Class: Immunomodulatory Agents
Ofatumumab is an immunomodulatory agent.
Uses for Ofatumumab
Ofatumumab has the following uses:
Ofatumumab is a CD20-directed cytolytic antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Ofatumumab Dosage and Administration
Ofatumumab is available in the following dosage form(s) and strength(s):
Injection: 20 mg/0.4 mL solution in a single-dose prefilled Sensoready Pen.
Injection: 20 mg/0.4 mL solution in a single-dose prefilled syringe.
It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:
Dosage and Administration
Hepatitis B virus (HBV) and quantitative serum immunoglobulins screening are required before the first dose.
Administer ofatumumab by subcutaneous injection only.
Initial Dosing: 20 mg administered at Week 0, 1, and 2.
Subsequent Dosing: 20 mg administered monthly starting at Week 4.
Cautions for Ofatumumab
Active HBV infection.
An increased risk of infections has been observed with other anti-CD20 B-cell depleting therapies.
Ofatumumab has the potential for an increased risk of infections, including serious bacterial, fungal, and new or reactivated viral infections; some of these infections have been fatal in patients treated with other anti-CD20 antibodies. In Study 1 and Study 2, the overall rate of infections and serious infections in patients treated with ofatumumab was similar to patients who were treated with teriflunomide (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common infections reported by ofatumumab-treated patients in the randomized clinical relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay ofatumumab administration in patients with an active infection until the infection is resolved.
Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants: When initiating ofatumumab after an immunosuppressive therapy or initiating an immunosuppressive therapy after ofatumumab, consider the potential for increased immunosuppressive effects. Ofatumumab has not been studied in combination with other MS therapies.
Hepatitis B Virus: There were no reports of HBV reactivation in patients with MS treated with ofatumumab. However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (CLL) (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment) and in patients treated with other anti-CD20 antibodies.
Ofatumumab is contraindicated in patients with active hepatitis B disease. Fatal infections caused by HBV in patients who have not been previously infected have occurred in patients being treated with ofatumumab for CLL (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). HBV screening should be performed in all patients before initiation of treatment with ofatumumab. At a minimum, screening should include Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with ofatumumab. These patients should be monitored and managed following local medical standards to prevent HBV infection or reactivation.
Progressive Multifocal Leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.
Although no cases of PML have been reported for ofatumumab in the RMS clinical studies, PML resulting in death has occurred in patients being treated with ofatumumab for CLL (at substantially higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). In addition, JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold ofatumumab and perform an appropriate diagnostic evaluation. Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. 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.
If PML is confirmed, treatment with ofatumumab should be discontinued.
Vaccinations: Administer all immunizations according to immunization guidelines 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.
Ofatumumab may interfere with the effectiveness of inactivated vaccines.
The safety of immunization with live or live-attenuated vaccines following ofatumumab therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion.
In infants of mothers treated with ofatumumab during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.
Inactivated vaccines may be administered, as indicated, prior to recovery from B-cell depletion, but an assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted.
In Study 1 and Study 2, systemic and local injection reactions were reported in 21% and 11% of patients treated with ofatumumab compared to 15% and 6% of patients treated with teriflunomide who received matching placebo injections, respectively.
Injection-related reactions with systemic symptoms observed in clinical studies occurred most commonly within 24 hours of the first injection, but were also observed with later injections. Symptoms observed included fever, headache, myalgia, chills, and fatigue, and were predominantly (99.8%) mild to moderate in severity. There were no life-threatening injection reactions in the RMS clinical studies.
Local injection-site reaction symptoms observed in clinical studies included erythema, swelling, itching, and pain.
Only limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen was observed in RMS clinical studies. The first injection of ofatumumab should be performed under the guidance of an appropriately trained healthcare professional. If injection-related reactions occur, symptomatic treatment is recommended.
Reduction In Immunoglobulins
As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Decrease in immunoglobulin M (IgM) was reported in 7.7% of patients treated with ofatumumab compared to 3.1% of patients treated with teriflunomide in RMS clinical trials. Treatment was discontinued because of decreased immunoglobulins in 3.4% of patients treated with ofatumumab and in 0.8% of patients treated with teriflunomide. No decline in immunoglobulin G (IgG) was observed at the end of the study. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing ofatumumab therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.
