OLUMIANT (baricitinib) tablet, film coated [Eli Lilly and Company]

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NDC Code(s): 0002-4182-30,0002-4182-61,0002-4479-30,0002-4479-61, view more 0002-4732-30 Packager: Eli Lilly and Company Category: HUMAN PRESCRIPTION DRUG LABEL Marketing Status: New Drug Application If you are a consumer or patient please visit this version. Download DRUG LABEL INFO: PDF XML Official Label (Printer Friendly) HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use OLUMIANT safely and effectively. See full prescribing information for OLUMIANT. OLUMIANT (baricitinib) tablets, for oral useInitial U. S. Approval: 2018 WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), and THROMBOSIS See full prescribing information for complete boxed warning. Increased risk of serious bacterial, fungal, viral and opportunistic infections leading to hospitalization or death, including tuberculosis (TB). Interrupt treatment with OLUMIANT if serious infection occurs until the infection is controlled. OLUMIANT should not be given to patients with active tuberculosis. Test for latent TB before and during therapy, except for COVID-19;

treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative, latent TB test. (5.1) Higher rate of all-cause mortality, including sudden cardiovascular death with another Janus kinase inhibitor (JAK) vs. TNF blockers in rheumatoid arthritis (RA) patients. (5.2) Malignancies have occurred in patients treated with OLUMIANT. Higher rate of lymphomas and lung cancers with another JAK inhibitor vs. TNF blockers in RA patients. (5.3) Higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) with another JAK inhibitor vs. TNF blockers in RA patients. (5.4) Thrombosis has occurred in patients treated with OLUMIANT. Increased incidence of pulmonary embolism, venous and arterial thrombosis with another JAK inhibitor vs. TNF blockers. (5.5) RECENT MAJOR CHANGES Warnings and Precaucoes (5.8) 06/2026 INDICATIONS AND USAGE OLUMIANT® is a Janus kinase (JAK) inhibitor indicated for: the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF blockers. (1.1) Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine. (1.1) the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO. (1.2) the treatment of adult patients with severe alopecia areata. (1.3) Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants. (1.3) DOSAGE AND ADMINISTRATION Administration Instructions: See the full prescribing information for recommended evaluations and immunizations prior to treatment. (2.1) Rheumatoid Arthritis and Alopecia Areata: Avoid initiation or interrupt OLUMIANT in patients with anemia (hemoglobin Table of Contents FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), and THROMBOSIS 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis 1.2 Coronavirus Disease 2019 (COVID-19) 1.3 Alopecia Areata 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation 2.2 Dosagemm Recommendations in Rheumatoid Arthritis 2.3 Dosagemm Recommendations in COVID-19 2.4 Dosagemm Recommendations in Alopecia Areata 2.5 Dosagemm Modifications Due to Infections, Cytopenias and Anemia 2.6 Dosagemm Modifications for Patients with Renal Impairment or Hepatic Impairment 2.7 Dosagemm Modifications Due to Drug Interactions 2.8 Alternative Administration for Patients Unable to Swallow Tablets 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections 5.2 Mortality 5.3 Malignancy and Lymphoproliferative Disorders 5.4 Major Adverse Cardiovascular Events 5.5 Thrombosis 5.6 Hypersensitivity 5.7 Gastrointestinal Perforations 5.8 Hypoglycemia in Patients with Diabetes 5.9 Laboratory Abnormalities 5.10 Vaccinations 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Strong OAT3 Inhibitors 7.2 Other JAK Inhibitors or Biologic DMARDs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis 14.2 COVID-19 14.3 Alopecia Areata 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. BOXED WARNING (What is this?

) WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), and THROMBOSIS SERIOUS INFECTIONS Patients treated with OLUMIANT are at risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precaucoes (5.1) and Adverse Reactions (6.1)]. Most patients with rheumatoid arthritis who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt OLUMIANT until the infection is controlled. Reported infections include: Active tuberculosis, which may present with pulmonary or extrapulmonary disease. OLUMIANT should not be given to patients with active tuberculosis. Patients, except those with COVID-19, should be tested for latent tuberculosis before initiating OLUMIANT and during therapy. If positive, start treatment for latent infection prior to OLUMIANT use. Invasive fungal infections, including candidiasis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral, and other infections due to opportunistic pathogens. The risks and benefits of treatment with OLUMIANT should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with OLUMIANT including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precaucoes (5.1)]. MORTALITY In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another Janus kinase (JAK) inhibitor to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor [see Warnings and Precaucoes (5.2)]. MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with OLUMIANT. In RA patients treated with another JAK inhibitor, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk [see Warnings and Precaucoes (5.3)]. MAJOR ADVERSE CARDIOVASCULAR EVENTS In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue OLUMIANT in patients that have experienced a myocardial infarction or stroke [see Warnings and Precaucoes (5.4)]. THROMBOSIS Thrombosis, including deep venous thrombosis and pulmonary embolism, has been observed at an increased incidence in patients treated with OLUMIANT compared to placebo. In addition, there were cases of arterial thrombosis. Many of these adverse events were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers. Avoid OLUMIANT in patients at risk. Patients with symptoms of thrombosis should discontinue OLUMIANT and be promptly evaluated. [see Warnings and Precaucoes (5.5)]. 1 INDICATIONS AND USAGE 1.1 Rheumatoid Arthritis OLUMIANT® (baricitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) blockers. Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine. 1.2 Coronavirus Disease 2019 (COVID-19) OLUMIANT is indicated for the treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). 