travenous immunoglobulins ( 2.1 , 5.4 ). 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 ). 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. 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. vaccinations 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. 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 pregnancy in 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 a qualified specialist, should be considered to determine whether a 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 a 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. a 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 6 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 m (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 g (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 m (igm< lower limit of normal [lln]) and g (igg

Dosage and Administration:

2 dosage and administration hepatitis b 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 ). 2.1 assessments prior to first dose of briu Read more...

mvi 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 )] . 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. pregnancy testing pregnancy 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 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 1 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 ). 2 infusion duration may take longer if the infusion is interrupted or slowed. 3 administer the first subsequent infusion 24 weeks after the first infusion. dose (mg) and volume (ml) of briumvi volume (ml) of 0.9% sodium chloride injection, usp 1 infusion rate (ml/hour) duration 2 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) 3 450 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 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. administration of infusion solution prior 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 a 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 2°c to 8°c (36°f to 46°f) 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 2 hours). the diluted solution can be stored for an additional 8 hours at room temperature up to 25°c (77°f), which includes the equilibration time and infusion time.

Dosage Forms and Strength:

3 dosage forms and strengths injection: 150 mg/6 ml (25 mg/ml) clear to opalescent, colorless to slightly yellow solution in a single-dose vial. injection: 150 mg/6 ml (25 mg/ml) in a single-dose vial ( 3 )

Contraindications:

4 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 )

Adverse Reactions:

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 )] 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 comm Read more...

on 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 adverse reactions briumvi 450 mg iv a (n=545) % teriflunomide 14 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. b 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. c includes the following: bronchitis, pneumonia, tracheitis, tracheobronchitis, covid-19 pneumonia, bronchitis bacterial, and pneumonia viral. d includes several related terms. infusion reactions 48 12 upper respiratory tract infections b 45 41 lower respiratory tract infections c 9 7 herpes virus-associated infections d 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 (

Adverse Reactions Table:

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

Adverse Reactions	BRIUMVI 450 mg IVa (N=545) %	Teriflunomide 14 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.
b 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.
c Includes the following: bronchitis, pneumonia, tracheitis, tracheobronchitis, COVID-19 pneumonia, bronchitis bacterial, and pneumonia viral.
d Includes several related terms.
Infusion reactions	48	12
Upper respiratory tract infections b	45	41
Lower respiratory tract infections c	9	7
Herpes virus-associated infections d	6	5
Pain in extremity	6	4
Insomnia	6	3
Fatigue	5	4

Drug Interactions:

7 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.

Use in Specific Population:

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 ) . the estimated background risk of major Read more...

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 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.

Use in Pregnancy:

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 ) . the estimated background risk of major birth defects and miscarriage Read more...

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.

Pediatric Use:

8.4 pediatric use safety and effectiveness in pediatric patients have not been established.

Geriatric Use:

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.

Description:

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 yellow, preservative-free solution. each ml of solution contains 25 mg ublituximab-xiiy, 0.4 mg hydrochloric acid, 0.7 mg polysorbate 80, 9.0 mg sodium chloride, 6.4 mg sodium citrate, and water for injection, usp. the ph is 6.5.

Clinical Pharmacology:

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, 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 7 Read more...

0.3 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 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 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.

Mechanism of Action:

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.

Pharmacodynamics:

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.

Pharmacokinetics:

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 ef Read more...

fect 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.

Nonclinical Toxicology:

13 nonclinical toxicology 13.1 carcinogenesis, mutagenesis, impairment of fertility carcinogenesis no carcinogenicity studies have been conducted to assess the carcinogenic potential of briumvi. mutagenesis as an antibody, briumvi is not expected to interact directly with dna. impairment of fertility no studies in animals have been conducted to assess the effects of briumvi on male or female fertility. no adverse effects on male or female reproductive organs were observed at the only dose level evaluated (30 mg/kg) in a 26-week intravenous toxicity study in monkeys, which was associated with plasma exposures (c ave ) approximately 24 times that in humans at the maximum recommended human dose (450 mg).

Carcinogenesis and Mutagenesis and Impairment of Fertility:

13.1 carcinogenesis, mutagenesis, impairment of fertility carcinogenesis no carcinogenicity studies have been conducted to assess the carcinogenic potential of briumvi. mutagenesis as an antibody, briumvi is not expected to interact directly with dna. impairment of fertility no studies in animals have been conducted to assess the effects of briumvi on male or female fertility. no adverse effects on male or female reproductive organs were observed at the only dose level evaluated (30 mg/kg) in a 26-week intravenous toxicity study in monkeys, which was associated with plasma exposures (c ave ) approximately 24 times that in humans at the maximum recommended human dose (450 mg).

