Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Propharma Group The Netherlands B.V., Schipholweg 73, 2316ZL Leiden, The Netherlands
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Symptoms of IRR may include pyrexia, chills, headache, tachycardia, nausea, abdominal pain, throat irritation, erythema, and anaphylactic reaction (see section 4.8).
Patients should premedicate with a corticosteroid and an antihistamine to reduce the frequency and severity of IRRs (see section 4.2). The addition of an antipyretic (e.g., paracetamol) may also be considered. Patients treated with ublituximab should be observed during infusions. Patients should be monitored for at least one hour after the completion of the first two infusions. Subsequent infusions do not require monitoring post-infusion unless IRR and/or hypersensitivity has been observed. Physicians should inform patients that IRRs can occur up to 24 hours after the infusion.
For guidance regarding posology for patients experiencing IRR symptoms, see section 4.2.
Administration must be delayed in patients with an active infection until the infection is resolved.
It is recommended to verify the patient’s immune status before dosing since severely immunocompromised patients (e.g. significant neutropenia or lymphopenia) should not be treated (see sections 4.3 and 4.8).
Ublituximab has the potential for serious, sometimes life-threatening or fatal, infections (see section 4.8).
Most of the serious infections that occurred in controlled clinical trials in relapsing forms of multiple sclerosis (RMS) resolved. There were 3 infection-related deaths that occurred, all in patients treated with ublituximab; the infections leading to death were post-measles encephalitis, pneumonia, and postoperative salpingitis following an ectopic pregnancy.
John Cunningham virus (JCV) infection resulting in PML has been observed very rarely in patients treated with anti-CD20 antibodies and mostly associated with risk factors (e.g., patient population, lymphopenia, advanced age, polytherapy with immunosuppressants).
Physicians should be vigilant for the early signs and symptoms of PML, which can include any new onset, or worsening of neurological signs or symptoms, as these can be similar to MS disease.
If PML is suspected, dosing with ublituximab must be withheld. Evaluation including Magnetic Resonance Imaging (MRI) scan preferably with contrast (compared with pre-treatment MRI), confirmatory cerebro-spinal fluid (CSF) testing for JCV Deoxyribonucleic acid (DNA) and repeat neurological assessments, should be considered. If PML is confirmed, treatment must be discontinued permanently.
HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has been observed in patients treated with anti-CD20 antibodies.
HBV screening should be performed in all patients before initiation of treatment as per local guidelines. Patients with active HBV (i.e. an active infection confirmed by positive results for HBsAg and anti HB testing) should not be treated with ublituximab. Patients with positive serology (i.e. negative for HBsAg and positive for HB core antibody (HBcAb+) or who are carriers of HBV (positive for surface antigen, HBsAg+) should consult liver disease experts before starting the treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
The safety of immunisation with live or live-attenuated vaccines, during or following therapy has not been studied and vaccination with live-attenuated or live vaccines is not recommended during treatment and not until B-cell repletion (see section 5.1).
All immunisations should be administered according to immunisation guidelines at least 4 weeks prior to treatment initiation for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to treatment initiation for inactivated vaccines.
In infants of mothers treated with ublituximab during pregnancy, live or live-attenuated vaccines should not be administered before the recovery of B-cell counts has been confirmed. Depletion of B cells in these infants may increase the risks associated with live or live-attenuated vaccines. Measuring CD19-positive B-cell levels, in neonates and infants, prior to vaccination is recommended.
Inactivated vaccines may be administered as indicated prior to recovery from B-cell depletion. However, assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted.
The safety and timing of vaccination should be discussed with the infant’s physician (see section 4.6).
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
No interaction studies have been performed.
The safety of immunisation with live or live-attenuated vaccines following ublituximab therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment or until B-cell repletion (see sections 4.4 and 5.1).
It is not recommended to use other immunosuppressives concomitantly with ublituximab except corticosteroids for symptomatic treatment of relapses.
When initiating Briumvi after an immunosuppressive therapy, or when initiating an immunosuppressive therapy after Briumvi, the potential for overlapping pharmacodynamic effects should be taken into consideration (see section 5.1 Pharmacodynamic effects). Caution should be exercised when prescribing Briumvi taking into consideration the pharmacodynamics of other disease modifying MS therapies.
Women of child-bearing potential should use effective contraception while receiving ublituximab and for at least 4 months after the last infusion (see below and sections 5.1 and 5.2).
