ofatumumab: prescribing information – dosing, contraindications, interactions, side effects

Kesimpta is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features (see section 5.1).

Treatment should be initiated by a physician experienced in the management of neurological conditions.

Posology

The recommended dose is 20 mg ofatumumab administered by subcutaneous injection with:
- initial dosing at weeks 0, 1 and 2, followed by
- subsequent monthly dosing, starting at week 4.

Missed doses
If an injection 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 old. Based on the limited data available, no dose adjustment is considered necessary in patients over 55 years old (see section 5.2).

Renal impairment
Patients with renal impairment are not expected to require dose modification (see section 5.2).

Hepatic impairment
Patients with hepatic impairment are not expected to require dose modification (see section 5.2).

Paediatric population
The safety and efficacy of Kesimpta in children aged 0 to 18 years have not yet been established. No data are available.

Method of administration

This medicinal product 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 should be performed under the guidance of a healthcare professional (see section 4.4).

Comprehensive instructions for administration are provided in the package leaflet.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Patients in a severely immunocompromised state (see section 4.4).
Severe active infection until resolution (see section 4.4).
Known active malignancy.

Summary of the safety profile

The most important and frequently reported adverse reactions are upper respiratory tract infections (39.4%), systemic injection-related reactions (20.6%), local injection-site reactions (10.9%) and urinary tract infections (11.9%) (see section 4.4 and below subsection “Description of selected adverse reactions” for further details).

Tabulated list of adverse reactions

Adverse reactions that have been reported in association with the use of ofatumumab in pivotal RMS clinical studies and from post-marketing experience are listed by MedDRA system organ class in Table 1. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse 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) and not known (cannot be estimated from the available data).

Table 1
Tabulated list of adverse reactions

Infections and infestations
Very common
Upper respiratory tract infections1
Urinary tract infections2
Common
Oral herpes
Immune system disorders
Not known
Hypersensitivity reactions3
Gastrointestinal disorders
Common
Nausea, vomiting4
Hepatobiliary disorders
Common
Hepatic enzymes increased5
General disorders and administration site conditions
Very common
Injection-site reactions (local)
Investigations
Common
Blood immunoglobulin M decreased
Injury, poisoning and procedural complications
Very common
Injection-related reactions (systemic)
1 Grouping of preferred terms (PTs) was considered for ADR frequency determination and includes the following: nasopharyngitis, upper respiratory tract infection, influenza, sinusitis, pharyngitis, rhinitis, viral upper respiratory infection, tonsillitis, acute sinusitis, pharyngotonsillitis, laryngitis, pharyngitis streptococcal, viral rhinitis, sinusitis bacterial, tonsillitis bacterial, viral pharyngitis, viral tonsillitis, chronic sinusitis, nasal herpes, tracheitis.
2 Grouping of preferred terms (PTs) was considered for ADR frequency determination and includes the following: urinary tract infection, cystitis, escherichia urinary tract infection, asymptomatic bacteriuria, bacteriuria.
3 Reported during post-marketing experience (see section 4.4).
4 Nausea and vomiting have been reported in association with systemic injection-related reactions (see below and section 4.4) 5 Grouping of PTs was considered for ADR frequency determination and includes the following: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzymes increased, transaminases increased, liver function test increased, hepatic function abnormal, liver function test abnormal

Description of selected adverse reactions

Infections
In the RMS phase III clinical studies, the overall rate of infections and serious infections in patients treated with ofatumumab was similar to patients who were treated with teriflunomide (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). Two patients (0.2%) discontinued and 11 patients (1.2%) temporarily interrupted study treatment due to a serious infection.

Upper respiratory tract infections
In these 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.

Systemic injection-related reactions
In the RMS phase III clinical studies, SIRRs were reported in 20.6% of patients treated with ofatumumab.

