Ublituximab (Monograph)

Brand name: Briumvi
Drug class: Immunomodulatory Agents
Chemical name: immunoglobulin G1, anti-(human CD20 (angigen))(human-mouse monocolonal γ1-chain), disulfide with human-mouse monoclonal κ-chain, dimer
CAS number: 1174014-05-1

Introduction

Ublituximab-xiiy, a recombinant anti-CD20 monoclonal IgG1 antibody, is an immunomodulatory agent.

Uses for Ublituximab

Ublituximab-xiiy has the following uses:

Ublituximab-xiiy is 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.

Ublituximab Dosage and Administration

General

Ublituximab-xiiy is available in the following dosage form(s) and strength(s):

Injection: 150 mg/6 mL (25 mg/mL) in a single-dose vial

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Hepatitis B virus screening and quantitative serum immunoglobulin screening are required before first dose.

• Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion. The addition of an antipyretic (e.g., acetaminophen) may also be considered.

• Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ublituximab-xiiy for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of the drug for non-live vaccines.

• Prior to every infusion of ublituximab-xiiy, determine whether there is an active infection. In case of active infection, delay infusion of the drug until the infection resolves.

• Pregnancy testing is recommended for females of reproductive potential prior to each infusion.

• Must be diluted in 0.9% sodium chloride injection prior to administration.

• Administer ublituximab-xiiy by intravenous infusion as follows:

  –First Infusion: 150 mg intravenous infusion over 4 hours

  –Second Infusion: 450 mg intravenous infusion over 1 hour, administered two weeks after the first infusion

  –Subsequent Infusions: 450 mg intravenous infusion over 1 hour, administered 24 weeks after the first infusion and every 24 weeks thereafter

  –Consult full prescribing information for recommended infusion rates and duration

• Monitor patients closely during and for at least one hour after completion of the first two infusions. Post-infusion monitoring of subsequent infusions is at physician discretion unless infusion reaction and/or hypersensitivity has been observed. Consult full prescribing information for recommendations on dosage modifications for infusion reactions.

Related/similar drugs

Ocrevus, Tecfidera, Rebif, Betaseron, Briumvi, Extavia, Vumerity

Cautions for Ublituximab

Contraindications

• Active hepatitis B virus infection

• History of life-threatening infusion reaction to ublituximab-xiiy

Warnings/Precautions

Infusion Reactions

Ublituximab-xiiy can cause infusion reactions, which can include pyrexia, chills, headache, influenza-like illness, tachycardia, nausea, throat irritation, erythema, and an anaphylactic reaction. In the main efficacy studies (Studies 1 and 2), patients received methylprednisolone (or an equivalent steroid), an antihistamine, and possibly other pre-medication (i.e., acetaminophen) to reduce the risk of infusion reactions prior to each infusion. The incidence of infusion reactions in Studies 1 and 2 in patients who received treatment with ublituximab-xiiy was 48%, with the highest incidence within 24 hours of the first infusion. In Studies 1 and 2, there were no fatal infusion reactions, but 0.6% of patients treated with ublituximab-xiiy experienced infusion reactions that were serious, some requiring hospitalization.

Observe patients treated with ublituximab-xiiy for infusion reactions during the infusion and for at least one hour after completion of the first two infusions. Post-infusion monitoring of subsequent infusions is at physician discretion unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion.

Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered.

Management recommendations for infusion reactions depend on the type and severity of the reaction. For life-threatening infusion reactions, stop the infusion immediately, permanently discontinue ublituximab-xiiy, and provide appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.

Infections

Serious, including life-threatening or fatal, bacterial and viral infections have been reported in patients receiving ublituximab-xiiy. An increased risk of infections, including serious and fatal bacterial, fungal, and new or reactivated viral infections, has been observed during and following completion of treatment with other anti-CD20 B-cell depleting therapies.

In Studies 1 and 2, the overall rate of infections in MS patients treated with ublituximab-xiiy was 56% compared to 54% in patients who were treated with teriflunomide. The rate of serious infections was higher in patients treated with ublituximab-xiiy compared to patients treated with teriflunomide (5% vs 3%, respectively). There were 3 infection-related deaths that occurred in controlled clinical trials in patients with relapsing forms of multiple sclerosis (RMS), all in patients treated with ublituximab-xiiy; the infections leading to death were post-measles encephalitis, pneumonia, and post-operative salpingitis following an ectopic pregnancy. In Studies 1 and 2, the most common infections reported in patients treated with ublituximab-xiiy included upper respiratory tract infection (45%) and urinary tract infection (10%).

Delay ublituximab-xiiy administration in patients with an active infection until the infection is resolved.

When initiating ublituximab-xiiy after an immunosuppressive therapy or initiating an immunosuppressive therapy after ublituximab-xiiy, consider the potential for increased immunosuppressive effects. Ublituximab-xiiy has not been studied in combination with other MS therapies.

