ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed in greater detail in other sections of the labeling:Infusion Reactions [see Warnings and Precautions 5.1)] Infections [see Warnings and Precautions 5.2)] Reduction in Immunoglobulins [see Warnings and Precautions 5.4)] Infusion Reactions [see Warnings and Precautions 5.1)] Infections [see Warnings and Precautions 5.2)] Reduction in Immunoglobulins [see Warnings and Precautions 5.4)] The most common adverse reactions (>=10%) were infusion reactions and upper respiratory tract infections 6.1). To report SUSPECTED ADVERSE REACTIONS, contact TG Therapeutics at 1-877-848-9462 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 and Study 2), 545 patients with RMS received BRIUMVI [see Clinical Studies 14)]. The most common adverse reactions in RMS trials (incidence of at least 10%) were infusion reactions and upper respiratory tract infections. Table summarizes the adverse reactions that occurred in RMS trials (Study and Study 2). The most common cause of discontinuation in patients treated with BRIUMVI was infection (1.3%). Table 2: Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for BRIUMVI and Higher than Teriflunomide from Study and Study 2Adverse ReactionsBRIUMVI450 mg IVa(N=545) %Teriflunomide14 mg PO(N=548)%a The first dose of BRIUMVI was given as an intravenous (IV) infusion of 150 mg. The second dose was given as an IV infusion of 450 mg two weeks after the first infusion. Includes the following: nasopharyngitis, upper respiratory tract infection, respiratory tract infection, respiratory tract infection viral, pharyngitis, rhinitis, sinusitis, acute sinusitis, tonsillitis, laryngitis, chronic sinusitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection, chronic tonsillitis, pharyngitis streptococcal, sinusitis bacterial, and tonsillitis bacterial. Includes the following: bronchitis, pneumonia, tracheitis, tracheobronchitis, COVID-19 pneumonia, bronchitis bacterial, and pneumonia viral. Includes several related terms. Infusion reactions4812Upper respiratory tract infections 4541Lower respiratory tract infections 97Herpes virus-associated infections 65Pain in extremity64Insomnia63Fatigue54. Infusion ReactionsThe incidence of infusion reactions was highest with the first infusion (43%), decreasing with subsequent infusions (10% with second, 8% with third infusion). Three (0.6%) patients treated with BRIUMVI reported serious infusion reactions. Most frequently reported symptoms (greater than 5%) included pyrexia, chills, headache, and influenza-like illness [see Warnings and Precautions 5.1)] . Laboratory Abnormalities. Decreased ImmunoglobulinsBRIUMVI decreased total immunoglobulins with the greatest decline seen in IgM levels. The proportion of BRIUMVI-treated patients at baseline reporting IgG, IgA, and IgM below the LLN was 6.3%, 0.6%, and 1.1%, respectively. Following treatment, the proportion of BRIUMVI-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 6.5%, 2.4%, and 20.9%, respectively.. Decreased Neutrophil LevelsIn Studies and 2, decreased neutrophil counts (<LLN) occurred in 15% of BRIUMVI-treated patients compared to 22% in teriflunomide-treated patients. The majority of decreased neutrophil counts were observed once for given patient treated with BRIUMVI, and were between 1.0 and 1.5 10 9/L. In RMS studies, 3% of patients in the BRIUMVI group had neutrophil counts less than 1.0 10 9/L, compared to 2% of patients in the teriflunomide group. Overall, 1% of patients in the BRIUMVI group had neutrophil counts less than 0.5 10 9/L, compared to 0% of patients in the teriflunomide group, and these were not associated with an infection.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 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, cell surface antigen present on pre-B and mature lymphocytes. Following cell surface binding to lymphocytes, ublituximab-xiiy results in cell lysis through mechanisms including antibody-dependent cellular cytolysis and complement-dependent cytolysis.. 12.2 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 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. 12.3 Pharmacokinetics. Ublituximab-xiiy exposures increased proportionally over dose range of 150 mg (0.33 times approved recommended dosage) to 600 mg (1.33 times the approved recommended dosage) in patients with RMS.Following administration of the approved recommended dosage of BRIUMVI, the geometric mean steady-state AUC was 3000 mcg/mL per day (CV=28%) and the mean maximum concentration was 139 mcg/mL (CV=15%).. DistributionThe estimated central volume of distribution of ublituximab-xiiy was 3.18 L.. EliminationThe estimated mean terminal half-life of ublituximab-xiiy was 22 days.. MetabolismUblituximab-xiiy is protein for which the expected metabolic pathway is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes.. Specific PopulationsThere were no clinically meaningful differences in the pharmacokinetics of ublituximab-xiiy based on age, sex, body weight, anti-drug antibodies (ADAs) presence, mild renal impairment, or mild hepatic impairment. The effect of moderate to severe renal impairment or moderate to severe hepatic impairment on the pharmacokinetics of ublituximab-xiiy is unknown.. Drug Interaction StudiesNo studies evaluating the drug interaction potential of ublituximab-xiiy have been conducted.. 12.6 Immunogenicity. The observed incidence of ADAs is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of ublituximab-xiiy or of other ublituximab products.In clinical studies (Study and Study 2), serum samples from patients with RMS were tested for antibodies to ublituximab-xiiy during the 96-week treatment period. Of the 534 BRIUMVI-treated patients, 434 (81%) tested positive for ADAs at one or more timepoints, and 34 (6.4%) tested positive for neutralizing antibodies (NAbs). However, the assay used to measure NAbs is subject to interference from serum ublituximab-xiiy, possibly resulting in underestimation of the incidence of NAb formation and limiting the ability to characterize the clinical impact of NAbs.The presence of ADAs had no observable impact on the safety or efficacy of BRIUMVI.