The incidence of SIRRs was highest with the first injection (14.4%), decreasing significantly with subsequent injections (4.4% with second, <3% from third injection). SIRRs were mostly (99.8%) mild to moderate in severity. Two (0.2%) ofatumumab-treated MS patients reported serious injection-related reactions but not life-threatening. The most frequently reported symptoms (≥2%) included fever, headache, myalgia, chills and fatigue. Additional reported symptoms included nausea (1.7%) and vomiting (0.6%).

Local injection-site reactions
In the RMS phase III clinical studies, local injection-site reactions were reported in 10.9% of patients treated with ofatumumab.

Local injection-site reactions were very common. They were all mild to moderate in severity and non- serious in nature. The most frequently reported symptoms (≥2%) included erythema, pain, itching and swelling.

Laboratory abnormalities
Immunoglobulins
During the course of the RMS phase III clinical studies, decrease in mean value of immunoglobulin M (IgM) (30.9% decrease after 48 weeks and 38.8% decrease after 96 weeks) was observed and no association with risk of infections, including serious infections, was shown.

In 14.3% of patients, treatment with ofatumumab resulted in a decrease in IgM that reached a value below 0.34 g/l.

Ofatumumab was associated with a transient decrease of 4.3% in mean IgG levels after 48 weeks of treatment but an increase of 2.2% after 96 weeks.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Systemic injection-related reactions

Patients should be informed that systemic injection-related reactions (SIRRs) could occur, generally within 24 hours and predominantly following the first injection (see section 4.8). Symptoms most frequently observed in RMS clinical studies include fever, headache, myalgia, chills, fatigue, nausea and vomiting and were predominantly (99.8%) mild to moderate in severity. There were no life- threatening SIRRs reported in RMS clinical studies (see section 4.8).

Additional SIRRs reported in the post-marketing setting include rash, urticaria, dyspnoea and angioedema (e.g. tongue, pharyngeal or laryngeal swelling), and rare cases which were reported as anaphylaxis. While there were some cases which were serious and resulted in discontinuation of ofatumumab treatment, there were also serious cases where patients were able to continue ofatumumab treatment without further incidents.

Some SIRR symptoms may be clinically indistinguishable from Type 1 acute hypersensitivity reactions (IgE-mediated). A hypersensitivity reaction may present during any injection, although typically would not present with the first injection. For subsequent injections, more severe symptoms than previously experienced, or new severe symptoms, should prompt consideration of a potential hypersensitivity reaction. Patients with known IgE-mediated hypersensitivity to ofatumumab must not be treated with ofatumumab (see section 4.3).

Only limited benefit of premedication with steroids was seen in RMS clinical studies. Injection-related reactions can be managed with symptomatic treatment, should they occur. Therefore, use of premedication is not required.

The first injection should be performed under the guidance of an appropriately trained healthcare professional (see section 4.2).

Local injection-site reactions

Local injection-site reaction symptoms observed in clinical studies included erythema, swelling, itching and pain (see section 4.8).

Infections

It is recommended to evaluate the patient’s immune status prior to initiating therapy.

Based on its mode of action and available clinical experience, ofatumumab has the potential for an increased risk of infections (see section 4.8).

Administration should be delayed in patients with an active infection until the infection is resolved.

Ofatumumab must not be given to patients in a severely immunocompromised state (e.g. significant neutropenia or lymphopenia).

Progressive multifocal leukoencephalopathy
Since John Cunningham (JC) virus infection resulting in progressive multifocal leukoencephalopathy (PML) has been observed in patients treated with anti-CD20 antibodies, other MS therapies, and ofatumumab at substantially higher doses in oncology indications, physicians should be vigilant for medical history of PML and for any clinical symptoms or MRI findings that may be suggestive of PML. If PML is suspected, treatment with ofatumumab should be suspended until PML has been excluded.

Hepatitis B virus reactivation
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 ofatumumab. HBV screening should be performed in all patients before initiation of treatment. 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.

Treatment of severely immunocompromised patients

Patients in a severely immunocompromised state must not be treated until the condition resolves (see section 4.3).

