Highlights

Indications and usage

Ofatumumab is indicated for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Dosage and administration

Assessments before first dose of ofatumumab

Hepatitis B virus screening. Before initiating ofatumumab, perform hepatitis B virus screening. Ofatumumab is contraindicated in patients with active hepatitis B virus confirmed by positive results for hepatitis B surface antigen (HbsAg) and anti-hepatitis B virus tests. For patients who are negative for HBsAg and positive for hepatitis B core antibody (HBcAb+) or are carriers of hepatitis B virus (HBsAg+), consult liver disease experts before starting and during treatment with ofatumumab.

Serum immunoglobulins. Before initiating ofatumumab, perform testing for quantitative serum immunoglobulins. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with ofatumumab.

Vaccinations. Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks before initiation of ofatumumab for live or live-attenuated vaccines, and whenever possible, at least 2 weeks before initiation of ofatumumab for inactivated vaccines.

Recommended dosage

The recommended dosage of ofatumumab is initial doses of 20 mg by subcutaneous injection at weeks 0, 1, and 2, followed by subsequent dosing of 20 mg by subcutaneous injection once monthly starting at week 4.

Missed doses. If an injection of ofatumumab is missed, it should be administered as soon as possible without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals.

Administration instructions

Administer by subcutaneous injection only.

Ofatumumab is intended for patient self-administration by subcutaneous injection.

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

The first injection of ofatumumab should be performed under the guidance of a healthcare professional.

Ofatumumab Sensoready® pens and syringes are for single-use only and should be discarded after use. For complete administration instructions, refer to the “Instructions for Use” section of the DAILYMED drug label information.

Preparation of ofatumumab

Refer to the “Instructions for Use” section of the DAILYMED drug label information for detailed instructions on the preparation of ofatumumab.

Before administration, remove the ofatumumab Sensoready Pen or prefilled syringe from the refrigerator and allow ofatumumab to reach room temperature for about 15 to 30 minutes. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature.

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not use if the liquid contains visible particles or is cloudy.

Dosage forms and strengths

Ofatumumab is a clear to slightly opalescent and colorless to slightly brownish-yellow solution available as follows:

Contraindications

Ofatumumab is contraindicated in patients with active hepatitis B virus infection or a history of hypersensitivity to ofatumumab or a life-threatening injection-related reaction to ofatumumab. Hypersensitivity reactions have included anaphylaxis and angioedema.

Warnings and precautions

Infections

Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies.

In the ofatumumab Studies 1 and 2, the overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients 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 multiple sclerosis trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Clinicians should 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. The safety and efficacy of ofatumumab in combination with other multiple sclerosis therapies have not been studied.

Hepatitis B virus.

Reactivation. There were no reports of hepatitis B virus reactivation in patients with multiple sclerosis treated with ofatumumab. However, hepatitis B virus reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (at higher intravenous doses than the recommended dose in multiple sclerosis but for a shorter duration of treatment) and in patients treated with other anti-CD20 antibodies.

Infection. Ofatumumab is contraindicated in patients with active hepatitis B disease. Fatal infections caused by hepatitis B virus in patients who have not been previously infected have occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (at higher intravenous doses than the recommended dose in multiple sclerosis but for a shorter duration of treatment). Hepatitis B virus 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 hepatitis B core antibody (HBcAb+) or are carriers of hepatitis B virus (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 hepatitis B virus infection or reactivation.

Progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy is an opportunistic viral infection of the brain caused by the JC virus that typically occurs in immunocompromised patients and usually leads to death or severe disability.

Although no cases of progressive multifocal leukoencephalopathy have been reported for ofatumumab in the relapsing multiple sclerosis clinical studies, progressive multifocal leukoencephalopathy resulting in death has occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (at substantially higher intravenous doses than the recommended dose in multiple sclerosis but for a shorter duration of treatment). In addition, JC virus infection resulting in progressive multifocal leukoencephalopathy has also been observed in patients treated with other anti-CD20 antibodies and other multiple sclerosis therapies. At the first sign or symptom suggestive of progressive multifocal leukoencephalopathy, withhold ofatumumab and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with progressive multifocal leukoencephalopathy 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 progressive multifocal leukoencephalopathy is confirmed, treatment with ofatumumab should be discontinued.

Vaccinations. Administer all immunizations according to immunization guidelines at least 4 weeks before initiation of ofatumumab for live or live-attenuated vaccines, and whenever possible, at least 2 weeks before 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.

