumumab for inactivated vaccines.

• Consult liver disease experts prior to and during ofatumumab therapy in patients who are HBsAg-negative and positive for HBcAb, or HBV carriers (i.e., HBsAg-positive).

Administration

Sub-Q Administration

Administer by Sub-Q injection.

Administer into abdomen, thigh, or outer upper arm. Do not inject into moles, scars, stretch marks or areas where the skin is tender, bruised, red, scaly, or hard.

Intended to be self-administered by the patient after appropriate instruction is given. Perform first injection under the guidance of a healthcare professional.

Commercially available as a prefilled single-use injection pen or syringe. Prior to administration, allow drug to reach room temperature for about 15–30 minutes.

Discard prefilled pens and syringes after use.

Dosage

Adults

Multiple Sclerosis

Relapsing Forms

Sub-Q

Initially, 20 mg at weeks 0, 1, and 2.

Maintenance dosage: 20 mg once monthly starting at week 4.

If a dose is missed, administer as soon as possible without waiting until the next scheduled dose. Administer subsequent doses at the recommended intervals.

Special Populations

Dosage in Hepatic Impairment

No specific dosage recommendations at this time.

Dosage in Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Ofatumumab

Contraindications

• Patients with active HBV infection.

Warnings/Precautions

Infectious Complications

Increased risk of infections (e.g., respiratory tract infection, urinary tract infection). Do not administer in patients with active infection; delay therapy until infection resolves.

Although not reported with ofatumumab in MS trials, reactivation of HBV infection reported in some patients treated with IV ofatumumab for chronic lymphocytic leukemia (CLL); also reported with other anti-CD20 monoclonal antibodies. Screen all patients for HBV infection with hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) tests at minimum prior to initiating therapy. Ofatumumab is contraindicated in patients with active HBV infection. Consult a liver disease expert prior to initiating and during ofatumumab therapy in patients who are HBsAg-negative and HBcAb-positive, or HBV carriers (i.e., HBsAg-positive).

Although not reported with ofatumumab in MS clinical studies, progressive multifocal leukoencephalopathy (PML; an opportunistic infection of the brain caused by the JC virus) reported with IV ofatumumab for CLL; also reported with other anti-CD20 monoclonal antibodies and MS therapies. If PML is suspected, withhold ofatumumab and perform diagnostic evaluation. MRI signs of PML may be apparent before clinical manifestations develop.

Concomitant use with immunosuppressant drugs may increase risk of infection. Consider additive immune suppressive effects. When switching therapies, consider duration and mechanism of action of these drugs to avoid unintended additive immunosuppressive effects.

Ofatumumab may interfere with the safety and effectiveness of vaccines; complete any necessary immunizations at least 4 weeks prior to initiation of ofatumumab for live or live attenuated vaccines, and whenever possible, at least 2 weeks prior to initiation of ofatumumab for inactivated vaccines.

Safety and effectiveness of live or live-attenuated vaccines administered concomitantly with ofatumumab not established; administration of these vaccines not recommended during and after ofatumumab therapy until B-cell repletion occurs.

Injection-related Reactions

Systemic and local injection reactions reported. Occurred most commonly within 24 hours of the first injection, but also observed with later injections.

Symptoms include fever, headache, myalgia, chills, and fatigue. Local injection-site reactions include erythema, swelling, itching, and pain.

Limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen.

Administer symptomatic treatment if injection-related reactions occur.

Reduction in Immunoglobulins

Decreased IgM concentrations reported.

Monitor levels of quantitative serum immunoglobulins during therapy, especially in patients with opportunistic or recurrent infections, and after discontinuance of therapy until B-cell repletion.

Consider discontinuing ofatumumab if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with IV immunoglobulins.

Fetal/Neonatal Morbidity and Mortality

Risk of fetal harm due to B-cell lymphopenia and reduced antibody response in infants exposed in utero.

Advise females of reproductive potential to use effective contraception while receiving ofatumumab and for ≥6 months after the last dose.

Immunogenicity

Potential for immunogenicity. Development of anti-ofatumumab antibodies reported. Clinical relevance of such antibodies not known.

Specific Populations

Pregnancy

No adequate data in pregnant women; may cause fetal harm. Advise females of childbearing potential to use effective contraception while receiving ofatumumab and for 6 months after the last dose.

Transient peripheral B-cell depletion and lymphocytopenia reported in infants born to women exposed to other anti-CD20 monoclonal antibodies during pregnancy. Effects of maternal exposure to ofatumumab on infant B-cell levels not known. Consider possibility of B-cell depletion in infants born to women who received ofatumumab during pregnancy.

