Ublituximab-xiiy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar Doraghi, M.D.[2]
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Black Box Warning
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Warning: Infusion Reactions
See full prescribing information for complete Boxed Warning.
Infusion reactions: Discontinue BRIUMVI if severe reactions occur.
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Overview
Ublituximab-xiiy is a CD20-directed cytolytic antibody that is FDA approved 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. There is a Black Box Warning for this drug as shown here. Common adverse reactions include infusion reactions and upper respiratory tract infections.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- 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.
- Administer BRIUMVI by intravenous infusion.
- First Infusion: 150 mg intravenous infusion.
- Second Infusion: 450 mg intravenous infusion two weeks after the first infusion.
- Subsequent Infusions: 450 mg intravenous infusion 24 weeks after the first infusion and every 24 weeks thereafter.
- Must be diluted in 0.9% Sodium Chloride Injection, USP prior to administration.
- Monitor patients closely during and for at least one hour after the 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
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ublituximab-xiiy FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
- Active hepatitis B virus infection
- History of life-threatening infusion reaction to BRIUMVI
Warnings
|
Warning: Infusion Reactions
See full prescribing information for complete Boxed Warning.
Infusion reactions: Discontinue BRIUMVI if severe reactions occur.
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- Infusion Reactions: BRIUMVI may cause infusion reactions, with symptoms including pyrexia, chills, headache, and more. Pre-medication before infusions can reduce the risk. In Studies 1 and 2, 48% of patients experienced infusion reactions, mostly within 24 hours of the first infusion, though none were fatal.
Monitor patients during and after infusions, with specific protocols for observation. Pre-medication with corticosteroids and antihistamines is recommended to mitigate reactions. Severe reactions warrant immediate discontinuation of BRIUMVI and appropriate supportive care. For milder reactions, consider temporary cessation, rate reduction, or symptomatic treatment.
- Infections: Patients receiving BRIUMVI are at risk of serious, potentially life-threatening bacterial and viral infections. Studies show a higher rate of infections, including serious cases, compared to other treatments like teriflunomide. Notably, infection-related deaths occurred in patients treated with BRIUMVI, with common infections including upper respiratory and urinary tract infections.
It's advised to delay BRIUMVI administration in patients with active infections until resolved. Additionally, caution is needed when using BRIUMVI with other immunosuppressive therapies, as it may increase immunosuppressive effects.
- Hepatitis B Virus (HBV) Reactivation:
Screen all patients for HBV before starting BRIUMVI. Treatment should not begin if active HBV is confirmed. Consult a liver specialist for HBsAg-negative, HBcAb-positive, or HBsAg-positive patients.
PML, a potentially fatal brain infection, has been seen in patients on immunosuppressive therapy, although not with BRIUMVI. Watch for symptoms like weakness, vision changes, and cognitive issues. MRI monitoring may help detect signs early. Discontinue BRIUMVI if PML is confirmed.
- Vaccinations:
Administer all vaccines at least 4 weeks before starting BRIUMVI. Non-live vaccines are preferred. Avoid live vaccines during treatment and until B-cell levels recover. Vaccination of Infants Born to Mothers Treated with BRIUMVI During Pregnancy: Delay live vaccines in infants born to mothers who received BRIUMVI during pregnancy until B-cell counts recover. Inactivated vaccines may be given, but immune response assessment is advisable.
- Fetal Risk:
BRIUMVI may pose risks to fetal development based on animal studies. Infants born to mothers exposed to similar medications during pregnancy showed temporary peripheral B-cell depletion and lymphocytopenia. Pregnancy tests are recommended before each infusion. Advise females of reproductive potential to use contraception during treatment and for 6 months after the last dose.
