U.S.  APPROVED DRUGS DURING 2022                                        

Serial No 36

Name-        BRIVMVI

Acive  Ingredient -  Ubiltuximab -Xiiy

Phar macological clssificiation-        To treat relapsing forms of Multiple Sclerosis                                                                                                                                                Date of Approved-         28/12/2022       

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use BRIUMVI safely and effectively. See full prescribing information for BRIUMVI. BRIUMVI™ (ublituximab-xiiy) injection, for intravenous use

Initial U.S. Approval: 2022

INDICATIONS AND USAGE-

 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.

DOSAGE AND ADMINISTRATION-

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

 • Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion

   BRIUMVI by intravenous infusion. o First Infusion: 150 mg intravenous infusion

 o Second Infusion: 450 mg intravenous infusion two weeks after the first infusion

 o 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 .

DOSAGE FORMS AND STRENGTHS-

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

CONTRAINDICATIONS-

 • Active hepatitis B virus infection

 • History of life-threatening infusion reaction to BRIUMVI 

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

 • 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

 • 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

• Fetal Risk: May cause fetal harm. 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).

ADVERSE REACTIONS-

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

DOSAGE AND ADMINISTRATION-

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

 • Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion

   BRIUMVI by intravenous infusion. o First Infusion: 150 mg intravenous infusion

 o Second Infusion: 450 mg intravenous infusion two weeks after the first infusion

 o 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 .

DOSAGE FORMS AND STRENGTHS-

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

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Infusion Reactions- Inform patients about the signs and symptoms of infusion reactions and that infusion reactions can occur up to 24 hours after infusion.

Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions.

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

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

Advise patients that PML has happened with drugs that are similar to BRIUMVI and may happen with BRIUMVI. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months.

Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML.

Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes..

Vaccination- Advise patients to complete any required live or live-attenuated vaccinations at least 4 weeks and, whenever possible, non-live vaccinations at least 2 weeks prior to initiation of BRIUMVI.

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

Fetal Risk- Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with BRIUMVI and for 6 months after the last BRIUMVI dose.

Advise patients to notify their healthcare provider if they are pregnant during treatment with BRIUMVI.

Man- by: TG Therapeutics, Inc. 3020 Carrington Mill Blvd Morrisville, NC 27560 U.S. License No. 2090 BRIUMVI is a trademark of TG Ther

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, 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. 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 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. 12 Reference ID: 5101565 12.3 Pharmacokinetics Ublituximab-xiiy exposures increased proportionally over a 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%). 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 is a protein for which the expected metabolic pathway is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes. Specific Populations There 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 Studies No 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 1 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 BRIUMVItreated 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis

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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There 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 a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Although there are no data on ublituximab-xiiy, monoclonal antibodies can be actively transported across the placenta, and 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). 10 Reference ID: 5101565 The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions 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 [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)]. Data Animal Data Weekly intravenous administration of ublituximab-xiiy (0 or 30 mg/kg) to separate groups of pregnant monkeys during the first, second, or third trimester of pregnancy produced a severe immunogenic response in dams, resulting in maternal morbidity and death and embryofetal loss. Dosing was terminated in dams after only two doses during the third trimester because of multiple deaths in dams dosed during the first and second trimesters. Ublituximab-related external, viscera, and skeletal abnormalities occurred in two infants from dams exposed during the second trimester of pregnancy. Histopathology evaluations revealed minimal to moderate degeneration/necrosis in the brain. Findings in infants included contractures and abnormal flexion of multiple limbs and tail, shortened mandible, elongate calvarium, enlargement of ears, and/or craniomandibular abnormalities which were attributed to brain necrosis. Abnormalities were absent in infants of dams exposed during the first trimester of pregnancy. A no-effect dose for adverse effects on embryofetal development in monkeys was not identified. 8.2 Lactation Risk Summary There are no data on the presence of ublituximab-xiiy in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Human IgG is excreted in human milk, and the potential for absorption of ublituximab-xiiy to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for 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 Testing 11 Reference ID: 5101565 Pregnancy 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 Females Females of reproductive potential should use effective contraception while receiving BRIUMVI and for 6 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.

11 DESCRIPTION Ublituximab-xiiy is a recombinant chimeric monoclonal IgG1 antibody with reduced fucose content directed against CD20-expressing B-cells. The molecular weight of the antibody is approximately 147 kDa. BRIUMVI (ublituximab-xiiy) injection for intravenous infusion is a sterile, clear to opalescent, colorless to slightly y