It is not recommended to use other immunosuppressants concomitantly with ofatumumab except corticosteroids for symptomatic treatment of relapses.

Vaccinations

All immunisations should be administered according to immunisation guidelines at least 4 weeks prior to initiation of ofatumumab for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ofatumumab for inactivated vaccines.

Ofatumumab may interfere with the effectiveness of inactivated vaccines.

The safety of immunisation with live or live-attenuated vaccines following ofatumumab 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 4.5). The median time to B-cell recovery to the lower limit of normal (LLN, defined as 40 cells/µl) or baseline value is 24.6 weeks post treatment discontinuation based on data from phase III studies (see section 5.1).

Vaccination of infants born to mothers treated with ofatumumab during pregnancy
In infants of mothers treated with ofatumumab during pregnancy live or live-attenuated vaccines should not be administered before it has been confirmed that the B-cell count is within normal range.
Depletion of B cells in these infants may increase the risks from live or live-attenuated vaccines.

Inactivated vaccines may be administered as indicated before it has been confirmed that the B-cell count is within normal range, 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).

Excipients with known effect

Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Polysorbates
This medicinal product contains 0.08 mg of polysorbate 80 per dose. Polysorbates may cause allergic reactions.

No interaction studies have been performed, as no interactions are expected via cytochrome P450 enzymes, other metabolising enzymes or transporters.

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 ofatumumab 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 ofatumumab.

When initiating ofatumumab after other immunosuppressive therapies with prolonged immune effects or initiating other immunosuppressive therapies with prolonged immune effects after ofatumumab, the duration and mode of action of these medicinal products should be taken into account because of potential additive immunosuppressive effects (see section 5.1).

Women of childbearing potential

Women of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving Kesimpta and for 2 months after the last administration of Kesimpta.

Pregnancy

Data from approximately 400 prospective reports of pregnancies with known outcomes following exposure to ofatumumab during the pre-conception period and/or during the first trimester of pregnancy, do not suggest an increased risk of adverse pregnancy outcomes, including major congenital malformations and foetal/neonatal toxicity; however, the available data are insufficient to draw firm conclusions. Experience with administration during the second and third trimesters of pregnancy is limited.

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 observed 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).

Treatment with ofatumumab should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus.

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 2 months after the last dose of ofatumumab to the marketing authorisation holder, in order to allow monitoring of the outcomes of these pregnancies through the PRegnancy outcomes Intensive Monitoring programme (PRIM). In addition, all adverse pregnancy events should be reported via the national reporting system listed in Appendix V.

Lactation

There are limited data on the use of ofatumumab in women during lactation. There are no data on the effects of ofatumumab on milk production. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards.
Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts.

An observational study reported that concentration of ofatumumab in breast milk was generally low, with Cavg and Cmax of less than 0.02 μg/ml in the breast milk of treated lactating women.

In the same observational study, five infants with available B cells had normal levels. Eight infants received live vaccines during/after exposure during breast-feeding with no complications. Infants (up to 24 months of age) did not show abnormalities in infections, antibiotic use, hospitalisations or developmental delays.

Consequently, a risk to the breast-fed child cannot be excluded during the first few days after birth.
Afterwards, ofatumumab could be used during breast-feeding if clinically needed. However, if the patient was treated with ofatumumab up to the last few months of pregnancy, breast-feeding can be started immediately after birth.

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.

Kesimpta has no or negligible influence on the ability to drive and use machines.

Doses up to 700 mg have been administered 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.

Ofatumumab has been previously used in chronic lymphocytic leukaemia (CLL) indications, at doses up to 2 000 mg administered intravenously via infusion. Ofatumumab administered via subcutaneous injection has not been assessed and is not approved for these indications, and must not be used for the treatment of oncology indications.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: immunosuppressants, monoclonal antibodies, ATC code: L04AG12

Mechanism of action

Ofatumumab is a fully human anti-CD20 monoclonal immunoglobulin G1 (IgG1) antibody. The CD20 molecule is a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature B lymphocyte stage. The CD20 molecule is also expressed on a small fraction of activated T cells. A subcutaneous route of administration of ofatumumab and subsequent release/absorption from the tissue allows a gradual interaction with B cells.

