DRUG INTERACTIONS

 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.

U.S.  APPROVED DRUGS DURING 2022                                        

Serial No 36

Name-        BRIUMVI

Acive  Ingredient -  Ubituximab-xiiy

Pharmacological clssificiation-  To treat relapsing multiple sclerosis                                                                                                                                    

  Date of  Approval-         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 .

ADVERSE REACTIONS

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

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 

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

 • Administer BRIUMVI by intravenous infusion. o First Infusion: 150 mg intravenous infusion (2.3) o Second Infusion: 450 mg intravenous infusion two weeks after the first infusion (2.3) 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 .

Manufactured by: TG Therapeutics, Inc. 3020 Carrington Mill Blvd Morrisville, NC 27560 U.S. License No. 2090

CLINICAL PHARMACOLOGY-

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.

2. Pharmacodynamics-                                                                                                     Treatment with BRIUMVI reduced CD19+ B-cell counts in blood by the first measured timepoint of 24 hours after infusion.

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.

 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 product

 USE IN SPECIFIC POPULATIONS

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 outcomes0.

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.              

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.

3. Females and Males of Reproductive Potential-                                                      Pregnancy Testing -Pregnancy testing is recommended for females of reproductive potential prior to each infusion.

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

4.Pediatric Use .Safety and effectiveness in pediatric patients have not been established.

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.