ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Adverse reactions (>=1%) include: upper respiratory tract infections, nausea, herpes simplex, and herpes zoster. (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 drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in broader patient population in clinical practice.The following data include six randomized double-blind placebo-controlled studies (three Phase 2, three Phase 3) and long-term extension study. All patients had moderately to severely active RA. Patients were randomized to placebo (1070 patients), OLUMIANT mg (479 patients), or baricitinib mg (997 patients).Patients could be switched to baricitinib mg from placebo or OLUMIANT mg from as early as Week 12 depending on the study design. All patients initially randomized to placebo were switched to baricitinib mg by Week 24.During the 16-week treatment period, adverse events leading to discontinuation of treatment were reported by 35 patients (11.4 events per 100 patient-years) treated with placebo, 17 patients (12.1 events per 100 patient-years) with OLUMIANT mg, and 40 patients (13.4 events per 100 patient-years) treated with baricitinib mg.During to 52-week exposure, adverse events leading to discontinuation of treatment were reported by 31 patients (9.2 events per 100 patient-years) with OLUMIANT mg, and 92 patients (10.2 events per 100 patient-years) treated with baricitinib mg.. Overall Infections- During the 16-week treatment period, infections were reported by 253 patients (82.1 events per 100 patient-years) treated with placebo, 139 patients (99.1 events per 100 patient-years) treated with OLUMIANT mg, and 298 patients (100.1 events per 100 patient-years) treated with baricitinib mg.During to 52 week exposure, infections were reported by 200 patients (59.6 events per 100 patients-years) treated with OLUMIANT mg, and 500 patients (55.3 events per 100 patient-years) treated with baricitinib mg.In the 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 events per 100 patient-years) treated with placebo, patients (3.6 events per 100 patient-years) treated with OLUMIANT mg, and 11 patients (3.7 events per 100 patient-years) treated with baricitinib mg.During to 52 week exposure, serious infections were reported in 14 patients (4.2 events per 100 patient-years) treated with OLUMIANT mg and 32 patients (3.5 events per 100 patient-years) treated with baricitinib mg.In the 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 to 52 week exposure, events of tuberculosis were reported in patients treated with OLUMIANT mg and patient (0.1 per 100 patient-years) treated with baricitinib 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 patients (0.6 per 100 patient-years) treated with placebo, patients treated with OLUMIANT mg and patients (0.7 per 100 patient-years) treated with baricitinib mg.During to 52 week exposure, opportunistic infections were reported in patient (0.3 per 100 patient-years) treated with OLUMIANT mg and patients (0.6 per 100 patient-years) treated with baricitinib mg [see Warnings and Precautions (5.1)].. Malignancy- During the 16-week treatment period, malignancies excluding non-melanoma skin cancers (NMSC) were reported in patients treated with placebo, patient (0.7 per 100 patient-years) treated with OLUMIANT mg, and patient (0.3 per 100 patient-years) treated with baricitinib mg.During the to 52 week treatment period, malignancies excluding NMSC were reported in patients (0.6 per 100 patient-years) treated with OLUMIANT mg and patients (0.7 per 100 patient-years) treated with baricitinib mg [see Warnings and Precautions (5.3)].Venous Thrombosis- During the 16-week treatment period, venous thromboses (deep vein thrombosis or pulmonary embolism) were reported in patients treated with placebo, patients treated with OLUMIANT mg, and patients (1.7 per 100 patient-years) treated with baricitinib mg.. During the to 52 week treatment period, venous thromboses were reported in patients (0.6 per 100 patient-years) treated with OLUMIANT mg and patients (0.8 per 100 patient-years) treated with baricitinib mg.. Arterial Thrombosis- During the 16-week treatment period, arterial thromboses were reported in patient treated with placebo (0.3 per 100 patient-years), patients (1.4 per 100 patient-years) treated with OLUMIANT mg, and patients (0.7 per 100 patient-years) treated with baricitinib mg.During the to 52 week treatment period, arterial thromboses were reported in patients (0.9 per 100 patient-years) treated with OLUMIANT mg and patients (0.3 per 100 patient-years) treated with baricitinib 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 mg, and 0.3% of patients treated with baricitinib mg. There were no neutrophil counts below 500 cells/mm3 observed in any treatment group [see Warnings and Precautions (5.1, 5.7)].. 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 mg, and 2.0% of patients treated with baricitinib 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 mg and by 23,000 cells/mm3 in patients treated with baricitinib 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 (5.7)].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 mg, and 1.4% of patients treated with baricitinib 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 mg, and 0.8% of patients treated with baricitinib mg.In phase 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 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib mg plus methotrexate.. 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 mg, and 1.4% of patients treated with baricitinib 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 mg, and 0.8% of patients treated with baricitinib mg.. In phase 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 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib 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 mg/dL in patients treated with OLUMIANT mg and by 14 mg/dL in patients treated with baricitinib mg.Mean HDL cholesterol increased by mg/dL in patients treated with OLUMIANT mg and by mg/dL in patients treated with baricitinib mg.The mean LDL/HDL ratio remained stable.Mean triglycerides increased by mg/dL in patients treated with OLUMIANT mg and by 15 mg/dL in patients treated with baricitinib mg.[See Warnings and Precautions (5.7)].. Mean LDL cholesterol increased by mg/dL in patients treated with OLUMIANT mg and by 14 mg/dL in patients treated with baricitinib mg.. Mean HDL cholesterol increased by mg/dL in patients treated with OLUMIANT mg and by mg/dL in patients treated with baricitinib mg.. The mean LDL/HDL ratio remained stable.. Mean triglycerides increased by mg/dL in patients treated with OLUMIANT mg and by 15 mg/dL in patients treated with baricitinib mg.. Creatine Phosphokinase (CPK)- OLUMIANT treatment was associated with increases in CPK within one week of starting OLUMIANT and plateauing after to 12 weeks. At 16 weeks, the mean change in CPK for OLUMIANT mg and baricitinib 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 mg. The clinical significance of the observed serum creatinine increases is unknown.. Other Adverse ReactionsOther adverse reactions are summarized in Table 4.Table 4: Adverse Reactions occurring in greater than or equal to 1% of OLUMIANT mg and Baricitinib mg Treated Patients in Placebo-Controlled Trialsa 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 0-16PlaceboOLUMIANT2 mgBaricitinib4 mgn=1070(%)n=479(%)n=997(%)Upper respiratory tract infectionsa 11.716.314.7Nausea1.62.72.8Herpes simplexb 0.70.81.8Herpes zoster0.41.01.4Additional adverse drug reactions occurring in fewer than 1% of patients: acne.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of OLUMIANT. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune System Disorders: Drug hypersensitivity (events such as rash, urticaria, and angioedema have been observed) [see Warnings and Precautions (5.9)].