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of BRIUMVI was demonstrated in two randomized, double-blind, double-dummy, parallel group, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks [Study (NCT03277261) and Study (NCT03277248)]. Patients were randomized to receive either BRIUMVI, given as an IV infusion of 150 mg for the first infusion, 450 mg two weeks after the first infusion for the second infusion/second dose, and 450 mg every 24 weeks after the first infusion for subsequent doses (third infusion and beyond) with oral placebo administered daily; or teriflunomide, the active comparator, given orally as 14 mg daily dose with IV placebo administered on the same schedule as BRIUMVI. Both studies enrolled patients who had experienced at least one relapse in the previous year, two relapses in the previous two years, or had the presence of T1 gadolinium (Gd)-enhancing lesion in the previous year. Patients were also required to have an Expanded Disability Status Scale (EDSS) score from to 5.5 at baseline. Neurological evaluations were performed at baseline, every 12 weeks, and at the time of suspected relapse. Brain MRI scans were performed at baseline and at Weeks 12, 24, 48, and 96.The primary outcome of both Study and Study was the annualized relapse rate (ARR) over the treatment period. Additional outcome measures included: the total number of MRI T1 Gd-enhancing lesions by Week 96, the total number of new or enlarging MRI T2 hyperintense lesions by Week 96, and time to confirmed disability progression for at least 12 weeks. Disability progression was defined as an increase of greater than or equal to 1.0 point from the baseline EDSS score that was attributable to MS when the baseline score was 5.5 or less, and greater than or equal to 0.5 points when the baseline score was above 5.5. Confirmed disability progression was evaluated in pooled analysis of Studies and 2. Disability progression was considered confirmed when the increase in the EDSS was confirmed at regularly scheduled visit 12 weeks after the initial documentation of neurological worsening.In Study 1, 274 patients were randomized to BRIUMVI and 275 to teriflunomide. Of those randomized to BRIUMVI, 88% completed the 96-week treatment period; of those randomized to teriflunomide, 92% completed the 96-week treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age was 37 years, 97% were White, and 63% were female.In Study 2, 272 patients were randomized to BRIUMVI and 273 to teriflunomide. Of those randomized to BRIUMVI, 93% completed the 96-week treatment period; of those randomized to teriflunomide, 88% completed the 96-week treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age was 35 years, 99% were White, and 65% were female.In Study and Study 2, BRIUMVI significantly lowered the ARR compared to teriflunomide. BRIUMVI statistically significantly reduced the number of T1 Gd-enhancing lesions and the number of new or enlarging T2 lesions in both studies compared to teriflunomide. There was no statistically significant difference in disability progression confirmed at 12 weeks between BRIUMVI-treated and teriflunomide-treated patients.Results for Study and Study are presented in Table 3. Table 3: Key Clinical and MRI Endpoints in RMS Patients from Study and Study 21 Based on Modified Intent-to-Treat (mITT) Population, defined as all randomized patients who received at least one infusion of study medication and had one baseline and post-baseline efficacy assessment. Study 1: BRIUMVI (N=271), teriflunomide (N=274). Study 2: BRIUMVI (N=272), teriflunomide (N=272). Data prospectively pooled from Study and Study 2: BRIUMVI (N=543), teriflunomide (N=546). Defined as an increase of 1.0 point or more from the baseline EDSS score for patients with baseline score of 5.5 or less, or 0.5 point or more when the baseline score is greater than 5.5, Kaplan-Meier estimates at Week 96. Based on Hazard Ratio. Based on MRI-mITT population (mITT patients who have baseline and post-baseline MRI). Study 1: BRIUMVI (N=265), teriflunomide (N=270). Study 2: BRIUMVI (N=272), teriflunomide (N=267). At Week 96. BRIUMVI dosing by intravenous infusion: first dose of 150 mg, second dose 450 mg two weeks after the first; subsequent doses 450 mg every 24 weeks; teriflunomide dosing: 14 mg by mouth once daily. Study 1Study 2EndpointsBRIUMVI450 mg7Teriflunomide14 mg7BRIUMVI450 mg7Teriflunomide14 mg7Clinical Endpoints1Annualized Relapse Rate (Primary Endpoint) Relative Reduction 0.0760.1880.0910.17859% (p<0.001) 49% (p 0.002) Proportion of Patients with 12-week Confirmed Disability Progression 2,3 Risk Reduction (Pooled Analysis) 5.2% BRIUMVI vs. 5.9% teriflunomide 16% (p 0.510) MRI Endpoints5Mean number of T1 Gd-enhancing lesions per MRI Relative Reduction 0.0160.4910.0090.25097% (p<0.001)97% (p<0.001)Mean number of new or enlarging T2 hyperintense lesions per MRI Relative Reduction 0.2132.7890.2822.83192% (p<0.001) 90% (p<0.001) In exploratory analyses of Study and Study 2, 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 years prior to study enrollment, and number of Gd-enhancing lesions at baseline.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 and Study 2), 545 patients with RMS received BRIUMVI [see Clinical Studies 14)]. The most common adverse reactions in RMS trials (incidence of at least 10%) were infusion reactions and upper respiratory tract infections. Table summarizes the adverse reactions that occurred in RMS trials (Study and Study 2). The most common cause of discontinuation in patients treated with BRIUMVI was infection (1.3%). Table 2: Adverse Reactions in Adult Patients with RMS with an Incidence of at least 5% for BRIUMVI and Higher than Teriflunomide from Study and Study 2Adverse ReactionsBRIUMVI450 mg IVa(N=545) %Teriflunomide14 mg PO(N=548)%a The first dose of BRIUMVI was given as an intravenous (IV) infusion of 150 mg. The second dose was given as an IV infusion of 450 mg two weeks after the first infusion. Includes the following: nasopharyngitis, upper respiratory tract infection, respiratory tract infection, respiratory tract