1.3 Alopecia Areata OLUMIANT is indicated for the treatment of adult patients with severe alopecia areata. Limitations of Use: Not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants. 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Evaluations and Immunization Prior to Treatment Initiation Prior to OLUMIANT treatment initiation, consider performing the following evaluations: Active and latent tuberculosis (TB) infection evaluation – OLUMIANT should not be given to patients with active tuberculosis (TB). If latent infection is positive in patients with rheumatoid arthritis or alopecia areata, consider treatment for TB prior to OLUMIANT use [see Warnings and Precaucoes (5.1)]. Viral hepatitis screening in accordance with clinical guidelines [see Warnings and Precaucoes (5.1)]. Complete blood count – Assess baseline values and verify whether treatment can be initiated: – In patients with rheumatoid arthritis or alopecia areata, OLUMIANT initiation is not recommended in patients with an absolute lymphocyte count (ALC) 3 DOSAGE FORMS AND STRENGTHS OLUMIANT is available as debossed, film-coated tablets: 1 mg tablet contains a recessed area on each face of the tablet surface, is very light pink, round, debossed with “Lilly” on one side and “1” on the other. 2 mg tablet contains a recessed area on each face of the tablet surface, is light pink, oblong, debossed with “Lilly” on one side and “2” on the other. 4 mg tablet contains a recessed area on each face of the tablet surface, is medium pink, round, debossed with “Lilly” on one side and “4” on the other. 5 WARNINGS AND PRECAUTIONS 5.1 Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients with rheumatoid arthritis receiving OLUMIANT. The most common serious infections reported with OLUMIANT included pneumonia, herpes zoster, and urinary tract infection [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus were reported with OLUMIANT. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. Avoid use of OLUMIANT in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating OLUMIANT in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or an opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses;

or with underlying conditions that may predispose them to infection. In patients with rheumatoid arthritis or alopecia areata, closely monitor for the development of signs and symptoms of infection during and after treatment with OLUMIANT. Interrupt OLUMIANT in patients with rheumatoid arthritis or alopecia areata, if the patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with OLUMIANT should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient;

appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and OLUMIANT should be interrupted if the patient is not responding to therapy. Do not resume OLUMIANT until the infection is controlled. In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment with OLUMIANT. There is limited information regarding the use of OLUMIANT in patients with COVID-19 and concomitant active serious infections. The risks and benefits of treatment with OLUMIANT in COVID-19 patients with other concurrent infections should be considered. Tuberculosis Evaluate patients for active infection prior to administration of OLUMIANT. OLUMIANT should not be given to patients with active TB. Test patients with rheumatoid arthritis or alopecia areata for latent tuberculosis. Patients with rheumatoid arthritis or alopecia areata and latent tuberculosis (TB) should be treated with standard antimycobacterial therapy before initiating OLUMIANT. Consider anti-TB therapy prior to initiation of OLUMIANT in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. During OLUMIANT use, monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e. g. , herpes zoster), were reported in clinical studies with OLUMIANT. If a patient develops herpes zoster, interrupt OLUMIANT treatment until the episode resolves. The impact of OLUMIANT on chronic viral hepatitis reactivation is unknown. Patients with evidence of active hepatitis B or C infection were excluded from clinical trials. In clinical trials in patients with rheumatoid arthritis or alopecia areata, patients who were positive for hepatitis C antibody but negative for hepatitis C virus RNA were permitted to enroll. Patients with positive hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were permitted to enroll;

such patients should be monitored for expression of hepatitis B virus (HBV) DNA. Should HBV DNA be detected, consult with a hepatologist. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with OLUMIANT. 5.2 Mortality In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OLUMIANT. 5.3 Malignancy and Lymphoproliferative Disorders Malignancies were observed in clinical studies of OLUMIANT [see Adverse Reactions (6.1)]. In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OLUMIANT, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers. Non-melanoma skin cancers Non-melanoma skin cancers (NMSCs) have been reported in patients treated with OLUMIANT. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. 5.4 Major Adverse Cardiovascular Events In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OLUMIANT, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue OLUMIANT in patients that have experienced a myocardial infarction or stroke. 5.5 Thrombosis Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with OLUMIANT compared to placebo. In addition, arterial thrombosis events in the extremities have been reported in clinical studies with OLUMIANT. Many of these adverse events were serious and some resulted in death. There was no clear relationship between platelet count elevations and thrombotic events. In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers. If clinical features of DVT/PE or arterial thrombosis occur, patients should discontinue OLUMIANT and be evaluated promptly and treated appropriately. Avoid OLUMIANT in patients that may be at increased risk of thrombosis. 5.6 Hypersensitivity Reactions such as angioedema, urticaria, and rash that may reflect drug hypersensitivity have been observed in patients receiving OLUMIANT, including serious reactions. If a serious hypersensitivity reaction occurs, promptly discontinue OLUMIANT while evaluating the potential causes of the reaction [see Adverse Reactions (6.2)]. 5.7 Gastrointestinal Perforations Gastrointestinal perforations have been reported in clinical studies with OLUMIANT. Monitor OLUMIANT-treated patients who may be at increased risk for gastrointestinal perforation (e. g. , patients with a history of diverticulitis). Evaluate promptly patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation. 