Vaccination of infants born to mothers treated with ofatumumab during pregnancy. 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, before 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.

Injection-related reactions and hypersensitivity reactions

Ofatumumab can result in systemic injection-related reactions and hypersensitivity reactions, which may be serious or life-threatening.

In Studies 1 and 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 relapsing multiple sclerosis clinical studies.

In the post-marketing setting, additional systemic injection-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, angioedema, pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, dizziness, nausea, and tachycardia. Most cases were non-serious and occurred with the first injection. Most serious cases resulted in permanent discontinuation of ofatumumab.

Symptoms of systemic injection-related reactions may be clinically indistinguishable from acute hypersensitivity reactions. A hypersensitivity reaction may occur with any injection. New or more severe symptoms compared to those experienced with previous injections should prompt consideration of a potential hypersensitivity reaction.

Only a limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen was observed in relapsing multiple sclerosis clinical studies. The first injection of ofatumumab should be performed under the guidance of an appropriately trained healthcare professional. If systemic injection-related reactions occur, initiate appropriate therapy. Patients who experience symptoms of systemic injection-related reactions or hypersensitivity reactions with ofatumumab should be instructed to seek immediate medical attention.

If a hypersensitivity reaction or life-threatening systemic injection-related reaction occurs, immediately and permanently discontinue ofatumumab. If restarting ofatumumab after a severe (but not life-threatening) injection-related systemic response or other event after which rechallenge is considered appropriate, administer the next ofatumumab injection under clinical observation. If a mild to moderate injection-related reaction occurs, consider rechallenge under clinical observation.

Local injection-site reaction symptoms observed in clinical studies included erythema, swelling, itching, and pain. If local injection-related reactions occur, symptomatic treatment is recommended.

Reduction in immunoglobulins

As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. A 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 relapsing multiple sclerosis 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.

Fetal risk

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.

Adverse reactions

Infections, injection-related reactions, hypersensitivity reactions, and reduced immunoglobulin levels are discussed in the warnings and precautions section of this article.

Clinical trials experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Approximately 1500 patients with relapsing multiple sclerosis received ofatumumab in clinical studies. In Studies 1 and 2, 1882 patients with relapsing multiple sclerosis were randomized, 946 of whom were treated with ofatumumab for a median duration of 85 weeks; 33% of patients receiving ofatumumab were treated for up to 120 weeks. The most common adverse reactions occurring in greater than 10% of patients treated with ofatumumab and more frequently than in patients treated with teriflunomide were upper respiratory tract infections, injection-related reactions (systemic), headache, and injection-site reactions (local). The most common cause of discontinuation in patients treated with ofatumumab was low immunoglobulin M (3.3%), defined in trial protocols as IgM at 10% below the lower limit of normal.

Table 1 summarizes the adverse drug reactions that occurred in Studies 1 and 2.

Table 1: Adverse reactions in patients with relapsing multiple sclerosis with an incidence of at least 5% with ofatumumab and a greater incidence than teriflunomide (Pooled Study 1 and Study 2)

Injection-related reactions and injection-site reactions. The incidence of injection-related reactions (systemic) was highest with the first injection (14.4%), decreasing with subsequent injections (4.4% with the second and less than 3% with the third injection). Injection-related reactions were mostly (99.8%) mild to moderate in severity. Two (0.2%) patients treated with ofatumumab reported serious injection-related reactions. There were no life-threatening injection-related reactions. Most frequently reported symptoms (2% or greater) included fever, headache, myalgia, chills, and fatigue.

In addition to systemic injection-related reactions, local reactions at the administration site were very common. Local injection-site reactions were all mild to moderate in severity. The most frequently reported symptoms (2% or greater) included erythema, pain, itching, and swelling.

Laboratory abnormalities.

Immunoglobulins. In Studies 1 and 2, a decrease in the mean level of IgM was observed in ofatumumab-treated patients, but was not associated with an increased risk of infections. In 14.3% of patients in Studies 1 and 2, treatment with ofatumumab resulted in a decrease in serum IgM that reached a value below 0.34 g/L. Ofatumumab was associated with a decrease of 4.3% in mean IgG levels after 48 weeks of treatment and an increase of 2.2% after 96 weeks.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and the underlying disease. For these reasons, comparing the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ofatumumab products may be misleading.

