Ublituximab

BRIUMVI برای درمان اشکال عودکننده مولتیپل اسکلروزیس (MS) که شامل سندرم بالینی ایزوله، بیماری عودکننده- فروکش کننده و بیماری پیشرونده ثانویه فعال در بزرگسالان است، نشان داده شده است. BRIUMVI یک آنتی بادی سیتولیتیک هدایت شده با CD20 است که برای درمان اشکال عودکننده مولتیپل اسکلروزیس (MS)، شامل سندرم بالینی ایزوله، بیماری عودکننده- فروکش کننده، و بیماری پیشرونده ثانویه فعال، در بزرگسالان نشان داده شده است (1، 14).

تزریق: 150 میلی گرم/6 میلی لیتر (25 میلی گرم در میلی لیتر) محلول شفاف تا مادی، بی رنگ تا کمی زرد در ویال تک دوز. تزریق: 150 میلی‌گرم/6 میلی‌لیتر (25 میلی‌گرم بر میلی‌لیتر) در یک ویال تک دوز (3)

BRIUMVI در بیماران مبتلا به: عفونت فعال HBV منع مصرف دارد [نگاه کنید به دوز و نحوه تجویز (2.1) و هشدارها و اقدامات احتیاطی (5.2)] سابقه واکنش انفوزیونی تهدید کننده حیات به BRIUMVI [به هشدارها و اقدامات احتیاطی (5.1) مراجعه کنید]] واکنش فعال هپاتیت B-عفونت هپاتیت B در عفونت حیاتی (4) BRIUMVI (4)

7.1 درمان‌های سرکوب‌کننده یا تعدیل‌کننده ایمنی استفاده همزمان از BRIUMVI با سایر داروهای تعدیل‌کننده ایمنی یا سرکوب‌کننده‌های ایمنی، از جمله دوزهای سرکوب‌کننده ایمنی کورتیکواستروئیدها، ممکن است خطر عفونت را افزایش دهد. هنگام تجویز همزمان درمان های سرکوب کننده سیستم ایمنی با BRIUMVI، خطر اثرات افزایشی سیستم ایمنی را در نظر بگیرید. هنگام جابجایی از درمان‌های دارای اثرات ایمنی، باید مدت و مکانیسم اثر این درمان‌ها را در نظر گرفت زیرا بالقوه اثرات سرکوب‌کننده ایمنی افزایشی در شروع BRIUMVI دارد.

عوارض جانبی جدی زیر با جزئیات بیشتر در بخش‌های دیگر برچسب مورد بحث قرار گرفته است: واکنش‌های انفوزیون [به هشدارها و اقدامات احتیاطی (5.1) مراجعه کنید] عفونت‌ها [به هشدارها و اقدامات احتیاطی (5.2) مراجعه کنید] کاهش در ایمونوگلوبولین‌ها [به هشدارها و اقدامات احتیاطی (5.4) مراجعه کنید] ] آسیب کبدی [به هشدارها و اقدامات احتیاطی مراجعه کنید (5.5 ≥ واکنش‌های جانبی) رایج‌ترین واکنش‌ها (5.5) بود] و عفونت های دستگاه تنفسی فوقانی (6.1). برای گزارش واکنش‌های نامطلوب مشکوک، با TG Therapeutics با شماره 1-877-848-9462 یا FDA با شماره 1-800-FDA-1088 یا www.fda.gov/medwatch تماس بگیرید.

