Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Novartis South Africa (Pty) Ltd., Magwa Crescent West, Waterfall City, Jukskei View, Johannesburg, 2090
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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.
It is recommended to evaluate the patient’s 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.
It is not recommended to use other immunosuppressants concomitantly with ofatumumab except corticosteroids for symptomatic treatment of relapses.
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.
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.
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).
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.
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).
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 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.
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).
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 mother’s clinical need for BONSPRI and any potential adverse effects on the breast-fed newborn/infant from BONSPRI.
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.
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.
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 (≥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).
Table 1. Tabulated list of adverse reactions in Study G2301 and Study G23021:
| Adverse drug reactions | Ofatumumab 20 mg N=946 % | Teriflunomide 14 mg N=936 % | Frequency category |
|---|---|---|---|
| Infections and infestations | |||
| Upper respiratory tract infection2 | 39,4 | 37,8 | Very common |
| General disorders and administration site conditions | |||
| Injection site reactions (local) | 10,9 | 5,63 | Very common |
| Injury, poisoning and procedural complications | |||
| Injection related reactions (systemic) | 20,6 | 15,33 | Very common |
1 Pooled data from treatment epochs of G2301 and G2302 (safety set)
2 Grouping of preferred terms (PTs) was considered for ADR frequency determination
3 Teriflunomide group received matching placebo injections
A higher proportion of ofatumumab-treated patients experienced upper respiratory tract infections compared to teriflunomide-treated patients. In the RMS clinical studies, 39,4% of ofatumumab-treated patients experienced upper respiratory tract infections compared to 37,8% of teriflunomide-treated patients. The infections were predominantly mild to moderate and mostly consisted of nasopharyngitis, upper respiratory tract infection and influenza.
In the RMS phase III clinical studies, injection-related reactions (systemic) and injection-site reactions (local) were reported in 20,6% and 10,9% of patients treated with ofatumumab, respectively.
The incidence of injection-related reactions was highest with the first injection (14,4%), decreasing significantly with subsequent injections (4,4% with second, <3% from third injection). Injection-related reactions were mostly (99,8%) mild to moderate in severity. Only two (0,2%) ofatumumab-treated MS patients reported serious injection-related reactions. There were no life-threatening injection-related reactions. The most frequently reported symptoms (≥2%) included fever, headache, myalgia, chills and fatigue.
Local reactions at the administration site were very common. Injection-site reactions were all mild to moderate in severity and non-serious in nature. The most frequently reported symptoms (≥2%) included erythema, pain, itching and swelling (see section 4.4).
During the course of the RMS phase III clinical studies, decrease in mean value of immunoglobulin M (IgM) was observed and was not associated with risk of infections, including serious infections.
In 14,3% of patients in RMS phase III clinical studies, treatment with BONSPRI resulted in a decrease in IgM that reached a value below 0,34 g/dl.
There was no decrease in mean values of immunoglobulin G (IgG).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
In the absence of compatibility studies, this medicine must not be mixed with other medicines.
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