- Reduction in Immunoglobulins:
BRIUMVI can lead to decreased immunoglobulin levels, particularly IgM. This decline, observed in a small percentage of patients, may increase the risk of serious infections. Monitor serum immunoglobulin levels during treatment, especially in those with recurrent infections. Consider discontinuing BRIUMVI if low immunoglobulin levels result in serious opportunistic infections or recurrent infections, or if prolonged hypogammaglobulinemia requires intravenous immunoglobulin treatment
Adverse Reactions
Clinical Trials Experience
The 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. In active-controlled clinical trials (Study 1 and Study 2), 545 patients with RMS received BRIUMVI. The most common adverse reactions in these trials, with an incidence of at least 10%, were infusion reactions and upper respiratory tract infections. TABLE 2 summarizes the adverse reactions observed in these trials. The most common reason for discontinuation among patients treated with BRIUMVI was infection, with a rate of 1.3%.
- The first dose of BRIUMVI was administered as an intravenous (IV) infusion of 150 mg, followed by a second dose of 450 mg given via IV infusion two weeks after the initial infusion.
- This category encompasses various upper respiratory tract infections, including nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, laryngitis, and related conditions.
- This category includes lower respiratory tract infections such as bronchitis, pneumonia, tracheitis, and related respiratory conditions, including COVID-19 pneumonia.
- This category encompasses various infections associated with the herpes virus and includes several related terms.
- Infusion Reactions:
During active-controlled clinical trials (Study 1 and Study 2), 545 patients with RMS received BRIUMVI, experiencing infusion reactions as the most common adverse event (48%). The incidence was highest with the first infusion (43%), decreasing with subsequent infusions (10% with the second, 8% with the third). A small percentage (0.6%) reported serious infusion reactions, with symptoms such as pyrexia, chills, headache, and influenza-like illness.
- Laboratory Abnormalities:
Decreased Immunoglobulins: BRIUMVI led to decreased total immunoglobulin levels, particularly IgM. At baseline, a small proportion of patients had IgG, IgA, and IgM below the lower limit of normal (LLN). Following treatment, the percentage of patients with IgG, IgA, and IgM below LLN increased, with IgM showing the greatest decline (Section 6.1). Decreased Neutrophil Levels: In Studies 1 and 2, a lower percentage of BRIUMVI-treated patients experienced decreased neutrophil counts compared to those on teriflunomide. The majority of these decreases were minor and not associated with infection. A small percentage of patients had neutrophil counts below 1.0 x 10^9/L or 0.5 x 10^9/L, with no infection reported
Postmarketing Experience
There is limited information regarding Ublituximab-xiiy Postmarketing Experience in the drug label.
Drug Interactions
Combining BRIUMVI with other immune-modulating or immunosuppressant medications, including high-dose corticosteroids, may heighten the risk of infection. Caution is advised when using such therapies concurrently with BRIUMVI due to potential additive effects on the immune system. When transitioning from other immune-modulating treatments, consider their duration and mode of action to mitigate potential cumulative immunosuppressive effects upon starting BRIUMVI.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is currently limited information regarding the developmental risks linked to the use of BRIUMVI in pregnant women. Data obtained from case reports of pregnancies that occurred during clinical trials with BRIUMVI are insufficient to conclusively determine any potential risks of major birth defects, miscarriage, or adverse outcomes for both the mother and the fetus. While specific data on ublituximab-xiiy's effects are lacking, it's important to note that monoclonal antibodies, including BRIUMVI, can pass through the placenta actively. This may result in immunosuppression in infants exposed to BRIUMVI while in utero.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ublituximab-xiiy in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ublituximab-xiiy during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Ublituximab-xiiy in women who are nursing.
Pediatric Use
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 BRIUMVI. 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 BRIUMVI in utero until B-cell recovery occurs
Geriatic Use
There is no FDA guidance on the use of Ublituximab-xiiy in geriatric settings.
Gender
There is no FDA guidance on the use of Ublituximab-xiiy with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ublituximab-xiiy with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Ublituximab-xiiy in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Ublituximab-xiiy in patients with hepatic impairment.
Females of Reproductive Potential and Males
- Pregnancy testing is recommended for females of reproductive potential prior to each infusion.
- Females of reproductive potential should use effective contraception while receiving BRIUMVI and for 6 months after the last dose of BRIUMV.
