Important Safety Information


Contraindication: KESIMPTA is contraindicated in patients with active hepatitis B virus infection.
Warnings and Precautions
Infections: An increased risk of infections has been observed with other anti-...

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Indication 
KESIMPTA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Demonstrated Safety Profile

KESIMPTA offers:

  • A targeted and precisely delivered B-cell therapy1,2
  • Favorable safety profile similar to Aubagio® as demonstrated in 2 pivotal trials1
  • Demonstrated tolerability profile1,3
  • Proportion of patients with infection was similar between KESIMPTA® and Aubagio1

See an Expert Perspective on KESIMPTA (ofatumumab) Safety

Dr Patricia Coyle, Director, Stony Brook MS Comprehensive Care Center, reviews the KESIMPTA safety profile

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Adverse Reactions

Safety across pooled ASCLEPIOS I and II studies1,4

Adverse reactions in patients with RMS with an incidence of at least 5% with KESIMPTA and a greater incidence than Aubagio.

Favorable
safety profile
comparable to
Aubagio1
Upper respiratory
tract infections* ............................................................................................................................................................................................................
Injection-related
reactions (systemic) ............................................................................................................................................................................................................
Headache ............................................................................................................................................................................................................
Injection site
reactions (local) ............................................................................................................................................................................................................
Urinary tract infection ............................................................................................................................................................................................................
Back pain ............................................................................................................................................................................................................
Blood
immunoglobulin M
decreased ............................................................................................................................................................................................................
Aubagio
N=936

38%

15%
12%

6%
8%
6%


2%
 
 
............................................................................................................................................................................................................
............................................................................................................................................................................................................
............................................................................................................................................................................................................
............................................................................................................................................................................................................
............................................................................................................................................................................................................
............................................................................................................................................................................................................
............................................................................................................................................................................................................
KESIMPTA
N=946

39%

21%
13%

11%
10%
8%


6%
 
Overall rate
of infections............................................................................................................................................................................................................
Serious infections
............................................................................................................................................................................................................
Aubagio
n=493

52.7%

1.8%
 
 
............................................................................................................................................................................................................
............................................................................................................................................................................................................
KESIMPTA
n=488

51.6%

2.5%

*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.

 

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Tolerability Profile

Demonstrated tolerability profile: injection-related reactions (systemic)1,5

  • Injection-related reactions (systemic) and injection-site reactions (local) were reported in 21% and 11% of patients treated with KESIMPTA, respectively compared to 15% and 6% in the Aubagio treated patients
  • The incidence of injection-related reactions (systemic) 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%) KESIMPTA-treated RMS patients reported serious injection-related reactions

KESIMPTA and Infection

  • In the Phase 3 pivotal clinical studies, 51.6% of KESIMPTA-treated patients experienced at least one infection compared to 52.7% of Aubagio-treated patients

Treatment Discontinuations

Pooled data from ASCLEPIOS I and II studies

  • Pooled data from both clinical trials show that treatment discontinuation rates due to adverse events were similar between KESIMPTA (5.7%) and Aubagio (5.2%)3
  • The most common cause of discontinuation in patients treated with KESIMPTA was low IgM (3.3%), defined in trial protocols as IgM at 10% below the LLN1
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IgG/IgM Data

Serum Ig levels can be predictors of infection risk when treating RMS patients with B-cell therapies

  • Immunoglobulins play a critical role in the immune response by working to destroy pathogens, including bacteria and viruses
3.5 years immunoglobulins chart
  • Treatment with B-cell therapies may lead to Ig decline in RMS patients7,8
  • Patients with any level of Ig decline may be at risk of infection9

KESIMPTA IgG data

Mean IgG levels remained stable for up to 3.5 years for patients on KESIMPTA10

  • In the Phase 3 ASCLEPIOS trials, no decline in IgG was observed at the end of the study1,11
  • In the extension analysis, mean IgG levels remained stable for up to 3.5 years in patients taking KESIMPTA10

IgG levels with KESIMPTA over 3.5 years10

IgG levels chart

Average IgG levels remained within the reference range (patients aged >18 years): 5.65-17.65 g/L.12

ALITHIOS Study Design: ALITHIOS is an ongoing open-label, umbrella extension Phase 3b, single-arm, multi-center study evaluating long-term (up to 5 years) safety, tolerability, and effectiveness of KESIMPTA (20 mg SC) in subjects with RMS. The study enrolled 1703 RMS patients from the APLIOS, APOLITOS, and ASCLEPIOS I and II trials who continued KESIMPTA treatment. A long-term safety analysis from ALITHIOS was conducted to evaluate IgM/IgG levels and their association with serious infection for up to 3.5 years.10

