KESIMPTA 20mg 50mg / ml solution for injection in pre-filled pen medication leaflet

Kesimpta 20 mg solution for injection in pre-filled syringe

Kesimpta 20 mg solution for injection in pre-filled pen

Kesimpta 20 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 20 mg ofatumumab in 0.4 ml solution (50 mg/ml).

Kesimpta 20 mg solution for injection in pre-filled pen

Each pre-filled pen contains 20 mg ofatumumab in 0.4 ml solution (50 mg/ml).

Ofatumumab is a fully human monoclonal antibody produced in a murine cell line (NS0) byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Solution for injection (injection) in pre-filled pen (Sensoready Pen)

The solution is clear to slightly opalescent, and colourless to slightly brownish-yellow.

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 neurologicalconditions.

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.

If an injection is missed, it should be administered as soon as possible without waiting until the nextscheduled dose. Subsequent doses should be administered at the recommended intervals.

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).

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

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

The safety and efficacy of Kesimpta in children aged 0 to 18 years have not yet been established. Nodata are available.

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 (seesection 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.

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

Systemic injection-related reactions

Patients should be informed that systemic injection-related reactions (SIRRs) could occur, generallywithin 24 hours and predominantly following the first injection (see section 4.8). Symptoms mostfrequently observed in RMS clinical studies include fever, headache, myalgia, chills, fatigue, nauseaand 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 andangioedema (e.g. tongue, pharyngeal or laryngeal swelling), and rare cases which were reported asanaphylaxis. While there were some cases which were serious and resulted in discontinuation ofofatumumab treatment, there were also serious cases where patients were able to continueofatumumab treatment without further incidents.

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

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

The first injection should be performed under the guidance of an appropriately trained healthcareprofessional (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).

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 anincreased 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. significantneutropenia or lymphopenia).

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, andofatumumab at substantially higher doses in oncology indications, physicians should be vigilant formedical 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 beenexcluded.

Hepatitis B reactivation has occurred in patients treated with anti-CD20 antibodies, which in somecases resulted in fulminant hepatitis, hepatic failure and death.

Patients with active hepatitis B disease should not be treated with ofatumumab. HBV screening shouldbe performed in all patients before initiation of treatment. As a minimum, screening should includehepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing. These can becomplemented 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 oftreatment 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 (seesection 4.3).

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

All immunisations should be administered according to immunisation guidelines at least 4 weeks priorto initiation of ofatumumab for live or live-attenuated vaccines and, whenever possible, at least2 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 hasnot been studied. Vaccination with live or live-attenuated vaccines is not recommended duringtreatment and after discontinuation until B-cell repletion (see section 4.5). The median time to B-cellrecovery to the lower limit of normal (LLN, defined as 40 cells/µl) or baseline value is 24.6 weekspost 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 vaccinesshould not be administered before the recovery of B-cell counts has been confirmed. Depletion of Bcells 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 (seesection 4.6).

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 allergicreactions.

No interaction studies have been performed, as no interactions are expected via cytochrome P450enzymes, other metabolising enzymes or transporters.

The safety of and the ability to generate a primary or anamnestic (recall) response to immunisationwith live, live-attenuated or inactivated vaccines during ofatumumab treatment has not beeninvestigated. The response to vaccination could be impaired when B cells are depleted. It isrecommended that patients complete immunisations prior to the start of ofatumumab therapy (seesection 4.4).

Other immunosuppressive or immune-modulating therapies

The risk of additive immune system effects should be considered when co-administeringimmunosuppressive therapies with ofatumumab.

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

Women of childbearing potential should use effective contraception (methods that result in less than1% pregnancy rates) while receiving Kesimpta and for 6 months after the last administration of

Kesimpta.

There is a limited amount of data from the use of ofatumumab in pregnant women. Ofatumumab maycross the placenta and cause foetal B-cell depletion based on findings from animal studies (seesection 5.3). No teratogenicity was observed after intravenous administration of ofatumumab topregnant monkeys during organogenesis.

Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born tomothers exposed to other anti-CD20 antibodies during pregnancy. The potential duration of B-celldepletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safetyand 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 themother outweighs the potential risk to the foetus.

To help determine the effects of ofatumumab in pregnant women, healthcare professionals areencouraged to report all pregnancy cases and complications that happen during treatment or within6 months after the last dose of ofatumumab to the local representative of the marketing authorisationholder, 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 thenational reporting system listed in Appendix V.