6.1 تجربه کارآزمایی‌های بالینی از آنجایی که کارآزمایی‌های بالینی تحت شرایط بسیار متفاوتی انجام می‌شوند، نرخ‌های واکنش نامطلوب مشاهده‌شده در کارآزمایی‌های بالینی یک دارو را نمی‌توان مستقیماً با نرخ‌های آزمایش‌های بالینی داروی دیگر مقایسه کرد و ممکن است نرخ‌های مشاهده‌شده در عمل بالینی را منعکس نکند. در کارآزمایی‌های بالینی با کنترل فعال (مطالعه 1 و مطالعه 2)، 545 بیمار مبتلا به RMS BRIUMVI دریافت کردند [به مطالعات بالینی (14) مراجعه کنید]. شایع ترین واکنش های جانبی در کارآزمایی های RMS (بروز حداقل 10٪) واکنش های انفوزیون و عفونت های دستگاه تنفسی فوقانی بود. جدول 2 واکنش های جانبی را که در کارآزمایی های RMS رخ داده اند خلاصه می کند (مطالعه 1 و مطالعه 2). شایع ترین علت قطع در بیماران تحت درمان با BRIUMVI عفونت (1.3%) بود. جدول 2: عوارض جانبی در بیماران بزرگسال مبتلا به RMS با بروز حداقل 5 درصد برای BRIUMVI و بالاتر از تری فلونوماید از مطالعه 1 و مطالعه 2 BRIUMVI 450 میلی گرم IV اولین دوز BRIUMVI به صورت انفوزیون داخل وریدی (IV) 150 میلی گرم داده شد. دوز دوم به صورت انفوزیون IV 450 میلی گرم دو هفته پس از انفوزیون اول داده شد. تریفلونوماید 14 میلی گرم PO عوارض جانبی (N=545) % (N=548) % واکنش های انفوزیون 48 12 عفونت های دستگاه تنفسی فوقانی شامل موارد زیر است: نازوفارنژیت، عفونت دستگاه تنفسی فوقانی، عفونت دستگاه تنفسی، عفونت دستگاه تنفسی ویروسی، فارنژیت، رینیت، سینوزیت، سینوزیت حاد، التهاب لوزه، لارنژیت، سینوزیت مزمن، فارنژیت ویروسی، رینیت ویروسی، رینیت ویروسی، عفونت مزمن دستگاه تنفسی فوقانی، عفونت تنفسی تونسیکو سینوزیت باکتریایی و لوزه باکتریایی. 45 41 عفونت‌های دستگاه تنفسی تحتانی شامل موارد زیر است: برونشیت، ذات‌الریه، تراکئیت، تراکئوبرونشیت، پنومونی COVID-19، برونشیت باکتریایی و پنومونی ویروسی. 9 7 عفونت های مرتبط با ویروس هرپس شامل چندین اصطلاح مرتبط است. 6 5 درد در اندام 6 4 بی خوابی 6 3 خستگی 5 4 واکنش های انفوزیون بروز واکنش های انفوزیون با اولین انفوزیون (43٪) بالاترین بود، و با انفوزیون بعدی کاهش یافت (10٪ با انفوزیون دوم، 8٪ با انفوزیون سوم). سه (0.6٪) از بیماران تحت درمان با BRIUMVI واکنش های تزریقی جدی را گزارش کردند. اغلب علائم گزارش شده (بیش از 5٪) شامل تب، لرز، سردرد و بیماری شبه آنفلوانزا بود [به هشدارها و اقدامات احتیاطی (5.1) مراجعه کنید]. ناهنجاری های آزمایشگاهی کاهش ایمونوگلوبولین ها BRIUMVI ایمونوگلوبولین های کل را با بیشترین کاهش در سطوح IgM کاهش داد. نسبت بیماران تحت درمان با BRIUMVI در ابتدای شروع گزارش IgG، IgA و IgM زیر LLN به ترتیب 6.3٪، 0.6٪ و 1.1٪ بود. پس از درمان، نسبت بیماران تحت درمان با BRIUMVI که IgG، IgA و IgM کمتر از LLN در هفته 96 گزارش کردند به ترتیب 6.5٪، 2.4٪ و 20.9٪ بود. کاهش سطح نوتروفیل در مطالعات 1 و 2، کاهش تعداد نوتروفیل ها (<LLN) در 15 درصد از بیماران تحت درمان با BRIUMVI در مقایسه با 22 درصد در بیماران تحت درمان با تری فلونوماید رخ داد. اکثر کاهش تعداد نوتروفیل ها یک بار برای یک بیمار معین تحت درمان با BRIUMVI مشاهده شد و بین 1.0 و 1.5 × 109 / L بود. در مطالعات RMS، 3٪ از بیماران در گروه BRIUMVI تعداد نوتروفیل های کمتر از 1.0 × 109 / L داشتند، در مقایسه با 2٪ از بیماران در گروه تری فلونوماید. به طور کلی، 1٪ از بیماران در گروه BRIUMVI دارای تعداد نوتروفیل کمتر از 0.5 × 109 / L بودند، در مقایسه با 0٪ از بیماران در گروه تری فلونومید، و اینها با عفونت مرتبط نبودند.