infection viral, pharyngitis, rhinitis, sinusitis, acute sinusitis, tonsillitis, laryngitis, chronic sinusitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection, chronic tonsillitis, pharyngitis streptococcal, sinusitis bacterial, and tonsillitis bacterial. Includes the following: bronchitis, pneumonia, tracheitis, tracheobronchitis, COVID-19 pneumonia, bronchitis bacterial, and pneumonia viral. Includes several related terms. Infusion reactions4812Upper respiratory tract infections 4541Lower respiratory tract infections 97Herpes virus-associated infections 65Pain in extremity64Insomnia63Fatigue54. Infusion ReactionsThe incidence of infusion reactions was highest with the first infusion (43%), decreasing with subsequent infusions (10% with second, 8% with third infusion). Three (0.6%) patients treated with BRIUMVI reported serious infusion reactions. Most frequently reported symptoms (greater than 5%) included pyrexia, chills, headache, and influenza-like illness [see Warnings and Precautions 5.1)] . Laboratory Abnormalities. Decreased ImmunoglobulinsBRIUMVI decreased total immunoglobulins with the greatest decline seen in IgM levels. The proportion of BRIUMVI-treated patients at baseline reporting IgG, IgA, and IgM below the LLN was 6.3%, 0.6%, and 1.1%, respectively. Following treatment, the proportion of BRIUMVI-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 6.5%, 2.4%, and 20.9%, respectively.. Decreased Neutrophil LevelsIn Studies and 2, decreased neutrophil counts (<LLN) occurred in 15% of BRIUMVI-treated patients compared to 22% in teriflunomide-treated patients. The majority of decreased neutrophil counts were observed once for given patient treated with BRIUMVI, and were between 1.0 and 1.5 10 9/L. In RMS studies, 3% of patients in the BRIUMVI group had neutrophil counts less than 1.0 10 9/L, compared to 2% of patients in the teriflunomide group. Overall, 1% of patients in the BRIUMVI group had neutrophil counts less than 0.5 10 9/L, compared to 0% of patients in the teriflunomide group, and these were not associated with an infection.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Hepatitis virus screening and quantitative serum immunoglobulin screening are required before first dose 2.1). Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion 2.2). Administer BRIUMVI by intravenous infusion. First Infusion: 150 mg intravenous infusion 2.3) Second Infusion: 450 mg intravenous infusion two weeks after the first infusion 2.3) Subsequent Infusions: 450 mg intravenous infusion 24 weeks after the first infusion and every 24 weeks thereafter 2.3) Must be diluted in 0.9% Sodium Chloride Injection, USP prior to administration 2.3, 2.6). 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 2.3, 5.1). Hepatitis virus screening and quantitative serum immunoglobulin screening are required before first dose 2.1). Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion 2.2). Administer BRIUMVI by intravenous infusion. First Infusion: 150 mg intravenous infusion 2.3) Second Infusion: 450 mg intravenous infusion two weeks after the first infusion 2.3) Subsequent Infusions: 450 mg intravenous infusion 24 weeks after the first infusion and every 24 weeks thereafter 2.3) First Infusion: 150 mg intravenous infusion 2.3) Second Infusion: 450 mg intravenous infusion two weeks after the first infusion 2.3) Subsequent Infusions: 450 mg intravenous infusion 24 weeks after the first infusion and every 24 weeks thereafter 2.3) Must be diluted in 0.9% Sodium Chloride Injection, USP prior to administration 2.3, 2.6). 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 2.3, 5.1). 2.1 Assessments Prior to First Dose of BRIUMVI. Hepatitis Virus ScreeningPrior to initiating BRIUMVI, perform Hepatitis virus (HBV) screening. BRIUMVI is contraindicated in patients with active HBV confirmed by positive results for Hepatitis surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for Hepatitis core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with BRIUMVI [see Warnings and Precautions 5.2)] . Serum ImmunoglobulinsPrior to initiating BRIUMVI, perform testing for quantitative serum immunoglobulins [see Warnings and Precautions 5.4)]. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with BRIUMVI. VaccinationsBecause 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 weeks prior to initiation of BRIUMVI for live or live-attenuated vaccines and, whenever possible, at least weeks prior to initiation of BRIUMVI for non-live vaccines [see Warnings and Precautions 5.2) and Clinical Pharmacology 12.2)] . 2.2 Assessment and Premedication Before Every Infusion. Infection AssessmentPrior to every infusion of BRIUMVI, determine whether there is an active infection. In case of active infection, delay infusion of BRIUMVI until the infection resolves [see Warnings and Precautions 5.2)] . Recommended PremedicationPre-medicate with 100 mg of methylprednisolone administered intravenously (or an equivalent oral dosage or equivalent corticosteroid) approximately 30 minutes prior to each BRIUMVI infusion to reduce the frequency and severity of infusion reactions [see Warnings and Precautions 5.1)] Pre-medicate with an antihistamine (e.g., diphenhydramine) administered orally or intravenously approximately 30-60 minutes prior to each BRIUMVI infusion to further reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered.. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to each infusion with BRIUMVI [see Warnings and Precautions 5.3) and Use in Specific Populations 8.1, 8.3)]. 