Bonspri 20mg Injection

BONSPRI is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS).

Posology
The recommended dose is 20 mg BONSPRI administered by subcutaneous injection with:
u2022 initial dosing at weeks 0, 1 and 2, followed by
u2022 subsequent monthly dosing, starting at week 4.
Missed Doses
If an injection of BONSPRI is missed, it should be administered as soon as possible without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals.
Special populations
Adults over 55 years old
No studies have been performed in MS patients over 55 years. Based on the limited data available, no dose adjustment is considered necessary in patients over 55 years old (see section 5.2). Patients enrolled in the ongoing clinical trials continue to be dosed with 20 mg ofatumumab monthly after they reach the age of 55.
Renal impairment
No specific studies of ofatumumab in patients with renal impairment have been performed. Patients with mild renal impairment were included in clinical studies. There is no experience in patients with moderate and severe renal impairment. However, as ofatumumab is not excreted via urine it is not expected that patients with renal impairment require dose modification (see section 5.2).
Hepatic impairment
No studies of ofatumumab in patients with hepatic impairment have been performed. Since hepatic metabolism of monoclonal antibodies such as ofatumumab is negligible, hepatic impairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patients with hepatic impairment require dose modification (see section 5.2).
Paediatric population
The safety and efficacy in paediatric MS patients below the age of 18 years have not yet been established. No data are available.
Method of administration
BONSPRI is intended for patient self-administration by subcutaneous injection. The usual sites for subcutaneous injections are the abdomen, the thigh and the upper outer arm. The first injection of BONSPRI should be performed under the guidance of a healthcare professional (see section 4.4). Comprehensive instructions for administration are provided in the PATIENT INFORMATION LEAFLET u201cInstructions for use of BONSPRI pre-filled syringe.u201d

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

Injection-related reactions
Injection site reaction (local) symptoms observed in clinical studies included erythema, swelling, itching and pain. Systemic injection-related reactions observed in clinical studies occurred predominantly with the first injection. Symptoms observed include fever, headache, myalgia, chills and fatigue and were predominantly (99,7 %) non-serious and mild to moderate in severity. There were no life-threatening injection reactions in RMS clinical studies. Patients should be informed that injection-related reactions generally occur within 24 hours and predominantly following the first injection. Injection-related reactions can be managed with symptomatic treatment, should they occur. Only limited benefit of premedication with steroids, antihistamines, or paracetamol was seen in RMS clinical studies. Ofatumumab-treated patients who received premedication with methylprednisolone (or an equivalent steroid) experienced fewer symptoms such as fever, myalgia, chills and nausea. However, the use of steroid premedication increased the occurrence of flushing, chest discomfort, hypertension, tachycardia and abdominal pain even in the absence of ofatumumab treatment (i.e. in patients receiving placebo injections). Therefore, use of premedication is not required. The first injection of BONSPRI should be performed under the guidance of an appropriately trained healthcare professional.
Infections
It is recommended to evaluate the patientu2019s immune status prior to initiating therapy. Based on its mode of action, ofatumumab has the potential for an increased risk of infections. Administration should be delayed in patients with an active infection until the infection is resolved. Ofatumumab should not be given to patients in a severely immunocompromised state until the condition is resolved. In RMS clinical studies, the proportion of patients with infections was similar in the ofatumumab and the teriflunomide treatment groups. In the phase III pivotal clinical studies, 51,6 % of ofatumumab treated patients experienced at least one infection, compared to 52,7 % of teriflunomide treated patients.
Treatment of severely immunocompromised patients
It is not recommended to use other immunosuppressants concomitantly with ofatumumab except corticosteroids for symptomatic treatment of relapses.
Progressive multifocal leukoencephalopathy
No cases of progressive multifocal leukoencephalopathy (PML) have been reported for ofatumumab in the RMS clinical studies. However, since John Cunningham (JC) virus infection resulting in PML has been observed in patients treated with anti CD20 antibodies and other MS therapies, physicians should be vigilant for any clinical symptoms or MRI findings that may be suggestive of PML. If PML is suspected, treatment with BONSPRI should be suspended until PML has been excluded.
Hepatitis B virus reactivation
No cases of hepatitis B virus (HBV) reactivation were identified in BONSPRI RMS clinical studies. However, hepatitis B reactivation has occurred in patients treated with anti CD20 antibodies, which in some cases resulted in fulminant hepatitis, hepatic failure and death. Patients with active hepatitis B disease should not be treated with BONSPRI. HBV screening should be performed in all patients before initiation of treatment with BONSPRI. As 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. Patients with positive hepatitis B serology (either HBsAg or HBcAb) should consult a liver disease expert before the start of treatment and should be monitored and managed following local medical standards to prevent hepatitis B reactivation.
Vaccinations
All immunisations should be administered according to immunisation 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 immunisation 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 section 5.1). Vaccination of infants born to mothers treated with BONSPRI during pregnancy: In infants of mothers treated with BONSPRI 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 from live or live attenuated vaccines. 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 (see section 4.6).