5.8 Hypoglycemia in Patients with Diabetes Hypoglycemia, including severe hypoglycemia, has been reported following initiation of OLUMIANT and other JAK inhibitors in patients with diabetes. During treatment with OLUMIANT, consider increased monitoring of blood glucose as clinically indicated in patients with diabetes. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia. 5.9 Laboratory Abnormalities Neutropenia – Treatment with OLUMIANT was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3) compared to placebo. In patients with rheumatoid arthritis or alopecia areata, avoid initiation or interrupt OLUMIANT treatment in patients with an ANC less than 1000 cells/mm3. In patients with COVID-19, there is limited information regarding use of OLUMIANT in patients with ANC less than 1000 cells/mm3. Avoid initiation or interrupt OLUMIANT treatment in patients with COVID-19 and an ANC less than 500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. Adjust dosing based on ANC [see Dosagemm and Administration (2.1,2.5) and Adverse Reactions (6.1)]. Lymphopenia – ALC less than 500 cells/mm3 were reported in OLUMIANT clinical trials. Lymphocyte counts less than the lower limit of normal were associated with infection in patients treated with OLUMIANT, but not placebo. In patients with rheumatoid arthritis or alopecia areata, avoid initiation or interrupt OLUMIANT treatment in patients with an ALC less than 500 cells/mm3. In patients with COVID-19, there is limited information regarding use of OLUMIANT in patients with ALC less than 200 cells/mm3. Avoid initiation or interrupt OLUMIANT treatment in patients with COVID-19 and an ALC less than 200 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. Adjust dosing based on ALC [see Dosagemm and Administration (2.1,2.5)]. Anemia – Decreases in hemoglobin levels to less than 8 g/dL were reported in OLUMIANT clinical trials. In patients with rheumatoid arthritis or alopecia areata, avoid initiation or interrupt OLUMIANT treatment in patients with hemoglobin less than 8 g/dL. Evaluate at baseline and thereafter according to routine patient management. Adjust dosing based on hemoglobin levels [see Dosagemm and Administration (2.1,2.5)]. In patients with COVID-19, there is limited information regarding use of OLUMIANT in patients with hemoglobin less than 8 g/dL. Liver Enzyme Elevations – Treatment with OLUMIANT was associated with increased incidence of liver enzyme elevation compared to placebo. Increases of ALT ≥5 times the upper limit of normal (ULN) and increases of AST ≥10 times the ULN were observed in patients in OLUMIANT clinical trials. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt OLUMIANT until this diagnosis is excluded [see Adverse Reactions (6.1)]. Lipid Elevations – Treatment with OLUMIANT was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Assessment of lipid parameters should be performed approximately 12 weeks following OLUMIANT initiation in patients with rheumatoid arthritis or alopecia areata [see Adverse Reactions (6.1)]. Manage patients according to clinical guidelines for the management of hyperlipidemia. 5.10 Vaccinations Avoid use of live vaccines with OLUMIANT. Update immunizations in patients with rheumatoid arthritis or alopecia areata prior to initiating OLUMIANT therapy in agreement with current immunization guidelines. 6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precaucoes (5.1)] Mortality [see Warnings and Precaucoes (5.2)] Malignancy and Lymphoproliferative Disorders [see Warnings and Precaucoes (5.3)] Major Adverse Cardiovascular Events [see Warnings and Precaucoes (5.4)] Thrombosis [see Warnings and Precaucoes (5.5)] Hypersensitivity [see Warnings and Precaucoes (5.6)] Gastrointestinal Perforations [see Warnings and Precaucoes (5.7)] Hypoglycemia in Patients with Diabetes [see Warnings and Precaucoes (5.8)] Laboratory Abnormalities [see Warnings and Precaucoes (5.9)] 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. Adverse Reactions in Patients with Rheumatoid Arthritis The safety of OLUMIANT was evaluated in six randomized double-blind placebo-controlled studies (three Phase 2, three Phase 3) and a long-term extension study in patients with moderately to severely active RA. Patients were randomized to placebo (1070 patients), OLUMIANT 2 mg (479 patients), or baricitinib 4 mg (997 patients). Patients could be switched to baricitinib 4 mg from placebo or OLUMIANT 2 mg from as early as Week 12 depending on the study design. All patients initially randomized to placebo were switched to baricitinib 4 mg by Week 24. During the 16-week treatment period, adverse events leading to discontinuation of treatment were reported by 35 patients (11.4 per 100 patient-years) treated with placebo, 17 patients (12.1 per 100 patient-years) with OLUMIANT 2 mg, and 40 patients (13.4 per 100 patient-years) treated with baricitinib 4 mg. During 0 to 52-week exposure, adverse events leading to discontinuation of treatment were reported by 31 patients (9.2 per 100 patient-years) with OLUMIANT 2 mg, and 92 patients (10.2 per 100 patient-years) treated with baricitinib 4 mg. Overall Infections – During the 16-week treatment period, infections were reported by 253 patients (82.1 per 100 patient-years) treated with placebo, 139 patients (99.1 per 100 patient-years) treated with OLUMIANT 2 mg, and 298 patients (100.1 per 100 patient-years) treated with baricitinib 4 mg. During 0 to 52-week exposure, infections were reported by 200 patients (59.6 per 100 patients-years) treated with OLUMIANT 2 mg, and 500 patients (55.3 per 100 patient-years) treated with baricitinib 4 mg. In the 0 to 52-week exposure population, the most commonly reported infections with OLUMIANT were viral upper respiratory tract infection, upper respiratory tract infection, urinary tract infection, and bronchitis. Serious Infections – During the 16-week treatment period, serious infections were reported in 13 patients (4.2 per 100 patient-years) treated with placebo, 5 patients (3.6 per 100 patient-years) treated with OLUMIANT 2 mg, and 11 patients (3.7 per 100 patient-years) treated with baricitinib 4 mg. During 0 to 52-week exposure, serious infections were reported in 14 patients (4.2 per 100 patient-years) treated with OLUMIANT 2 mg and 32 patients (3.5 per 100 patient-years) treated with baricitinib 4 mg. In the 0 to 52-week exposure population, the most commonly reported serious infections with OLUMIANT were pneumonia, herpes zoster, and urinary tract infection [see Warnings and Precaucoes (5.1)]. Tuberculosis – During the 16-week treatment period, no events of tuberculosis were reported. During 0 to 52-week exposure, events of tuberculosis were reported in 0 patients treated with OLUMIANT 2 mg and 1 patient (0.1 per 100 patient-years) treated with baricitinib 4 mg [see Warnings and Precaucoes (5.1)]. Cases of disseminated tuberculosis were also reported. Opportunistic Infections (excluding tuberculosis) – During the 16-week treatment period, opportunistic infections were reported in 2 patients (0.6 per 100 patient-years) treated with placebo, 0 patients treated with OLUMIANT 2 mg and 2 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg. During 0 to 52-week exposure, opportunistic infections were reported in 1 patient (0.3 per 100 patient-years) treated with OLUMIANT 2 mg and 5 patients (0.6 per 100 patient-years) treated with baricitinib 4 mg [see Warnings and Precaucoes (5.1)]. Malignancies During the 16-week treatment period, malignancies excluding non-melanoma skin cancers (NMSC) were reported in 0 patients treated with placebo, 1 patient (0.7 per 100 patient-years) treated with OLUMIANT 2 mg, and 1 patient (0.3 per 100 patient-years) treated with baricitinib 4 mg. During the 0 to 52-week treatment period, malignancies excluding NMSC were reported in 2 patients (0.6 per 100 patient-years) treated with OLUMIANT 2 mg and 6 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg [see Warnings and Precaucoes (5.3)]. Thrombosis Venous Thrombosis – During the 16-week treatment period, venous thromboses (deep vein thrombosis or pulmonary embolism) were reported in 0 patients treated with placebo, 0 patients treated with OLUMIANT 2 mg, and 5 patients (1.7 per 100 patient-years) treated with baricitinib 4 mg. During the 0 to 52-week treatment period, venous thromboses were reported in 2 patients (0.6 per 100 patient-years) treated with OLUMIANT 2 mg and 7 patients (0.8 per 100 patient-years) treated with baricitinib 4 mg. Arterial Thrombosis – During the 16-week treatment period, arterial thromboses were reported in 1 patient treated with placebo (0.3 per 100 patient-years), 2 patients (1.4 per 100 patient-years) treated with OLUMIANT 2 mg, and 2 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg. During the 0 to 52-week treatment period, arterial thromboses were reported in 3 patients (0.9 per 100 patient-years) treated with OLUMIANT 2 mg and 3 patients (0.3 per 100 patient-years) treated with baricitinib 4 mg. Laboratory Abnormalities Neutropenia – During the 16-week treatment period, neutrophil counts below 1000 cells/mm3 occurred in 0% of patients treated with placebo, 0.6% of patients treated with OLUMIANT 2 mg, and 0.3% of patients treated with baricitinib 4 mg. There were no neutrophil counts below 500 cells/mm3 observed in any treatment group [see Warnings and Precaucoes (5.1,5.9)]. Platelet Elevations – During the 16-week treatment period, increases in platelet counts above 600,000 cells/mm3 occurred in 1.1% of patients treated with placebo, 1.1% of patients treated with OLUMIANT 2 mg, and 2.0% of patients treated with baricitinib 4 mg. Mean platelet count increased by 3000 cells/mm3 at 16 weeks in patients treated with placebo, by 15,000 cells/mm3 at 16 weeks in patients treated with OLUMIANT 2 mg and by 23,000 cells/mm3 in patients treated with baricitinib 4 mg. Liver Enzyme Elevations – Events of increases in liver enzymes ≥3 times the ULN were observed in patients treated with OLUMIANT [see Warnings and Precaucoes (5.9)]. During the 16-week treatment period, ALT elevations ≥3 times the ULN occurred in 1.0% of patients treated with placebo, 1.7% of patients treated with OLUMIANT 2 mg, and 1.4% of patients treated with baricitinib 4 mg. During the 16-week treatment period, AST elevations ≥ 3 times the ULN occurred in 0.8% of patients treated with placebo, 1.3% of patients treated with OLUMIANT 2 mg, and 0.8% of patients treated with baricitinib 4 mg. In a phase 3 study of DMARD naive patients, during the 24-week treatment period, ALT and AST elevations ≥3 times the ULN occurred in 1.9% and 0% of patients treated with methotrexate monotherapy, 1.9% and 1.3% of patients treated with baricitinib 4 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib 4 mg plus methotrexate. Lipid Elevations – In controlled clinical trials, OLUMIANT treatment was associated with dose-related increases in lipid parameters including total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. Elevations were observed at 12 weeks and remained stable thereafter. During the 12-week treatment period, changes in lipid parameters are summarized below: Mean LDL cholesterol increased by 8 mg/dL in patients treated with OLUMIANT 2 mg and by 14 mg/dL in patients treated with baricitinib 4 mg. Mean HDL cholesterol increased by 7 mg/dL in patients treated with OLUMIANT 2 mg and by 9 mg/dL in patients treated with baricitinib 4 mg. The mean LDL/HDL ratio remained stable. Mean triglycerides increased by 7 mg/dL in patients treated with OLUMIANT 2 mg and by 15 mg/dL in patients treated with baricitinib 4 mg. [See Warnings and Precaucoes (5.9)]. Creatine Phosphokinase (CPK) – OLUMIANT treatment was associated with increases in CPK within one week of starting OLUMIANT and plateauing after 8 to 12 weeks. At 16 weeks, the mean change in CPK for OLUMIANT 2 mg and baricitinib 4 mg was 37 IU/L and 52 IU/L, respectively. Creatinine – In controlled clinical trials, dose-related increases in serum creatinine were observed with OLUMIANT treatment. At 52 weeks, the mean increase in serum creatinine was less than 0.1 mg/dL with baricitinib 4 mg. The clinical significance of the observed serum creatinine increases is unknown. Other Adverse Reactions Other adverse reactions are summarized in Table 8. Table 8: Adverse Reactions Occurring in Greater Than or Equal to 1% of OLUMIANT 2 mg and Baricitinib 4 mg Treated Patients in Placebo-Controlled Trials for Rheumatoid Arthritis a Includes acute sinusitis, acute tonsillitis, chronic tonsillitis, epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinobronchitis, sinusitis, tonsillitis, tracheitis, and upper respiratory tract infection. b Includes eczema herpeticum, genital herpes, herpes simplex, ophthalmic herpes simplex, and oral herpes. EventsWeeks 0-16 PlaceboOLUMIANT 2 mgBaricitinib 4 mg n=1070 (%)n=479 (%)n=997 (%) Upper respiratory tract infectionsa11.7 16.3 14.7 Nausea 1.6 2.7 2.8 Herpes simplexb0.7 0.8 1.8 Herpes zoster 0.4 1.0 1.4 Additional adverse drug reactions occurring in fewer than 1% of patients: acne. Adverse Reactions in