2.3 Recommended Dosage and Dose Administration. Administer BRIUMVI under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions, such as serious infusion reactions.First Infusion: 150 mg intravenous infusionSecond Infusion: 450 mg intravenous infusion administered two weeks after the first infusionSubsequent Infusions: 450 mg intravenous infusion administered 24 weeks after the first infusion and every 24 weeks thereafterObserve the patient 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 in association with the current or any prior infusion [see Warnings and Precautions 5.1)]. Table 1: Recommended Dose, Infusion Rate, and Infusion Duration for MS1 Withdraw and discard the required volume of 0.9% Sodium Chloride Injection, USP from the infusion bag following the preparation instructions in Preparation and Administration 2.6). Infusion duration may take longer if the infusion is interrupted or slowed. Administer the first subsequent infusion 24 weeks after the first infusion. Dose (mg) and Volume (mL) of BRIUMVIVolume (mL) of 0.9% Sodium Chloride Injection, USP1Infusion Rate (mL/hour)Duration2First Infusion150 mg (6 mL) 250 mLStart at 10 mL per hour for the first 30 minutesIncrease to 20 mL per hour for the next 30 minutesIncrease to 35 mL per hour for the next hourIncrease to 100 mL per hour for the remaining hours4 hoursSecond Infusion (2 weeks later) 450 mg (18 mL) 250 mLStart at 100 mL per hour for the first 30 minutesIncrease to 400 mL per hour for the remaining 30 minutes1 hourSubsequent Infusions (once every 24 weeks) 450 mg (18 mL) 250 mLStart at 100 mL per hour for the first 30 minutesIncrease to 400 mL per hour for the remaining 30 minutes1 hour. First Infusion: 150 mg intravenous infusion. Second Infusion: 450 mg intravenous infusion administered two weeks after the first infusion. Subsequent Infusions: 450 mg intravenous infusion administered 24 weeks after the first infusion and every 24 weeks thereafter. Observe the patient 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 in association with the current or any prior infusion [see Warnings and Precautions 5.1)]. Start at 10 mL per hour for the first 30 minutes. Increase to 20 mL per hour for the next 30 minutes. Increase to 35 mL per hour for the next hour. Increase to 100 mL per hour for the remaining hours. Start at 100 mL per hour for the first 30 minutes. Increase to 400 mL per hour for the remaining 30 minutes. Start at 100 mL per hour for the first 30 minutes. Increase to 400 mL per hour for the remaining 30 minutes. 2.4 Delayed or Missed Doses. If planned infusion of BRIUMVI is missed, administer BRIUMVI 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 administered. Infusions of BRIUMVI must be separated by at least months.. 2.5 Dosage Modifications Because of Infusion Reactions. Dose modifications in response to infusion reactions depend on the severity.. Life-Threatening Infusion ReactionsImmediately stop infusion and permanently discontinue BRIUMVI if there are signs of life-threatening or disabling infusion reaction [see Warnings and Precautions 5.1)] Provide appropriate supportive treatment. Severe Infusion ReactionsImmediately interrupt the infusion and administer appropriate supportive treatment, as necessary [see Warnings and Precautions 5.1)] Restart the infusion only after all symptoms have resolved. When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction [see Dosage and Administration 2.3)] If this rate is tolerated, increase the rate as described in Table 1. This change in rate will increase the total duration of the infusion but not the total dose. Mild to Moderate Infusion ReactionsReduce the infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes [see Warnings and Precautions 5.1)] If the reduced rate is tolerated, increase the rate as described in Table 1. This change in rate will increase the total duration of the infusion but not the total dose. 2.6 Preparation and Administration. PreparationOnly use 0.9% Sodium Chloride Injection, USP to dilute BRIUMVI.BRIUMVI must be prepared by healthcare professional using aseptic technique. Prepare the solution for infusion as follows:BRIUMVI should be clear to opalescent, colorless to slightly yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the solution if discolored or if the solution contains discrete foreign particulate matter.Preparation of Solution for First Infusion:Prepare infusion bag for First Infusion (150 mg) using one vial (150 mg/6 mL) of BRIUMVI.Withdraw mL 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard.Withdraw mL BRIUMVI solution from the vial.Add mL (150 mg) BRIUMVI into the infusion bag containing 0.9% Sodium Chloride Injection, USP.Preparation of Solution for Second Infusion and Subsequent Infusions:Prepare infusion bag for Second Infusion (450 mg) and Subsequent Infusions (450 mg) using three vials (150 mg/6 mL) of BRIUMVI.Withdraw 18 mL 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard.Withdraw 18 mL BRIUMVI solution from the vials (6 mL/vial).Add 18 mL (450 mg) BRIUMVI into the infusion bag containing 0.9% Sodium Chloride Injection, USP.Mix diluted solution by gentle inversion. Do not shake.. BRIUMVI should be clear to opalescent, colorless to slightly yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the solution if discolored or if the solution contains discrete foreign particulate matter.. Prepare infusion bag for First Infusion (150 mg) using one vial (150 mg/6 mL) of BRIUMVI.. Withdraw mL 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard.. Withdraw mL BRIUMVI solution from the vial.. Add mL (150 mg) BRIUMVI into the infusion bag containing 0.9% Sodium Chloride Injection, USP.. Prepare infusion bag for Second Infusion (450 mg) and Subsequent Infusions (450 mg) using three vials (150 mg/6 mL) of BRIUMVI.. Withdraw 18 mL 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard.. Withdraw 18 mL BRIUMVI solution from the vials (6 mL/vial).. Add 18 mL (450 mg) BRIUMVI into the infusion bag containing 0.9% Sodium Chloride Injection, USP.. Administration of Infusion SolutionPrior to the start of the intravenous infusion, the contents of the infusion bag should be at room temperature [see Dosage and Administration 2.7)] Administer the diluted infusion solution through dedicated line.No incompatibilities between BRIUMVI and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous (IV) administration sets have been observed.. 2.7 Storage Instructions for the Prepared Infusion Solution. Use the prepared infusion solution immediately. If the diluted solution is not administered immediately, store refrigerated at 2C to 8C (36F to 46F) for up to 24 hours. Do not freeze. If the diluted solution is stored refrigerated, allow it to equilibrate to room temperature prior to administration (approximately hours). The diluted solution can be stored for an additional hours at room temperature up to 25C (77F), which includes the equilibration time and infusion time.