BOXED WARNING SECTION.

WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS. SERIOUS INFECTIONSPatients treated with OLUMIANT are at risk for developing serious infections that may lead to hospitalization or death[see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.If serious infection develops, interrupt OLUMIANT until the infection is controlled.Reported infections include:Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients 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 Precautions (5.1)].MORTALITYIn 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, higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor [see Warnings and Precautions (5.2)].MALIGNANCIESLymphoma and other malignancies have been observed in patients treated with OLUMIANT. In RA patients treated with another JAK inhibitor, 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 Precautions (5.3)].MAJOR ADVERSE CARDIOVASCULAR EVENTSIn RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, 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 myocardial infarction or stroke [see Warnings and Precautions (5.4)].THROMBOSISThrombosis, 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, 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 Precautions (5.5)].. Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients 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.. WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE), AND THROMBOSISSee 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. Test for latent TB before and during therapy; 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). 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. Test for latent TB before and during therapy; 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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 or 25 mg/kg/day, respectively (approximately 12 and 55 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 113 and 169 times the MRHD in males and females, respectively, on an AUC basis) based upon findings that of 19 (36.8%) drug-treated females with evidence of mating were not gravid compared to 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 25 and 48 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 mg/kg/day and were mated to males that received the same dose (approximately 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 113 and 169 times the MRHD in males and females, respectively, on an AUC basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Baricitinib is 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 dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed approximately 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 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 hour. 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 to 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 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 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 substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution.. Elimination- The total body clearance of baricitinib is 8.9 L/h in patients with RA. Elimination half-life in patients with rheumatoid arthritis is approximately 12 hours.. 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 substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies. In 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 AgeBody weight, gender, race, ethnicity, and age did not have 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. [See Use in Specific Populations (8.5)].. Renal ImpairmentBaricitinib 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)].. Hepatic ImpairmentBaricitinib 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,ba 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.. Figure 1. Drug Interactions. Potential for Baricitinib to Influence the PK of Other DrugsIn vitro, baricitinib did not significantly inhibit or induce the activity of cytochrome P450 enzymes (CYPs 3A, 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6). In clinical pharmacology studies, there were no clinically meaningful changes in the pharmacokinetics (PK) of simvastatin, ethinyl estradiol, or levonorgestrel (CYP3A substrates) when co-administered with baricitinib.In vitro studies suggest that baricitinib is not an inhibitor of the transporters, P-glycoprotein (Pgp) or Organic Anion Transporting Polypeptide (OATP) 1B1. In vitro data indicate baricitinib does inhibit organic anionic transporter (OAT) 1, OAT2, OAT3, organic cationic transporter (OCT) 1, OCT2, OATP1B3, Breast Cancer Resistance Protein (BCRP) and Multidrug and Toxic Extrusion Protein (MATE) and MATE2-K, but clinically meaningful changes in the pharmacokinetics of drugs that are substrates for these transporters are unlikely. In clinical pharmacology studies there were no clinically meaningful effects on the PK of digoxin (Pgp substrate) or methotrexate (substrate of several transporters) when co-administered with baricitinib.Exposure changes of drugs following co-administration with baricitinib are shown in Figure 2. Figure 2: Impact of Baricitinib on the Pharmacokinetics of Other Drugsaa Reference group is administration of concomitant drug alone.. Figure 2. Potential for Other Drugs to Influence the PK of BaricitinibIn vitro studies suggest that baricitinib is CYP3A4 substrate. In clinical pharmacology studies there was no effect on the PK of baricitinib when co-administered with ketoconazole (CYP3A inhibitor). There were no clinically meaningful changes in the PK of baricitinib when co-administered with fluconazole (CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin (CYP3A inducer).In vitro studies suggest that baricitinib is substrate for OAT3, Pgp, BCRP and MATE2-K. In clinical study, probenecid administration (strong OAT3 inhibitor) resulted in an approximately 2-fold increase in baricitinib AUC0- with no effect on Cmax and tmax [see Dosage and Administration (2.5) and Drug Interactions (7.1)]. However, simulations with diclofenac and ibuprofen (OAT3 inhibitors with less inhibition potential) predicted minimal effect on the PK of baricitinib. In clinical pharmacology studies there was no clinically meaningful effect on the PK of baricitinib when co-administered with cyclosporine (Pgp and BCRP inhibitor). Co-administration with methotrexate (substrate of several transporters) did not have clinically meaningful effect on the PK of baricitinib.Exposure changes of baricitinib following co-administration with CYP inhibitors or inducers, transporter inhibitors, as well as methotrexate and the proton pump inhibitor, omeprazole, are shown in Figure 3. Figure 3: Impact of Other Drugs on the Pharmacokinetics of Baricitinibba Values are based on simulated studies.b Reference group is administration of baricitinib alone.. Figure 3.