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Medical information request

Fingolimod and COVID-19

Novartis routinely monitors cases of Covid-19 in patients on therapy with fingolimod. Based on the totality of the data available from the COVID-19 case reports in clinical trial and post-marketing setting as well as comprehensive data analysis by the MS Data Alliance Global Data sharing initiative1

  • A conclusion cannot be drawn if a higher risk of COVID-19 exists in patients treated with fingolimod compared to the general population​
  • Available data indicates a similar COVID-19 disease course in MS patients treated with fingolimod compared to the general population​
  • As of 28 February 2023, Novartis has received 1,547 confirmed cases of COVID-19 including 1,508 confirmed COVID-19 cases in fingolimod-treated patients in the post-marketing setting and 39 confirmed COVID-19 cases from clinical trials2a 

 

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*Cumulative patient exposure through 28th February 2023; **Includes a 10-week-old neonate with paternal exposure to fingolimod during pregnancy who developed COVID-19 concurrently with beta hemolytic Streptococcus infection and deep vein thrombosis. The neonate was hospitalized, treated, recovered, and was discharged. It was reported that neonate’s father was COVID-19 positive.

aThis section provides a summary of cases of fingolimod-treated patients either suspected as having or reported to have COVID-19 as reported in the Novartis safety database, including spontaneous reports submitted voluntarily and cases identified in the scientific literature. There is typically underreporting in this setting; therefore, the true numerator is unknown. The denominator is also unknown as the actual number of patients on therapy with fingolimod is not readily available. Many of the cases contain very limited information, and cases lost to follow up are included. Therefore, due to these limitations, it is not possible to draw any meaningful conclusions concerning the incidence of COVID-19 or course of illness in patients receiving fingolimod.

COVID-19 infection confirmed cases​2,3

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* A case may have more than one serious criteria ; **PARADIGMS study: Safety and efficacy of fingolimod in pediatric patients with multiple sclerosis, Cutoff date 04th Aug 2021; #Cut-off date 31st August 2022; ##Excludes a 10-week-old neonate with paternal exposure to fingolimod during pregnancy developed COVID-19 concurrently with beta hemolytic streptococcus infection and deep vein thrombosis. The neonate was hospitalized, treated, recovered, and was discharged. It was reported that neonate’s father was COVID-19 positive.

Clinical response to COVID-19 vaccination

  • Novartis routinely monitors COVID-19 vaccine clinical response in patients on therapy with fingolimod  received from clinical trials or from the post marketing setting
  • Of the 1,508 confirmed COVID-19 cases, 58 are reported to have received COVID-19 vaccine:
    • 46 were non-serious cases of COVID[1]19. Outcome was favorable in 18/20 (90%) cases where outcome was provided
    • 12 were reported as serious cases: 1 case had fatal outcome, 7 patients were hospitalized, and 4 patients had medically significant COVID-19 (2 recovered, 1 reported condition improving, and 1 no outcome provided)
Note: No reliable information or estimates of number of fingolimod patients receiving COVID-19 vaccination in post-marketing setting is available.

Impact of COVID-19 in MS in a real world setting​

  • MS is an autoimmune, chronic inflammatory, neurodegenerative disorder of CNS where patients are generally treated with immunosuppressants or immunomodulators.4 The current COVID-19 pandemic has raised concerns regarding the immune response to viral infections and post- vaccination in patients with MS treated with disease modifying therapies5
  • Comprehensive data sharing and analyses regarding the effect of COVID-19 in people with MS have been conducted by the COVID-19 in MS - GDSI.1 The GDSI initiative is a joint initiative of the MS International Federation and the MS Data Alliance, acting under the umbrella of the European Charcot Foundation and in collaboration with many (data) partners across the globe​
  • In people with MS, the incidence of COVID-19 varies from 0.5% to 1.13%.6 The mortality due to COVID-19 has been reported from 1.6% to 4.2%6,7
  • According to the MS International Federation, the evidence available suggests that people with MS taking fingolimod do not have an increased risk of more severe COVID-19 symptoms8

Additional information

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Fingolimod and COVID-19 - Guidance to HCPs

  • Novartis is committed to patients' health and safety. We are striving to keep patients, care partners, and healthcare providers up to date and provide the latest information to help inform decisions related to the use of our products. Novartis continues to collect data to address concerns related to the impact of COVID-19 on patients treated with fingolimod
  • In general, patients and prescribers should act in accordance with local government and health authority guidance concerning the COVID-19 pandemic (including guidance on social distancing and self-isolation, as applicable). HCPs may also consult advice specific to patients with multiple sclerosis provided by international or local healthcare professional and patient organizations9-11
  • HCPs should be aware that the immune system effects of fingolimod, integral to the mechanism of action in multiple sclerosis, may increase the risk of infections (including viral infections), as disclosed in the product label. Novartis believes that treatment decisions should be made between a patient and their treating health care professional based on a benefit-risk assessment specific to the individual patient
     