KESIMPTA IgM data

IgM levels remained above the lower limit of normal (LLN)10†

  • In the Phase 3 ASCLEPIOS trials, 14.3% patients treated with KESIMPTA experienced a decrease in IgM1
  • In the long-term analysis, mean IgM declined over time but remained above the LLN for up to 3.5 years10

IgM levels with KESIMPTA over 3.5 years10

IgM Levels chart

Rate of IgM decline slowed over the 3.5-year period Rate of IgM decline slowed over the 3.5-year period

Average IgM levels remained within the reference range (patients aged >18 years): 0.4-2.3 g/L.12

*Switching period refers to the patients started with Aubagio and not applicable to the patients treated with KESIMPTA in the core period; for Aubagio/KESIMPTA group data from first dose of Aubagio until last dose of KESIMPTA plus 100 days/analyses cutoff dates have been used.

For all pooled analyses, a fixed value of LLN (using ALITHIOS study reference) was used: IgG: 5.65 g/L/IgM: 0.4 g/L.

In the extension study analysis

KESIMPTA: No increased risk of serious infection associated with change in IgG/IgM levels was observed at 3.5 years10

KESIMPTA has the potential for an increased risk of infections, including serious bacterial, fungal, and new or reactivated viral infections; some of these infections have been fatal in patients treated with other anti-CD20 antibodies.

Patients with at least 1 serious infection within 1 month prior and until 1 month after any series of drops in IgM/IgG <LLN10

  IgM IgG Overall
  <LLN
(N=454*)
≥LLN
(N=1512)
<LLN
(N=30*)
≥LLN
(N=1936)
N=1969
  n (%) IR n (%) IR n (%) IR n (%) IR n (%) IR
Patients with ≥1
serious infection
3 (0.7) 0.8 44 (2.9) 1.38 1 (3.3) 7.02 55 (2.8) 1.34 58 (2.9) 1.39
Herpes zoster (PT) 1 (0.2) 0.27 0 0 0 0 1 (0.1) 0.02 1 (0.1) 0.02
URTI (PT) 1 (0.2) 0.27 0 0 0 0 1 (0.1) 0.02 1 (0.1) 0.02
UTI (PT) 1 (0.2) 0.27 3 (0.2) 0.09 0 0 6 (0.3) 0.14 6 (0.3) 0.14
Escherichia UTI (PT) 0 0 1 (0.1) 0.03 NA NA NA NA 1 (0.1) 0.02
Kidney infection (PT) 0 0 1 (0.1) 0.03 NA NA NA NA 1 (0.1) 0.02
Pneumonia (PT) 0 0 8 (0.5) 0.25 1 (3.3) 7.02 8 (0.4) 0.19 9 (0.5) 0.21
  • The overall incidence of serious infections in KESIMPTA-treated patients was low for up to 3.5 years10§

*Number of patients with IgM/IgG <LLN at least once at any time during the post-baseline visits.

Number of patients with no occurrence of IgM/IgG <LLN at least once at any time during the post-baseline visit.

IR per 100 PY estimated via a Poisson regression model with only treatment as the factor and with the log-link and natural logarithm of time as the offset variable. For all pooled analyses, a fixed value of LLN (using ALITHIOS study reference) was used: IgM: 0.4 g/L; and IgG: 5.65 g/L.

§Low incidence of serious infection defined as 1.39 incidence rate per 100 PY.

Ig testing and monitoring can help manage increased risk of serious infection

  • Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with KESIMPTA until B-cell repletion 
  • Consider discontinuing KESIMPTA if a patient develops a serious opportunistic infection or recurrent infections if immunoglobulin levels indicate immune compromise

Consider efficacy. Consider safety. Consider 3.5 years of Ig data.

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KESIMPTA & Vaccinations

Start icon
For new patients planning to start KESIMPTA

Live vaccines1,13

live-attenuated
(eg, chickenpox, measles)*

Administer at least 4 weeks prior to initiation of KESIMPTA

Non-live and inactivated vaccines1,13,14

(eg, hepatitis A, polio, influenza, 
and SARS-CoV-2 vaccines)*

Whenever possible, administer at least 2 weeks prior to initiation of KESIMPTA

Checkmark
For patients already taking KESIMPTA

Live vaccines1,13

live-attenuated
(eg, chickenpox, measles)*

  • Not recommended during treatment
  • Administer live vaccines only after B-cell repletion

Non-live and inactivated vaccines1,13,14

(eg, hepatitis A, polio, influenza, 
and SARS-CoV-2 vaccines)*

  • In the pivotal trials, concomitant treatment with non-live vaccines was permitted
  • The use of non-live vaccines is not contraindicated with KESIMPTA therapy
  • KESIMPTA may interfere with the effectiveness of inactivated vaccines

Vaccination of infants born to mothers treated with KESIMPTA during pregnancy1*

  • In infants of mothers treated with KESIMPTA during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts. 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, but an assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted

Currently available COVID-19 vaccines on the market, by Pfizer/BioNTech, Moderna, and Janssen, are non-live vaccines.14

Any vaccine used in patients taking KESIMPTA should be administered in accordance with the KESIMPTA full Prescribing Information.

