Infections: An increased risk of infections has been observed with other anti-CD20 B-cell depleting therapies.
BONSPRI has the potential for an increased risk of infections, including serious bacterial, fungal, and new or reactivated viral infections; some of these infections have been fatal in patients treated with other anti-CD20 antibodies. In Study 1 and Study 2 [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions], the overall rate of infections and serious infections in patients treated with BONSPRI was similar to patients who were treated with teriflunomide (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common infections reported by BONSPRI-treated patients in the randomized clinical relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay BONSPRI administration in patients with an active infection until the infection is resolved.
Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants: When initiating BONSPRI after an immunosuppressive therapy or initiating an immunosuppressive therapy after BONSPRI, consider the potential for increased immunosuppressive effects [see Interactions and Pharmacology: Pharmacodynamics under Actions]. BONSPRI has not been studied in combination with other MS therapies.
Hepatitis B Virus: Reactivation: There were no reports of HBV reactivation in patients with MS treated with BONSPRI.
However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (CLL) (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment) and in patients treated with other anti-CD20 antibodies.
Infection: BONSPRI is contraindicated in patients with active hepatitis B disease. Fatal infections caused by HBV in patients who have not been previously infected have occurred in patients being treated with ofatumumab for CLL (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). HBV screening should be performed in all patients before initiation of treatment with BONSPRI. At a minimum, screening should include Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with BONSPRI. These patients should be monitored and managed following local medical standards to prevent HBV infection or reactivation.
Progressive Multifocal Leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.
Although no cases of PML have been reported for BONSPRI in the RMS clinical studies, PML resulting in death has occurred in patients being treated with ofatumumab for CLL (at substantially higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). In addition, JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold BONSPRI and perform an appropriate diagnostic evaluation. Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. 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.
If PML is confirmed, treatment with BONSPRI should be discontinued.
Vaccinations: Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of BONSPRI for live or live-attenuated vaccines, and whenever possible, at least 2 weeks prior to initiation of BONSPRI for inactivated vaccines.
BONSPRI may interfere with the effectiveness of inactivated vaccines.
The safety of immunization with live or live-attenuated vaccines following BONSPRI therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion [see Pharmacology: Pharmacodynamics under Actions].
Vaccination of Infants Born to Mothers Treated with BONSPRI During Pregnancy: In infants of mothers treated with BONSPRI during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.
Inactivated 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.
Injection-Related Reactions: In Study 1 and Study 2, systemic and local injection reactions were reported in 21% and 11% of patients treated with BONSPRI compared to 15% and 6% of patients treated with teriflunomide who received matching placebo injections, respectively [see Clinical Trials Experience under Adverse Reactions and Pharmacology: Pharmacodynamics: Clinical Studies under Actions].
Injection-related reactions with systemic symptoms observed in clinical studies occurred most commonly within 24 hours of the first injection, but were also observed with later injections. Symptoms observed included fever, headache, myalgia, chills, and fatigue, and were predominantly (99.8%) mild to moderate in severity. There were no life-threatening injection reactions in the RMS clinical studies.
Local injection-site reaction symptoms observed in clinical studies included erythema, swelling, itching, and pain.
Only limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen was observed in RMS clinical studies. The first injection of BONSPRI should be performed under the guidance of an appropriately trained healthcare professional. If injection-related reactions occur, symptomatic treatment is recommended.
Reduction in Immunoglobulins: As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Decrease in immunoglobulin M (IgM) was reported in 7.7% of patients treated with BONSPRI compared to 3.1% of patients treated with teriflunomide in RMS clinical trials [see Clinical Trials Experience under Adverse Reactions]. Treatment was discontinued because of decreased immunoglobulins in 3.4% of patients treated with BONSPRI and in 0.8% of patients treated with teriflunomide. No decline in immunoglobulin G (IgG) was observed at the end of the study. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing BONSPRI therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.
Fetal Risk: Based on animal data, BONSPRI can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to BONSPRI in utero. 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 while receiving BONSPRI and for at least 6 months after the last dose [see Pregnancy under Use in Pregnancy & Lactation].
Use in Children: Safety and effectiveness in pediatric patients have not been established.
Use in the Elderly: Clinical studies of BONSPRI did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger subjects.