Ublituximab

INDICATIONS AND USAGE BRIUMVI 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. BRIUMVI is a CD20-directed cytolytic antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults ( 1 , 14 ).

DOSAGE AND ADMINISTRATION Before initiating BRIUMVI, screen for Hepatitis B virus (HBV) and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin ( 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 ). 2.1 Assessments Prior to First Dose of BRIUMVI Hepatitis B Virus Screening Prior to initiating BRIUMVI, perform Hepatitis B virus (HBV) screening. BRIUMVI is contraindicated in patients with active HBV confirmed by positive results for Hepatitis B surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for Hepatitis B 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 Immunoglobulins Prior 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. Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of BRIUMVI for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of BRIUMVI for non-live vaccines [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] . Liver Function Tests Prior to initiating BRIUMVI, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels [see Warnings and Precautions (5.5) ] . 2.2 Assessment and Premedication Before Every Infusion Infection Assessment Prior 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 Premedication Pre-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. 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 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) ]. Table 1: Recommended Dose, Infusion Rate, and Infusion Duration for MS Dose (mg) and Volume (mL) of BRIUMVI Volume (mL) of 0.9% Sodium Chloride Injection, USP 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 Rate (mL/hour) Duration Infusion duration may take longer if the infusion is interrupted or slowed. First Infusion 150 mg (6 mL) 250 mL 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 2 hours 4 hours Second Infusion (2 weeks later) 450 mg (18 mL) 250 mL Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes 1 hour Subsequent Infusions (once every 24 weeks) Administer the first subsequent infusion 24 weeks after the first infusion. 450 mg (18 mL) 250 mL Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes 1 hour 2.4 Delayed or Missed Doses If a 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 5 months. 2.5 Dosage Modifications Because of Infusion Reactions Dose modifications in response to infusion reactions depend on the severity. Life-Threatening Infusion Reactions Immediately stop infusion and permanently discontinue BRIUMVI if there are signs of a life-threatening or disabling infusion reaction [see Warnings and Precautions (5.1) ] . Provide appropriate supportive treatment. Severe Infusion Reactions Immediately 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 Reactions Reduce 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 Preparation Only use 0.9% Sodium Chloride Injection, USP to dilute BRIUMVI. BRIUMVI must be prepared by a healthcare professional using aseptic technique. Prepare the solution for infusion as follows: BRIUMVI should be a 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 6 mL 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard. Withdraw 6 mL BRIUMVI solution from the vial. Add 6 mL (150 mg) BRIUMVI into the infusion bag containing 0.9% Sodium Chloride Injection, USP. Preparation of Solution for Second Infusion and Subseq

WARNINGS AND PRECAUTIONS Infusion Reactions : Management recommendations for infusion reactions depend on the type and severity of the reaction. Permanently discontinue BRIUMVI if a 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 based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for at least 6 months after stopping BRIUMVI ( 5.3 , 8.1 , 8.3 ). Liver Injury : Clinically significant liver injury has occurred. Obtain serum aminotransferases, alkaline phosphatase, and bilirubin levels before initiating BRIUMVI, and during treatment as clinically indicated. Discontinue BRIUMVI in patients with evidence of liver injury in the absence of an alternative etiology ( 5.5 ). 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 1 and 2 [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 1 and 2 in patients who received treatment with BRIUMVI 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 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 Reactions Administer 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 1 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 3 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 1 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 Immunosuppressants When 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 B Virus (HBV) Reactivation HBV 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 a 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. JCV infection resulting in PML has been observed in patients treated with anti-CD20 antibodies, including BRIUMVI, 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. Vaccinat

CONTRAINDICATIONS BRIUMVI is contraindicated in patients with: Active HBV infection [see Dosage and Administration (2.1) and Warnings and Precautions (5.2) ] A history of life-threatening infusion reaction to BRIUMVI [see Warnings and Precautions (5.1) ] Active hepatitis B virus infection ( 4 ) History of life-threatening infusion reaction to BRIUMVI ( 4 )

DRUG INTERACTIONS 7.1 Immunosuppressive or Immune-Modulating Therapies The concomitant usage of BRIUMVI with other immune-modulating or immunosuppressant drugs, including immunosuppressant doses of corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when co-administering immunosuppressive therapies with BRIUMVI. When switching from therapies with immune effects, the duration and mechanism of action of these therapies should be taken into account because of potential additive immunosuppressive effects when initiating BRIUMVI.

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) ] Liver Injury [see Warnings and Precautions (5.5) ] 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 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 [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 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 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 1 and Study 2 BRIUMVI 450 mg IV 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. Teriflunomide 14 mg PO Adverse Reactions (N=545) % (N=548) % Infusion reactions 48 12 Upper respiratory tract infections 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. 45 41 Lower respiratory tract infections Includes the following: bronchitis, pneumonia, tracheitis, tracheobronchitis, COVID-19 pneumonia, bronchitis bacterial, and pneumonia viral. 9 7 Herpes virus-associated infections Includes several related terms. 6 5 Pain in extremity 6 4 Insomnia 6 3 Fatigue 5 4 Infusion Reactions The 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 Immunoglobulins BRIUMVI 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 Levels In Studies 1 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 a 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of BRIUMVI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary Disorders: Liver injury [see Warnings and Precautions (5.5) ] Infections and Infestations: Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2) ]

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.