Ofatumumab does not share a common clearance pathway with medicines that are metabolised by the cytochrome P450 system or other medicine metabolising enzymes. Additionally, there is no evidence that CD20 monoclonal antibodies (mAbs) are involved in the regulation of the expression of drug metabolising enzymes. Interactions between BONSPRI and other medicinal products have not been investigated in formal studies.
Vaccinations
The safety of and the ability to generate a primary or anamnestic (recall) response to immunisation with live, live-attenuated or inactivated vaccines during ofatumumab treatment has not been investigated. The response to vaccination could be impaired when B cells are depleted. It is recommended that patients complete immunisations prior to the start of BONSPRI therapy (see section 4.4).
Other immunosuppressive or immune-modulating therapies
The risk of additive immune system effects should be considered when co-administering immunosuppressive therapies with BONSPRI. When switching from medicinal products with prolonged immune effects, such as ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone or dimethyl fumarate, the duration and mode of action of these medicinal products should be taken into account because of potential additive immunosuppressive effects when initiating BONSPRI.

Women of childbearing potential / contraception in males and females
Women of childbearing potential should use effective contraception (methods that result in less than 1 % pregnancy rates) while receiving BONSPRI and for 6 months after the last administration of BONSPRI.
Pregnancy
There is a limited amount of data from the use of ofatumumab in pregnant women. Ofatumumab may cross the placenta and cause foetal B-cell depletion based on findings from animal studies (see section 5.3). No teratogenicity was observed after intravenous administration of ofatumumab to pregnant monkeys during organogenesis. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown (see sections 4.4 and 5.1). To help determine the effects of ofatumumab in pregnant women, healthcare professionals are encouraged to report all pregnancy cases and complications that happen during treatment or within 6 months after the last dose of BONSPRI to the marketing authorisation holder, in order to allow monitoring of these patients through the PRegnancy outcomes Intensive Monitoring program (PRIM).
Breastfeeding
The use of ofatumumab in women during lactation has not been studied. It is unknown whether ofatumumab is transferred into human milk; however, human IgG is present in human milk. There are no data on the effects of BONSPRI on the breast-fed newborn/infant or on milk production. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The developmental and health benefits of breast-feeding should be considered along with the motheru2019s clinical need for BONSPRI and any potential adverse effects on the breast-fed newborn/infant from BONSPRI.
Fertility
There are no data on the effect of ofatumumab on human fertility. Non-clinical data did not indicate potential hazards for humans based on male and female fertility parameters assessed in monkeys.

BONSPRI is expected to have no or negligible influence on the ability to drive and use machines.

Summary of the safety profile
Approximately 1 500 patients with RMS received ofatumumab in clinical studies. In the two phase III pivotal studies, 1 882 patients with RMS were randomised, 946 of whom were treated with ofatumumab for a median duration of 85 weeks; 33 % of patients receiving ofatumumab were treated for more than 96 weeks (see section 5.1). The proportion of patients with adverse events (AEs) (83,6 % vs 84,2 %) and the AEs leading to drug discontinuation (5,7 % vs 5,2 %) were similar in the ofatumumab and teriflunomide groups.
Tabulated list of adverse reactions
Adverse drug reactions (ADRs) that have been reported in association with the use of ofatumumab in pivotal RMS clinical studies are listed by MedDRA system organ class in Table 1. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (u22651/10); common (u22651/100 to <1/10); uncommon (u22651/1,000 to <1/100); rare (u22651/10,000 to <1/1,000); very rare (<1/10,000).

No cases of overdose have been reported in RMS clinical studies. Doses up to 700 mg have been administered intravenously in clinical studies with MS patients without dose-limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted as necessary.