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The OLUMIANT clinical development program included two dose-ranging trials and four confirmatory phase trials. Although other doses have been studied, the recommended dose of OLUMIANT is mg once daily.. Dose-Ranging StudiesThe dose-ranging studies (NCT01185353) and II (NCT01469013) included 12-week randomized comparison of baricitinib 1, 2, 4, and mg versus placebo in 301 and 145 patients, respectively.The results from the dose-ranging studies are shown in Table 5. In dose-ranging Study I, the observed ACR response was similar for baricitinib and mg daily and for baricitinib and mg daily, with the highest response for baricitinib mg daily. In dose-ranging Study II, there was not clear trend of dose response, with similar response rates for mg and mg and mg and mg.Table 5: Proportion of Patients with ACR20 Response at Week 12 in Dose-Ranging Studies% ACR20 RespondersDose-Ranging StudyPlaceboBaricitinib1 mg dailyBaricitinib2 mg dailyBaricitinib4 mg dailyBaricitinib8 mg dailyI (N=301)4157547578II (N=145)3167836788. Confirmatory StudiesThe efficacy and safety of OLUMIANT mg once daily was assessed in two confirmatory phase 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 tender and swollen joints were present at baseline. The two studies (Studies III and IV) evaluated OLUMIANT mg and baricitinib mg.Study III (NCT01721057) was 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 mg or mg once daily or placebo added to existing background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.Study IV (NCT01721044) was 24-week trial in 527 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to or more TNF inhibitor therapies with or without other biologic DMARDs (TNFi-IR). Patients received OLUMIANT mg or baricitinib mg once daily or placebo added to background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.. Clinical ResponseThe percentages of OLUMIANT-treated patients achieving ACR20, ACR50, and ACR70 responses, and Disease Activity Score (DAS28-CRP) <2.6 in Studies III and IV are shown in Table 6.Patients treated with OLUMIANT had higher rates of ACR response and DAS28-CRP <2.6 versus placebo-treated patients at Week 12 (Studies III and IV) (Table 6).In Study IV, higher ACR20 response rates (Figure 4) were observed as early as week with OLUMIANT mg versus placebo.In Study IV, the proportions of patients achieving DAS28-CRP <2.6 who had at least active joints at the end of Week 24 were 18.2% and 10.5%, in the placebo and OLUMIANT mg arms, respectively.Table 6: Clinical Responsea Patients who were rescued or discontinued treatment were considered as non-responders in the analyses.b 95% confidence interval for the difference () in response rate between OLUMIANT treatment and placebo (Study III, Study IV).Percent of PatientscDMARD-IRTNFi-IRStudy IIIStudy IVPlacebo cDMARDs OLUMIANT2 mg/day cDMARDs (95% CI)bPlacebo cDMARDs OLUMIANT2 mg/day cDMARDs (95% CI)bN228229176174ACR 20Week 12%396627 (18, 35)274922 (12, 32)Week 24%426119 (10, 28)274518 (8, 27)ACR 50Week 12%133421 (13, 28)82012 (5, 19)Week 24%214120 (12, 28)132310 (2, 18)ACR 70Week 12%31815 (9, 20)21311 (5, 16)Week 24%82517 (11, 24)31310 (4, 16)DAS28-CRP<2.6Week 12%926(10, 24)411(2, 12)Week 24%1131(13, 27)611(-1, 11)The effects of OLUMIANT treatment on the components of the ACR response criteria for Studies III and IV are shown in Table 7.Table 7: Components of ACR Response at Week 12 in Studies III and IVa Data shown are mean (standard deviation).b Visual analog scale: 0=best, 100=worst.c Health Assessment Questionnaire-Disability Index: 0=best, 3=worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.cDMARD-IRTNFi-IRStudy IIIStudy IVPlacebo+ cDMARDsOLUMIANT2 mg/day+ cDMARDsPlacebo+ cDMARDsOLUMIANT2 mg/day+ cDMARDsN228229176174Number of Tender Joints (0-68)Baseline24 (15)24 (14)28 (16)31 (16)Week 1215 (14)11 (13)20 (16)19 (18)Number of Swollen Joints (0-66)Baseline13 (7)14 (9)17 (11)19 (12)Week 128 (8)5 (6)12 (10)10 (12)PainbBaseline57 (23)60 (21)65 (19)62 (22)Week 1243 (24)34 (25)55 (25)46 (28)Patient Global AssessmentbBaseline60 (21)62 (20)66 (19)67 (19)Week 1244 (23)36 (25)56 (25)46 (26)Physician Global AssessmentbBaseline62 (17)64 (17)67 (19)67 (17)Week 1241 (24)33 (22)50 (26)36 (24)Disability Index (HAQ-DI)cBaseline1.50 (0.60)1.51 (0.62)1.78 (0.57)1.71 (0.55)Week 121.17 (0.62)0.96 (0.69)1.59 (0.68)1.31 (0.72)hsCRP (mg/L)Baseline17.7 (20.4)18.2 (21.5)20.6 (25.3)19.9 (22.5)Week 1217.2 (19.3)8.6 (14.6)19.9 (23.0)13.5 (20.1)Figure 4: Percent of Patients Achieving ACR20. Figure 4. Physical Function ResponseImprovement in physical function was measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Patients receiving OLUMIANT mg demonstrated greater improvement from baseline in physical functioning compared to placebo at Week 24. The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 24 was -0.24 (-0.35, -0.14) in Study III and -0.23 (-0.35, -0.12) in Study IV.. Other Health Related OutcomesGeneral health status was assessed by the Short Form health survey (SF-36). In Studies III and IV, compared to placebo, patients treated with OLUMIANT mg demonstrated greater improvement from baseline in the physical component summary (PCS) score and the physical function, role physical, bodily pain, vitality, and general health domains at Week 12, with no consistent improvements in the mental component summary (MCS) scores or the role emotional, mental health, and social functioning domains.