Olumiant. (baricitinib) 2 mg and 4 mg, film-coated tablets. Summary of Risk Management Plan (RMP) Version 2.0, Page 1

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1 Olumiant (baricitinib) 2 mg and 4 mg, film-coated tablets Summary of Risk Management Plan (RMP) Version 2.0, Page 1

2 Summary of the risk management plan (RMP) for Olumiant (baricitinib) The Risk Management Plan (RMP) is a comprehensive document submitted as part of the application dossier for market approval of a medicine. The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate and follow the risks as well as to prevent or minimize them. The RMP summary of Olumiant is a concise document and does not claim to be exhaustive. As the RMP is an international document, the summary might differ from the Arzneimittelinformation / Information sur le médicament approved and published in Switzerland, e.g. by mentioning risks occurring in populations or indications not included in the Swiss authorization. Please note that the reference document which is valid and relevant for the effective and safe use of Olumiant in Switzerland is the Arzneimittelinformation/ Information sur le médicament (see approved and authorized by Swissmedic. Eli Lilly is fully responsible for the accuracy and correctness of the content of this published summary RMP of Olumiant. Overview of disease epidemiology Olumiant is a medicine that is used to treat adults with rheumatoid arthritis. Rheumatoid arthritis is a long-term condition that causes inflammation in the joints of the body. The main symptoms are pain, swelling, and stiffness in the joints. The hands, feet, and wrists are commonly affected, but it can also cause problems in other parts of the body. There may be periods where symptoms become worse, known as a flare-up or flare. Over the longer term the condition may result in permanent damage to the joints. Summary of treatment benefits The efficacy of Olumiant was assessed in 4 large completed clinical studies and 1 ongoing long-term clinical study in patients with moderate to severe rheumatoid arthritis, In the completed studies, Olumiant was either compared against placebo (dummy medicine) or medicines that are already used to treat rheumatoid arthritis. The effect of Olumiant was measured by examining the improvement in the signs and symptoms of the disease, whether the severity of the disease decreased, or if the disease went into remission. The studies also looked at whether patients could carry out their normal daily functions better with treatment. Some studies looked at the effects over time on the deterioration of the joints. In all studies, Olumiant at the recommended dose was more effective than placebo and other comparators at improving signs and symptoms and ensuring better daily functioning. Olumiant treatment also was Version 2.0, Page 2

3 better than placebo at decreasing the severity of the disease and more patients were in remission. Olumiant was more effective at preventing joint deterioration and the number of patients who had no further joint deterioration was higher with Olumiant than with placebo. Better or similar results were seen when Olumiant was compared to the other comparators. Unknowns relating to treatment benefits Olumiant should not be used in patients under 18 years old, as its benefit has not been studied. Clinical data showing the effect of Olumiant over periods of time longer than 2 years or in patients aged 75 years or over are limited. Summary of safety concerns Important Identified Risks Risk Shingles (herpes zoster) Increases in fats (lipids) in the blood What is known [about this risk?] In Olumiant clinical trials, some patients have developed shingles. Most patients recovered but a small proportion developed pain in the part of the body affected (post-herpetic neuralgia). Increases in lipids in the blood, including increases in blood cholesterol levels, are very common during treatment with Olumiant clinical trials. These increases respond well to treatment with statin medicines and have not been associated with heart or blood vessel problems. Preventability [Ways to lower this risk] Shingles may be prevented by vaccination before starting treatment. The increases in blood lipids are unlikely to be preventable but the lipid levels can be easily monitored with a blood test during treatment and if they increase, treatment with statins is effective. Version 2.0, Page 3

4 Important Potential Risks Risk The unknown potential for abnormalities to an unborn child exposed to Olumiant while in the womb Problems with the liver (hepatic risks) Serious infections and other infections like tuberculosis Heart and blood vessel problems (cardiovascular events) including heart attack, heart failure and stroke What is known (including Reason Why it is Considered a Potential Risk) There is limited information about the use of Olumiant in women who are pregnant. This information has not yet shown an adverse effect on the unborn baby but it is insufficient to make firm conclusions, therefore the potential risk to unborn babies is unknown. Olumiant must not be used during pregnancy, unless it is clearly necessary. Increases in liver enzymes have been seen in Olumiant clinical trials, but these have not been associated with any symptoms of evidence of damage to the liver. These increases are seen in particular when Olumiant is given with another medicine (methotrexate) used to treat rheumatoid arthritis, and this medicine is known to be associated with effects on the liver. The long-term effects of these increases, and the risk that they may lead to damage to the liver, are not yet known for Olumiant. Most of the infections seen during treatment with Olumiant are not of a serious nature, although a small proportion has been assessed as serious.since the number of patients treated in the clinical trials and the duration of the trials is relatively limited, the potential exists that more frequent serious infections and socalled opportunistic infections like tuberculosis or different serious infections may be seen in everyday clinical practice, which is different to a clinical trial. Increases in lipids in the blood, including cholesterol, have been seen in Olumiant clinical trials. These changes have not been directly linked to any heart and blood vessel problems in the clinical trials. However, since the numbers of patients treated in the clinical trials and the duration of the trials is relatively limited, the potential exists that these lipid changes could lead to heart and blood vessel problems when Olumiant is used in everyday clinical practice and for long periods of time. Version 2.0, Page 4