Ublituximab is a monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier.
There is a limited amount of data from the use of ublituximab in pregnant women. Postponing vaccination with live or live-attenuated vaccines should be considered for neonates and infants born to mothers who have been exposed to ublituximab during pregnancy. No B-cell count data have been collected in neonates and infants exposed to ublituximab and the potential duration of B-cell depletion in neonates and infants is unknown (see section 4.4).
Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy.
Reproductive toxicity was observed in a pre- and post-natal development studies (see section 5.3).
Briumvi should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus.
It is unknown whether ublituximab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, ublituximab could be used during breast-feeding if clinically needed.
Preclinical data reveal no special hazard on reproductive organs based on studies of general toxicity in cynomolgus monkeys (see section 5.3).
Briumvi has no or negligible influence on the ability to drive and use machines.
The most important and frequently reported adverse reactions are IRRs (45.3%) and infections (55.8%).
Table 2 summarises the adverse reactions that have been reported in association with the use of ublituximab. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each System Organ Class and frequency grouping, adverse reactions are presented in order of decreasing frequency.
Table 2. Adverse reactions:
| MedDRA System Organ Class (SOC) | Very common | Common |
|---|---|---|
| Infections and infestations | Upper respiratory tract infections, Respiratory tract infections | Herpes virus infections, Lower respiratory tract infections |
| Blood and lymphatic system disorders | Neutropenia | |
| Musculoskeletal and connective tissue disorders | Pain in extremity | |
| Injury, poisoning and procedural complications | Infusion-related reactions1 |
1 Symptoms reported as IRRs within 24 hours of the infusion are described below in ‘Infusion-related reactions’.
In active-controlled RMS trials, symptoms of IRR included pyrexia, chills, headache, tachycardia, nausea, abdominal pain, throat irritation, erythema, and anaphylactic reaction. IRRs were primarily mild to moderate in severity. The incidence of IRRs in patients treated with ublituximab was 45.3%, with the highest incidence with the first infusion (40.4%). The incidence of IRRs was 8.6% with the second infusion and decreased thereafter. 1.7% of patients experienced IRRs that led to treatment interruption. 0.4% of patients experienced IRRs that were serious. There were no fatal IRRs.
In active-controlled RMS trials, the proportion of patients who experienced a serious infection with ublituximab was 5.0% compared to 2.9% in the teriflunomide group. The overall rate of infections in patients treated with ublituximab was similar to patients who were treated with teriflunomide (55.8% vs 54.4%, respectively). The infections were predominantly mild to moderate in severity and consisted primarily of respiratory tract-related infections (mostly nasopharyngitis and bronchitis). Upper respiratory tract infections occurred in 33.6% of ublituximab treated patients and 31.8% teriflunomide treated patients. Lower respiratory tract infections occurred in 5.1% of ublituximab treated patients and 4.0% of teriflunomide treated patients.
In active-controlled RMS trials, treatment with ublituximab resulted in a decrease in total immunoglobulins over the controlled period of the studies, mainly driven by the reduction in IgM. The proportion of patients at baseline reporting IgG, IgA, and IgM below the lower limit of normal (LLN) in ublituximab treated patients was 6.3%, 0.6%, and 1.1%, respectively. Following treatment, the proportion of ublituximab treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 6.5%, 2.4%, and 20.9%, respectively.
In active controlled RMS trials, a transient decrease in lymphocytes was observed in 91% of ublituximab patients at Week 1. The majority of lymphocyte decreases were observed only once for a given patient treated with ublituximab and resolved by Week 2 at which time only 7.8% of the patients reported a decrease in lymphocytes. All decreases in lymphocytes were Grade 1 (< LLN-800 cells/mm³) and 2 (between 500 and 800 cells/mm³) in severity.
In active-controlled RMS trials, a decrease in neutrophils counts < LLN was observed in 15% of ublituximab patients compared with 22% of patients treated with teriflunomide. The majority of the neutrophil decreases were transient (only observed once for a given patient treated with ublituximab) and were Grade 1 (between < LLN and 1500 cells/mm³) and 2 (between 1000 and 1500 cells/mm³) in severity. Approximately 1% of the patients in the ublituximab group had Grade 4 neutropenia vs. 0% in the teriflunomide group. One ublituximab treated patient with Grade 4 (<500 cells/mm³) neutropenia required specific treatment with granulocyte-colony stimulating factor.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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