Briumvi

BRIUMVI is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

• Before initiating BRIUMVI, screen for Hepatitis B virus (HBV) and obtain serum quantitative immunoglobulins, aminotransferases, alkaline phosphatase, and bilirubin (
  
  
  2.1 Assessments Prior to First Dose of BRIUMVI

  Hepatitis B Virus Screening

  Prior to initiating BRIUMVI, perform Hepatitis B virus (HBV) screening. BRIUMVI is contraindicated in patients with active HBV confirmed by positive results for Hepatitis B surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for Hepatitis B core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with BRIUMVI

  [see Warnings and Precautions (5.2)]

  .

  Serum Immunoglobulins

  Prior to initiating BRIUMVI, perform testing for quantitative serum immunoglobulins

  [see Warnings and Precautions (5.4)].

  For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with BRIUMVI.

  Vaccinations

  Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of BRIUMVI for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of BRIUMVI for non-live vaccines

  [see Warnings and Precautions (5.2)

  and

  Clinical Pharmacology (12.2)]

  .

  Liver Function Tests

  Prior to initiating BRIUMVI, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels

  [see Warnings and Precautions (5.5)]

  .
  ).
  
• Pre-medicate with methylprednisolone (or an equivalent corticosteroid) and an antihistamine (e.g., diphenhydramine) prior to each infusion (
  
  
  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.
  ).
  
• Administer BRIUMVI by intravenous infusion.
  
  
  • First Infusion: 150 mg intravenous infusion (
    
    
    2.3 Recommended Dosage and Dose Administration

    Administer BRIUMVI under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions, such as serious infusion reactions.

    • First Infusion: 150 mg intravenous infusion
    • Second Infusion: 450 mg intravenous infusion administered two weeks after the first infusion
    • Subsequent Infusions: 450 mg intravenous infusion administered 24 weeks after the first infusion and every 24 weeks thereafter
    • Observe the patient for at least one hour after the completion of the first two infusions. Post-infusion monitoring of subsequent infusions is at physician discretion unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion
      [see Warnings and Precautions (5.1)].

    Table 1: Recommended Dose, Infusion Rate, and Infusion Duration for MS

    	Dose (mg) and Volume (mL) of BRIUMVI	Volume (mL) of 0.9% Sodium Chloride Injection, USPWithdraw and discard the required volume of 0.9% Sodium Chloride Injection, USP from the infusion bag following the preparation instructions in Preparation and Administration (2.6).	Infusion Rate (mL/hour)	DurationInfusion duration may take longer if the infusion is interrupted or slowed.
    First Infusion	150 mg (6 mL)	250 mL	Start at 10 mL per hour for the first 30 minutes Increase to 20 mL per hour for the next 30 minutes Increase to 35 mL per hour for the next hour Increase to 100 mL per hour for the remaining 2 hours	4 hours
    Second Infusion (2 weeks later)	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
    Subsequent Infusions (once every 24 weeks)Administer the first subsequent infusion 24 weeks after the first infusion.	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
    )
    
    
  • Second Infusion: 450 mg intravenous infusion two weeks after the first infusion (
    
    
    2.3 Recommended Dosage and Dose Administration

    Administer BRIUMVI under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions, such as serious infusion reactions.

    • First Infusion: 150 mg intravenous infusion
    • Second Infusion: 450 mg intravenous infusion administered two weeks after the first infusion
    • Subsequent Infusions: 450 mg intravenous infusion administered 24 weeks after the first infusion and every 24 weeks thereafter
    • Observe the patient for at least one hour after the completion of the first two infusions. Post-infusion monitoring of subsequent infusions is at physician discretion unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion
      [see Warnings and Precautions (5.1)].

    Table 1: Recommended Dose, Infusion Rate, and Infusion Duration for MS

    	Dose (mg) and Volume (mL) of BRIUMVI	Volume (mL) of 0.9% Sodium Chloride Injection, USPWithdraw and discard the required volume of 0.9% Sodium Chloride Injection, USP from the infusion bag following the preparation instructions in Preparation and Administration (2.6).	Infusion Rate (mL/hour)	DurationInfusion duration may take longer if the infusion is interrupted or slowed.
    First Infusion	150 mg (6 mL)	250 mL	Start at 10 mL per hour for the first 30 minutes Increase to 20 mL per hour for the next 30 minutes Increase to 35 mL per hour for the next hour Increase to 100 mL per hour for the remaining 2 hours	4 hours
    Second Infusion (2 weeks later)	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
    Subsequent Infusions (once every 24 weeks)Administer the first subsequent infusion 24 weeks after the first infusion.	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
    )
    
    
  • Subsequent Infusions: 450 mg intravenous infusion 24 weeks after the first infusion and every 24 weeks thereafter (
    
    
    2.3 Recommended Dosage and Dose Administration

    Administer BRIUMVI under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions, such as serious infusion reactions.