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in broader patient population in clinical practice.The following data include six randomized double-blind placebo-controlled studies (three Phase 2, three Phase 3) and long-term extension study. All patients had moderately to severely active RA. Patients were randomized to placebo (1070 patients), OLUMIANT mg (479 patients), or baricitinib mg (997 patients).Patients could be switched to baricitinib mg from placebo or OLUMIANT mg from as early as Week 12 depending on the study design. All patients initially randomized to placebo were switched to baricitinib mg by Week 24.During the 16-week treatment period, adverse events leading to discontinuation of treatment were reported by 35 patients (11.4 events per 100 patient-years) treated with placebo, 17 patients (12.1 events per 100 patient-years) with OLUMIANT mg, and 40 patients (13.4 events per 100 patient-years) treated with baricitinib mg.During to 52-week exposure, adverse events leading to discontinuation of treatment were reported by 31 patients (9.2 events per 100 patient-years) with OLUMIANT mg, and 92 patients (10.2 events per 100 patient-years) treated with baricitinib mg.. Overall Infections- During the 16-week treatment period, infections were reported by 253 patients (82.1 events per 100 patient-years) treated with placebo, 139 patients (99.1 events per 100 patient-years) treated with OLUMIANT mg, and 298 patients (100.1 events per 100 patient-years) treated with baricitinib mg.During to 52 week exposure, infections were reported by 200 patients (59.6 events per 100 patients-years) treated with OLUMIANT mg, and 500 patients (55.3 events per 100 patient-years) treated with baricitinib mg.In the 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 events per 100 patient-years) treated with placebo, patients (3.6 events per 100 patient-years) treated with OLUMIANT mg, and 11 patients (3.7 events per 100 patient-years) treated with baricitinib mg.During to 52 week exposure, serious infections were reported in 14 patients (4.2 events per 100 patient-years) treated with OLUMIANT mg and 32 patients (3.5 events per 100 patient-years) treated with baricitinib mg.In the 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 to 52 week exposure, events of tuberculosis were reported in patients treated with OLUMIANT mg and patient (0.1 per 100 patient-years) treated with baricitinib 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 patients (0.6 per 100 patient-years) treated with placebo, patients treated with OLUMIANT mg and patients (0.7 per 100 patient-years) treated with baricitinib mg.During to 52 week exposure, opportunistic infections were reported in patient (0.3 per 100 patient-years) treated with OLUMIANT mg and patients (0.6 per 100 patient-years) treated with baricitinib mg [see Warnings and Precautions (5.1)].. Malignancy- During the 16-week treatment period, malignancies excluding non-melanoma skin cancers (NMSC) were reported in patients treated with placebo, patient (0.7 per 100 patient-years) treated with OLUMIANT mg, and patient (0.3 per 100 patient-years) treated with baricitinib mg.During the to 52 week treatment period, malignancies excluding NMSC were reported in patients (0.6 per 100 patient-years) treated with OLUMIANT mg and patients (0.7 per 100 patient-years) treated with baricitinib mg [see Warnings and Precautions (5.3)].Venous Thrombosis- During the 16-week treatment period, venous thromboses (deep vein thrombosis or pulmonary embolism) were reported in patients treated with placebo, patients treated with OLUMIANT mg, and patients (1.7 per 100 patient-years) treated with baricitinib mg.. During the to 52 week treatment period, venous thromboses were reported in patients (0.6 per 100 patient-years) treated with OLUMIANT mg and patients (0.8 per 100 patient-years) treated with baricitinib mg.. Arterial Thrombosis- During the 16-week treatment period, arterial thromboses were reported in patient treated with placebo (0.3 per 100 patient-years), patients (1.4 per 100 patient-years) treated with OLUMIANT mg, and patients (0.7 per 100 patient-years) treated with baricitinib mg.During the to 52 week treatment period, arterial thromboses were reported in patients (0.9 per 100 patient-years) treated with OLUMIANT mg and patients (0.3 per 100 patient-years) treated with baricitinib 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 mg, and 0.3% of patients treated with baricitinib mg. There were no neutrophil counts below 500 cells/mm3 observed in any treatment group [see Warnings and Precautions (5.1, 5.7)].. 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 mg, and 2.0% of patients treated with baricitinib 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 mg and by 23,000 cells/mm3 in patients treated with baricitinib 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 (5.7)].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 mg, and 1.4% of patients treated with baricitinib 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 mg, and 0.8% of patients treated with baricitinib mg.In phase 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 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib mg plus methotrexate.. 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 mg, and 1.4% of patients treated with baricitinib 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 mg, and 0.8% of patients treated with baricitinib mg.. In phase 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 mg monotherapy, and 4.7% and 1.9% of patients treated with baricitinib 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 mg/dL in patients treated with OLUMIANT mg and by 14 mg/dL in patients treated with baricitinib mg.Mean HDL cholesterol increased by mg/dL in patients treated with OLUMIANT mg and by mg/dL in patients treated with baricitinib mg.The mean LDL/HDL ratio remained stable.Mean triglycerides increased by mg/dL in patients treated with OLUMIANT mg and by 15 mg/dL in patients treated with baricitinib mg.[See Warnings and Precautions (5.7)].. Mean LDL cholesterol increased by mg/dL in patients treated with OLUMIANT mg and by 14 mg/dL in patients treated with baricitinib mg.. Mean HDL cholesterol increased by mg/dL in patients treated with OLUMIANT mg and by mg/dL in patients treated with baricitinib mg.. The mean LDL/HDL ratio remained stable.. Mean triglycerides increased by mg/dL in patients treated with OLUMIANT mg and by 15 mg/dL in patients treated with baricitinib mg.. Creatine Phosphokinase (CPK)- OLUMIANT treatment was associated with increases in CPK within one week of starting OLUMIANT and plateauing after to 12 weeks. At 16 weeks, the mean change in CPK for OLUMIANT mg and baricitinib 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 mg. The clinical significance of the observed serum creatinine increases is unknown.. Other Adverse ReactionsOther adverse reactions are summarized in Table 4.Table 4: Adverse Reactions occurring in greater than or equal to 1% of OLUMIANT mg and Baricitinib mg Treated Patients in Placebo-Controlled Trialsa 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 0-16PlaceboOLUMIANT2 mgBaricitinib4 mgn=1070(%)n=479(%)n=997(%)Upper respiratory tract infectionsa 11.716.314.7Nausea1.62.72.8Herpes simplexb 0.70.81.8Herpes zoster0.41.01.4Additional adverse drug reactions occurring in fewer than 1% of patients: acne.