Briumvi Drug Information
Generic name: UBLITUXIMAB
CD20-directed Cytolytic Antibody [EPC]
Uses of 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. BRIUMVI is a CD20-directed cytolytic antibody indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Dosage & Administration of Briumvi
| First Infusion | 150 mg (6 mL) |
|---|---|
| Second Infusion (2 weeks later) | 450 mg (18 mL) |
| Subsequent Infusions (once every 24 weeks) | 450 mg (18 mL) |
Side Effects of Briumvi
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. The most common 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 BRIUMVI 450 mg IV 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. Teriflunomide 14 mg PO Adverse Reactions (N=545) % (N=548) % Infusion reactions 48 12 Upper respiratory tract infections 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. 45 41 Lower respiratory tract infections Includes the following: bronchitis, pneumonia, tracheitis, tracheobronchitis, COVID-19 pneumonia, bronchitis bacterial, and pneumonia viral. 9 7 Herpes virus-associated infections Includes several related terms. 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 . 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 ( The majority of decreased neutrophil counts were observed once for a given patient treated with BRIUMVI, and were between 1.0 and 1.5 × 10 9 /L. In RMS studies, 3% of patients in the BRIUMVI group had neutrophil counts less than 1.0 × 10 9 /L, compared to 2% of patients in the teriflunomide group. Overall, 1% of patients in the BRIUMVI group had neutrophil counts less than 0.5 × 10 9 /L, compared to 0% of patients in the teriflunomide group, and these were not associated with an infection. The following adverse reactions have been identified during postapproval use of BRIUMVI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary Disorders: Liver injury Infections and Infestations: Progressive multifocal leukoencephalopathyPostmarketing Experience
Warnings & Cautions for Briumvi
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 . In Studies 1 and 2 , 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 . The addition of an antipyretic (e.g., acetaminophen) may also be considered. 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 . For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
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 . 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 and positive for HB core antibody or are carriers of HBV, 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. JCV infection resulting in PML has been observed in patients treated with anti-CD20 antibodies, including BRIUMVI, 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 .
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. Advise females of reproductive potential to use effective contraception during BRIUMVI treatment and for 6 months after the last dose .
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 . 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 ) and G (IgG Consider discontinuing BRIUMVI therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins. been reported in the postmarketing setting in patients treated with anti-CD20 B-cell depleting therapies approved for the treatment of MS, including BRIUMVI. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred from weeks to months after administration. Patients treated with BRIUMVI found to have an alanine aminotransaminase (ALT) or aspartate aminotransferase (AST) greater than 3× the upper limit of normal (ULN) with serum total bilirubin greater than 2× ULN are potentially at risk for severe drug-induced liver injury. Obtain liver function tests prior to initiating treatment with BRIUMVI , and monitor for signs and symptoms of any hepatic injury during treatment. Measure serum aminotransferases, alkaline phosphatase, and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. If liver injury is present and an alternative etiology is not identified, discontinue BRIUMVI.Liver Injury Clinically significant liver injury, without findings of viral hepatitis, has
Drug Interactions with Briumvi
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.
Pregnancy Safety for Briumvi
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. 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. 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.
Pediatric Use of Briumvi
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Contraindications for Briumvi
is contraindicated in patients with: Active HBV infection A history of life-threatening infusion reaction to BRIUMVI Active hepatitis B virus infection History of life-threatening infusion reaction to BRIUMVI
Clinical Studies of Briumvi
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. 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 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 Study 1 Study 2 Endpoints BRIUMVI 450 mg 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. Teriflunomide 14 mg BRIUMVI 450 mg Teriflunomide 14 mg Clinical Endpoints 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). Annualized Relapse Rate (Primary Endpoint) 0.076 0.188 0.091 0.178 Relative Reduction 59% (p<0.001) 49% (p = 0.002) Proportion of Patients with 12-week Confirmed Disability Progression Data prospectively pooled from Study 1 and Study 2: BRIUMVI (N=543), teriflunomide (N=546)., 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. 5.2% BRIUMVI vs. 5.9% teriflunomide Risk Reduction (Pooled Analysis) Based on Hazard Ratio. 16% (p = 0.510) MRI Endpoints 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). Mean number of T1 Gd-enhancing lesions per MRI At Week 96. 0.016 0.491 0.009 0.250 Relative Reduction 97% (p<0.001) 97% (p<0.001) Mean number of new or enlarging T2 hyperintense lesions per MRI 0.213 2.789 0.282 2.831 Relative Reduction 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.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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