Patients with COVID-19 The safety of OLUMIANT was evaluated in two randomized, double-blind, placebo-controlled clinical trials of hospitalized adults with COVID-19 for up to 29 days, in which 1307 patients received at least one dose of OLUMIANT 4 mg once daily, and 1310 patients received placebo, for up to 14 days or until hospital discharge, whichever occurred first. In these studies, prophylaxis for venous thromboembolic event (VTEs) was recommended or required for all patients unless a major contraindication was noted. Overall, the safety profile observed in patients with COVID-19 treated with OLUMIANT was consistent with the safety profile in patients with rheumatoid arthritis. Overall Infections – During the first 29 days of the randomized clinical trials, infections were reported in 194 patients (14.8%) treated with OLUMIANT 4 mg and by 219 patients (16.7%) treated with placebo. The most commonly reported infection with OLUMIANT was pneumonia (3.1%). Serious Infections – During the first 29 days of the randomized clinical trials, serious infections were reported in 98 patients (7.5%) treated with OLUMIANT 4 mg and 120 patients (9.2%) treated with placebo. The most commonly reported serious infections with OLUMIANT were COVID-19 pneumonia (2.1%) and septic shock (2.1%). Opportunistic Infections – During the first 29 days of the randomized clinical trials, opportunistic infections were reported in 12 patients (0.9%) treated with OLUMIANT 4 mg and 14 patients (1.1%) treated with placebo. Tuberculosis was reported in 1 patient (0.1%) treated with OLUMIANT 4 mg and 0 patients treated with placebo. Venous Thrombosis Events – During the first 29 days of the randomized clinical trials, pulmonary embolism was reported in 20 patients (1.5%) treated with OLUMIANT 4 mg and 11 patients (0.8%) treated with placebo. Deep vein thrombosis was reported in 20 patients (1.5%) treated with OLUMIANT 4 mg and 18 patients (1.4%) treated with placebo. Adverse drug reactions in greater than or equal to 1% of patients in trials for COVID-19 are summarized in Table 9. Table 9: Adverse Reactions That Occurred in Greater Than or Equal to 1% of Patients Treated with OLUMIANT 4 mg During the First 29 Days in Placebo-Controlled Trials for COVID-19 a As assessed by measured values within the clinical trial database. Frequencies are based on shifts from pre-treatment to post-treatment (with number at risk as the denominator), except for ALT and AST for which frequencies are based on observed elevation during treatment. b Creatine phosphokinase frequencies presented in the table were available for a single trial (COVID II) in patients with COVID-19 and do not represent integrated data. Placebo N = 1310 n (%)OLUMIANT 4 mgN = 1307 n (%) ALT ≥3 x ULNa201(16.0) 230 (18.1) AST ≥3 x ULNa117 (9.4) 149 (11.8) Thrombocytosis >600,000 cells/mm3a34 (4.6) 59 (7.9) Creatine phosphokinase (CPK) >5 x ULNa, b38 (4.7) 36 (4.5) Neutropenia 7 DRUG INTERACTIONS 7.1 Strong OAT3 Inhibitors Baricitinib exposure is increased when OLUMIANT is co-administered with strong OAT3 inhibitors (such as probenecid), hence the dosage of baricitinib should be reduced by half the recommended dose [see Dosagemm and Administration (2.2,2.3) and Clinical Pharmacology (12.3)]. 7.2 Other JAK Inhibitors or Biologic DMARDs OLUMIANT has not been studied in combination with other JAK inhibitors or with biologic DMARDs [see Indicacoes and Usage (1.1,1.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on the findings from animal reproduction studies, OLUMIANT may cause fetal harm during pregnancy. Available data from clinical trials and postmarketing case reports with OLUMIANT exposure in pregnancy are insufficient to inform a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are no human data on chronic baricitinib exposure throughout pregnancy. There are risks to the mother and the fetus associated with rheumatoid arthritis in pregnancy (see Clinical Considerations). Consider the risks and benefits with chronic use of OLUMIANT during pregnancy. In animal embryo-fetal development studies, oral baricitinib administration to pregnant rats and rabbits at exposures equal to and greater than approximately 11 and 46 times the maximum recommended human dose (MRHD) of 4 mg/day, respectively, resulted in reduced fetal body weights, increased embryolethality (rabbits only), and dose-related increases in skeletal malformations. No developmental toxicity was observed in pregnant rats and rabbits treated with oral baricitinib during organogenesis at approximately 2 and 7 times the exposure at the MRHD, respectively. In a pre- and post-natal development study in pregnant female rats, oral baricitinib administration at exposures approximately 24 times the MRHD resulted in reduction in pup viability (increased incidence of stillborn pups and early neonatal deaths), decreased fetal birth weight, reduced fetal body weight gain, decreased cytotoxic T cells on post-natal day (PND) 35 with evidence of recovery by PND 65, and developmental delays that might be attributable to decreased body weight gain. No developmental toxicity was observed at an exposure approximately 5 times the exposure at the MRHD (see Data). The background risks of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U. S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Report pregnancies to Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979). Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth. Data Animal Data In an embryofetal development study in pregnant rats, dosed orally during the period of organogenesis from gestation days 6 to 17, baricitinib was teratogenic (skeletal malformations that consisted of bent limb bones and rib anomalies) at exposures equal to or greater than approximately 11 times the MRHD (on an AUC basis at maternal oral doses of 10 mg/kg/day and higher). No developmental toxicity was observed in rats at an exposure approximately 2 times the MRHD (on an AUC basis at a maternal oral dose of 2 mg/kg/day). In an embryofetal development study in pregnant rabbits, dosed orally during the period of organogenesis from gestation days 7 to 20, embryolethality, decreased fetal body weights, and skeletal malformations (rib anomalies) were observed in the presence of maternal toxicity at an exposure approximately 46 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both early and late resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 7 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day). In a pre- and post-natal development study in pregnant female rats dosed orally from gestation day 6 through lactation day 20, adverse findings observed in pups included decreased survival from birth to post-natal day 4 (due to increased stillbirths and early neonatal deaths), decreased birth weight, decreased body weight gain during the pre-weaning phase, increased incidence of malrotated forelimbs during the pre-weaning phase, and decreased cytotoxic T cells on PND 35 with recovery by PND 65 at exposures approximately 24 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Developmental delays (that may be secondary to decreased body weight gain) were observed in males and females at exposures approximately 24 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). These findings included decreased forelimb and hindlimb grip strengths, and delayed mean age of sexual maturity. No developmental toxicity was observed in rats at an exposure approximately 5 times the MRHD (on an AUC basis at a maternal oral dose of 5 mg/kg/day). 