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11 DESCRIPTION. OLUMIANT (baricitinib) is Janus kinase (JAK) inhibitor with the chemical name 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-ylacetonitrile. Baricitinib has an empirical formula of C16H17N7O2S and molecular weight of 371.42. Baricitinib has the following structural formula:OLUMIANT tablets contain recessed area on each face of the tablet surface and are available for oral administration as debossed, film-coated, immediate-release tablets. The mg tablet is very light pink, round, debossed with Lilly on one side and 1 on the other. The mg tablet is light pink, oblong, debossed with Lilly on one side and 2 on the other.Each tablet contains or mg of baricitinib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dose of OLUMIANT is mg once daily. (2.1)OLUMIANT may be used as monotherapy or in combination with methotrexate or other DMARDs. (2.1)Cytopenias: Avoid initiation or interrupt OLUMIANT in patients with anemia (hemoglobin <8 g/dL), lymphopenia (ALC <500 cells/mm3) and neutropenia (ANC <1000 cells/mm3). (2.2, 2.3, 5.7)Moderate Renal Impairment: Reduce dose to mg once daily. (2.4). The recommended dose of OLUMIANT is mg once daily. (2.1). OLUMIANT may be used as monotherapy or in combination with methotrexate or other DMARDs. (2.1). Cytopenias: Avoid initiation or interrupt OLUMIANT in patients with anemia (hemoglobin <8 g/dL), lymphopenia (ALC <500 cells/mm3) and neutropenia (ANC <1000 cells/mm3). (2.2, 2.3, 5.7). Moderate Renal Impairment: Reduce dose to mg once daily. (2.4). 2.1 Dosage in Rheumatoid Arthritis. The recommended dose of OLUMIANT is mg once daily.OLUMIANT may be used as monotherapy or in combination with methotrexate or other DMARDs.OLUMIANT is given orally with or without food [see Clinical Pharmacology (12.3)].. 2.2 General Considerations for Administration. OLUMIANT initiation is not recommended in patients with an absolute lymphocyte count (ALC) less than 500 cells/mm3, absolute neutrophil count (ANC) less than 1000 cells/mm3, or hemoglobin level less than g/dL [see Warnings and Precautions (5.7)].Avoid use of OLUMIANT in patients with active, serious infection, including localized infections [see Warnings and Precautions (5.1)].Prior to initiating OLUMIANT, test patients for latent tuberculosis (TB). If positive, start treatment for TB prior to OLUMIANT use [see Warnings and Precautions (5.1)].. OLUMIANT initiation is not recommended in patients with an absolute lymphocyte count (ALC) less than 500 cells/mm3, absolute neutrophil count (ANC) less than 1000 cells/mm3, or hemoglobin level less than g/dL [see Warnings and Precautions (5.7)].. Avoid use of OLUMIANT in patients with active, serious infection, including localized infections [see Warnings and Precautions (5.1)].. 2.3 Dose Modifications Due to Serious Infections and Cytopenias. If patient develops serious infection, hold treatment with OLUMIANT until the infection is controlled.Modify dosage in cases of lymphopenia, neutropenia or anemia (Tables 1, 2, and 3). For treatment initiation criteria [see Dosage and Administration (2.2)].Table 1: Dose Adjustments for LymphopeniaLow Absolute Lymphocyte Count (ALC)Lab Value (cells/mm3)RecommendationALC greater than or equal to 500Maintain doseALC less than 500Interrupt OLUMIANT until ALC greater than or equal to 500Table 2: Dose Adjustments for NeutropeniaLow Absolute Neutrophil Count (ANC)Lab Value (cells/mm3)RecommendationANC greater than or equal to 1000Maintain doseANC less than 1000Interrupt OLUMIANT until ANC greater than or equal to 1000Table 3: Dose Adjustments for AnemiaLow Hemoglobin ValueLab Value (g/dL)RecommendationGreater than or equal to 8Maintain doseLess than 8Interrupt OLUMIANT until hemoglobin greater than or equal to 8. 2.4 Dose Modifications in Patients with Renal or Hepatic Impairment. The recommended dose of OLUMIANT in patients with moderate renal impairment (estimated glomerular filtration rate (GFR) between 30 and 60 mL/min/1.73 m2) is mg once daily. OLUMIANT is not recommended for use in patients with severe renal impairment (estimated GFR of less than 30 mL/min/1.73 m2) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].OLUMIANT is not recommended for use in patients with severe hepatic impairment.. The recommended dose of OLUMIANT in patients with moderate renal impairment (estimated glomerular filtration rate (GFR) between 30 and 60 mL/min/1.73 m2) is mg once daily. OLUMIANT is not recommended for use in patients with severe renal impairment (estimated GFR of less than 30 mL/min/1.73 m2) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].. OLUMIANT is not recommended for use in patients with severe hepatic impairment.. 2.5 Dose Modifications Due to Drug Interactions. The recommended dose of OLUMIANT in patients taking strong Organic Anion Transporter (OAT3) inhibitors, such as probenecid, is mg once daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. OLUMIANT for oral administration is available as debossed, film-coated, immediate-release tablets:1 mg tablet contains 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 recessed area on each face of the tablet surface, is light pink, oblong, debossed with Lilly on one side and 2 on the other.. mg tablet contains 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.. mg tablet contains recessed area on each face of the tablet surface, is light pink, oblong, debossed with Lilly on one side and 2 on the other.. Tablets: mg, mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. The recommended dose of OLUMIANT in patients taking strong Organic Anion Transporter (OAT3) inhibitors (e.g., probenecid) is mg once daily. (2.5, 7.1). 7.1 Strong OAT3 Inhibitors. Baricitinib exposure is increased when OLUMIANT is co-administered with strong OAT3 inhibitors (such as probenecid) [see Dosage and Administration (2.5) 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 Indications and Usage (1.1)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 3100 patients treated in the four phase studies, total of 537 rheumatoid arthritis patients were 65 years of age and older, including 71 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)].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 elderly 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 Dosing and Administration (2.4)].

HEPATIC IMPAIRMENT SUBSECTION.