Immune response

  • B cells are part of a complex immune response to both viruses and vaccinations13,14
  • T cells are also involved and play a fundamental role in viral infections by helping B cells produce antibodies. They also orchestrate the response for other immune cells. Some T cells kill infected cells to reduce the viral burden13,14
  • Data from an RMS clinical study also showed that T cells remained largely unaffected in ofatumumab-treated patients. T cells are an important part of a response to viral infections, including COVID-1914,15

KESIMPTA is a targeted and precisely delivered B-cell therapy

  • When delivered subcutaneously, KESIMPTA is thought to promote preferential depletion of B cells in the lymph nodes16
  • Preclinical evidence suggests that KESIMPTA may preserve B cells in the spleen that help maintain immune function17

The precise mechanism by which KESIMPTA exerts its therapeutic effects is unknown.

Read more on KESIMPTA vaccine-related information

*As of March 2021, KESIMPTA has not been studied with vaccines.

Post vaccination, an assessment of vaccine immune responses, including consultation with qualified specialists, should be considered to determine whether a protective immune response was mounted. It is unknown whether KESIMPTA may interfere with vaccine efficacy.

Data from RMS clinical studies indicate B-cell recoveries over the lower limit of normal in at least 50% of patients in 24 to 36 weeks post treatment discontinuation. Modeling and simulation for repletion corroborate these data, predicting median time to B-cell recovery of 40 weeks post treatment discontinuation.

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Dosing & Administration>

BL=baseline; Ig=immunoglobulin; IR=incidence rate; PT=preferred term; PY=patient-year; RMS=relapsing multiple sclerosis; SC=subcutaneous; SE=standard error.

References:

1. Kesimpta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020.
2. Huck C, Leppert D, Wegert V, et al. Low-dose subcutaneous anti-CD20 treatment depletes disease relevant B cell subsets and attenuates neuroinflammation. J Neuroimmune Pharmacol. 2019;14(4):709-719.
3. Data on file. OMB157G (ofatumumab). Summary of clinical safety. Novartis Pharmaceuticals Corp; East Hanover, NJ. January 2020.
4. Hauser SL, Bar-Or A, Cohen JA, et al; for the ASCLEPIOS I and ASCLEPIOS II trial groups. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020;383(6):546-557.
5. Hauser SL, Bar-Or A, Cohen JA, et al; for the ASCLEPIOS I and ASCLEPIOS II trial groups. Ofatumumab versus teriflunomide in multiple sclerosis [supplemental appendix]. N Engl J Med. 2020;383(6):546-557.
6. Immunoglobulins (IgA, IgG, IgM)—What’s being tested?: Merck Manual. Available at: https://www.merckmanuals.com/-/media/Manual/LabTests/ImmunoglobulinsIgAIgGIgM. Accessed June 22, 2021.
7. Ocrevus [package insert]. San Francisco, CA: Genentech, Inc; 2021.
8. Rituxan [package insert]. South San Francisco, CA: Biogen and Genentech USA, Inc; 2021.
9. Derfuss T, Weber MS, Hughes R, et al. Serum immunoglobulin levels and risk of serious infections in the pivotal phase III trials of ocrelizumab in multiple sclerosis and their open label extensions [OPR-65]. Presented at: 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS); 11-13 September 2019; Stockholm, Sweden.
10. Jasinska E, Habek M, Wynn D, et al. Impact of ofatumumab on immune responses post-vaccination in RMS patients: ALITHIOS vaccination sub-study design [OPR-207]. Presented at: 7th Congress of the European Academy of Neurology; 19-22 June, 2021; Virtual Congress.
11. de Seze J, Bar-Or A, Correale J, et al. Effect of ofatumumab on serum immunoglobulin levels and infection risk in relapsing multiple sclerosis patients from the phase 3 ASCLEPIOS I and II trials. Presented at: the 6th Congress of the European Academy of Neurology; 23-26 May, 2020; Virtual Congress.
12. Data on file. Novartis Pharmaceuticals Corp; East Hanover, NJ. June 2021.
13. Understanding How COVID-19 Vaccines Work. Updated March 8, 2021. Centers for Disease Control and Prevention website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html. Accessed October 20, 2021.
14. Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: current state of the science. Immunity. 2020;52(6):910-941. doi:10.1016j.immuni.2020.05.002
15. Weindl H, Fox E, Goodyear A, et al. Effect of Subcutaneous ofatumumab on lymphocyte subsets in patients with RMS: analysis from the APLIOS study. Poster presented at: 6th Congress of the European Academy of Neurology, May 23-26, 2020. Paris, France (Virtual). LB129.
16. Torres JB, Roodselaar J, Sealey M, et al. Distribution and efficacy of ofatumumab and ocrelizumab in humanized-CD20 mice following subcutaneous or intravenous administration. Poster P2.2-052. Poster presented at: 71st American Academy of Neurology Annual Meeting; May 4-10, 2019; Philadelphia, PA.
17. Theil D, Smith P, Huck C, et al. Imaging mass cytometry and single-cell genomics reveal differential depletion and repletion of B-cell populations following ofatumumab treatment in cynomolgus monkeys. Front lmmunol. 2019;10:1-11.

