Briumvi 150 mg concentrate for solution for infusion

Briumvi is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features (see section 5.1).

Treatment should be initiated and supervised by specialised physicians experienced in the diagnosis and treatment of neurological conditions and who have access to appropriate medical support to manage severe reactions such as serious infusion related reactions (IRRs).

Premedication for infusion-related reactions

The following two premedications must be administered (orally, intravenously, intramuscular, or subcutaneously) prior to each infusion to reduce the frequency and severity of IRRs (see section 4.4 for additional steps to reduce IRRs):

• 100 mg methylprednisolone or 10-20 mg dexamethasone (or an equivalent) approximately 30-60 minutes prior to each infusion;

• diphenhydramine approximately 30-60 minutes prior to each infusion;

In addition, premedication with an antipyretic (e.g. paracetamol) may also be considered.

Posology

First and second doses

The first dose is administered as a 150 mg intravenous infusion (first infusion), followed by a 450 mg intravenous infusion (second infusion) 2 weeks later (see Table 1).

Subsequent doses

Subsequent doses are administered as a single 450 mg intravenous infusion every 24 weeks (Table 1). The first subsequent dose of 450 mg should be administered 24 weeks after the first infusion.

A minimal interval of 5 months should be maintained between each dose of ublituximab.

Infusion adjustments in case of IRRs

Life-threatening IRRs

If there are signs of a life-threatening or disabling IRR during an infusion, the infusion must be stopped immediately and the patient should receive appropriate treatment. Treatment must be permanently discontinued in these patients (see section 4.4).

Severe IRRs

If a patient experiences a severe IRR, the infusion should be interrupted immediately and the patient should receive symptomatic treatment. The infusion should be restarted only after all symptoms have resolved. When restarting, the infusion rate should be at half of the infusion rate at the time of onset of the IRR. If the rate is tolerated, the rate should be increased as described in Table 1.

Mild to moderate IRRs

If a patient experiences a mild to moderate IRR, the infusion rate should be reduced to half the rate at the onset of the event. This reduced rate should be maintained for at least 30 minutes. If the reduced rate is tolerated, the infusion rate may then be increased as described in Table 1.

Dose modifications during treatment

No dose reductions are recommended. In case of dose interruption or infusion rate reduction due to IRR, the total duration of the infusion would be increased, but not the total dose.

Delayed or missed doses

If an infusion is missed, it should be administered as soon as possible; administration after a delayed or missed dose should not wait until the next planned dose. The treatment interval of 24 weeks (with a minimum of 5 months) should be maintained between doses (see Table 1).

Special populations

Adults over 55 years old and elderly

Based on the limited data available (see section 5.1 and section 5.2), no dose adjustment is considered necessary in patients over 55 years of age.

Renal impairment

No dose adjustment is expected to be required for patients with renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is expected to be required for patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Briumvi in children and adolescents aged 0 to 18 years have not yet been established. No data are available.

Method of administration

After dilution, Briumvi is administered as an intravenous infusion through a dedicated line. Infusions should not be administered as an intravenous push or bolus.

Table 1 : Dose and schedule

¹Infusion duration may take longer if the infusion is interrupted or slowed.

²The first subsequent infusion should be administered 24 weeks after the first infusion.

Solutions for intravenous infusion are prepared by dilution of the medicinal product into an infusion bag containing sodium chloride 9 mg/ml (0.9%) solution for injection, to a final concentration of 0.6 mg/ml for the first infusion and 1.8 mg/ml for the second infusion and all subsequent infusions.

For instructions on dilution of the medicinal product before administration, see section 6.6.

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

• Severe active infection (see section 4.4).

• Patients in a severely immunocompromised state (see section 4.4).

• Known active malignancies.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infusion-related reactions (IRRs)

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.

Infection

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 post-operative salpingitis following an ectopic pregnancy.

Progressive multifocal leukoencephalopathy (PML)

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.

Hepatitis B virus (HBV) reactivation

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.

Vaccinations

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.

Vaccination of infants born to mothers treated with ublituximab during pregnancy

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).

Sodium

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.

Vaccinations

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).

Immunosuppressants

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

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).

Pregnancy

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.

Breast-feeding

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.

Fertility

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.

Summary of the safety profile

The most important and frequently reported adverse reactions are IRRs (45.3%) and infections (55.8%).

Tabulated list of adverse reactions

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

¹ Symptoms reported as IRRs within 24 hours of the infusion are described below in 'Infusion-related reactions'.

Description of selected adverse reactions

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.

Infection

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.

Laboratory abnormalities

Immunoglobulins decrease

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.

Lymphocytes

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.