5 Risk Decrease in bone marrow activity and decreased white blood cell counts Serious Muscle disorders Holes in the stomach or bowel (gastrointestinal perforation) What is known (including Reason Why it is Considered a Potential Risk) Decreases in white blood cells that are produced by the bone marrow and are responsible for fighting infection have been seen in some people during treatment with Olumiant in clinical trials, These decreases were not associated with more frequent infections or serious infections. Since the number of patients treated in the clinical trials and the duration of the trials is relatively limited, the potential exists that more severe falls in white cell counts that lead to infection could occur in everyday clinical practice. Increases in a blood enzyme that can be associated with muscle disorders have been seen in patients treated with Olumiant in clinical trials but in most patients the changes were temporary. Although there was no clear link with any muscle disorders, muscle symptoms (such as muscle aches and pain) were reported by some patients but almost all reports were considered to be not to be serious. Since the number of patients treated in the clinical trials and the duration of the trials is relatively limited, the potential exists that more severe muscle effects could occur in everyday clinical practice. Gastrointestinal perforations happen very rarely in patients with rheumatoid arthritis and have been linked with some common treatments. At this time, only very few perforations have occurred in Olumiant clinical trials. However, due to the number of patients treated in the clinical trials and the relatively short duration of the trials, the potential exists that more of these events may be seen in everyday clinical practice which is different than a clinical trial. Version 2.0, Page 5

6 Risk Cancers Blood clots in the vein What is known (including Reason Why it is Considered a Potential Risk) Patients with rheumatoid arthritis have an increased risk of certain cancers, and the number and type of cancers seen in Olumiant clinical trials was similar to those expected in such patients. However, since the numbers of patients treated in the clinical trials and the duration of the trials is relatively limited, the potential exists that more cancers could be seen when Olumiant is used in everyday clinical practice and for long periods of time. Some patients who received Olumiant in clinical trials developed blood clots in the veins of their leg or lungs. However, these events occurred at a similar rate to what would be expected in patients with rheumatoid arthritis. Because the number of patients treated in the clinical trials and the duration of the trials is relatively limited, the potential exists that more blood clots in the veins of the legs and lungs could be seen when Olumiant is used in everyday clinical practice and for long periods of time. Missing Information Risk Long-term safety data Safety and efficacy of Olumiant in patients 75 years of age and over Use in patients with evidence of hepatitis B or hepatitis C infection What is Known While the available clinical trial information does not suggest that Olumiant is less safe with long-term use, the long-term studies were limited in duration and further long-term data will be needed to collect more information on safety in general, and on cancers and heart problems in particular. While the available clinical trial information does not suggest that Olumiant is less safe or effective in patients 75 years or over compared with younger patients, there is limited information about Olumiant use in this age group. As there is limited information about Olumiant use in these patients, the safety in patients with hepatitis B or hepatitis C is not known. Version 2.0, Page 6