Indication

KESIMPTA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Important Safety Information

Contraindication: KESIMPTA is contraindicated in patients with active hepatitis B virus infection.

Warnings and Precautions

Infections: An increased risk of infections has been observed with other anti-CD20 B-cell depleting therapies. KESIMPTA has the potential for an increased risk of infections including serious bacterial, fungal, and new or reactivated viral infections; some have been fatal in patients treated with other anti-CD20 antibodies. The overall rate of infections and serious infections in KESIMPTA-treated patients was similar to teriflunomide-treated patients (51.6% vs 52.7%, and 2.5% vs 1.8%, respectively). The most common infections reported by KESIMPTA-treated patients in relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay KESIMPTA administration in patients with an active infection until resolved.

Consider the potential increased immunosuppressive effects when initiating KESIMPTA after an immunosuppressive therapy or initiating an immunosuppressive therapy after KESIMPTA.

Hepatitis B Virus: Reactivation: No reports of hepatitis B virus (HBV) reactivation in patients with MS treated with KESIMPTA. However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ofatumumab at higher intravenous doses for chronic lymphocytic leukemia (CLL) than the recommended dose in MS and in patients treated with other anti-CD20 antibodies.

Infection: KESIMPTA is contraindicated in patients with active hepatitis B disease. Fatal infections caused by HBV in patients who have not been previously infected have occurred in patients treated with ofatumumab at higher intravenous doses for CLL than the recommended dose in MS. Perform HBV screening in all patients before initiation of KESIMPTA. Patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], should consult liver disease experts before starting and during KESIMPTA treatment.

Progressive Multifocal Leukoencephalopathy: No cases of progressive multifocal leukoencephalopathy (PML) have been reported for KESIMPTA in RMS clinical studies; however, PML resulting in death has occurred in patients being treated with ofatumumab at higher intravenous doses for CLL than the recommended dose in MS. In addition, JC virus infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. If PML is suspected, withhold KESIMPTA and perform an appropriate diagnostic evaluation. If PML is confirmed, KESIMPTA should be discontinued.

Vaccinations: Administer all immunizations according to immunization guidelines: for live or live-attenuated vaccines at least 4 weeks and, whenever possible at least 2 weeks prior to starting KESIMPTA for inactivated vaccines. The safety of immunization with live or live-attenuated vaccines following KESIMPTA therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion.

Vaccination of Infants Born to Mothers Treated with KESIMPTA During Pregnancy. For infants whose mother was treated with KESIMPTA during pregnancy, assess B-cell counts prior to administration of live or live-attenuated vaccines. If the B-cell count has not recovered in the infant, do not administer the vaccine as having depleted B-cells may pose an increased risk in these infants. 

Injection-Related Reactions: Injection-related reactions with systemic symptoms occurred most commonly within 24 hours of the first injection, but were also observed with later injections. There were no life-threatening injection reactions in RMS clinical studies. 

The first injection of KESIMPTA should be performed under the guidance of an appropriately trained health care professional. If injection-related reactions occur, symptomatic treatment is recommended. 

Reduction in Immunoglobulins: As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections and after discontinuation of therapy until B-cell repletion. Consider discontinuing KESIMPTA therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.  

Fetal Risk: Based on animal data, KESIMPTA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to KESIMPTA in utero. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving KESIMPTA and for at least 6 months after the last dose.

Most common adverse reactions (>10%) are upper respiratory tract infection, headache, injection-related reactions, and local injection-site reactions. 

Please see full Prescribing Information, including Medication Guide.

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