Ublituximab

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.

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.

Ublituximab 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.

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.

Fertility

Preclinical data reveal no special hazard on reproductive organs based on studies of general toxicity in cynomolgus monkeys.

Ublituximab 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

The table below 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.

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.