Neutrophils counts

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 of suspected adverse reactions

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects, you can help provide more information on the safety of this medicine.

There is limited clinical trial experience in RMS with doses higher than the approved intravenous dose of ublituximab. The highest dose tested to date in RMS patients is 600 mg (Phase II dose finding study in RMS). The adverse reactions were consistent with the safety profile for ublituximab in the pivotal clinical studies.

There is no specific antidote in the event of an overdose; the infusion should be immediately interrupted and the patient should be observed for IRRs (see section 4.4).

Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AG14.

Mechanism of action

Ublituximab is a chimeric monoclonal antibody that selectively targets CD20-expressing cells.

CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells. The binding of ublituximab to CD20 induces lysis of CD20+ B cells primarily through antibody-dependent cell-mediated cytotoxicity (ADCC) and, to a lesser extent through complement-dependent cytotoxicity (CDC). Due to a specific glycosylation pattern of its Fc region, ublituximab displays an increased affinity for the Fcγ RIIIa (CD16) and antibody-dependent cellular cytolysis against B cells.

Pharmacodynamic effects

Treatment with ublituximab leads to rapid depletion of CD19+ cells in blood by the first day post treatment as an expected pharmacologic effect. This was sustained throughout the treatment period. For the B cell counts, CD19 is used, as the presence of ublituximab interferes with the recognition of CD20 by the assay.

In the Phase III studies, treatment with ublituximab resulted in a median reduction of 97% of CD19+ B cell counts from baseline values after the first infusion in both studies and remained depleted at this level for the duration of dosing.

In the Phase III studies, between each dose of ublituximab, 5.5% of patients showed B-cell repletion (> lower limit of normal (LLN) or baseline) at least at one time point.

The longest follow up time after the last ublituximab infusion in the Phase III studies indicates that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was 70 weeks.

Clinical efficacy and safety

Efficacy and safety of ublituximab were evaluated in two randomised, double-blind, double-dummy, active comparator-controlled clinical trials (ULTIMATE I and ULTIMATE II), with identical design, in patients with RMS (in accordance with McDonald criteria 2010) and evidence of disease activity (as defined by clinical or imaging features) within the previous two years. Study design and baseline characteristics of the study population are summarised in Table 3.

Demographic and baseline characteristics were well balanced across the two treatment groups. Patients were to receive either: (1) ublituximab 450 mg plus oral placebo; or (2) teriflunomide 14 mg plus placebo infusion. Oral treatment (active or placebo) was to start on Week 1 Day 1 and treatment was to continue until the last day of Week 95. Infusions (active or placebo) were to begin on Week 1 Day 1 at 150 mg then increase to 450 mg on Week 3 Day 15, and continue at 450 mg on Week 24, Week 48, and Week 72.

Table 3: Study design, demographic and baseline characteristics

*Expanded Disability Status Scale

**Patients who had not been treated with any RMS medication in the 5 years prior to randomization.

Key clinical and MRI efficacy results are presented in Table 4.

The results of these studies show that ublituximab significantly suppressed relapses and sub-clinical disease activity measured by MRI compared with oral teriflunomide 14 mg.

Table 4: Key clinical and MRI endpoints from studies ULTIMATE I and ULTIMATE II

¹Based on Modified Intent to Treat (mITT) Population, defined as all randomised patients who received at least one infusion of study medication and had one baseline and post-baseline efficacy assessment. ULTIMATE I: ublituximab (N=271), teriflunomide (N=274). ULTIMATE II: ublituximab (N=272), teriflunomide (N=272).

² Data prospectively pooled from Study 1 and Study 2: ublituximab (N=543), teriflunomide (N=546).

³Defined 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 or more when the baseline score is greater than 5.5, Kaplan-Meier estimates at Week 96.

⁴Based on Hazard Ratio.

⁵Based on MRI-mITT population (mITT patients who have baseline and post-baseline MRI). ULTIMATE I: ublituximab (N=265), teriflunomide (N=270). ULTIMATE II: ublituximab (N=272), teriflunomide (N=267).

⁶At Week 96.

⁷Nominal p-value.

Immunogenicity

Serum samples from patients with RMS were tested for antibodies to ublituximab during the treatment period. 81% of ublituximab-treated patients tested positive for anti-drug antibodies (ADA) at one or more timepoints during the 96-week treatment period in clinical efficacy and safety trials. ADA was generally transient (at Week 96, 18.5% of patients were positive for ADA). Neutralising activity was detected in 6.4% of ublituximab-treated patients. The presence of ADA or neutralising antibodies had no observable impact on the safety or efficacy of ublituximab.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with ublituximab in one or more subsets of the paediatric population in the treatment of multiple sclerosis (see section 4.2 for information on paediatric use).