The use of ofatumumab in women during lactation has not been studied. It is unknown whetherofatumumab is excreted in human milk. In humans, excretion of IgG antibodies in milk occurs duringthe 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 wastreated with ofatumumab up to the last few months of pregnancy, breast-feeding can be startedimmediately after birth.

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 fertilityparameters assessed in monkeys.

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

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%) andurinary tract infections (11.9%) (see section 4.4 and below subsection “Description of selected adversereactions” for further details).

Adverse reactions that have been reported in association with the use of ofatumumab in pivotal RMSclinical 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 mostfrequent reactions first. Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness. In addition, the corresponding frequency category for each adverse reaction isbased 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 beestimated from the available data).

Table 1 Tabulated list of adverse reactions

Very common Upper respiratory tract infections1

Urinary tract infections2

Common Oral herpes

Not known Hypersensitivity reactions3

Common Nausea, vomiting4

Very common Injection-site reactions (local)

Common Blood immunoglobulin M decreased

Very common Injection-related reactions (systemic)1 Grouping of preferred terms (PTs) was considered for ADR frequency determination and includes thefollowing: nasopharyngitis, upper respiratory tract infection, influenza, sinusitis, pharyngitis, rhinitis, viralupper respiratory infection, tonsillitis, acute sinusitis, pharyngotonsillitis, laryngitis, pharyngitisstreptococcal, viral rhinitis, sinusitis bacterial, tonsillitis bacterial, viral pharyngitis, viral tonsillitis, chronicsinusitis, nasal herpes, tracheitis.2 Grouping of preferred terms (PTs) was considered for ADR frequency determination and includes thefollowing: 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 (seebelow and section 4.4)

In the RMS phase III clinical studies, the overall rate of infections and serious infections in patientstreated with ofatumumab was similar to patients who were treated with teriflunomide (51.6% vs52.7%, 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 infectionscompared to 37.8% of teriflunomide-treated patients. The infections were predominantly mild tomoderate 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 withofatumumab.

The incidence of SIRRs was highest with the first injection (14.4%), decreasing significantly withsubsequent injections (4.4% with second, <3% from third injection). SIRRs were mostly (99.8%) mildto moderate in severity. Two (0.2%) ofatumumab-treated MS patients reported seriousinjection-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 patientstreated 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 andswelling.

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 noassociation 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 valuebelow 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses up to 700 mg have been administered in clinical studies with MS patients without dose-limitingtoxicity. In the event of overdose, it is recommended that the patient be monitored for any signs orsymptoms of adverse reactions and appropriate symptomatic treatment be instituted as necessary.

Ofatumumab has been previously used in chronic lymphocytic leukaemia (CLL) indications, at dosesup to 2 000 mg administered intravenously via infusion. Ofatumumab administered via subcutaneousinjection has not been assessed and is not approved for these indications, and must not be used for thetreatment of oncology indications.

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

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 tomature B lymphocyte stage. The CD20 molecule is also expressed on a small fraction of activated Tcells. A subcutaneous route of administration of ofatumumab and subsequent release/absorption fromthe 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-mediatedcytotoxicity (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.

B-cell depletion

In the RMS clinical studies using ofatumumab 20 mg every 4 weeks, after an initial dose regimen of20 mg on days 1, 7, and 14, administration resulted in a rapid and sustained reduction of B cells tobelow LLN (defined as 40 cells/µl) as early as two weeks after treatment initiation. Before initiation ofthe maintenance phase starting at week 4, total B-cell levels of <10 cells/µl were reached in 94% ofpatients, 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 baselinevalue of 24.6 weeks post treatment discontinuation. PK-B cell modelling and simulation for B-cellrepletion corroborate this data, predicting median time to B-cell recovery to LLN of 23 weeks posttreatment discontinuation.

In RMS phase III studies, the overall incidence of treatment-induced anti-drug antibodies (ADAs) was0.2% (2 of 914) in ofatumumab-treated patients and no patients with treatment enhancing orneutralising ADA were identified. The impact of positive ADA titers on PK, safety profile or B-cellkinetics cannot be assessed given the low incidence of ADA associated with ofatumumab.

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 disabilitystatus at screening with an Expanded Disability Status Scale (EDSS) score from 0 to 5.5, and who hadexperienced at least one documented relapse during the previous year or two relapses during theprevious two years or positive gadolinium (Gd)-enhancing MRI scan during the previous year. Bothnewly diagnosed patients and patients switching from their current treatment were enrolled.

