1 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 ) 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions ( 5.1 )] Mortality [see Warnings and Precautions ( 5.2 )] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions ( 5.3 )] Major Adverse Cardiovascular Events [see Warnings and Precautions ( 5.4 )] Thrombosis [see Warnings and Precautions ( 5.5 )] Hypersensitivity [see Warnings and Precautions ( 5.6 )] Gastrointestinal Perforations [see Warnings and Precautions ( 5.7 )] Laboratory Abnormalities [see Warnings and Precautions ( 5.8 )] Adverse reactions reported in clinical trials (≥1%) are: Rheumatoid Arthritis : upper respiratory tract infections (URTIs), nausea, herpes simplex, and herpes zoster.

( 6.1 ) COVID-19: increases of liver enzymes, thrombocytosis, creatine phosphokinase increases, neutropenia, deep vein thrombosis, pulmonary embolism, and urinary tract infection (UTI) ( 6.1 ) Alopecia Areata : URTIs, headache, acne, hyperlipidemia, creatine phosphokinase increase, UTI, liver enzyme elevations, folliculitis, fatigue, lower respiratory tract infections, nausea, genital Candida infections, anemia, neutropenia, abdominal pain, herpes zoster, and weight increase ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 Precautions ( 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 Precautions ( 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 Precautions ( 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 Precautions ( 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/mm 3 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/mm 3 observed in any treatment group [see Warnings and Precautions ( 5.1 , 5.8 )] .

Platelet Elevations – During the 16-week treatment period, increases in platelet counts above 600,000 cells/mm 3 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/mm 3 at 16 weeks in patients treated with placebo, by 15,000 cells/mm 3 at 16 weeks in patients treated with OLUMIANT 2 mg and by 23,000 cells/mm 3 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 Precautions ( 5.8 )] .

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 Precautions ( 5.8 )].

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.

Events Weeks 0-16 Placebo OLUMIANT 2 mg Baricitinib 4 mg n=1070 (%) n=479 (%) n=997 (%) Upper respiratory tract infections a 11.7 16.3 14.7 Nausea 1.6 2.7 2.8 Herpes simplex b 0.7 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 mg N = 1307 n (%) ALT ≥3 x ULN a 201(16.0) 230 (18.1) AST ≥3 x ULN a 117 (9.4) 149 (11.8) Thrombocytosis >600,000 cells/mm 3a 34 (4.6) 59 (7.9) Creatine phosphokinase (CPK) >5 x ULN a, b 38 (4.7) 36 (4.5) Neutropenia <1000 cells/mm 3a 22 (1.8) 26 (2.2) Deep vein thrombosis 18 (1.4) 20 (1.5) Pulmonary embolism 11 (0.8) 20 (1.5) Urinary tract infection 13 (1.0) 19 (1.5) Adverse Reactions in Patients with Alopecia Areata The safety of OLUMIANT was evaluated in two placebo-controlled trials in patients with severe alopecia areata.

Patients were randomized to placebo (371 patients), OLUMIANT 2 mg (365 patients), or OLUMIANT 4 mg (540 patients).

Of these, a total of 845 patients were treated with OLUMIANT for at least 1 year.

Table 10 summarizes adverse reactions that occurred at a frequency of at least 1% in patients treated with OLUMIANT 2 mg once daily or OLUMIANT 4 mg once daily and more frequently than in patients treated with placebo during the 36-week placebo-controlled period of the alopecia areata clinical trials.

Table 10: Adverse Reactions That Occurred in ≥1% of Patients Treated with OLUMIANT 2 mg or OLUMIANT 4 mg in Alopecia Areata Trials a %-study size adjusted percentages.

b URTI includes: acute sinusitis, influenza, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral upper respiratory tract infection, viral sinusitis, viral pharyngitis, respiratory tract infection viral, rhinovirus infection and adenoiditis c Acne includes: acne and dermatitis acneiform.

d Hyperlipidemia includes: hyperlipidaemia, hypercholesterolaemia, hypertriglyceridaemia, dyslipidaemia, lipids increased, low density lipoprotein increased, blood cholesterol increased, and blood triglycerides increased.

e UTI includes: cystitis, urinary tract infection, white blood cells urine positive, urinary tract infection bacterial, and pyelonephritis.

f Liver enzyme elevations includes: transaminases increased, aspartate aminotransferase increased, alanine aminotransferase increased, hepatic enzyme increased, gamma-glutamyl transferase increased, and hepatic function abnormal.

g Folliculitis was most commonly localized in the scalp region associated with hair regrowth h LRTI includes: bronchitis, bronchiolitis, lower respiratory tract infection, pneumonia, COVID-19 pneumonia, and respiratory tract infection.

i Genital Candida infections includes: vulvovaginal candidiasis, vulvovaginal mycotic infection, and genital infection fungal.

j Neutropenia includes: neutropenia and neutrophil count decreased.

k Abdominal pain includes: abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal discomfort.

Adverse Reaction Weeks 0-36 Placebo OLUMIANT 2 mg OLUMIANT 4 mg N=371 (%) a N=365 (%) a N=540 (%) a Upper respiratory tract infections b (URTI) 19.9 18.4 21.3 Headache 5.4 5.5 6.6 Acne c 2.2 5.8 5.9 Hyperlipidemia d 3.0 3.6 5.9 Blood creatine phosphokinase increased 1.3 0.8 4.3 Urinary tract infections (UTI) e 2.2 3.8 3.7 Liver enzyme elevations f 2.4 1.1 3.0 Folliculitis g 0.8 1.4 2.2 Fatigue 1.1 0.8 2.2 Lower respiratory tract infections (LRTI) h 0.8 2.2 2.0 Nausea 1.6 2.7 2.0 Genital Candida infections i 0.3 2.2 1.3 Anemia 0.3 0.3 1.3 Neutropenia j 0.8 0.3 1.3 Abdominal pain k 2.2 3.8 0.9 Herpes zoster 0.5 1.4 0.9 Weight increased 0.3 1.6 0.9 In patients treated with any dose of baricitinib, adverse reactions that occurred in fewer than 1% of patients include arterial thrombosis, B cell lymphoma, lymphopenia, and fungal skin infections.

Additional adverse reactions observed after Week 52: venous thromboembolic events (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), and malignancy including non-melanoma skin cancer.

Overall, the adverse reactions observed in patients with alopecia areata treated with OLUMIANT were consistent with the adverse reactions in patients with rheumatoid arthritis.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of OLUMIANT.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Immune System Disorders : Drug hypersensitivity (events such as rash, urticaria, and angioedema have been reported) [see Warnings and Precautions ( 5.6 )] .