Based on animal data, ofatumumab can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to ofatumumab in utero. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving ofatumumab and for at least 6 months after the last dose.
Risk Summary: There are no adequate data on the developmental risk associated with the use of ofatumumab in pregnant women. Ofatumumab may cross the placenta and cause fetal B-cell depletion based on findings from animal studies.
Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. B-cell levels in infants following maternal exposure to ofatumumab have not been studied in clinical trials. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown. Avoid administering live vaccines to neonates and infants exposed to ofatumumab in utero until B-cell recovery occurs.
Following administration of ofatumumab to pregnant monkeys, increased mortality, depletion of B-cell populations, and impaired immune function were observed in the offspring, in the absence of maternal toxicity, at plasma levels substantially higher than that in humans.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Animal Data: Intravenous administration of ofatumumab (weekly doses of 0, 20, or 100 mg/kg) to pregnant monkeys during the period of organogenesis (gestations days 20 to 50) resulted in no adverse effects on embryofetal development; however, B-cell depletion was observed in fetuses at both doses when assessed on gestation day 100. Plasma exposure (Cave) at the no-effect dose (100 mg/kg) for adverse effects on embryofetal development was greater than 5000 times that in humans at the recommended human maintenance dose of 20 mg. A no-effect dose for effects on B-cells was not identified; plasma exposure (Cave) at the low-effect dose (20 mg/kg) was approximately 780 times that in humans at the recommended human maintenance dose (RHMD) of 20 mg/month.
Intravenous administration of ofatumumab (5 weekly doses of 0, 10, and 100 mg/kg, followed by biweekly doses of 0, 3, and 20 mg/kg) to pregnant monkeys throughout pregnancy resulted in no adverse effects on the development of the offspring. However, postnatal death, B-cell depletion, and impaired immune function were observed in the offspring at the high dose. The deaths at the high dose were considered secondary to B-cell depletion. Plasma exposure (Cave) in dams at the no-effect dose (100/20 mg/kg) for adverse developmental effects was approximately 500 times that in humans at RHMD. A no-effect level for mortality and immune effects in offspring was not established because of the limited number of evaluable offspring at the low dose.
Risk Summary: There are no data on the presence of ofatumumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Human IgG is excreted in human milk, and the potential for absorption of ofatumumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ofatumumab and any potential adverse effects on the breastfed infant from ofatumumab or from the underlying maternal condition.
Females and Males of Reproductive Potential
Females of childbearing potential should use effective contraception while receiving ofatumumab and for 6 months after the last treatment of ofatumumab.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of ofatumumab did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger subjects.
Common Adverse Effects
Most common adverse reactions (incidence greater than 10%) are upper respiratory tract infection, headache, injection-related reactions, and local injection site reactions.
It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:
Please see product labeling for drug interaction information.
Mechanism of Action
The precise mechanism by which ofatumumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ofatumumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.
Advice to Patients
Patient Counseling Information
Advise the patient to read FDA-approved patient labeling (Medication Guide and Instructions for Use).
Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, constant cough, or dysuria.
Advise patients that ofatumumab may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk.
Advise patients that PML has happened with an intravenous form of ofatumumab administered at a higher intravenous dosage in patients with CLL, as well as with drugs that are similar to ofatumumab, and may happen with 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. Inform the patient that 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 treatment of ofatumumab.
Patients or caregivers should be instructed by a healthcare professional on how to administer ofatumumab.
Instruct patients or caregivers in the technique of proper syringe and needle disposal, and advise them not to reuse these items. Instruct patients to inject the full amount of ofatumumab according to the directions provided in the Instructions for Use. Dispose of pens and syringes in a puncture-resistant container.
AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
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.
20 mg/0.4 mL
Novartis Pharmaceuticals Corporation
AHFS Drug Information. © Copyright 2021, Selected Revisions August 31, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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