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no data on the developmental risk associated with the use of BRIUMVI in pregnant women. Data from case reports of pregnancies occurring during clinical trials with BRIUMVI are insufficient to identify 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 BRIUMVI may cause immunosuppression in the in-utero exposed infant [see Clinical Considerations, Warnings and Precautions 5.2, 5.3), and Clinical Pharmacology 12.1, 12.2)]. 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 (see Data) The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsTransport 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 [see Warnings and Precautions 5.2) and Clinical Pharmacology 12.2)]. Data. Animal DataWeekly 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 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. no-effect dose for adverse effects on embryofetal development in monkeys was not identified.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug AdministrationApproved: 12/2022MEDICATION GUIDEBRIUMVI(TM) (bree-UM-vee) (ublituximab-xiiy) injection, for intravenous use What is the most important information should know about BRIUMVIBRIUMVI can cause serious side effects, including:Infusion reactions. Infusion reactions are one of the most common side effects of BRIUMVI. Infusion reactions can be serious and may require you to be hospitalized. You will be monitored during your infusion and may be monitored after each infusion of BRIUMVI for signs and symptoms of an infusion reaction. Tell your healthcare provider if you get any of these symptoms: feverchillsheadacheflu-like symptomsfast heartbeathivesitchy skindizzinessfeeling faintswelling of tongue or throattrouble breathingwheezingnauseaabdominal painthroat irritationredness of the face or skinThese infusion reactions can happen over 24 hours after your infusion. It is important that you call your healthcare provider right away if you get any of the signs or symptoms listed above after each infusion. If you get an infusion reaction, your healthcare provider may need to stop or slow down the rate of your infusion. Infections. Infections are common side effect, and upper respiratory tract infections are one of the most common side effects of BRIUMVI. BRIUMVI increases your risk of getting infections caused by bacteria or viruses that may be life-threatening or cause death. Tell your healthcare provider if you have an infection or have any of the following signs of infection including fever, chills, cough that does not go away, or painful urination. Your healthcare provider should delay your treatment with BRIUMVI until your infection is gone. Hepatitis virus (HBV) reactivation: Before starting treatment with BRIUMVI, your healthcare provider will do blood tests to check for hepatitis viral infection. If you have ever had hepatitis virus infection, the hepatitis virus may become active again during or after treatment with BRIUMVI. Hepatitis virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis virus reactivation during treatment and after you stop receiving BRIUMVI. Weakened immune system: BRIUMVI taken before or after other medicines that weaken the immune system could increase your risk of getting infections. Progressive Multifocal Leukoencephalopathy (PML): PML may happen with BRIUMVI. PML is rare, serious brain infection caused by virus that may get worse over days or weeks. PML can result in death or severe disability. Tell your healthcare provider right away if you have any new or worsening neurologic signs or symptoms. These symptoms may include weakness on one side of your body, loss of coordination in arms and legs, vision problems, changes in thinking and memory which may lead to confusion, and personality changes. Low immunoglobulins: BRIUMVI may cause decrease in some types of antibodies. Your healthcare provider will do blood tests to check your blood immunoglobulin levels. What is BRIUMVIBRIUMVI is prescription medicine used to treat adults with relapsing forms of multiple sclerosis (MS), including: clinically isolated syndromerelapsing-remitting diseaseactive secondary progressive diseaseIt is not known if BRIUMVI is safe or effective in children.Do not receive BRIUMVI if you:have active hepatitis virus (HBV) infection.have had life-threatening allergic reaction to BRIUMVI. Tell your healthcare provider if you have had an allergic reaction to BRIUMVI. See What are the ingredients in BRIUMVI for complete list of ingredients in BRIUMVI. Before receiving BRIUMVI, tell your healthcare provider about all of your medical conditions, including if you:have or think you have an infection. See What is the most important information should know about BRIUMVI take or plan to take medicines that affect your immune system. These medicines may increase your risk of getting an infection.have ever had hepatitis or are carrier of the hepatitis virus.have had recent vaccination or are scheduled to receive any vaccinations. You should receive any required live or live-attenuated vaccines at least weeks before you start treatment with BRIUMVI. You should not receive live or live-attenuated vaccines while you are being treated with BRIUMVI and until your healthcare provider tells you that your immune system is no longer weakened. When possible, you should receive any non-live vaccines at least weeks before you start treatment with BRIUMVI. If you would like to receive any non-live vaccines while you are being treated with BRIUMVI, talk to your healthcare provider. If you have baby and you received BRIUMVI during your pregnancy, it is important to tell your babys healthcare provider about receiving BRIUMVI so they can decide when your baby should be vaccinated. are pregnant, think that you might be pregnant, or plan to become pregnant. BRIUMVI may harm your unborn baby. You should use birth control (contraception) during treatment with BRIUMVI and for at least months after your last infusion of BRIUMVI. Talk with your healthcare provider about what birth control method is right for you during this time.are breastfeeding or plan to breastfeed. It is not known if BRIUMVI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take BRIUMVI. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How will receive BRIUMVIBRIUMVI is given through needle placed in your vein (intravenous infusion) in your arm.Your healthcare provider may do pregnancy test before each infusion of BRIUMVI.Before treatment with BRIUMVI, you will receive corticosteroid and an antihistamine medicine to help reduce the risk of infusion reactions by making them less frequent and less severe. You may also receive other medicines to help reduce the risk of an infusion reaction. See What is the most important information should know about BRIUMVI Your first dose of BRIUMVI will last about hours.Your second dose of BRIUMVI will be given weeks after your first dose. This infusion will last about hour.Your next doses of BRIUMVI will be given as infusion every 24 weeks. These infusions will last about hour.What are the possible side effects of BRIUMVISee What is the most important information should know about BRIUMVI The most common side effects of BRIUMVI include:Infusion reactions, upper and lower respiratory tract infections, herpes infections, extremity pain, insomnia, and fatigue. See What is the most important information should know about BRIUMVI These are not all the possible side effects of BRIUMVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of BRIUMVI.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about BRIUMVI that is written for health professionals. What are the ingredients in BRIUMVIActive ingredient: ublituximab-xiiy. Inactive ingredients: hydrochloric acid, polysorbate 80, sodium chloride, sodium citrate, Water for Injection, USP. BRIUMVI is trademark of TG Therapeutics, Inc. (C)TG Therapeutics, Inc. 2021-2022. All rights reserved. Manufactured by: TG Therapeutics, Inc., 3020 Carrington Mill Blvd, Morrisville, NC 27560 U.S. License No. 2090 For more information, go to www.briumvi.com or call 1-877-848-9462 Infusion reactions. Infusion reactions are one of the most common side effects of BRIUMVI. Infusion reactions can be serious and may require you to be hospitalized. You will be monitored during your infusion and may be monitored after each infusion of BRIUMVI for signs and symptoms of an infusion reaction. Tell your healthcare provider if you get any of these symptoms: fever. chills. headache. flu-like symptoms. fast heartbeat. hives. itchy skin. dizziness. feeling faint. swelling of tongue or throat. trouble breathing. wheezing. nausea. abdominal pain. throat irritation. redness of the face or skin. Infections. Infections are common side effect, and upper respiratory tract infections are one of the most common side effects of BRIUMVI. BRIUMVI increases your risk of getting infections caused by bacteria or viruses that may be life-threatening or cause death. Tell your healthcare provider if you have an infection or have any of the following signs of infection including fever, chills, cough that does not go away, or painful urination. Your healthcare provider should delay your treatment with BRIUMVI until your infection is gone. Hepatitis virus (HBV) reactivation: Before starting treatment with BRIUMVI, your healthcare provider will do blood tests to check for hepatitis viral infection. If you have ever had hepatitis virus infection, the hepatitis virus may become active again during or after treatment with BRIUMVI. Hepatitis virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis virus reactivation during treatment and after you stop receiving BRIUMVI. Weakened immune system: BRIUMVI taken before or after other medicines that weaken the immune system could increase your risk of getting infections. Progressive Multifocal Leukoencephalopathy (PML): PML may happen with BRIUMVI. PML is rare, serious brain infection caused by virus that may get worse over days or weeks. PML can result in death or severe disability. Tell your healthcare provider right away if you have any new or worsening neurologic signs or symptoms. These symptoms may include weakness on one side of your body, loss of coordination in arms and legs, vision problems, changes in thinking and memory which may lead to confusion, and personality changes. Hepatitis virus (HBV) reactivation: Before starting treatment with BRIUMVI, your healthcare provider will do blood tests to check for hepatitis viral infection. If you have ever had hepatitis virus infection, the hepatitis virus may become active again during or after treatment with BRIUMVI. Hepatitis virus becoming active again (called reactivation) may cause serious liver problems including liver failure or death. Your healthcare provider will monitor you if you are at risk for hepatitis virus reactivation during treatment and after you stop receiving BRIUMVI. Weakened immune system: BRIUMVI taken before or after other medicines that weaken the immune system could increase your risk of getting infections. Progressive Multifocal Leukoencephalopathy (PML): PML may happen with BRIUMVI. PML is rare, serious brain infection caused by virus that may get worse over days or weeks. PML can result in death or severe disability. Tell your healthcare provider right away if you have any new or worsening neurologic signs or symptoms. These symptoms may include weakness on one side of your body, loss of coordination in arms and legs, vision problems, changes in thinking and memory which may lead to confusion, and personality changes. Low immunoglobulins: BRIUMVI may cause decrease in some types of antibodies. Your healthcare provider will do blood tests to check your blood immunoglobulin levels. clinically isolated syndrome. relapsing-remitting disease. active secondary progressive disease. have active hepatitis virus (HBV) infection.. have had life-threatening allergic reaction to BRIUMVI. Tell your healthcare provider if you have had an allergic reaction to