In the two studies, 927 and 955 patients with RMS, respectively, were randomised 1:1 to receive eitherofatumumab 20 mg subcutaneous injections every 4 weeks starting at week 4 after an initial dosingregimen of three weekly 20 mg doses in the first 14 days (on days 1, 7 and 14) or teriflunomide 14 mgcapsules orally once daily. Patients also received matching placebo corresponding to the othertreatment arm to ensure blinding (double-dummy design).

The treatment duration for individual patients was variable based on when the end of study criteriawere met. Across both studies, the median treatment duration was 85 weeks, 33.0% of patients in theofatumumab group vs 23.2% of patients in the teriflunomide group were treated more than 96 weeks.

Demographics and baseline characteristics were well-balanced across treatment arms and both studies(see Table 2). Mean age was 38 years, mean disease duration was 8.2 years since onset of firstsymptom, and mean EDSS score was 2.9; 40% of patients had not been previously treated with adisease-modifying therapy (DMT) and 40% had gadolinium (Gd)-enhancing T1 lesions on theirbaseline MRI scan.

The primary efficacy endpoint of both studies was the annualised rate of confirmed relapses (ARR)based on EDSS. Key secondary efficacy endpoints included the time to disability worsening on EDSS(confirmed at 3 months and 6 months), defined as an increase in EDSS of ≥1.5, ≥1, or ≥0.5 in patientswith a baseline EDSS of 0, 1 to 5, or ≥5.5, respectively. Further key secondary endpoints included thenumber of Gd-enhancing T1 lesions per MRI scan, the annualised rate of new or enlarging T2 lesionsand the neurofilament light chain (NfL) concentration in serum. Disability-related key secondaryendpoints were evaluated in a meta-analysis of combined data from ASCLEPIOS Study 1 and Study 2,as defined in the study protocols.

Table 2 Demographics and baseline characteristics

Characteristics Study 1 Study 2(ASCLEPIOS I) (ASCLEPIOS II)

Ofatumumab Teriflunomide Ofatumumab Teriflunomide(N=465) (N=462) (N=481) (N=474)

Age (mean ± standard deviation; 39±9 38±9 38±9 38±9years)

Sex (female; %) 68.4 68.6 66.3 67.3

Duration of MS since diagnosis 5.77/3.94 5.64/3.49 5.59/3.15 5.48/3.10(mean/median; years)

Previously treated with DMTs (%) 58.9 60.6 59.5 61.8

Number of relapses in last 12 months 1.2 1.3 1.3 1.3

EDSS score (mean/median) 2.97/3.00 2.94/3.00 2.90/3.00 2.86/2.50

Mean total T2 lesion volume (cm3) 13.2 13.1 14.3 12.0

Patients with Gd+ T1 lesions (%) 37.4 36.6 43.9 38.6

Number of Gd+ T1 lesions (mean) 1.7 1.2 1.6 1.5

The efficacy results for both studies are summarised in Table 3, Figure 1 and Figure 2.

In both phase III studies, ofatumumab compared to teriflunomide demonstrated a significant reductionin the annualised relapse rate of 50.5% and 58.4%, respectively.

The pre-specified meta-analysis of combined data showed that ofatumumab compared toteriflunomide significantly reduced the risk of 3-month confirmed disability progression (CDP) by34.3% and the risk of 6-month CDP by 32.4% (see Figure 1).

Ofatumumab compared to teriflunomide significantly reduced the number of Gd-enhancing T1 lesionsby 95.9% and the rate of new or enlarging T2 lesions by 83.5% (values represent mean reductions forthe combined studies).

Ofatumumab compared to teriflunomide significantly reduced NfL concentrations from the firstassessment at 3 months (see Table 3 and Figure 2).

A similar effect of ofatumumab on the key efficacy results compared to teriflunomide was observedacross the two phase III studies in exploratory subgroups defined by sex, age, body weight, prior non-steroid MS therapy, and baseline disability and disease activity.