8.2 Lactation Risk Summary No information is available on the presence of OLUMIANT in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Baricitinib is present in the milk of lactating rats (see Data). Because of the potential for serious adverse reactions in nursing infants advise women not to breastfeed during treatment with OLUMIANT and for 4 days after the last dose (approximately 5 to 6 elimination half-lives). Data A single oral dose of 25 mg/kg radiolabeled baricitinib was administered to lactating female Sprague-Dawley rats on post-partum day 13. Drug exposure was approximately 45-fold greater in milk than in plasma based on AUC0-t values. 8.3 Females and Males of Reproductive Potential Contraception Based on animal studies, OLUMIANT may cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Consider pregnancy planning and prevention for females of reproductive potential. 8.4 Pediatric Use The safety and effectiveness of OLUMIANT in pediatric patients have not been established. 8.5 Geriatric Use Of the 3100 patients treated in the rheumatoid arthritis clinical trials, a total of 537 patients were 65 years of age and older, including 71 patients 75 years of age and older. Of the 2558 patients treated in the COVID-19 clinical trials, a total of 791 were 65 years of age and older, including 295 patients 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)]. Of the 1200 patients in the alopecia areata clinical trials, a total of 29 patients were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they respond differently from younger patients. OLUMIANT is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because geriatric patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosagemm and Administration (2.6)]. 8.6 Hepatic Impairment No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The use of OLUMIANT has not been studied in patients with rheumatoid arthritis or alopecia areata and severe hepatic impairment and is therefore not recommended. OLUMIANT has not been studied in patients with COVID-19 and severe hepatic impairment. OLUMIANT should only be used in patients with COVID-19 and severe hepatic impairment if the potential benefit outweighs the potential risk [see Dosagemm and Administration (2.6) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Renal function was found to significantly affect baricitinib exposure. Rheumatoid Arthritis and Alopecia Areata – The recommended dosage of OLUMIANT in patients with moderate renal impairment (estimated glomerular filtration rate (GFR) between 30 and 10 OVERDOSAGE Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have been administered in clinical trials without dose-limiting toxicity. Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate that more than 90% of the administered dose is expected to be eliminated within 24 hours. In case of an overdose, it is recommended that the patient should be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment. 11 DESCRIPTION OLUMIANT (baricitinib) is a Janus kinase (JAK) inhibitor with the chemical name {1-(ethylsulfonyl)-3- pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. Baricitinib has an empirical formula of C16H17N7O2S and a molecular weight of 371.42. Baricitinib has the following structural formula: OLUMIANT tablets contain a recessed area on each face of the tablet surface and are available for oral administration as debossed, film-coated tablets. The 1 mg tablet is very light pink, round, debossed with “Lilly” on one side and “1” on the other. The 2 mg tablet is light pink, oblong, debossed with “Lilly” on one side and “2” on the other. The 4 mg tablet is medium pink, round, debossed with “Lilly” on one side and “4” on the other. Each tablet contains 1,2, or 4 mg of baricitinib and the following inactive ingredients: croscarmellose sodium, ferric oxide, lecithin (soya), magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Baricitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Baricitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through their pairing (e. g. , JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In cell-free isolated enzyme assays, baricitinib had greater inhibitory potency at JAK1, JAK2 and TYK2 relative to JAK3. In human leukocytes, baricitinib inhibited cytokine induced STAT phosphorylation mediated by JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 with comparable potencies. However, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. 12.2 Pharmacodynamics Baricitinib inhibition of IL-6 induced STAT3 phosphorylation – Baricitinib administration resulted in a dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed approximately 1 hour after dosing, which returned to near baseline by 24 hours. Similar levels of inhibition were observed using either IL-6 or TPO as the stimulus. Immunoglobulins – Mean serum IgG, IgM, and IgA values decreased by 12 weeks after starting treatment with OLUMIANT, and remained stable through at least 52 weeks. For most patients, changes in immunoglobulins occurred within the normal reference range. C-reactive protein – In patients with rheumatoid arthritis, decreases in serum C-reactive protein (CRP) were observed as early as one week after starting treatment with OLUMIANT and were maintained throughout dosing. Cardiac Electrophysiology – At a dose 10 times the maximum recommended dose, baricitinib does not prolong the QT interval to any clinically relevant extent. 