Fingolimod and SARS-CoV-2 vaccination consideration

 

  • To date all of the SARS-CoV-2 vaccines currently approved and available or in development  belong to several categories/platforms, namely: (1) mRNA based; (2) non-replicating viral-vector vaccines; (3) inactivated vaccines; (4) protein vaccines, and (5) live attenuated vaccines
  • As with inactivated vaccines, the use of non-replicating viral-vector or mRNA based SARS-CoV-2 vaccines in patients receiving immunomodulant/immunosuppressant therapies such as fingolimod may have a diminished immune response
  • Novartis is conducting in Germany an open label, multicenter, clinical trial, to evaluate the humoral and cellular immune response post-vaccination (mRNA based vaccines) in people living with SPMS (active) receiving treatment with siponimod according to the regular clinical practice  ​​​​​​

  • Additional information: For more information, please go to the AMA VACC article12

  • A second study was conducted by Novartis in the US to evaluate the humoral immune response to mRNA COVID-19 vaccines in siponimod-treated patients with advancing forms of RMS in the context of the phase 3b EXCHANGE trial: COVID-19 vaccination substudy. A first interim analysis results were presented at the Annual ACTRIMS Forum 2022. For more information, please go to 'COVID-19 vaccine EXCHANGE sub study'
  • To date the available data of the occurrence and severity of breakthrough infections after a full course of vaccination in people living with MS (plwMS) is very scarce. Its frequency varies from 2% for Delta variant to 6% for Omicron variant13,14
  • There is presently no contraindication for the use of inactivated, (non-replicating) viral-vector, or mRNA-based SARS-CoV-2 vaccines while on treatment with fingolimod, even if vaccinations may be less effective15,16
  • There were patients who received non-live vaccines including SARS-CoV-2  concomitantly with the study drug during the PARADIGMS study (core and extension phases). Although,  vaccine immune response in those patients was not measured during the clinical study and is not available, Novartis is trying to gather all the relevant information concerning clinical outcomes in participants who received any of the available SARS-CoV-2 vaccines, with special attention to the occurrence and severity of the breakthrough infections17
  • Vaccination against SARS-CoV-2 should be considered on a case-by-case basis at the discretion of the treating physician and adhere to immunization guidelines in the local vaccine label​18
    • Please review local prescribing information for any specific SARS-CoV-2 vaccine and comply with local prescribing information requirements for specific contraindications and special warnings and precautions for use
    • People with MS who are immunocompromised should receive an additional dose of COVID-19 depending on local recommendations of their countries8
    • The guidance provided by National Multiple Sclerosis Society (NMSS) suggests that people with MS who are fully vaccinated with a mRNA vaccine and using S1PR modulators, alemtuzumab, and anti-CD20 therapies may benefit from an additional dose of mRNA vaccine and from the use of Evusheld* (tixagevimab co-packaged with cilgavimab)
    • There are also considered some pre- and post-exposure prophylaxis* agents used in some people on higher risk of more severe course of COVID-19 (plwMS could be included in this category)19
    • In some countries, an additional dose of vaccine is recommended in people with immunosuppressive conditions (due to their disease or their treatment)20,21,22 