Immunocompromised Patients
Combining BRIUMVI with other immune-modulating or immunosuppressant medications, including high-dose corticosteroids, may heighten the risk of infection. Caution is advised when using such therapies concurrently with BRIUMVI due to potential additive effects on the immune system. When transitioning from other immune-modulating treatments, consider their duration and mode of action to mitigate potential cumulative immunosuppressive effects upon starting BRIUMVI.
Administration and Monitoring
Administration
- Prior to administering the first dose of BRIUMVI, several assessments are recommended:
- Hepatitis B Virus Screening: Check for Hepatitis B virus (HBV) presence. BRIUMVI should not be given to patients with active HBV, confirmed by positive results for Hepatitis B surface antigen HBsAg and anti-HBV tests. For patients negative for HBsAg but positive for Hepatitis B core antibody [HBcAb+] or carriers of HBV HBsAg+, consultation with liver disease experts is advised before and during BRIUMVI treatment.
- Serum Immunoglobulins Testing: Evaluate quantitative serum immunoglobulins levels. If levels are low, consult with immunology experts before starting BRIUMVI.
- Vaccinations: Live-attenuated or live vaccines are not recommended during and after BRIUMVI treatment until B-cell repletion. Administer all immunizations according to guidelines, preferably at least 4 weeks before BRIUMVI initiation for live or live-attenuated vaccines, and ideally at least 2 weeks before for non-live vaccines.
- Before each infusion of BRIUMVI, the following assessments and premedications are advised:
- Infection Assessment: Determine if there's an active infection prior to each infusion. If an active infection is present, postpone BRIUMVI infusion until the infection resolves.
- Recommended Premedication: Administer 100 mg of methylprednisolone intravenously (or equivalent oral dosage) around 30 minutes before each BRIUMVI infusion to mitigate the frequency and severity of infusion reactions. Additionally, administer an antihistamine (e.g., diphenhydramine) orally or intravenously approximately 30-60 minutes before each infusion to further alleviate the frequency and severity of infusion reactions. Consideration may also be given to adding an antipyretic (e.g., acetaminophen).
- Pregnancy Testing: It is advisable to conduct pregnancy testing for females of reproductive potential before each infusion with BRIUMVI.
- Withdraw and discard the necessary volume of 0.9% Sodium Chloride Injection.
- Note that the infusion duration may be extended if the infusion is interrupted or slowed down.
- Administer the first subsequent infusion 24 weeks following the initial infusion.
Delayed or Missed Doses: If a scheduled infusion of BRIUMVI is missed, administer it as soon as possible; do not wait until the next scheduled infusion. Reset the infusion schedule to administer the next sequential infusion 24 weeks after the missed infusion is given. Infusions of BRIUMVI must be separated by at least 5 months. Dosage Modifications Due to Infusion Reactions: Adjustments to the dosage of BRIUMVI in response to infusion reactions are contingent upon their severity. Life-Threatening Infusion Reactions: Immediately halt the infusion and permanently discontinue BRIUMVI if there are indications of a life-threatening or incapacitating infusion reaction. Provide appropriate supportive treatment.
- Severe Infusion Reactions:
Promptly pause the infusion and administer suitable supportive treatment, as required. Restart the infusion only after all symptoms have resolved. Upon resumption, begin at half of the infusion rate at the onset of the reaction. If tolerated, gradually increase the rate according to Table 1. This alteration in rate will extend the total duration of the infusion but not the total dose.
- Mild to Moderate Infusion Reactions:
Reduce the infusion rate to half the rate at the initiation of the reaction and maintain this reduced rate for at least 30 minutes. If the reduced rate is well-tolerated, increase it as per Table 1. This change in rate will prolong the total duration of the infusion but not the total dose. Preparation and Administration:
- Preparation:
Use only 0.9% Sodium Chloride Injection, USP to dilute BRIUMVI. BRIUMVI should be prepared by a healthcare professional using aseptic technique. Inspect the solution for visual anomalies before administration. Do not use if discolored or if foreign particulate matter is present. First Infusion:
- Prepare the infusion bag for the first infusion (150 mg) using one vial (150 mg/6 mL) of BRIUMVI.
