Study: Biosimilar of Rituxan Safe in Children

Natalia Riva

A large prospective study of the use of Rituxan (rituximab) and a biosimilar called Novex in pediatric patients across multiple disease types and transplantations has demonstrated safety in comparison with Rituxan use in adults, according to a study by lead author Natalia Riva, Ph.D., of the Hospital de Pediatria JP Garrahan in Buenos Aires, Argentina, and her co-investigators.

“The results of this study … provide evidence that biosimilar rituximab is safe in children with a range of complex diseases,” Riva and her co-authors wrote.

They said the study was prompted by an urgent need for elucidation of the safety of Rituxan and its biosimilars in pediatric patients, owing to a paucity of prior studies for this population.

The most common problems with Rituxan are adverse drug reactions such as hypersensitivity, which are the direct action of the drug on the immune system and its ability to provoke an immune response. Among those hypersensitivity reactions are infusion-related reactions (IRR), which are generally limited to a patient’s first exposure to rituximab.

The study has some important limitation. It was conducted at a single , Hospital de Pediatria JP Garrahan. Moreover, patients were not randomized to Rituxan and Novex; rather, data were collected d as patients received either the innovator drug or biosimilar based on health plan preference or hospital policy.

Significantly more patients received Novex than Rituxan. The biosimilar form of Rituxan was administered in 83% of infusion cycles, and one-third of administrations were first infusions.

Investigators enrolled patients (N = 77) younger than 19 (average 11.8 years) from March 2019 to February 2020. Chief disease categories for which patients were treated were neurological (n = 19), immune-hematologicrheumatic (n = 24), solid organ transplantation (n = 20), and oncologic-hematopoietic stem cell transplantation (n = 14).

Adverse drug reactions were defined as any harmful event believed to be caused by rituximab, including hypersensitivity and delayed adverse drug reactions.

Riva and her colleagues found that the most common adverse drug reactions were, in order of frequency, hypogammaglobulinemia, febrile neutropenia, thrombocytopenia, anemia and neutropenia; and the most common symptoms were rash, dyspnea, tachycardia, tachypnea, hypertension, fever and sore throat. They tallied a total of 87 adverse drug reactions, which affected 48 of the 77 patients included in the study.

“No difference was observed in the proportion of infusions with IRR severe IRR, dADR (delayed adverse drug reaction), and severe dADR when comparing innovator and biosimilar rituximab,” Riva and her colleagues said. But they qualified the statement, noting the relatively small number of people who were treated with Rituxan. There were 187 total infusions, and just 32 of those were for Rituxan.

Rituximab IRR occurred in 35.1% of patients, and 92.6% of patients with IRR experienced just one IRR. “Interestingly, 69% of the IRR developed during the first rituximab infusion compared to only 7% in subsequent infusions,” Riva wrote. The IRR were group were grouped into moderate, mild and severe categories, based on World Health Organization criteria. Most (79.3%) were in the moderate category.

In all but two patients, IRR was dealt with successfully by stopping and restarting infusion at a slower rate. The two severe cases (pruritic morbilliform rash, anaphylactic shock) resulted in complete stoppage of rituximab treatment.

The skin was the main organ system affected by IRR, with 27.8% of IRR (15/54) among the study population. The most common IRRs, however, were respiratory and chest symptoms (29.6%).

Investigators said adverse drug reactions (n = 58) developed in 23% of infusions and in 37.7% of patients at a median of seven days following rituximab administration. Patients with cancer (63.8%) were commonly affected by adverse drug reactions. Hypogammaglobulinemia accounted for 37.9% of delayed adverse drug reactions, occurring in 28.6% of patients (22/77).

“The incidence of rituximab-related ADRs (adverse drug reactions)was as expected based on previous studies evaluating the use of innovator rituximab in children and adults,” Riva and her co-authors wrote.

Riva and her colleagues pointed out that note all but one of patients in study population received rituximab as an off-label prescription for more than 20 different indications. “This shows the widespread use of rituximab in children with rare diseases and highlights the key role of active pharmacovigilance in special populations with off-label prescriptions of rituximab and limited reports,” Riva said.

The high proportion of IRR that developed during first infusion indicates that it is important to rigorously monitor the use of monoclonal antibodies in pediatric patients, “especially at first administration,” she wrote.

The first rituximab infusion and a diagnosis of a neurological condition or animmune-hematologic-rheumatic one were positively correlated with occurrence of IRR. For pediatric patients in the study, those with either a neurologic or immune-hematologic-rheumatic diagnosis had a 133% higher risk of IRR than people with conditions. This may have been due to differences in rituximab doses and absolute lymphocyte counts between groups.

Further, boys had a 66% lower risk of developing IRR than girls. The reason may be that boys clear rituximab from the body at a faster rate than girls.

“Our study has the advantage of reflecting real-world clinical practice at a pediatric tertiary referral hospital and the results are supportive of the use of Novex in children,” Riva concluded.