12.3 Pharmacokinetics Following oral administration of OLUMIANT, peak plasma concentrations are reached approximately at 1 hour. A dose-proportional increase in systemic exposure was observed in the therapeutic dose range. The pharmacokinetics of baricitinib do not change over time. Steady-state concentrations are achieved in 2 to 3 days with minimal accumulation after once-daily administration. Absorption – The absolute bioavailability of baricitinib is approximately 80%. An assessment of food effects in healthy subjects showed that a high-fat meal decreased the mean AUC and Cmax of baricitinib by approximately 11% and 18%, respectively, and delayed the tmax by 0.5 hours. Administration with meals is not associated with a clinically relevant effect on exposure. In clinical studies, OLUMIANT was administered without regard to meals. Distribution – After intravenous administration, the volume of distribution is 76 L, indicating distribution of baricitinib into tissues. Baricitinib is approximately 50% bound to plasma proteins and 45% bound to serum proteins. Baricitinib is a substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution. Elimination Rheumatoid Arthritis and Alopecia Areata: The total body clearance of baricitinib is 8.9 L/h in patients with rheumatoid arthritis and 11 L/h in patients with alopecia areata. Elimination half-life in patients with rheumatoid arthritis and alopecia areata is approximately 12 to 16 hours. COVID-19: The total body clearance and half-life of baricitinib is 14.2 L/h and 10.8 hours, respectively, in patients with COVID-19 who are intubated and have baricitinib administered via NG or OG tube. Metabolism – Approximately 6% of the orally administered baricitinib dose is identified as metabolites (three from urine and one from feces), with CYP3A4 identified as the main metabolizing enzyme. No metabolites of baricitinib were quantifiable in plasma. Excretion – Renal elimination is the principal clearance mechanism for baricitinib through filtration and active secretion as baricitinib is identified as a substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies. In a clinical pharmacology study, approximately 75% of the administered dose was eliminated in the urine, while about 20% of the dose was eliminated in the feces. Baricitinib was excreted predominately as unchanged drug in urine (69%) and feces (15%). Specific Populations Effects of Body Weight, Gender, Race, and Age Body weight, gender, race, ethnicity, and age did not have a clinically relevant effect on the PK (AUC and Cmax) of baricitinib (Figure 1). The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the inter-subject PK variability of baricitinib. The inter-subject variabilities (% coefficients of variation) in AUC and Cmax of baricitinib are approximately 41% and 22%, respectively, in patients with rheumatoid arthritis [see Use in Specific Populations (8.5)]. Patients with Renal Impairment Baricitinib systemic exposure in AUC was increased by 1.41-, 2.22-, 4.05- and 2.41-fold for mild, moderate, severe, and ESRD (with hemodialysis) renal impairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in Cmax were 1.16-, 1.46-, 1.40- and 0.88-fold, respectively (Figure 1) [see Use in Specific Populations (8.7)]. Patients with Hepatic Impairment Baricitinib systemic exposure and Cmax increased by 1.19- and 1.08-fold for the moderate hepatic impairment group, respectively, compared to subjects with normal hepatic function (Figure 1) [see Use in Specific Populations (8.6)]. Figure 1: Impact of Intrinsic Factors on Baricitinib Pharmacokineticsa, b a Reference values for weight, age, gender, and race comparisons are 70 kg, 54 years, male, and white, respectively;

reference groups for renal and hepatic impairment are subjects with normal renal and hepatic function, respectively. b Effects of renal and hepatic impairment on baricitinib exposure were summarized from dedicated renal and hepatic impairment studies, respectively. Effects of other intrinsic factors on baricitinib exposure were summarized from population PK analysis. c The recommended dose for patients with COVID-19 and severe renal impairment (eGFR 15 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of baricitinib was evaluated in Sprague-Dawley rats and Tg. rasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received baricitinib for 91 to 94 weeks at oral doses up to 8 or 25 mg/kg/day, respectively (approximately 7 and 30 times the MRHD on an AUC basis). No evidence of tumorigenicity was observed in Tg. rasH2 mice that received baricitinib for 26 weeks at oral doses up to 300 and 150 mg/kg/day in male and female mice, respectively. Baricitinib tested negative in the following genotoxicity assays: the in vitro bacterial mutagenicity assay (Ames assay), in vitro chromosome aberration assay in human peripheral blood lymphocytes, and in vivo rat bone marrow micronucleus assay. Fertility (achievement of pregnancy) was reduced in male and female rats that received baricitinib at oral doses of 50 and 100 mg/kg/day respectively (approximately 62 and 93 times the MRHD in males and females, respectively, on an AUC basis) based upon findings that 7 of 19 (36.8%) drug-treated females with evidence of mating were not gravid compared to 1 of 19 (5.3%) control females. It could not be determined from the study design if these findings were attributable to toxicities in one sex or both. Fertility was unaffected in male and female rats at oral doses of 15 mg/kg and 25 mg/kg, respectively (approximately 13 and 26 times the MRHD on an AUC basis). However, maintenance of pregnancy was adversely affected at these doses based upon findings of increased post-implantation losses (early resorptions) and decreased numbers of mean viable embryos per litter. The number of viable embryos was unaffected in female rats that received baricitinib at an oral dose of 5 mg/kg/day and were mated to males that received the same dose (approximately 6 times the MRHD on an AUC basis). Reproductive performance was unaffected in male and female rats that received baricitinib at oral doses up to 50 and 100 mg/kg/day respectively (approximately 62 and 93 times the MRHD in males and females, respectively, on an AUC basis). 