      * All pre and post-exposure prophylaxis should be administered according to local guidelines and the corresponding product information.
  • An individual benefit-risk assessment should be made in relation to either interrupting or continuing fingolimod treatment​15,23
    • Stopping treatment: If a decision is made for stopping fingolimod for vaccination, a 2 months interval without therapy is needed, based on half-life, to clear fingolimod from the circulation. Caution is also indicated when stopping fingolimod therapy due to the risk of a return of disease activity. If discontinuation of fingolimod is deemed necessary, patients should be monitored during this time for relevant signs of a possible return of disease activity 
    • Reintroducing Treatment: The duration of treatment interruption will depend on clinical judgment and evaluation of the risk/benefit of extending interruption vs reintroducing fingolimod. Vaccinations may be less effective if administered during fingolimod treatment and for up to 2 months after treatment with fingolimod. When reintroducing fingolimod, refer to local guidance on initiation of treatment to evaluate the need for first-dose monitoring, and for other treatment initiation guidance
  • For patients getting started on fingolimod, it is recommended to initiate treatment at least 1 month following the second dose of SARS-CoV-2 vaccine15,23,24
    • The use of live attenuated vaccines should be avoided for patients on fingolimod and for 2 months after stopping treatment15,23
    • A full course of vaccination with varicella vaccine is recommended for antibody-negative patients prior to commencing treatment with fingolimod15,23
    • Vaccination against human papilloma virus should be considered prior to treatment initiation with fingolimod taking into account vaccination recommendations
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Abbreviations
CNS, central nervous system; COVID-19, corona virus disease-19; CPAP, continuous positive airway pressure; GDSI, Global Data Sharing Initiative; HCP, healthcare professional; ICU, intensive care unit; mRNA, messenger ribonucleic acid; MS, multiple sclerosis; plwMS, people living with MS; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
References
1. Simpson-Yap S, et al. medRxiv 2021.02.08.21251316; doi: https://doi.org/10.1101/2021.02.08.21251316.
2. Data on File, Novartis safety database, cutoff date 28-Feb-2023. Novartis Pharma AG.
3. Data on File, Novartis safety database, cutoff date 28-Feb-2023. Novartis Pharma AG.
4. Oh J, et al. Curr Opin Neurol. 2018;31(6):752-759.
5. Rostami Mansoor S, et al. J Med Virol. 2021;93:1314-1319.
6. Reder A.T et al. CNS Drugs (2021) https://doi.org/10.1007/s40263-021-00804-1
7. Sormani MP, Salvetti M, Labauge P et al. DMTs and COVID-19 severity in MS: a pooled analysis from Italy and France. Annals of Clinical and Translational Neurology 2021.
doi:10.1002/acn3.51408
8. MS International Federation. Global COVID-19 advice for people with MS. Last updated on 4 June 2021. Accessed 19-Nov-2021.
http://www.msif.org/wp-content/uploads/2021/06/June-2021-MSIF_Global-advice-on-COVID-19-for-people-with-MS_FINAL.pdf
9. World Health Organization. Coronavirus disease (COVID-19) outbreak. Accessed 4-Dec-2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
10. European Centre for Disease Prevention and Control. COVID-19. Accessed 4-Dec-2020. https://www.ecdc.europa.eu/en/novel-coronavirus-china
11. US Centers for Disease Control and Prevention. Coronavirus Disease 2019 (COVID-19). Accessed 4-Dec-2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinicalguidancemanagement-
patients.html#clinical-management-treatment%3C
12. Ziemssen T, Groth M, Rauser B, Bopp T. Ther Adv Neurol Disord. 2022 Nov 8;15:17562864221135305
13. Stærke NSea. Levels of SARS-CoV-2 antibodies among fully-vaccinated individuals with delta or omicron variant breakthrough infections: a prospective cohort study. Accessed on 23rd May 2022. Lancet (preprint). 2022
14. Sormani MP, Schiavetti I, Inglese M, et al. Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy. EBioMedicine 2022. doi:10.1016/j.ebiom.2022.104042
15. Fingolimod (Gilenya®) EU Summary of Product Characteristics. Last updated 3-August-2021. Accessed on 6-December-
2021 https://www.ema.europa.eu/en/medicines/human/EPAR/gilenya
16. Ufer M, et al. Neurol Neuroimmunol Neuroinflamm. 2017;4(6):e398.
17. Novartis Data on File. EXPAND core CSR Novartis Pharmaceuticals Corp.
18. Centers for Disease Control and Prevention. Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines Currently Authorized in the United States. Updated February 10, 2021.
Accessed February 10, 2021. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html
19. National Multiple Sclerosis Society.MS, the coronavirus and vaccines – updated global advice. Accessed May 20, 2022. The coronavirus and MS – updated global advice (msif.org)
20. US Food and Drug Administration. Coronavirus (COVID-19) Update: FDA Authorizes Additional Vaccine Dose for Certain Immunocompromised Individuals. Accessed November 20, 2021. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-additional-vaccine-dose-certain-immunocompromised
21.United Nations. WHO advisory group recommends extra COVID-19 vaccine dose for immunocompromised. Accessed November 20, 2021. https://news.un.org/en/story/2021/10/1102732
22. Reuters. Factbox - Countries weigh need for booster COVID-19 shots. Accessed October 27, 2021. https://www.reuters.com/article/us-health-coronavirus-booster-idUKKBN2GA190
23. Mayzent Prescribing information. Novartis Pharmaceuticals Corp; 2020
24. National Multiple Sclerosis Society. Timing MS medications with COVID-19 mRNA vaccines. Accessed November 2023. https://www.nationalmssociety.org/coronavirus-covid-19-
information/multiple-sclerosis-and-coronavirus/covid-19-vaccine-guidance/Timing-MS_Medications-with-COVID-19-mRNA_Vaccines
* Indication wording varies in different countries. The current website is a global information resource. Local Prescribing Information/ Summary of Product Characteristics approved by individual country’s regulatory authority is the primary source of information for the indication of fingolimod in the individual country.