BRIUMVI. See What are the ingredients in BRIUMVI for complete list of ingredients in BRIUMVI. have or think you have an infection. See What is the most important information should know about BRIUMVI take or plan to take medicines that affect your immune system. These medicines may increase your risk of getting an infection.. have ever had hepatitis or are carrier of the hepatitis virus.. have had recent vaccination or are scheduled to receive any vaccinations. You should receive any required live or live-attenuated vaccines at least weeks before you start treatment with BRIUMVI. You should not receive live or live-attenuated vaccines while you are being treated with BRIUMVI and until your healthcare provider tells you that your immune system is no longer weakened. When possible, you should receive any non-live vaccines at least weeks before you start treatment with BRIUMVI. If you would like to receive any non-live vaccines while you are being treated with BRIUMVI, talk to your healthcare provider. If you have baby and you received BRIUMVI during your pregnancy, it is important to tell your babys healthcare provider about receiving BRIUMVI so they can decide when your baby should be vaccinated. You should receive any required live or live-attenuated vaccines at least weeks before you start treatment with BRIUMVI. You should not receive live or live-attenuated vaccines while you are being treated with BRIUMVI and until your healthcare provider tells you that your immune system is no longer weakened. When possible, you should receive any non-live vaccines at least weeks before you start treatment with BRIUMVI. If you would like to receive any non-live vaccines while you are being treated with BRIUMVI, talk to your healthcare provider. If you have baby and you received BRIUMVI during your pregnancy, it is important to tell your babys healthcare provider about receiving BRIUMVI so they can decide when your baby should be vaccinated.. are pregnant, think that you might be pregnant, or plan to become pregnant. BRIUMVI may harm your unborn baby. You should use birth control (contraception) during treatment with BRIUMVI and for at least months after your last infusion of BRIUMVI. Talk with your healthcare provider about what birth control method is right for you during this time.. are breastfeeding or plan to breastfeed. It is not known if BRIUMVI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take BRIUMVI. BRIUMVI is given through needle placed in your vein (intravenous infusion) in your arm.. Your healthcare provider may do pregnancy test before each infusion of BRIUMVI.. Before treatment with BRIUMVI, you will receive corticosteroid and an antihistamine medicine to help reduce the risk of infusion reactions by making them less frequent and less severe. You may also receive other medicines to help reduce the risk of an infusion reaction. See What is the most important information should know about BRIUMVI Your first dose of BRIUMVI will last about hours.. Your second dose of BRIUMVI will be given weeks after your first dose. This infusion will last about hour.. Your next doses of BRIUMVI will be given as infusion every 24 weeks. These infusions will last about hour.. Infusion reactions, upper and lower respiratory tract infections, herpes infections, extremity pain, insomnia, and fatigue. See What is the most important information should know about BRIUMVI.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no data on the developmental risk associated with the use of BRIUMVI in pregnant women. Data from case reports of pregnancies occurring during clinical trials with BRIUMVI are insufficient to identify 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 BRIUMVI may cause immunosuppression in the in-utero exposed infant [see Clinical Considerations, Warnings and Precautions 5.2, 5.3), and Clinical Pharmacology 12.1, 12.2)]. 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 (see Data) The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsTransport 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 [see Warnings and Precautions 5.2) and Clinical Pharmacology 12.2)]. Data. Animal DataWeekly 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 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. no-effect dose for adverse effects on embryofetal development in monkeys was not identified.. 8.2 Lactation. Risk SummaryThere 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 mothers clinical need for BRIUMVI and any potential adverse effects on the breastfed infant from BRIUMVI or from the underlying maternal condition.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingPregnancy testing is recommended for females of reproductive potential prior to each infusion [see Warnings and Precautions 5.3) and Use in Specific Populations 8.1)]. Contraception. FemalesFemales of reproductive potential should use effective contraception while receiving BRIUMVI and for months after the last dose of BRIUMVI [see Warnings and Precautions 5.3) and Use in Specific Populations 8.1)] . 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of BRIUMVI did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Infusion Reactions: Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue BRIUMVI if life-threatening or disabling infusion reaction occurs 2.3, 5.1). Infections: Serious, including life-threatening and fatal infections, have occurred. Delay BRIUMVI administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with BRIUMVI and after discontinuation, until B-cell repletion 5.2). Reduction in Immunoglobulins: Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with BRIUMVI, until B-cell repletion, and especially when recurrent serious infections are suspected. Consider discontinuing BRIUMVI in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins 2.1, 5.4). Fetal Risk: May cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception during treatment and for at least months after stopping BRIUMVI 5.3, 8.1, 8.3). Infusion Reactions: Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue BRIUMVI if life-threatening or disabling infusion reaction occurs 2.3, 5.1). Infections: Serious, including life-threatening and fatal infections, have occurred. Delay BRIUMVI administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with BRIUMVI and after discontinuation, until B-cell repletion 5.2). Reduction in Immunoglobulins: Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with BRIUMVI, until B-cell repletion, and especially when recurrent serious infections are suspected. Consider discontinuing BRIUMVI in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins 2.1, 5.4). Fetal Risk: May cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception during treatment and for at least months after stopping BRIUMVI 5.3, 8.1, 8.3). 