- Withdraw 6 mL of 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard.
- Withdraw 6 mL of BRIUMVI solution from the vial and add it to the infusion bag containing 0.9% Sodium Chloride Injection, USP.
Second Infusion and Subsequent Infusions:
- Prepare the infusion bag for the second and subsequent infusions (450 mg) using three vials (150 mg/6 mL) of BRIUMVI.
- Withdraw 18 mL of 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard.
- Withdraw 18 mL of BRIUMVI solution from the vials (6 mL/vial) and add it to the infusion bag containing 0.9% Sodium Chloride Injection, USP.
- Mix the diluted solution gently by inversion; do not shake.
Administration of Infusion Solution: Ensure that the contents of the infusion bag are at room temperature before starting the intravenous infusion. Administer the diluted infusion solution through a dedicated line. No incompatibilities between BRIUMVI and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous (IV) administration sets have been observed.
Monitoring
- Administer the first subsequent infusion 24 weeks following the initial infusion.
Infusions of BRIUMVI must be separated by at least 5 months.
IV Compatibility
There is limited information regarding the compatibility of Ublituximab-xiiy and IV administrations.
Overdosage
There is limited information regarding Ublituximab-xiiy overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Ublituximab-xiiy Pharmacology in the drug label.
Mechanism of Action
The exact mechanism through which ublituximab-xiiy achieves its therapeutic effects in multiple sclerosis remains unclear. However, it is hypothesized to involve attaching to CD20, a surface antigen found on pre-B and mature B lymphocytes. Upon binding to B lymphocytes, ublituximab-xiiy induces cell lysis through mechanisms such as antibody-dependent cellular cytolysis and complement-dependent cytolysis.
Structure
There is limited information regarding Ublituximab-xiiy Structure in the drug label.
Pharmacodynamics
For B-cell counts, assays for CD19 + B-cells are used because the presence of ublituximab-xiiy interferes with the CD20 assay. Treatment with BRIUMVI reduced CD19 + B-cell counts in blood by the first measured timepoint of 24 hours after infusion. In clinical studies (Study 1 and Study 2), B-cell counts rose to above the LLN or above baseline counts between infusions of BRIUMVI at least one time in 30 of 545 (5.5%) of patients. The median time for CD19 + B-cell counts to return to either baseline or LLN was 70.3 weeks (range 0.1-75.1 weeks) after the last BRIUMVI infusion. Within 1.5 years after the last infusion, B-cell counts rose to either baseline or LLN in 58% of patients.
Pharmacokinetics
Ublituximab-xiiy exposure levels increased proportionally within a dosage range of 150 mg to 600 mg in patients with RMS. Following administration of the approved recommended dosage of BRIUMVI, steady-state AUC and maximum concentration were 3000 mcg/mL per day and 139 mcg/mL, respectively.
- Distribution: The estimated central volume of distribution of ublituximab-xiiy was 3.18 L.
- Elimination: The estimated mean terminal half-life of ublituximab-xiiy was 22 days.
- Metabolism: Ublituximab-xiiy undergoes degradation to small peptides and amino acids via ubiquitous proteolytic enzymes.
- Specific Populations: No clinically meaningful differences were observed in the pharmacokinetics of ublituximab-xiiy based on age, sex, body weight, presence of anti-drug antibodies (ADAs).
- Immunogenicity: In clinical studies, the presence of ADAs and neutralizing antibodies (NAbs) was observed in BRIUMVI-treated patients. However, the assay used for NAbs may underestimate their incidence due to interference from serum ublituximab-xiiy. The presence of ADAs did not affect the safety or efficacy of BRIUMVI.
Nonclinical Toxicology
- Carcinogenesis:
No carcinogenicity studies have been undertaken to evaluate the potential for BRIUMVI to cause cancer.
- Mutagenesis:
Given its nature as an antibody, BRIUMVI is not anticipated to directly interact with DNA.