14 CLINICAL STUDIES 14.1 Rheumatoid Arthritis The OLUMIANT clinical development program included two dose-ranging trials and four confirmatory phase 3 trials in patients with rheumatoid arthritis (RA). Although other doses have been studied, the recommended dosage of OLUMIANT is 2 mg once daily. Dose-Ranging Studies The dose-ranging studies RA-1 (NCT01185353) and RA-2 (NCT01469013) included a 12-week randomized comparison of baricitinib 1,2,4, and 8 mg orally once daily versus placebo in 301 and 145 patients, respectively. The results from the dose-ranging studies are shown in Table 11. In dose-ranging Study RA-1, the observed ACR response was similar for baricitinib 1 and 2 mg daily and for baricitinib 4 and 8 mg daily, with the highest response for baricitinib 8 mg daily. In dose-ranging Study RA-2, there was not a clear trend of dose response, with similar response rates for 1 mg and 4 mg and 2 mg and 8 mg. Table 11: Proportion of Patients with ACR20 Response at Week 12 in Dose-Ranging RA Studies % ACR20 Responders Dose-Ranging StudyPlaceboBaricitinib 1 mg dailyBaricitinib 2 mg dailyBaricitinib 4 mg dailyBaricitinib 8 mg daily RA-1 (N=301) 41 57 54 75 78 RA-2 (N=145) 31 67 83 67 88 Confirmatory Studies The efficacy and safety of OLUMIANT 2 mg once daily was assessed in two confirmatory phase 3 trials. These trials were randomized, double-blind, multicenter studies in patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR)/European League Against Rheumatism 2010 criteria. Patients over 18 years of age were eligible if at least 6 tender and 6 swollen joints were present at baseline. The two studies (Studies RA-3 and RA-4) evaluated OLUMIANT 2 mg and baricitinib 4 mg. Study RA-3 (NCT01721057) was a 24-week trial in 684 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to conventional DMARDs (cDMARDs). Patients received OLUMIANT 2 mg or 4 mg once daily or placebo added to existing background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. Study RA-4 (NCT01721044) was a 24-week trial in 527 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to 1 or more TNF inhibitor therapies with or without other biologic DMARDs (TNFi-IR). Patients received OLUMIANT 2 mg or baricitinib 4 mg once daily or placebo added to background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12. Clinical Response The percentages of OLUMIANT-treated patients achieving ACR20, ACR50, and ACR70 responses, and Disease Activity Score (DAS28-CRP) 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied OLUMIANT for oral administration is available as debossed, film-coated, tablets. Each tablet contains a recessed area on each face of the tablet surface. OLUMIANT Tablets1 mg 2 mg 4 mg ColorVery Light Pink Light Pink Medium Pink ShapeRound Oblong Round IdentificationLilly Lilly Lilly 1 2 4 NDC Codes Bottle of 300002-4732-30 0002-4182-30 0002-4479-30 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F);

excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep out of reach of children. PACKAGE LABEL – OLUMIANT 2 mg 30ct Bottle Rx Only Always Dispense with Medication Guide NDC 0002-4182-30 Olumiant® (baricitinib) tablets 2 mg 30 tablets Lilly PACKAGE LABEL – OLUMIANT 1 mg 30ct Bottle Rx Only Always Dispense with Medication Guide NDC 0002-4732-30 Olumiant® (baricitinib) tablets 1 mg 30 tablets Lilly PACKAGE LABEL – OLUMIANT 4 mg 30ct Bottle Rx Only Always Dispense with Medication Guide NDC 0002-4479-30 Olumiant® (baricitinib) tablets 4 mg 30 tablets Lilly INGREDIENTS AND APPEARANCE OLUMIANT baricitinib tablet, film coated Informacoes do produtormation Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0002-4182 Route of AdministrationORAL Active Ingredient/Active Moiety Ingredient NameBasis of StrengthStrength baricitinib (UNII: ISP4442I3Y) (baricitinib – UNII: ISP4442I3Y) baricitinib2 mg Inactive Ingredients Ingredient NameStrength Mannitol (UNII: 3OWL53L36A) Microcrystalline Cellulose (UNII: OP1R32D61U) Croscarmellose Sodium (UNII: M28OL1HH48) Magnesium Stearate (UNII: 70097M6I30) Polyvinyl Alcohol, Unspecified (UNII: 532B59J990) Titanium Dioxide (UNII: 15FIX9V2JP) Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A) Talc (UNII: 7SEV7J4R1U) Soybean Lecithin (UNII: 1DI56QDM62) Ferric Oxide Red (UNII: 1K09F3G675) Product Characteristics Colorpink (light pink) Scoreno score ShapeOVAL (oblong) Size9mm FlavorImprint Code Lilly;

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Type 0: Not a Combination Product05/31/2018 Marketing Information Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date NDANDA20792405/31/2018 OLUMIANT baricitinib tablet, film coated Informacoes do produtormation Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0002-4732 Route of AdministrationORAL Active Ingredient/Active Moiety Ingredient NameBasis of StrengthStrength baricitinib (UNII: ISP4442I3Y) (baricitinib – UNII: ISP4442I3Y) baricitinib1 mg Inactive Ingredients Ingredient NameStrength Mannitol (UNII: 3OWL53L36A) Microcrystalline Cellulose (UNII: OP1R32D61U) Croscarmellose Sodium (UNII: M28OL1HH48) Magnesium Stearate (UNII: 70097M6I30) Polyvinyl Alcohol, Unspecified (UNII: 532B59J990) Titanium Dioxide (UNII: 15FIX9V2JP) Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A) Talc (UNII: 7SEV7J4R1U) Soybean Lecithin (UNII: 1DI56QDM62) Ferric Oxide Red (UNII: 1K09F3G675) Product Characteristics Colorpink (very light pink) Scoreno score ShapeROUND (round) Size7mm FlavorImprint Code Lilly;

1 Contains Packaging #Item CodePackage DescriçãoMarketing Start DateMarketing End Date 1NDC: 0002-4732-3030 in 1 BOTTLE;

Type 0: Not a Combination Product10/08/2019 Marketing Information Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date NDANDA20792410/08/2019 OLUMIANT baricitinib tablet, film coated Informacoes do produtormation Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0002-4479 Route of AdministrationORAL Active Ingredient/Active Moiety Ingredient NameBasis of StrengthStrength baricitinib (UNII: ISP4442I3Y) (baricitinib – UNII: ISP4442I3Y) baricitinib4 mg Inactive Ingredients Ingredient NameStrength Mannitol (UNII: 3OWL53L36A) Microcrystalline Cellulose (UNII: OP1R32D61U) Croscarmellose Sodium (UNII: M28OL1HH48) Magnesium Stearate (UNII: 70097M6I30) Polyvinyl Alcohol, Unspecified (UNII: 532B59J990) Titanium Dioxide (UNII: 15FIX9V2JP) Polyethylene Glycol, Unspecified (UNII: 3WJQ0SDW1A) Talc (UNII: 7SEV7J4R1U) Soybean Lecithin (UNII: 1DI56QDM62) Ferric Oxide Red (UNII: 1K09F3G675) Product Characteristics Colorpink (medium pink) Scoreno score ShapeROUND (round) Size9mm FlavorImprint Code Lilly;

4 Contains Packaging #Item CodePackage DescriçãoMarketing Start DateMarketing End Date 1NDC: 0002-4479-3030 in 1 BOTTLE; Type 0: Not a Combination Product05/10/2022 2NDC: 0002-4479-6130 in 1 BOTTLE;

Type 0: Not a Combination Product05/10/2022 Marketing Information Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date NDANDA20792405/10/2022 Labeler – Eli Lilly and Company (006421325) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. 1.2 Coronavirus Disease 2019 (COVID-19)