The binding of ofatumumab to CD20 induces lysis of CD20+ B cells primarily through complement- dependent cytotoxicity (CDC) and, to a lesser extent, through antibody-dependent cell-mediated cytotoxicity (ADCC). Ofatumumab has also been shown to induce cell lysis in both high and low CD20 expressing cells. CD20-expressing T cells are also depleted by ofatumumab.

Pharmacodynamic effects

B-cell depletion
In the RMS clinical studies using ofatumumab 20 mg every 4 weeks, after an initial dose regimen of 20 mg on days 1, 7, and 14, administration resulted in a rapid and sustained reduction of B cells to below LLN (defined as 40 cells/µl) as early as two weeks after treatment initiation. Before initiation of the maintenance phase starting at week 4, total B-cell levels of <10 cells/µl were reached in 94% of patients, increasing to 98% of patients at week 12, and were sustained for as long as 120 weeks (i.e.
while on study treatment).

B-cell repletion
Data from RMS phase III clinical studies indicate a median time to B-cell recovery to LLN or baseline value of 24.6 weeks post treatment discontinuation. PK-B cell modelling and simulation for B-cell repletion corroborate this data, predicting median time to B-cell recovery to LLN of 23 weeks post treatment discontinuation.

Immunogenicity
In RMS phase III studies, the overall incidence of treatment-induced anti-drug antibodies (ADAs) was 0.2% (2 of 914) in ofatumumab-treated patients and no patients with treatment enhancing or neutralising ADA were identified. The impact of positive ADA titers on PK, safety profile or B-cell kinetics cannot be assessed given the low incidence of ADA associated with ofatumumab.

Clinical efficacy and safety

The efficacy and safety of ofatumumab were evaluated in two randomised, double-blind, active- controlled phase III pivotal studies of identical design (Study 1 [ASCLEPIOS I] and Study 2 [ASCLEPIOS II]) in patients with relapsing forms of MS (RMS) aged 18 to 55 years, a disability status at screening with an Expanded Disability Status Scale (EDSS) score from 0 to 5.5, and who had experienced at least one documented relapse during the previous year or two relapses during the previous two years or positive gadolinium (Gd)-enhancing MRI scan during the previous year. Both newly diagnosed patients and patients switching from their current treatment were enrolled.

Absorption

After subcutaneous administration, ofatumumab has a prolonged release/absorption profile (Tmax of 4.3 days) and is predominantly absorbed via the lymphatic system.

A monthly subcutaneous dose of 20 mg leads to a mean AUCtau of 483 µg*h/ml and a mean Cmax of 1.43 µg/ml at steady state.

Distribution

The volume of distribution at steady state was estimated to be 5.42 litres following repeated subcutaneous administration of ofatumumab at a dose of 20 mg.

Biotransformation

Ofatumumab is a protein for which the expected metabolic pathway is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes.

Elimination

Ofatumumab is eliminated in two ways: a target-mediated route that is related to binding to B cells and a target-independent route mediated by non-specific endocytosis followed by intracellular catabolism, as with other IgG molecules. B cells present at baseline result in a greater component of target-mediated clearance of ofatumumab at the start of therapy. Ofatumumab dosing leads to potent depletion of B cells resulting in reduced overall clearance.

The half-life at steady state was estimated to be approximately 11 days following repeated subcutaneous administration of ofatumumab at a dose of 20 mg.

Linearity/non-linearity

Ofatumumab had non-linear pharmacokinetics related to its decreasing clearance over time.

Special populations

Adults over 55 years old
There are no dedicated pharmacokinetic studies of ofatumumab in patients over 55 years old due to limited clinical experience (see section 4.2).

Paediatric population
No studies have been conducted to investigate the pharmacokinetics of ofatumumab in paediatric patients below the age of 18 years.

Gender