Table 3 Overview of key results from phase III studies in RMS

Endpoints Study 1 Study 2(ASCLEPIOS I) (ASCLEPIOS II)

Ofatumumab Teriflunomide Ofatumumab Teriflunomide20 mg 14 mg 20 mg 14 mg(n=465) (n=462) (n=481) (n=474)

Endpoints based on separate studies

Annualised relapse rate (ARR)0.11 0.22 0.10 0.25(primary endpoint)1

Rate reduction 50.5% (p<0.001) 58.4% (p<0.001)

Mean number of T1 Gd-enhancing0.0115 0.4555 0.0317 0.5172lesions per MRI scan

Relative reduction 97.5% (p<0.001) 93.9% (p<0.001)

Number of new or enlarging T20.72 4.00 0.64 4.16lesions per year

Relative reduction 81.9% (p<0.001) 84.6% (p<0.001)

NfL at 3 months (pg/ml) 8.80 9.41 8.92 10.02

Relative reduction 7% (p=0.011) 11% (p<0.001)

Endpoints based on pre-specified meta-analyses

Proportion of patients with 3-month 10.9% ofatumumab vs. 15.0% teriflunomideconfirmed disability progression2

Risk reduction 34.3% (p=0.003)

Proportion of patients with 6-month 8.1% ofatumumab vs. 12.0% teriflunomideconfirmed disability progression2

Risk reduction 32.4% (p=0.012)1 Confirmed relapses (accompanied by a clinically relevant change in the EDSS).2 Kaplan-Meier estimates at 24 months. 3- and 6-month CDP were assessed based on prospectively plannedanalysis of the combined data from the two phase III studies and defined as a clinically meaningfulincrease in the EDSS sustained for at least 3 or 6 months, respectively. A clinically meaningful increase in

EDSS is defined as an increase of at least 1.5 points if the baseline EDSS score was 0, an increase of atleast 1.0 point if the baseline EDSS score was 1.0-5.0, and an increase of at least 0.5 points if the baseline

EDSS score was 5.5 or greater.

Figure 1 Time to first 3-month CDP by treatment (ASCLEPIOS Study 1 and Study 2 combined,full analysis set)16 15.0%112 10.9%16 Risk reduction: 34.3%, p=0.0034 Teriflunomide (N=932)2 Ofatumumab (N=944)0 3 6 9 12 15 18 21 24 27 30 33

Study month

Number of patients at risk

Ofatumumab 944 908 878 844 810 784 533 319 176 49 1 0

Teriflunomide 932 901 841 804 756 718 477 297 146 41 1 01 The numbers shown on the curves represent Kaplan-Meier estimates of the risk of the event at 24 months (marked by the vertical dashedline).

Figure 2 NfL concentrations in serum by treatment (ASCLEPIOS Study 1 and Study 2combined, full analysis set)3 Ofatumumab

Teriflunomide0 3 12 24

Time (months)

The line plots represent the adjusted geometric means with 95% CI at each time point which are from Repeated measures model. Geometricmeans at baseline are derived as exponentiated arithmetic mean of natural logarithmic of raw values of NfL concentrations in serum.

Kaplan-Meier estimate of cumulative event rate

Geometric mean NfL concentration (pg/ml)(%)

In the phase III studies, the proportion of patients with adverse events (AEs) (83.6% vs 84.2%) and the

AEs leading to discontinuation (5.7% vs 5.2%) were similar in the ofatumumab and teriflunomidegroups.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Kesimpta in one or more subsets of the paediatric population in the treatment of multiple sclerosis (seesection 4.2 for information on paediatric use).

After subcutaneous administration, ofatumumab has a prolonged release/absorption profile (Tmax of4.3 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 of1.43 µg/ml at steady state.

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

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

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

The half-life at steady state was estimated to be approximately 16 days following repeatedsubcutaneous administration of ofatumumab at a dose of 20 mg.

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

Adults over 55 years old

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

No studies have been conducted to investigate the pharmacokinetics of ofatumumab in paediatricpatients below the age of 18 years.

Gender had a modest (12%) effect on ofatumumab central volume of distribution in a cross-studypopulation analysis, with higher Cmax and AUC values observed in female patients (48% of thepatients in this analysis were male and 52% were female); these effects are not considered clinicallyrelevant, and no dose adjustment is recommended.

Based on the results of a cross-study population analysis, body weight was identified as a covariate ofexposure (Cmax and AUC) to ofatumumab in RMS subjects. However, body weight did not affectsafety and efficacy measures evaluated in the clinical studies; therefore, dose adjustment is notrequired.

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 inpatients with moderate and severe renal impairment. However, as ofatumumab is not excreted viaurine, it is not expected that patients with renal impairment require dose modification.

No studies of ofatumumab in patients with hepatic impairment have been performed.

Since hepatic metabolism of monoclonal antibodies such as ofatumumab is negligible, hepaticimpairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patientswith hepatic impairment require dose modification.