6.2 تجارب پس از بازاریابی عوارض جانبی زیر در طول استفاده پس از تایید BRIUMVI شناسایی شده است. از آنجایی که این واکنش ها به طور داوطلبانه از جمعیتی با اندازه نامشخص گزارش می شوند، همیشه نمی توان به طور قابل اعتماد فراوانی آنها را تخمین زد یا یک رابطه علّی با قرار گرفتن در معرض دارو ایجاد کرد. اختلالات کبدی صفراوی: آسیب کبدی [به هشدارها و اقدامات احتیاطی (5.5) مراجعه کنید] عفونت ها و آلودگی ها: لوکوآنسفالوپاتی چند کانونی پیشرونده [به هشدارها و اقدامات احتیاطی (5.2) مراجعه کنید]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BRIUMVI during pregnancy. Eligible patients are women who become pregnant either while taking BRIUMVI or within 6 months following their last dose of BRIUMVI. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-411-4546 or visiting www.briumvipregnancyregistry.com. 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) ]. In pregnant transgenic huCD20 mice, a pharmacologically relevant animal model, weekly intravenous administration of ublituximab-xiiy during organogenesis resulted in no adverse pregnancy or embryofetal outcomes (see Data ) . 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 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. External, visceral, 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. The findings in cynomolgus monkey were considered secondary to an immunogenic reaction and are not considered relevant to humans. In a subsequent study conducted in pregnant CD20 (huCD20) transgenic mice, a pharmacologically relevant animal model, intravenous administration of ublituximab-xiiy (0, 5, 20, or 50 mg/kg) during organogenesis (gestation day 6 and 12) resulted in no adverse effects on embryofetal development. There was a marked reduction in B-cells in fetal blood at all but the lowest dose tested.

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 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.

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BRIUMVI during pregnancy. Eligible patients are women who become pregnant either while taking BRIUMVI or within 6 months following their last dose of BRIUMVI. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-411-4546 or visiting www.briumvipregnancyregistry.com. 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) ]. In pregnant transgenic huCD20 mice, a pharmacologically relevant animal model, weekly intravenous administration of ublituximab-xiiy during organogenesis resulted in no adverse pregnancy or embryofetal outcomes (see Data ) . 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 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. External, visceral, 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. The findings in cynomolgus monkey were considered secondary to an immunogenic reaction and are not considered relevant to humans. In a subsequent study conducted in pregnant CD20 (huCD20) transgenic mice, a pharmacologically relevant animal model, intravenous administration of ublituximab-xiiy (0, 5, 20, or 50 mg/kg) during organogenesis (gestation day 6 and 12) resulted in no adverse effects on embryofetal development. There was a marked reduction in B-cells in fetal blood at all but the lowest dose tested.

Safety and effectiveness in pediatric patients have not been established.

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.

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.

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.

12.3 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.

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.

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.

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.

, 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).

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 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 [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 or plan to become pregnant during treatment with BRIUMVI [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1 , 8.3) ] . Pregnancy Registry Instruct patients that if they are pregnant or plan to become pregnant while taking BRIUMVI they should inform their healthcare provider [see Use in Specific Populations (8.1) ] . Encourage patients to enroll in the BRIUMVI Pregnancy Registry if they become pregnant while taking BRIUMVI or within 6 months following the last dose of BRIUMVI [see Use in Specific Populations (8.1) ] . Liver Injury Inform patients that liver injury has been reported with anti-CD20 B-cell depleting therapies, including BRIUMVI. Instruct patients treated with BRIUMVI to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. A blood test should be obtained before patients start therapy, and during treatment as clinically indicated [see Warnings and Precautions (5.5) ] .

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.