Treatment-induced anti-drug antibodies were detected in 2 of 914 (0.2%) ofatumumab-treated patients; no patients with treatment-enhancing or neutralizing anti-drug antibodies were identified. There was no impact of positive anti-drug antibody titers on pharmacokinetics, safety profile, or B-cell kinetics in any patient; however, these data are insufficient to assess the impact of anti-drug antibodies on the safety and efficacy of ofatumumab.

Drug interactions

Immunosuppressive or immune-modulating therapies

Concomitant usage of ofatumumab with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with ofatumumab.

When switching from therapies with immune effects, the duration and mechanism of action of these therapies should be taken into account because of potential additive immunosuppressive effects when initiating ofatumumab.

Use in specific populations

Pregnancy

Pregnancy exposure registry. A pregnancy exposure registry monitors pregnancy outcomes in women exposed to ofatumumab during pregnancy. Healthcare providers are encouraged to enroll pregnant patients, or pregnant women may register themselves in the MotherToBaby Pregnancy Study in Multiple Sclerosis by calling 1-877-311-8972, by sending an email to MotherToBaby@health.ucsd.edu, or by going to www.mothertobaby.org/join-study.

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 (see Data).

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 those in humans (see Data).

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.

Data.

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 of 20 mg/month.

Intravenous administration of ofatumumab (five 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 the recommended human maintenance dose. 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.

Lactation

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

Contraception. Females of childbearing potential should use effective contraception while receiving ofatumumab and for 6 months after the last treatment of ofatumumab.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

Clinical studies of ofatumumab did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger subjects.

Description

Ofatumumab is a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody that binds to human CD20 expressed on B-cells. Ofatumumab is produced in a murine NS0 cell line and consists of two IgG1 heavy chains and two kappa light chains with a molecular weight of approximately 146 kDa.

Ofatumumab (ofatumumab) injection is a sterile, preservative-free solution for subcutaneous use.

Each 20 mg/0.4 mL ofatumumab Sensoready Pen or prefilled syringe delivers 0.4 mL of solution. Each 0.4 mL contains 20 mg of ofatumumab, arginine (4 mg), disodium edetate (0.007 mg), polysorbate 80 (0.08 mg), sodium acetate trihydrate (2.722 mg), sodium chloride (1.192 mg), and water for injection, USP with a pH of 5.5. Hydrochloric acid may have been added to adjust pH.

Clinical pharmacology

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.

Pharmacodynamics

B-cell depletion. For B-cell counts, assays for CD19+ B-cells are used because the presence of ofatumumab interferes with the CD20 assay. In Studies 1 and 2, ofatumumab administered as recommended resulted in a reduction of CD19+ B-cells to below the lower limit of normal in 77.0% and 78.8% of patients, respectively, 1 week after treatment initiation, and in 95.0% and 95.8% of patients, respectively, 2 weeks after treatment initiation. At Week 12, 99.3% to 99.5% of patients had CD19+ B-cell counts below the lower limit of normal. The CD19+ B-cell counts remained below the lower limit of normal for approximately 97% of patients in Study 1 and 92% of patients in Study 2 from 12 weeks through 120 weeks while on ofatumumab treatment.

In a study of bioequivalence using the same dosing regimen as in Studies 1 and 2, before initiation of the maintenance phase, total CD19+ B-cell levels below the defined threshold of 10 cells/µL were achieved in 94% of patients starting at Week 4 and 98% of patients at Week 12.

B-cell repletion. Data from Studies 1 and 2 indicate a median time to B-cell recovery to either the lower limit of normal or baseline value of 24.6 weeks post-treatment discontinuation. Pharmacokinetics and pharmacodynamics modeling and simulation for B-cell repletion corroborate these data, predicting median time to B-cell recovery to the lower limit of normal of 23 weeks post-treatment discontinuation.

Pharmacokinetics

Absorption. A subcutaneous dose of 20 mg every 4 weeks leads to a mean AUCtau of 483 mcg h/mL and a mean Cmax of 1.43 mcg/mL at steady state.

After subcutaneous administration, ofatumumab is believed to be predominantly absorbed via the lymphatic system, similarly to other therapeutic monoclonal antibodies.

Distribution. The volume of distribution at steady-state was estimated to be 5.42 L following subcutaneous administration of repeated ofatumumab 20 mg doses.