Non-clinical data revealed no special hazard for humans based on conventional studies of repeateddose toxicity including safety pharmacology endpoints.

Neither carcinogenicity nor mutagenicity studies have been conducted with ofatumumab. As anantibody, ofatumumab is not expected to interact directly with DNA.

The embryo-foetal development (EFD) and the enhanced pre/post-natal development (ePPND) studiesin monkeys showed that exposure to ofatumumab given intravenously during gestation caused nomaternal toxicity, no teratogenicity, and no adverse effects on embryo-foetal and pre/post-nataldevelopment.

In these studies, ofatumumab was detected in the blood of the foetuses and infants, confirmingplacental transfer and foetal exposure to ofatumumab persisting post-natally (long half-life of themonoclonal antibody). Exposure to ofatumumab during gestation led to the expected depletion of

CD20+ B cells in maternal animals and their foetuses and infants, along with a reduced spleen weight(without histological correlate) in foetuses and a reduced humoral immune response to keyhole limpethaemocyanin (KLH) in infants at high doses. All these changes were reversible during the 6-monthpost-natal period. In infants, early post-natal mortality was observed at a dose 160 times higher thanthe therapeutic dose (on AUC basis) and was likely due to potential infections secondary toimmunomodulation. The NOAEL related to the pharmacological activity of ofatumumab in infants ofthe ePPND study leads to an AUC-based safety margin of at least 22-fold when maternal exposure atthe NOAEL is compared with human exposure at the therapeutic dose of 20 mg monthly.

In a dedicated monkey fertility study, male and female fertility endpoints were unaffected.

L-arginine

Sodium acetate trihydrate

Sodium chloride

Polysorbate 80 (E 433)

Disodium edetate dihydrate

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Kesimpta 20 mg solution for injection in pre-filled syringe

Store in a refrigerator (2°C - 8°C). Do not freeze.

If necessary, Kesimpta may be stored unrefrigerated for a single period of up to 7 days at roomtemperature (not above 30°C). If not used during this period, Kesimpta can then be returned to therefrigerator for a maximum of 7 days.

Keep the pre-filled syringe in the outer carton in order to protect from light.

Kesimpta 20 mg solution for injection in pre-filled pen

Store in a refrigerator (2°C - 8°C). Do not freeze.

If necessary, Kesimpta may be stored unrefrigerated for a single period of up to 7 days at roomtemperature (not above 30°C). If not used during this period, Kesimpta can then be returned to therefrigerator for a maximum of 7 days.

Keep the pre-filled pen in the outer carton in order to protect from light.

Kesimpta 20 mg solution for injection in pre-filled syringe

Kesimpta is supplied in a single-use glass syringe, equipped with a stainless steel needle, a plungerstopper and a rigid needle shield. The syringe is assembled with a plunger rod and a needle safetydevice.

Kesimpta is available in unit packs containing 1 pre-filled syringe and in multipacks containing3 (3 packs of 1) pre-filled syringes.

Not all pack sizes may be marketed.

Kesimpta 20 mg solution for injection in pre-filled pen

Kesimpta is supplied in a single-use glass syringe, equipped with a stainless steel needle, a plungerstopper and a rigid needle shield. The syringe is assembled into an auto-injector.

Kesimpta is available in unit packs containing 1 pre-filled pen and in multipacks containing 3 (3 packsof 1) pre-filled pens.

Not all pack sizes may be marketed.

Instructions for handling of the pre-filled syringe

Before injection, the pre-filled syringe should be taken out of the refrigerator for about 15 to30 minutes to allow it to reach room temperature. The pre-filled syringe should be kept in the originalcarton until ready to use, and the needle cap should not be removed until just before the injection isperformed. Prior to use, the solution should be inspected visually by looking through the viewingwindow. The pre-filled syringe should not be used if the liquid contains visible particles or is cloudy.

Comprehensive instructions for administration are given in the package leaflet.

Instructions for handling of the pre-filled pen

Before injection, the pre-filled pen should be taken out of the refrigerator for about 15 to 30 minutes toallow it to reach room temperature. The pre-filled pen should be kept in the original carton until readyto use, and the cap should not be removed until just before the injection is performed. Prior to use, thesolution should be inspected visually by looking through the viewing window. The pre-filled penshould not be used if the liquid contains visible particles or is cloudy.

Comprehensive instructions for administration are given in the package leaflet.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/21/1532/001-004

Date of first authorisation: 26 March 2021

Date of latest renewal: 9 January 2026

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.