In the RMS studies, the pharmacokinetics (PK) of ublituximab following repeated intravenous infusions was described by a two-compartment model with first-order elimination and with PK parameters typical for an IgG1 monoclonal antibody. Ublituximab exposures increased in a dose-proportional manner (i.e., linear pharmacokinetics) over the dose range of 150 to 450 mg in patients with RMS. Administration of 150 mg ublituximab by intravenous infusion on Day 1 followed by 450 mg ublituximab by intravenous infusion over one hour on Day 15, Week 24 and Week 48 led to a geometric mean steady-state AUC of 3000 μ g/ml per day (CV=28%) and a mean maximum concentration of 139 μ g/ml (CV=15%).

Absorption

Ublituximab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.

Distribution

In the population pharmacokinetic analysis of ublituximab, the central volume of distribution was estimated to be 3.18 L and the peripheral volume of distribution was estimated to be 3.6 L.

Biotransformation

The metabolism of ublituximab has not been directly studied, as antibodies are cleared principally by catabolism (i.e. breakdown into peptides and amino acids).

Elimination

Following intravenous infusion of 150 mg ublituximab on Day 1 followed by 450 mg ublituximab on Day 15, Week 24 and Week 48, the mean terminal elimination half-life of ublituximab was estimated to be 22 days.

Special populations

Paediatrics

No studies have been conducted to investigate the pharmacokinetics of ublituximab in children and adolescents < 18 years of age.

Adults over 55 years old

There are no dedicated PK studies of ublituximab in patients ≥ 55 years due to limited clinical experience (see section 4.2).

Renal impairment

No specific studies of ublituximab in patients with renal impairment have been performed.

Patients with mild renal impairment were included in the clinical studies. There is no experience in patients with moderate and severe renal impairment. However, as ublituximab is not excreted via urine, it is not expected that patients with renal impairment require dose modification.

Hepatic impairment

No specific studies of ublituximab in patients with hepatic impairment have been performed.

Since hepatic metabolism of monoclonal antibodies such as ublituximab is negligible, hepatic impairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patients with hepatic impairment require dose modification.

Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies and in vitro mutagenicity studies. Carcinogenicity studies have not been conducted with ublituximab.

In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys were administered weekly intravenous doses of 30 mg/kg ublituximab (corresponding to AUC 26 times the AUC in patients at the maximum recommended dose) during either the first, second or third trimester of pregnancy, which resulted in maternal moribundity and foetal loss. Pathological observations in exposed dams involved multiple organ systems (thrombi in multiple organs, vascular necrosis in the intestine and liver, inflammation and oedema in the lungs and heart) as well as the placenta and these findings were consistent with immune-mediated adverse effects secondary to immunogenicity.

Infant abnormalities were absent in dams exposed during the first trimester of pregnancy. Ublituximab-related external, visceral and skeletal abnormalities were noted in two infants from dams treated during the second trimester of pregnancy. Histopathology evaluations revealed minimal to moderate degeneration/necrosis in the brain. Foetal findings 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. These findings were potentially related to the immunogenic response of ublituximab in the mothers, which affected the placental exchange of nutrients.

The presence of ublituximab in mother's milk was not assessed.

Sodium chloride

Sodium citrate (E331)

Polysorbate 80 (E433)

Hydrochloric acid (for pH adjustment) (E507)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened vial

3 years

Diluted solution for intravenous infusion

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 ° C – 8 ° C and subsequently for 8 hours at room temperature.

From a microbiological point of view, the prepared infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 ° C – 8 ° C and subsequently for 8 hours at room temperature, unless dilution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2 ° C – 8 ° C).

Do not shake or freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6 ml concentrate in a glass vial. Pack size of 1 vial.

Instructions for dilution

Briumvi should be prepared by a healthcare professional using aseptic technique. Do not shake the vial.

The product is intended for single use only.

Do not use the solution if it is discoloured or if it contains foreign particulate matter.

This medicinal product must be diluted before administration. The solution for intravenous administration is prepared by dilution of the product into an infusion bag containing isotonic sodium chloride 9 mg/ml (0.9%) solution for injection.

No incompatibilities between ublituximab and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous administration sets have been observed.

For the first infusion, dilute one vial of product into the infusion bag (150 mg / 250 ml) to a final concentration of approximately 0.6 mg/ml.

For subsequent infusions, dilute three vials of product into the infusion bag (450 mg / 250 ml) to a final concentration of approximately 1.8 mg/ml.

Prior to the start of the intravenous infusion, the content of the infusion bag should be at room temperature (20-25° C).

In case an intravenous infusion cannot be completed the same day, the remaining solution should be discarded.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.