5.1 Infusion Reactions. BRIUMVI can cause infusion reactions, which can include pyrexia, chills, headache, influenza-like illness, tachycardia, nausea, throat irritation, erythema, and an anaphylactic reaction [see Adverse Reactions 6.1)] In Studies and [see Clinical Studies 14)] 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 and in patients who received treatment with BRIUMVI was 48%, with the highest incidence within 24 hours of the first infusion. In Studies and 2, there were no fatal infusion reactions, but 0.6% of patients treated with BRIUMVI experienced infusion reactions that were serious, some requiring hospitalization. Observe patients treated with BRIUMVI for infusion reactions during the infusion 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 in association with the current or any prior infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion.. Reducing the Risk of Infusion Reactions and Managing Infusion ReactionsAdminister pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions [see Dosage and Administration 2.2)] The addition of an antipyretic (e.g., acetaminophen) may also be considered [see Dosage and Administration 2.2)]. Management recommendations for infusion depend on the type and severity of the reaction. For life-threatening infusion reactions, stop the infusion immediately, permanently discontinue BRIUMVI, and provide appropriate supportive treatment [see Dosage and Administration 2.5)] For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment. 5.2 Infections. Serious, including life-threatening or fatal, bacterial and viral infections have been reported in patients receiving BRIUMVI. 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 and 2, the overall rate of infections in MS patients treated with BRIUMVI was 56% compared to 54% in patients who were treated with teriflunomide. The rate of serious infections was higher in patients treated with BRIUMVI compared to patients treated with teriflunomide (5% vs 3%, respectively). There were infection-related deaths that occurred in controlled clinical trials in patients with relapsing forms of multiple sclerosis (RMS), all in patients treated with BRIUMVI; the infections leading to death were post-measles encephalitis, pneumonia, and post-operative salpingitis following an ectopic pregnancy. In Studies and 2, the most common infections reported in patients treated with BRIUMVI included upper respiratory tract infection (45%) and urinary tract infection (10%).Delay BRIUMVI administration in patients with an active infection until the infection is resolved.. Possible Increased Risk of Immunosuppressant Effects with Other ImmunosuppressantsWhen initiating BRIUMVI after an immunosuppressive therapy or initiating an immunosuppressive therapy after BRIUMVI, consider the potential for increased immunosuppressive effects [see Drug Interactions 7.1) and Clinical Pharmacology 12.2)] BRIUMVI has not been studied in combination with other MS therapies. Hepatitis Virus (HBV) ReactivationHBV reactivation occurred in an MS patient treated with BRIUMVI 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 BRIUMVI. Do not start treatment with BRIUMVI 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 liver disease expert before starting and during treatment.. Progressive Multifocal Leukoencephalopathy (PML)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 BRIUMVI, 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 BRIUMVI 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 BRIUMVI should be discontinued.. VaccinationsAdminister all immunizations according to immunization guidelines at least weeks prior to initiation of BRIUMVI for live or live-attenuated vaccines and, whenever possible, at least weeks prior to initiation of BRIUMVI for non-live vaccines.BRIUMVI may interfere with the effectiveness of non-live vaccines.The safety of immunization with live or live-attenuated vaccines during or following administration of BRIUMVI has not been studied. Vaccination with live virus vaccines is not recommended during treatment with BRIUMVI and until B-cell repletion.Vaccination of Infants Born to Mothers Treated with BRIUMVI During PregnancyIn infants of mothers exposed to BRIUMVI 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 qualified specialist, should be considered to determine whether protective immune response was mounted [see Use in Specific Populations 8.1)] . 5.3 Fetal Risk. Based on data from animal studies, BRIUMVI may cause fetal harm when administered to 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. pregnancy test is recommended in females of reproductive potential prior to each infusion with BRIUMVI. Advise females of reproductive potential to use effective contraception during BRIUMVI treatment and for months after the last dose [see Use in Specific Populations 8.1, 8.3)] . 5.4 Reduction in Immunoglobulins. As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed with BRIUMVI. Decrease in immunoglobulin (IgM) was reported in 0.6% of patients treated with BRIUMVI compared to none of the patients treated with teriflunomide in RMS clinical trials [see Adverse Reactions 6.1)] No decline in immunoglobulin (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 (IgM< lower limit of normal [LLN]) and (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 BRIUMVI therapy if patient with low immunoglobulins develops serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.