7 Use in patients with reduced liver function Use in patients with an increased production of lymphoid cells Use in patients with cancer Use in children and adolescent patients Effect on fertility, on pregnancy and the unborn child, and use in breastfeeding Use in combination with certain medicines used to treat rheumatoid arthritis (RA) Although it is not expected that Olumiant will be given to these patients, there is limited information about Olumiant use in patients with reduced liver function, so the safety profile is unknown. While the available clinical trial information does not suggest that Olumiant is less safe or effective in patients with increased production of lymphoid cells, there is limited information about Olumiant use in these patients. While the available clinical trial information does not suggest that Olumiant is less safe or effective in patients with cancer, there is limited information about Olumiant use in these patients. Olumiant has not been studied in patients <18 years so the safety profile in children and adolescents is not known. There is limited information about the use of Olumiant in women who are pregnant. This information from clinical studies has not shown an adverse effect on the unborn baby but it is insufficient to make firm conclusions, so the potential risk to unborn babies is unknown. Olumiant should not be used during pregnancy or while breast feeding, and women should be advised to avoid becoming pregnant while taking the drug. Although there was no evidence of an effect on the fertility of woman taking Olumiant, experience is limited. Although use of Olumiant with other common medicines for RA is not expected, current Olumiant experience with a number of these medicines is limited. Summary of risk minimisation measures by safety concern All medicines have a product information ( Arzneimittelinformation/ Information sur le médicament ) which provides physicians, pharmacists and other healthcare professionals with details on how to use the medicine, and also describes the risks and recommendations for minimising them. Information for patients is available in lay language in the package leaflet. The measures listed in these documents are known as routine risk minimisation measures. The product information ( Arzneimittelinformation/ Information sur le médicament ) and the information for patients (Patienteninformation / Information destinée aux patients ) for Olumiant can be found on Version 2.0, Page 7

8 This medicine has additional risk minimisation measures (Patient Alert Card) for its safe and effective use. The Patient Alert Card addresses the following risks: Infections Pregnancy Vaccinations Post-authorisation development plan List of studies in post-authorisation development plan Study/Activity Objectives Safety Concerns/ Status Planned Date for (including Study Efficacy Issue Final Results Number) Addressed A study to collect To find out more Important Planned Availability of the and analyse about the Identified Risks final results will be safety data, frequency and Shingles, high dependent upon during normal use nature of levels of fat in the when the medicine of Olumiant in the shingles, serious blood is made available US infections, Important to patients. (observational problems with the potential risks: Final report is post marketing liver or cancer expected early in safety registry) gastrointestinal serious tract, and heart infections (such and blood as tuberculosis, vessels, serious viral infection muscle disorders, affecting the effects on white brain, or fungal cell counts, infections) tumours, and blood clots in the the liver veins of the leg or heart and blood in the lungs vessel following normal problems use of Olumiant, particularly long term use. Version 2.0, Page 8

9 development of a hole in the gastrointestinal tract, like the stomach or intestines low white cell counts muscles blood clots in the veins of the leg or in the lungs Version 2.0, Page 9

10 Study/Activity Safety Concerns/ (including Study Efficacy Issue Planned Date for Number) Objectives Addressed Status Final Results A study to collect To find out more Important Planned Availability of final and analyse safety about the Identified Risks results will be information from frequency and Shingles dependent upon electronic nature of High levels of fat when the medicine is healthcare records shingles, serious in the blood made available to in the US following infections, patients normal use of problems with the Important Final report: Olumiant liver or potential risks: anticipated early in (Observational gastrointestinal cancer 2032 safety study using tract, heart and serious an existing blood vessel infections (such database) problems, serious as tuberculosis muscle disorders, or viral infection effects on white affecting the cell counts, brain, or fungal tumours, and infections) blood clots in the veins of the leg or the liver in the lungs heart and blood during normal use vessel of Olumiant problems (particularly long development of term use). a hole in the To confirm the gastrointestinal findings from the tract, like the first study in an stomach or independent intestines population using a different low white cell approach. counts muscles blood clots in the veins of the leg or in the lungs Version 2.0, Page 10

11 Study/Activity Safety Concerns/ (including Study Efficacy Issue Planned Date for Number) Objectives Addressed Status Final Results A study to collect To find out more Important potential risks: Planned Availability of the and analyse safety about the cancer final results will be data, during frequency and heart and blood dependent upon normal use of nature of problems vessel problems when the medicine Olumiant in some with heart and blood clots in the is made available European blood vessels and veins of the leg or in to patients in the countries cancers following the lungs EU. (observational post normal use of Missing information: The final results marketing safety Olumiant over long-term safety are expected registry) several years. approximately Q3 2027, depending on market availability Abbreviations: EU = European Union; Q = quarter; US = United States. Studies which are a condition of the marketing authorisation None of the above studies are a condition of the marketing authorisation. Summary of changes to the risk management plan over time Major Changes to the Risk Management Plan over Time June 2017: VTE was added as an important potential risk. June 2017: The in vitro study to investigate the inhibitory effect of baricitinib on OAT2 was completed and refutes any potentially clinically significant inhibitory effect on OAT2. September 2017: The vaccine study was completed. This summary was last updated in Version 2.0, Page 11