B-cell depletion can affect vaccine immune response in infants. Confirm recovery of B-cell counts before administering live or live-attenuated vaccines to these infants. May administer inactivated vaccines prior to recovery from B-cell depletion, but consider assessing vaccine immune response in consultation with a qualified specialist.

Lactation

Not known whether distributed into human milk or if the drug has any effect on milk production or the breast-fed infant.

Consider known benefits of breast-feeding along with the mother's clinical need for ofatumumab and any potential adverse effects of the drug or disease on the infant.

Females of Reproductive Potential

Advise females of childbearing potential to use effective contraception while receiving ofatumumab and for 6 months after the last dose.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in geriatric patients to determine whether they respond differently than younger adults.

Hepatic Impairment

Pharmacokinetics not studied.

Renal Impairment

Pharmacokinetics not studied.

Common Adverse Effects

Adverse effects occurring in >10% of patients: Upper respiratory tract infections, injection-related reactions, headache, local injection site reactions, urinary tract infection.

Interactions for Ofatumumab

No formal drug interaction studies performed to date. Drug interactions mediated by CYP enzymes or other drug metabolizing enzymes not expected.

Vaccines

Safety and effectiveness of live or live-attenuated vaccines administered concomitantly with ofatumumab not established; administration of these vaccines not recommended during and after ofatumumab therapy until B-cell repletion occurs.

Complete any necessary immunizations at least 4 weeks prior to initiation of ofatumumab for live or live attenuated vaccines, and whenever possible, at least 2 weeks prior to initiation of ofatumumab for inactivated vaccines.

Consider possibility of B-cell depletion in infants born to women who received ofatumumab during pregnancy. B-cell depletion can affect vaccine immune response in infants. Confirm recovery of B-cell counts before administering live or live-attenuated vaccines to these infants. May administer inactivated vaccines prior to recovery from B-cell depletion, but consider assessing vaccine immune response in consultation with a qualified specialist.

Specific Drugs

Ofatumumab Pharmacokinetics

Absorption

Bioavailability

Following sub-Q administration, predominantly absorbed via the lymphatic system.

Onset

Circulating CD19+ B-cells are reduced to below the lower limit of normal (LLN) in approximately 95% of patients 14 days after treatment initiation.

Duration

Recovery of B-cells over the LLN in at least 50% of patients occurred 24–36 weeks after treatment discontinuance. The median predicted time to B-cell recovery is 40 weeks after drug is discontinued.

Special Populations

Pharmacokinetics do not appear to be affected by body weight, sex, age, race, or baseline B-cell count.

Distribution

Extent

Not known whether drug is distributed into human milk. May cross placenta.

Elimination

Metabolism

Degradation to small peptides and amino acids by ubiquitous proteolytic enzymes.

Elimination Route

Eliminated by a target-independent route (similar to other IgG molecules) and a target-mediated route (related to binding to B-cells). Higher baseline B-cell count results in greater target-mediated elimination clearance and a shorter ofatumumab half-life upon initiation of therapy.

Half-life

Approximately 16 days.

Stability

Storage

Parenteral

Prefilled Pen and Syringe

2–8°C in original carton; protect from light until time of use. Do not freeze or shake.

Actions

• A recombinant human monoclonal IgG1 antibody that binds specifically to CD20 (expressed on pre-B cells and mature B lymphocytes).

• Binding to CD20 triggers host immune response involving antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which results in depletion of CD20-expressing B cells.

• Although exact mechanism in MS not fully elucidated, depletion of B cells is thought to result in the drug's immunomodulatory effects.

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

• Advise patients to contact their healthcare provider for any signs of infection (e.g., fever, chills, constant cough, dysuria) during treatment or after the last dose.

• Advise patients that ofatumumab may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk.

• Potential risk of PML. Advise patients that PML has occurred with an IV form of ofatumumab administered at a higher IV dosage in patients with CLL, as well as with drugs that are similar to ofatumumab. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

• Advise patients to complete any required live or live-attenuated vaccinations at least 4 weeks and, whenever possible at least 2 weeks prior to initiation of ofatumumab for inactivated vaccines.

• Administration of live-attenuated or live vaccines is not recommended during ofatumumab treatment and until B-cell recovery.

• Inform patients about the signs and symptoms of injection-related reactions, and that these reactions generally occur within 24 hours and predominantly following the first injection. Advise patients to contact their healthcare provider if they experience signs or symptoms of injection-related reactions.

• Advise females of childbearing potential to use effective contraception while receiving ofatumumab and for 6 months after the last dose.

• Patients or caregivers should be instructed by a healthcare professional on how to administer sub-Q injections of ofatumumab.

• Instruct patients or caregivers in the technique of proper syringe and needle disposal (in a puncture-resistant container), and advise them not to reuse these items. Instruct patients to inject the full amount of ofatumumab according to the directions provided by the manufacturer.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information.

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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