    • First Infusion: 150 mg intravenous infusion
    • Second Infusion: 450 mg intravenous infusion administered two weeks after the first infusion
    • Subsequent Infusions: 450 mg intravenous infusion administered 24 weeks after the first infusion and every 24 weeks thereafter
    • Observe the patient for at least one hour after the completion of the first two infusions. Post-infusion monitoring of subsequent infusions is at physician discretion unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion
      [see Warnings and Precautions (5.1)].

    Table 1: Recommended Dose, Infusion Rate, and Infusion Duration for MS

    	Dose (mg) and Volume (mL) of BRIUMVI	Volume (mL) of 0.9% Sodium Chloride Injection, USPWithdraw and discard the required volume of 0.9% Sodium Chloride Injection, USP from the infusion bag following the preparation instructions in Preparation and Administration (2.6).	Infusion Rate (mL/hour)	DurationInfusion duration may take longer if the infusion is interrupted or slowed.
    First Infusion	150 mg (6 mL)	250 mL	Start at 10 mL per hour for the first 30 minutes Increase to 20 mL per hour for the next 30 minutes Increase to 35 mL per hour for the next hour Increase to 100 mL per hour for the remaining 2 hours	4 hours
    Second Infusion (2 weeks later)	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
    Subsequent Infusions (once every 24 weeks)Administer the first subsequent infusion 24 weeks after the first infusion.	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
    )
    
    
• Must be diluted in 0.9% Sodium Chloride Injection, USP prior to administration (
  
  
  2.3 Recommended Dosage and Dose Administration

  Administer BRIUMVI under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions, such as serious infusion reactions.

  • First Infusion: 150 mg intravenous infusion
  • Second Infusion: 450 mg intravenous infusion administered two weeks after the first infusion
  • Subsequent Infusions: 450 mg intravenous infusion administered 24 weeks after the first infusion and every 24 weeks thereafter
  • Observe the patient for at least one hour after the completion of the first two infusions. Post-infusion monitoring of subsequent infusions is at physician discretion unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion
    [see Warnings and Precautions (5.1)].

  Table 1: Recommended Dose, Infusion Rate, and Infusion Duration for MS

  	Dose (mg) and Volume (mL) of BRIUMVI	Volume (mL) of 0.9% Sodium Chloride Injection, USPWithdraw and discard the required volume of 0.9% Sodium Chloride Injection, USP from the infusion bag following the preparation instructions in Preparation and Administration (2.6).	Infusion Rate (mL/hour)	DurationInfusion duration may take longer if the infusion is interrupted or slowed.
  First Infusion	150 mg (6 mL)	250 mL	Start at 10 mL per hour for the first 30 minutes Increase to 20 mL per hour for the next 30 minutes Increase to 35 mL per hour for the next hour Increase to 100 mL per hour for the remaining 2 hours	4 hours
  Second Infusion (2 weeks later)	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
  Subsequent Infusions (once every 24 weeks)Administer the first subsequent infusion 24 weeks after the first infusion.	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
  ,
  
  
  2.6 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.
  ).
  
• 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 Recommended Dosage and Dose Administration

  Administer BRIUMVI under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions, such as serious infusion reactions.

  • First Infusion: 150 mg intravenous infusion
  • Second Infusion: 450 mg intravenous infusion administered two weeks after the first infusion
  • Subsequent Infusions: 450 mg intravenous infusion administered 24 weeks after the first infusion and every 24 weeks thereafter
  • Observe the patient for at least one hour after the completion of the first two infusions. Post-infusion monitoring of subsequent infusions is at physician discretion unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion
    [see Warnings and Precautions (5.1)].

  Table 1: Recommended Dose, Infusion Rate, and Infusion Duration for MS

  	Dose (mg) and Volume (mL) of BRIUMVI	Volume (mL) of 0.9% Sodium Chloride Injection, USPWithdraw and discard the required volume of 0.9% Sodium Chloride Injection, USP from the infusion bag following the preparation instructions in Preparation and Administration (2.6).	Infusion Rate (mL/hour)	DurationInfusion duration may take longer if the infusion is interrupted or slowed.
  First Infusion	150 mg (6 mL)	250 mL	Start at 10 mL per hour for the first 30 minutes Increase to 20 mL per hour for the next 30 minutes Increase to 35 mL per hour for the next hour Increase to 100 mL per hour for the remaining 2 hours	4 hours
  Second Infusion (2 weeks later)	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
  Subsequent Infusions (once every 24 weeks)Administer the first subsequent infusion 24 weeks after the first infusion.	450 mg (18 mL)	250 mL	Start at 100 mL per hour for the first 30 minutes Increase to 400 mL per hour for the remaining 30 minutes	1 hour
  ,
  
  
  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.
  ).
  

Injection: 150 mg/6 mL (25 mg/mL) clear to opalescent, colorless to slightly yellow solution in a single-dose vial.

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.

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 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

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.

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

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.