Hepatitis B virus (HBV) reactivation occurred in an MS patient treated with ublituximab-xiiy in clinical trials. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with ublituximab-xiiy. Do not start treatment with ublituximab-xiiy in patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult a liver disease expert before starting and during treatment.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML have occurred in MS patients treated with ublituximab-xiiy, JCV infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold ublituximab-xiiy and perform an appropriate diagnostic evaluation. 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. Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients. If PML is confirmed, treatment with ublituximab-xiiy should be discontinued.

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ublituximab-xiiy for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ublituximab-xiiy for non-live vaccines. Ublituximab-xiiy may interfere with the effectiveness of non-live vaccines. The safety of immunization with live or live-attenuated vaccines during or following administration of ublituximab-xiiy has not been studied. Vaccination with live virus vaccines is not recommended during treatment with ublituximab-xiiy and until B-cell repletion.

In infants of mothers exposed to ublituximab-xiiy during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19⁺ B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines. Inactivated or non-live 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.

Fetal Risk

Based on data from animal studies, ublituximab-xiiy may cause fetal harm when administered to a pregnant woman. 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.

A pregnancy test is recommended in females of reproductive potential prior to each infusion with ublituximab-xiiy. Advise females of reproductive potential to use effective contraception during ublituximab-xiiy treatment and for 6 months after the last dose.

Reduction in Immunoglobulins

As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed with ublituximab-xiiy. Decrease in immunoglobulin M (IgM) was reported in 0.6% of patients treated with ublituximab-xiiy compared to none of the patients treated with teriflunomide in RMS clinical trials. No decline in immunoglobulin G (IgG) was observed at the end of the studies. Data from clinical studies using other anti-CD20 monoclonal antibody therapies have shown an association between decreased levels of immunoglobulin M (IgM< lower limit of normal [LLN]) and immunoglobulin G (IgG<LLN) and increased rates of serious infections.

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 ublituximab-xiiy therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

Specific Populations

Pregnancy

There are no data on the developmental risk associated with the use of ublituximab-xiiy in pregnant women. Data from case reports of pregnancies occurring during clinical trials with ublituximab-xiiy are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Although there are no data on ublituximab-xiiy, monoclonal antibodies can be actively transported across the placenta, and ublituximab-xiiy may cause immunosuppression in the in-utero exposed infant.

Weekly intravenous administration of ublituximab-xiiy to pregnant monkeys during the first, second, or third trimester of pregnancy resulted in embryofetal loss; administration during the second trimester resulted in external, skeletal, and visceral abnormalities in infants.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses and peaks during the third trimester. There are no data on B-cell levels in human neonates following maternal exposure to ublituximab-xiiy. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. Avoid administering live vaccines to neonates and infants exposed to ublituximab-xiiy in utero until B-cell recovery occurs.

Weekly intravenous administration of ublituximab-xiiy (0 or 30 mg/kg) to separate groups of pregnant monkeys during the first, second, or third trimester of pregnancy produced a severe immunogenic response in dams, resulting in maternal morbidity and death and embryofetal loss. Dosing was terminated in dams after only two doses during the third trimester because of multiple deaths in dams dosed during the first and second trimesters.

Ublituximab-related external, viscera, and skeletal abnormalities occurred in two infants from dams exposed during the second trimester of pregnancy. Histopathology evaluations revealed minimal to moderate degeneration/necrosis in the brain. Findings in infants included contractures and abnormal flexion of multiple limbs and tail, shortened mandible, elongate calvarium, enlargement of ears, and/or craniomandibular abnormalities which were attributed to brain necrosis. Abnormalities were absent in infants of dams exposed during the first trimester of pregnancy. A no-effect dose for adverse effects on embryofetal development in monkeys was not identified.

Lactation

There are no data on the presence of ublituximab-xiiy 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 ublituximab-xiiy 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 ublituximab-xiiy and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

Females and Males of Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential prior to each infusion.

Females of reproductive potential should use effective contraception while receiving ublituximab-xiiy and for 6 months after the last dose of the drug.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of ublituximab-xiiy did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

Common Adverse Effects

The most common adverse reactions (≥10%) were infusion reactions and upper respiratory tract infections.

Drug Interactions

Specific Drugs

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.

Actions

Mechanism of Action

The precise mechanism by which ublituximab-xiiy 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, ublituximab-xiiy results in cell lysis through mechanisms including antibody-dependent cellular cytolysis and complement-dependent cytolysis.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling.

• Inform patients about the signs and symptoms of infusion reactions and that infusion reactions can occur up to 24 hours after infusion. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions.

• Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last infusion. Signs can include fever, chills, constant cough, or dysuria.

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

• Advise patients that PML has occurred with drugs that are similar to ublituximab-xiiy and may occur with ublituximab-xiiy. 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 doctor 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, non-live vaccinations at least 2 weeks prior to initiation of ublituximab-xiiy. Administration of live-attenuated or live vaccines is not recommended during ublituximab-xiiy treatment and until B-cell recovery.

• Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ublituximab-xiiy and for 6 months after the last dose. Advise patients to notify their healthcare provider if they are pregnant during treatment with ublituximab-xiiy.

Additional Information

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.

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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