Clinical Studies:

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 1 (nct03277261) and study 2 (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 a 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 a t1 gadolinium (gd)-enhancing lesion in the previous year. patients were also required to have Read more...

an expanded disability status scale (edss) score from 0 to 5.5 at baseline. neurological evaluations were performed at baseline, every 12 weeks, and at the time of a suspected relapse. brain mri scans were performed at baseline and at weeks 12, 24, 48, and 96. the primary outcome of both study 1 and study 2 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 a pooled analysis of studies 1 and 2. disability progression was considered confirmed when the increase in the edss was confirmed at a 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 1 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 1 and study 2 are presented in table 3 . table 3: key clinical and mri endpoints in rms patients from study 1 and study 2 1 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). 2 data prospectively pooled from study 1 and study 2: briumvi (n=543), teriflunomide (n=546). 3 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. 4 based on hazard ratio. 5 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). 6 at week 96. 7 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 1 study 2 endpoints briumvi 450 mg 7 teriflunomide 14 mg 7 briumvi 450 mg 7 teriflunomide 14 mg 7 clinical endpoints 1 annualized relapse rate (primary endpoint) relative reduction 0.076 0.188 0.091 0.178 59% (p<0.001) 49% (p = 0.002) proportion of patients with 12-week confirmed disability progression 2,3 risk reduction (pooled analysis) 4 5.2% briumvi vs. 5.9% teriflunomide 16% (p = 0.510) mri endpoints 5 mean number of t1 gd-enhancing lesions per mri 6 relative reduction 0.016 0.491 0.009 0.250 97% (p<0.001) 97% (p<0.001) mean number of new or enlarging t2 hyperintense lesions per mri 6 relative reduction 0.213 2.789 0.282 2.831 92% (p<0.001) 90% (p<0.001) in exploratory analyses of study 1 and study 2, a similar effect of briumvi on the arr was observed in subgroups defined by gender, prior non-steroid ms therapy, baseline disability (edss 3.5 or lower versus greater than 3.5), the number of relapses in the 2 years prior to study enrollment, and number of gd-enhancing lesions at baseline.

How Supplied:

16 how supplied/storage and handling 16.1 how supplied briumvi (ublituximab-xiiy) injection is a sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution for intravenous use supplied as a carton containing one 150 mg/6 ml (25 mg/ml) single-dose vial (ndc 73150-150-06). 16.2 storage and handling store briumvi vials refrigerated at 2°c to 8°c (36°f to 46°f) in the outer carton to protect from light. do not freeze. do not shake.

Information for Patients:

17 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 [see warnings and precautions ( 5.1 )] . 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 [see warnings and precautions ( 5.2 )] . advise patients that briumvi may cause reactivation of hepatitis b infection and that monitoring will be required if they are at risk [see warnings and precautions ( 5.2 )] . 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 Read more...

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 [see warnings and precautions ( 5.2 )] . 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 [see warnings and precaution ( 5.2 )] . 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 [see warnings and precautions ( 5.3 ) and use in specific populations ( 8.1 , 8.3 )] . manufactured by: tg therapeutics, inc. 3020 carrington mill blvd morrisville, nc 27560 u.s. license no. 2090 briumvi is a trademark of tg therapeutics, inc. © tg therapeutics, inc. 2021-2022. all rights reserved.

Package Label Principal Display Panel:

Principal display panel - 6 ml carton label ndc 73150-150-06 briumvi™ (ublituximab-xiiy) injection 150 mg/6 ml (25 mg/ml) for intravenous infusion after dilution. discard unused portion. attention: dispense the enclosed medication guide to each patient. rx only contains one 6 ml single-dose vial. tg therapeutics principal display panel - 6 ml carton label

Principal display panel - 6 ml vial label ndc 73150-150-06 briumvi™ (ublituximab-xiiy) injection rx only 150 mg/6 ml (25 mg/ml) for intravenous infusion after dilution. single-dose vial. discard unused portion. no preservative. dosage: see prescribing information. tg therapeutics principal display panel - 6 ml vial label

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