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 severe hepatic impairment and is therefore not recommended [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. OLUMIANT for oral administration is available as debossed, film-coated, immediate-release tablets. Each tablet contains recessed area on each face of the tablet surface.OLUMIANT Tablets1 mg2 mgColorVery Light PinkLight PinkShapeRoundOblongIdentificationLillyLilly12NDC Codes:Bottle of 300002-4732-300002-4182-30. 16.2 Storage and Handling. Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Keep out of reach of children.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. OLUMIANT(R) is 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)Limitation 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). 1.1 Rheumatoid Arthritis. OLUMIANT(R) (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.Limitation 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Patient CounselingAdvise patients of the potential benefits and risks of OLUMIANT.InfectionsInform patients that they may be more likely to develop infections when taking OLUMIANT. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection [see Warnings and Precautions (5.1)].Advise patients that the risk of herpes zoster is increased in patients treated with OLUMIANT and some cases can be serious [see Warnings and Precautions (5.1)].Malignancies and Lymphoproliferative DisordersInform patients that OLUMIANT may increase their risk of developing lymphomas and other malignancies, including of the skin. Instruct patients to inform their healthcare provider if they have ever had any type of cancer [see Warnings and Precautions (5.3)].Major Adverse Cardiovascular EventsInform patients that OLUMIANT may increase their risk of major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.4)]. ThrombosisAdvise patients that events of DVT and PE have been reported in clinical studies with OLUMIANT. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of DVT or PE [see Warnings and Precautions (5.5)].Laboratory AbnormalitiesInform patients that OLUMIANT may affect certain lab tests, and that blood tests are required before and during OLUMIANT treatment [see Warnings and Precautions (5.7)].LactationAdvise woman not to breastfeed during treatment with OLUMIANT [see Use in Specific Populations (8.2)].Literature revised: 12/2021Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USAwww.olumiant.com Copyright (C) 2018, 2021, Eli Lilly and Company. All rights reserved.OLM-0005-USPI-20211203.

LACTATION SECTION.

8.2 Lactation. Risk SummaryNo 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. Due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. Because of the potential for serious adverse reactions in nursing infants, advise an OLUMIANT-treated woman not to breastfeed.. DataA 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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Baricitinib is 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.

NONCLINICAL TOXICOLOGY SECTION.

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 or 25 mg/kg/day, respectively (approximately 12 and 55 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 113 and 169 times the MRHD in males and females, respectively, on an AUC basis) based upon findings that of 19 (36.8%) drug-treated females with evidence of mating were not gravid compared to 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 25 and 48 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 mg/kg/day and were mated to males that received the same dose (approximately 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 113 and 169 times the MRHD in males and females, respectively, on an AUC basis).

OVERDOSAGE SECTION.

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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL OLUMIANT mg 30ct Bottle. Rx OnlyAlways Dispense with Medication GuideNDC 0002-4182-30Olumiant(R) (baricitinib) tablets2 mg30 tabletsLilly. PACKAGE LABEL OLUMIANT mg 30ct Bottle.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of OLUMIANT in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Baricitinib inhibition of IL-6 induced STAT3 phosphorylation- Baricitinib administration resulted in dose dependent inhibition of IL-6 induced STAT3 phosphorylation in whole blood from healthy subjects with maximal inhibition observed approximately 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 dose 10 times the maximum recommended dose, baricitinib does not prolong the QT interval to any clinically relevant extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following oral administration of OLUMIANT, peak plasma concentrations are reached approximately at hour. 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 to 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 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 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 substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution.. Elimination- The total body clearance of baricitinib is 8.9 L/h in patients with RA. Elimination half-life in patients with rheumatoid arthritis is approximately 12 hours.. 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 substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies. In 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 AgeBody weight, gender, race, ethnicity, and age did not have 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. [See Use in Specific Populations (8.5)].. Renal ImpairmentBaricitinib 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)].. Hepatic ImpairmentBaricitinib 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,ba 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.. Figure 1. Drug Interactions. Potential for Baricitinib to Influence the PK of Other DrugsIn vitro, baricitinib did not significantly inhibit or induce the activity of cytochrome P450 enzymes (CYPs 3A, 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6). In clinical pharmacology studies, there were no clinically meaningful changes in the pharmacokinetics (PK) of simvastatin, ethinyl estradiol, or levonorgestrel (CYP3A substrates) when co-administered with baricitinib.In vitro studies suggest that baricitinib is not an inhibitor of the transporters, P-glycoprotein (Pgp) or Organic Anion Transporting Polypeptide (OATP) 1B1. In vitro data indicate baricitinib does inhibit organic anionic transporter (OAT) 1, OAT2, OAT3, organic cationic transporter (OCT) 1, OCT2, OATP1B3, Breast Cancer Resistance Protein (BCRP) and Multidrug and Toxic Extrusion Protein (MATE) and MATE2-K, but clinically meaningful changes in the pharmacokinetics of drugs that are substrates for these transporters are unlikely. In clinical pharmacology studies there were no clinically meaningful effects on the PK of digoxin (Pgp substrate) or methotrexate (substrate of several transporters) when co-administered with baricitinib.Exposure changes of drugs following co-administration with baricitinib are shown in Figure 2. Figure 2: Impact of Baricitinib on the Pharmacokinetics of Other Drugsaa Reference group is administration of concomitant drug alone.. Figure 2. Potential for Other Drugs to Influence the PK of BaricitinibIn vitro studies suggest that baricitinib is CYP3A4 substrate. In clinical pharmacology studies there was no effect on the PK of baricitinib when co-administered with ketoconazole (CYP3A inhibitor). There were no clinically meaningful changes in the PK of baricitinib when co-administered with fluconazole (CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampicin (CYP3A inducer).In vitro studies suggest that baricitinib is substrate for OAT3, Pgp, BCRP and MATE2-K. In clinical study, probenecid administration (strong OAT3 inhibitor) resulted in an approximately 2-fold increase in baricitinib AUC0- with no effect on Cmax and tmax [see Dosage and Administration (2.5) and Drug Interactions (7.1)]. However, simulations with diclofenac and ibuprofen (OAT3 inhibitors with less inhibition potential) predicted minimal effect on the PK of baricitinib. In clinical pharmacology studies there was no clinically meaningful effect on the PK of baricitinib when co-administered with cyclosporine (Pgp and BCRP inhibitor). Co-administration with methotrexate (substrate of several transporters) did not have clinically meaningful effect on the PK of baricitinib.Exposure changes of baricitinib following co-administration with CYP inhibitors or inducers, transporter inhibitors, as well as methotrexate and the proton pump inhibitor, omeprazole, are shown in Figure 3. Figure 3: Impact of Other Drugs on the Pharmacokinetics of Baricitinibba Values are based on simulated studies.b Reference group is administration of baricitinib alone.. Figure 3.