Elimination. Ofatumumab is eliminated by both linear catabolic pathways and a non-linear B-cell mediated pathway, resulting in non-constant elimination half-life. Initially, a higher baseline B-cell count results in greater B-cell-mediated elimination and a shorter ofatumumab half-life. As the B-cells are depleted, the catabolic pathway predominates, resulting in a relatively longer ofatumumab half-life compared to earlier in therapy when both elimination pathways were available. Following B-cell depletion, clearance was estimated to be 0.34 L/day following repeated subcutaneous administration of ofatumumab 20 mg injections. The half-life at steady state was estimated to be approximately 16 days following subcutaneous administration of repeated ofatumumab 20 mg dosages.

Metabolism. Ofatumumab is a protein for which the expected metabolic pathway is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes.

Excretion. Ofatumumab, a monoclonal antibody, is not likely to undergo renal excretion.

Specific populations. The following population characteristics do not have a clinically meaningful effect on the pharmacokinetics of ofatumumab: body weight, sex, age, race, or baseline B-cell count.

Patients with renal or hepatic impairment. Pharmacokinetics of ofatumumab in patients with renal or hepatic impairment have not been studied.

Drug interaction studies. Ofatumumab does not share a common clearance pathway with chemical drugs that are metabolized by the cytochrome P450 system or other drug-metabolizing enzymes. Additionally, there is no evidence that CD20 monoclonal antibodies are involved in the regulation of drug-metabolizing enzyme expression. Interactions between ofatumumab and other medicinal products have not been formally investigated.

Nonclinical toxicology

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis. No carcinogenicity studies have been conducted to assess the carcinogenic potential of ofatumumab.

Mutagenesis. No studies have been conducted to assess the mutagenic potential of ofatumumab. As an antibody, ofatumumab is not expected to interact directly with DNA.

Impairment of fertility. No effects on reproductive parameters, including hormones, menstrual cycle, sperm analysis, or histopathological evaluation of reproductive organs, were observed in male or female monkeys administered ofatumumab by intravenous injection (5 weekly doses of 0, 10, and 100 mg/kg, followed by biweekly doses of 0, 3, and 20 mg/kg). Plasma exposures (Cave) at the high dose tested in monkeys are greater than 500 times that in humans at the recommended human maintenance dose of 20 mg/month.

Clinical studies

The efficacy of ofatumumab was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials of identical design, in patients with relapsing forms of multiple sclerosis (Study 1 [ASCLEPIOS I, NCT02792218] and Study 2 [ASCLEPIOS II, NCT02792231]). Both studies enrolled patients with at least one relapse in the previous year, two relapses in the previous 2 years, or the presence of a T1 gadolinium-enhancing (GdE) lesion in the previous year. Patients were also required to have an Expanded Disability Status Scale (EDSS) score from 0 to 5.5.

Patients were randomized to receive either ofatumumab, 20 mg subcutaneously on Days 1, 7, and 14, followed by 20 mg every 4 weeks thereafter, starting at Week 4, with a daily oral placebo, or the active comparator, teriflunomide, at a dose of 14 mg orally once daily with a placebo administered subcutaneously on Days 1, 7, 14, and every 4 weeks thereafter. The treatment duration for an individual patient was variable based on when the end-of-study criteria were met. The maximal duration of treatment for an individual patient was 120 weeks. Neurologic evaluations were performed at baseline, every 3 months during blinded treatment, and at the time of a suspected relapse. Brain MRI scans were performed at baseline, 1 year, and 2 years.

The primary endpoint of both trials was the annualized relapse rate over the treatment period. Additional outcome measures included: (1) the time to 3-month confirmed disability progression for the pooled populations, (2) the number of T1 GdE lesions per scan at Weeks 48 and 96, and (3) the annualized rate of new or enlarging T2 MRI lesions. Disability progression was defined as an increase in EDSS of at least 1.5, 1, or 0.5 points in patients with a baseline EDSS of 0, 1 to 5, or 5.5 or greater, respectively.

In Study 1, a total of 927 patients were randomized to receive ofatumumab (n = 465) or teriflunomide (n = 462). Of those randomized to ofatumumab, 90% completed the study; of those randomized to teriflunomide, 81% completed the study. Demographics and disease characteristics were balanced across treatment arms. The mean age was 38 years, 89% were White, and 69% were female. The mean time since multiple sclerosis diagnosis was 5.7 years, and the median EDSS score at baseline was 3.0; 60% had been treated with a nonsteroid therapy for multiple sclerosis. At baseline, the mean number of relapses in the previous year was 1, and the mean number of T1 GdE lesions on MRI scan was 1.5.

