4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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.

4.3. Contraindications

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.

4.4. Special warnings and precautions for use

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.

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.

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

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

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 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).

Sodium content

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

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

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 6 months after the last administration of Kesimpta.

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).

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 6 months after the last dose of ofatumumab to the local representative of the marketing authorisation holder, in order to allow monitoring of these patients through the PRegnancy outcomes Intensive Monitoring programme (PRIM). In addition, all adverse pregnancy events should be reported via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Lactation

The use of ofatumumab in women during lactation has not been studied. It is unknown whether ofatumumab is excreted in human milk. In humans, excretion of IgG antibodies in milk occurs during the first few days after birth, which is decreasing to low concentrations soon afterwards. Consequently, a risk to the breast-fed child cannot be excluded during this short period. 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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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%), 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

General disorders and administration site conditions

Very common

Injection-site reactions (local)

Injury, poisoning and procedural complications

Very common

Injection-related reactions (systemic)

Gastrointestinal disorders

Common

Nausea, vomiting4

Investigations

Common

Blood immunoglobulin M decreased

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)

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.

Injection-related reactions

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

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. 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%).

Injection-site reactions

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

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.

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 immunoglobulin G (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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.