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of OLUMIANT. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Immune System Disorders: Drug hypersensitivity (events such as rash, urticaria, and angioedema have been observed) [see Warnings and Precautions (5.9)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe limited human data on use of OLUMIANT in pregnant women are not sufficient to inform drug-associated risk for major birth defects or miscarriage. In animal embryo-fetal development studies, oral baricitinib administration to pregnant rats and rabbits at exposures equal to and greater than approximately 20 and 84 times the maximum recommended human dose (MRHD), 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 and 13 times the exposure at the MRHD, respectively. In pre- and post-natal development study in pregnant female rats, oral baricitinib administration at exposures approximately 43 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 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 times the exposure at the MRHD [see Animal Data].The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have 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.. Data. Animal DataIn an embryofetal development study in pregnant rats, dosed orally during the period of organogenesis from gestation days to 17, baricitinib was teratogenic (skeletal malformations that consisted of bent limb bones and rib anomalies) at exposures equal to or greater than approximately 20 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 times the MRHD (on an AUC basis at maternal oral dose of mg/kg/day).In an embryofetal development study in pregnant rabbits, dosed orally during the period of organogenesis from gestation days to 20, embryolethality, decreased fetal body weights, and skeletal malformations (rib anomalies) were observed in the presence of maternal toxicity at an exposure approximately 84 times the MRHD (on an AUC basis at 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 12 times the MRHD (on an AUC basis at maternal oral dose of 10 mg/kg/day).In pre- and post-natal development study in pregnant female rats dosed orally from gestation day through lactation day 20, adverse findings observed in pups included decreased survival from birth to post-natal day (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 cells on PND 35 with recovery by PND 65 at exposures approximately 43 times the MRHD (on an AUC basis at 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 43 times the MRHD (on an AUC basis at 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 times the MRHD (on an AUC basis at maternal oral dose of mg/kg/day).

RECENT MAJOR CHANGES SECTION.

Boxed Warning12/2021Warnings and Precautions, Mortality (5.2)12/2021Warnings and Precautions, Malignancy and Lymphoproliferative Disorders (5.3)12/2021Warnings and Precautions, Major Adverse Cardiovascular Events (5.4)12/2021Warnings and Precautions, Thrombosis (5.5)12/2021.

RENAL IMPAIRMENT SUBSECTION.

8.7 Renal Impairment. Renal function was found to significantly affect baricitinib exposure. The recommended dose of OLUMIANT in patients with moderate renal impairment (estimated glomerular filtration rate (GFR) between 30 and 60 mL/min/1.73 m2) is mg once daily. OLUMIANT is not recommended for use in patients with severe renal impairment (estimated GFR of less than 30 mL/min/1.73 m2) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug AdministrationRevised: 12/2021MEDICATION GUIDEOLUMIANT(R)(O-loo-me-ant)(baricitinib)tablets, for oral useWhat is the most important information should know about OLUMIANTOLUMIANT may cause serious side effects, including:1. Serious infections. OLUMIANT is medicine that affects your immune system. OLUMIANT can lower the ability of your immune system to fight infections. Some people have had serious infections while taking OLUMIANT, including tuberculosis (TB), and infections caused by bacteria, fungi, or viruses that can spread throughout the body. Some people have died from these infections.Your healthcare provider should test you for TB before starting treatment with OLUMIANT.Your healthcare provider should watch you closely for signs and symptoms of TB during treatment with OLUMIANT. You should not start taking OLUMIANT if you have any kind of infection unless your healthcare provider tells you it is okay. You may be at higher risk of developing shingles.Before starting OLUMIANT, tell your healthcare provider if you: are being treated for an infection.have an infection that does not go away or that keeps coming back.have diabetes, chronic lung disease, HIV, or weak immune system. People with these conditions have higher chance for infections.have TB or have been in close contact with someone with TB.have had hepatitis or C.live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections. These infections may happen or become more severe if you use OLUMIANT. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.think you have an infection or have symptoms of an infection such as: fever, sweating, or chillsshortness of breathwarm, red, or painful skin or sores on your bodyfeeling tiredmuscle achesblood in your phlegmdiarrhea or stomach paincoughweight lossburning when you urinate or urinating more often than normalAfter starting OLUMIANT, call your healthcare provider right away if you have any symptoms of an infection. OLUMIANT can make you more likely to get infections or make worse any infection that you have. 2. Increased risk of death in people 50 years of age and older who have at least heart disease (cardiovascular) risk factor and are taking medicine in the class of medicines called Janus kinase (JAK) inhibitors. OLUMIANT is JAK inhibitor medicine.3. Cancer and immune system problems. OLUMIANT may increase your risk of certain cancers by changing the way your immune system works. Lymphoma and other cancers including skin cancers can happen in people taking OLUMIANT. People taking medicine in the class of medicines called Janus kinase (JAK) inhibitors have higher risk of certain cancers including lymphoma and lung cancer, especially if you are current or past smoker. Tell your healthcare provider if you have ever had any type of cancer. 