In Study 2, a total of 955 patients were randomized to receive ofatumumab (n = 481) or teriflunomide (n = 474). Of those randomized to ofatumumab, 83% completed the study; of those randomized to teriflunomide, 82% completed the study. Demographics and disease characteristics were balanced across treatment arms. The mean age was 38 years, 87% were White, and 67% were female. The mean time since multiple sclerosis diagnosis was 5.5 years, and the median EDSS score at baseline was 2.5; 61% had been treated with a nonsteroid therapy for multiple sclerosis. At baseline, the mean number of relapses in the previous year was 1.3, and the mean number of T1 GdE lesions on MRI scan was 1.6.

In both studies, ofatumumab significantly lowered the annualized relapse rate compared to teriflunomide.

Ofatumumab significantly reduced the risk of 3-month confirmed disability progression compared to teriflunomide.

Ofatumumab significantly reduced the number of T1 GdE lesions and the rate of new or enlarging T2 lesions in both studies.

For key results from Studies 1 and 2, see Table 2 and Figure 1 in the Clinical studies section of the DAILYMED drug label information.

A similar effect of ofatumumab on the key efficacy results compared to teriflunomide was observed across the two studies in exploratory subgroups defined by sex, age, body weight, prior non-steroid multiple sclerosis therapy, and baseline disability and disease activity.

How supplied: storage and handling

How supplied

Ofatumumab injection is a preservative-free, clear to slightly opalescent and colorless to slightly brownish-yellow solution for subcutaneous administration, which is supplied as follows.

Ofatumumab Sensoready Pen. Carton of one 20 mg/0.4 mL single-dose prefilled Sensoready Pen (NDC 0078-1007-68)

Ofatumumab prefilled syringe. Carton of one 20 mg/0.4 mL single-dose prefilled syringe (NDC 0078-1007-69)

Storage and handling

Ofatumumab Sensoready pens and prefilled syringes must be refrigerated at 2°C to 8°C (36°F to 46°F). Keep the product in the original carton to protect from light until the time of use. Do not freeze. To avoid foaming, do not shake.

If necessary, ofatumumab may be stored for up to 7 days at room temperature, not to exceed 30°C (86°F). Write the date removed from the refrigerator in the space provided on the carton labeling. If stored below 30°C (86°F), unused ofatumumab may be returned to the refrigerator and must be used within the next 7 days or discarded after 7 days.

Patient counseling information

Advise the patient to read FDA-approved patient labeling.

Infections. Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, a 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 progressive multifocal leukoencephalopathy has happened with an intravenous form of ofatumumab administered at a higher intravenous dosage in patients with chronic lymphocytic leukemia, as well as with drugs that are similar to ofatumumab, and may happen with ofatumumab. Inform the patient that progressive multifocal leukoencephalopathy 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 progressive multifocal leukoencephalopathy. Inform the patient that typical symptoms associated with progressive multifocal leukoencephalopathy 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.

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

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

Injection-related reactions and hypersensitivity reactions. Inform patients about the signs and symptoms of injection-related reactions and hypersensitivity reactions. Inform patients that injection-related reactions generally occur within 24 hours and predominantly following the first injection. A hypersensitivity reaction may occur with any injection, and any new or worsening symptoms with subsequent ofatumumab injections should prompt consideration of a hypersensitivity reaction. Advise patients to seek immediate medical attention if they experience signs or symptoms of a severe or life-threatening injection-related reaction or hypersensitivity reaction, and to contact their healthcare provider if they experience any signs or symptoms of a injection-related reaction or hypersensitivity reaction.

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

Pregnancy exposure registry. Instruct patients that if they are pregnant or plan to become pregnant while taking ofatumumab, they should inform their healthcare provider. Encourage patients to enroll in the MotherToBaby Pregnancy Study in Multiple Sclerosis if they become pregnant while taking ofatumumab.

Instruction on injection technique. 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.

Manufacturer. Manufactured by Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936. U.S. License No.: 1244.

Kesimpta and Sensoready are registered trademarks of Novartis AG. T2024-31

Medication guide and Instructions for use

See “Medication guide” and “Instructions for use” sections of the DAILYMED drug label information.