- Impairment of Fertility:
Animal studies assessing the impact of BRIUMVI on male and female fertility have not been conducted. In a 26-week intravenous toxicity study in monkeys, where the highest dose administered was 30 mg/kg, no adverse effects on reproductive organs were observed. Plasma exposures in monkeys at this dose level were approximately 24 times higher than those observed in humans at the maximum recommended human dose (450 mg).
Clinical Studies
The efficacy of BRIUMVI was demonstrated in two 96-week clinical trials (Study 1 and Study 2) involving patients with RMS. Patients were randomized to receive BRIUMVI or teriflunomide, the active comparator, with assessments performed every 12 weeks and at suspected relapses. MRI scans were conducted at baseline and throughout the study. Primary outcomes included the annualized relapse rate (ARR), total number of MRI T1 Gd-enhancing lesions, total number of new or enlarging MRI T2 hyperintense lesions, and time to confirmed disability progression. Both studies showed that BRIUMVI significantly reduced the ARR and the number of T1 Gd-enhancing lesions and new/enlarging T2 lesions compared to teriflunomide. No significant difference in confirmed disability progression was observed between the two treatments. Study 1 enrolled 274 patients on BRIUMVI and 275 on teriflunomide, while Study 2 included 272 patients on BRIUMVI and 273 on teriflunomide. BRIUMVI showed high completion rates in both studies, with baseline characteristics well-balanced between treatment groups. Overall, BRIUMVI demonstrated superior efficacy compared to teriflunomide in reducing disease activity in RMS patients.
In exploratory analyses of Study 1 and Study 2, a similar effect of BRIUMVI on the ARR was observed in subgroups defined by gender, prior non-steroid MS therapy, baseline disability (EDSS 3.5 or lower versus greater than 3.5), the number of relapses in the 2 years prior to study enrollment, and number of Gd-enhancing lesions at baseline.
How Supplied
BRIUMVI (ublituximab-xiiy) injection is a sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution for intravenous use supplied as a carton containing one 150 mg/6 mL (25 mg/mL) single-dose vial (NDC 73150-150-06).
Storage
Store BRIUMVI vials refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light. Do not freeze. Do not shake.
Images
Drug Images
{{#ask: Page Name::Ublituximab-xiiy |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}
Package and Label Display Panel
Principal Display Panel - 6 mL Vial Label
NDC 73150-150-06
Briumvi™
(ublituximab-xiiy) injection
Rx only
150 mg/6 mL (25 mg/mL)
For Intravenous Infusion After Dilution.
Single-Dose Vial. Discard Unused Portion. No preservative. Dosage: See prescribing information. TG Therapeutics {{#ask: Label Page::Ublituximab-xiiy |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}
Patient Counseling Information
- Infusion Reactions:
Patients should be informed about the signs and symptoms of infusion reactions and the possibility of these reactions occurring up to 24 hours after infusion. They should be advised to promptly contact their healthcare provider if they experience any signs or symptoms of infusion reactions.
- Infection:
Patients should be instructed to contact their healthcare provider if they develop any signs of infection during or after treatment, such as fever, chills, persistent cough, or painful urination. Additionally, patients should be made aware of the potential for hepatitis B reactivation and the need for monitoring if they are at risk. Progressive Multifocal Leukoencephalopathy (PML): Patients should be educated about the risk of PML associated with BRIUMVI and similar drugs. They should be informed about the progressive nature of PML symptoms, which can include weakness, vision changes, and cognitive impairment. Patients should be advised to promptly report any symptoms suggestive of PML to their doctor.
- Vaccination:
Patients should be encouraged to complete any required vaccinations, including live or live-attenuated vaccines, at least 4 weeks before starting BRIUMVI. Administration of live vaccines during BRIUMVI treatment and until B-cell recovery is not recommended.
- Fetal Risk:
Pregnant women and females of reproductive potential should be informed about the potential risk of fetal harm associated with BRIUMVI. Effective contraception should be used during treatment and for 6 months after the last dose of BRIUMVI. Patients should notify their healthcare provider if pregnancy occurs during BRIUMVI treatment.
Precautions with Alcohol
Alcohol-Ublituximab-xiiy interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Ublituximab-xiiy Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Ublituximab-xiiy Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.