4. Increased risk of major cardiovascular events such as heart attack, stroke or death in people 50 years of age and older who have at least heart disease (cardiovascular) risk factor and taking medicine in the class of medicines called JAK inhibitors, especially if you are current or past smoker. Get emergency help right away if you have any symptoms of heart attack or stroke while taking OLUMIANT, including:discomfort in the center of your chest that lasts for more than few minutes, or that goes away and comes backsevere tightness, pain, pressure, or heaviness in your chest, throat, neck, or jawpain or discomfort in your arms, back, neck, jaw, or stomachshortness of breath with or without chest discomfortbreaking out in cold sweatnausea or vomitingfeeling lightheadedweakness in one part or on one side of your bodyslurred speech 5. Blood Clots.Blood clots in the veins of your legs (deep vein thrombosis, DVT) or lungs (pulmonary embolism, PE) can happen in some people taking OLUMIANT. This may be life-threatening and cause death. Blood clots in the veins of the legs (deep vein thrombosis, DVT) and lungs (pulmonary embolism, PE) have happened more often in people who are 50 years of age and older and with at least heart disease (cardiovascular) risk factor taking medicine in the class of medicines called Janus kinase (JAK) inhibitors. Tell your healthcare provider if you have had blood clots in the veins of your legs or lungs in the past.Tell your healthcare provider right away if you have any signs and symptoms of blood clots during treatment with OLUMIANT, including: swelling, pain or tenderness in the leg, sudden unexplained chest pain, or shortness of breath. 6. Tears (perforation) in the stomach or intestines.Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking OLUMIANT can get tears in their stomach or intestines. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate.Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and change in your bowel habits. 7. Changes in certain laboratory test results.Your healthcare provider should do blood tests before you start taking OLUMIANT and while you take OLUMIANT to check for the following:low lymphocyte counts. Lymphocytes are white blood cells that help the body fight off infections.low neutrophil counts. Neutrophils are white blood cells that help the body fight off infections.low red blood cell counts. This may mean that you have anemia, which may make you feel weak and tired. Your healthcare provider should routinely check certain liver tests.You should not receive OLUMIANT if your lymphocyte count, neutrophil count, or red blood cell count is too low or your liver tests are too high.Your healthcare provider may stop your OLUMIANT treatment for period of time if needed because of changes in these blood test results.You may also have changes in other laboratory tests, such as your blood cholesterol levels. Your healthcare provider should do blood tests to check your cholesterol levels approximately 12 weeks after you start taking OLUMIANT, and as needed after that. Normal cholesterol levels are important to good heart health. 8. Allergic Reactions. Symptoms such as rash, swelling of your lips, tongue, or throat, or hives (raised, red patches of skin that are often very itchy) that may mean you are having an allergic reaction have been seen in patients taking OLUMIANT. Some of these reactions were serious. If any of these symptoms occur while you are taking OLUMIANT, stop taking OLUMIANT and call your healthcare provider right away.See What are the possible side effects of OLUMIANT for more information about side effects.What is OLUMIANTOLUMIANT is prescription medicine used to treat adults with moderately to severely active rheumatoid arthritis after treatment with or more medicines called tumor necrosis factor (TNF) blockers have been used, and did not work well enough or could not be tolerated.It is not known if OLUMIANT is safe and effective in children.Before taking OLUMIANT, tell your healthcare provider about all your medical conditions, including if you:See What is the most important information should know about OLUMIANThave an infection.are current or past smoker.have had heart attack, other heart problems or stroke.have kidney problems.have liver problems.have low red or white blood cell counts.have recently received or are scheduled to receive vaccine. People who take OLUMIANT should not receive live vaccines.have any stomach area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines.are pregnant or plan to become pregnant. It is not known if OLUMIANT will harm an unborn baby.are breastfeeding or plan to breastfeed. It is not known if OLUMIANT passes into your breast milk. You and your healthcare provider should decide if you will take OLUMIANT or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. OLUMIANT and other medicines may affect each other causing side effects.Especially tell your healthcare provider if you take:a medicine called probenecid.any other medicines to treat your rheumatoid arthritis. For example, you should not take tocilizumab (Actemra(R)), etanercept (Enbrel(R)), adalimumab (Humira(R)), infliximab (Remicade(R)), rituximab (Rituxan(R)), abatacept (Orencia(R)), anakinra (Kineret(R)), certolizumab pegol (Cimzia(R)), golimumab (Simponi(R)), tofacitinib (Xeljanz(R), Xeljanz(R) XR), sarilumab (Kevzara(R)), azathioprine or cyclosporine while you are taking OLUMIANT. Taking OLUMIANT with these medicines may increase your risk of infection. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take OLUMIANTTake OLUMIANT exactly as your healthcare provider tells you to take it.Take OLUMIANT time day with or without food.What are the possible side effects of OLUMIANTOLUMIANT can cause serious side effects including:See What is the most important information should know about OLUMIANTCommon side effects of OLUMIANT include (these are not all of the possible side effects of OLUMIANT):upper respiratory tract infections (common cold, sinus infections)nauseacold soresshingles Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store OLUMIANTStore OLUMIANT at room temperature between 68F to 77F (20C to 25C). Keep OLUMIANT and all medicines out of the reach of children. General Information about the safe and effective use of OLUMIANT.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use OLUMIANT for condition for which it was not prescribed. Do not give OLUMIANT to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about OLUMIANT that is written for health professionals.What are the ingredients in OLUMIANTActive ingredient: baricitinib Inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide.OLUMIANT is registered trademark of Eli Lilly and Company. Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA Copyright (C) 2018, 2021, Eli Lilly and Company. All rights reserved.For more information, call 1-800-545-5979 or go to the following website: www.olumiant.com.OLM-0003-MG-20211203. Your healthcare provider should test you for TB before starting treatment with OLUMIANT.. Your healthcare provider should watch you closely for signs and symptoms of TB during treatment with OLUMIANT. You should not start taking OLUMIANT if you have any kind of infection unless your healthcare provider tells you it is okay. You may be at higher risk of developing shingles.Before starting OLUMIANT, tell your healthcare provider if you: are being treated for an infection.. have an infection that does not go away or that keeps coming back.. have diabetes, chronic lung disease, HIV, or weak immune system. People with these conditions have higher chance for infections.. have TB or have been in close contact with someone with TB.. have had hepatitis or C.. live or have lived, or have traveled to certain parts of the country (such as the Ohio and Mississippi River valleys and the Southwest) where there is an increased chance for getting certain kinds of fungal infections. These infections may happen or become more severe if you use OLUMIANT. Ask your healthcare provider if you do not know if you have lived in an area where these infections are common.. think you have an infection or have symptoms of an infection such as: fever, sweating, or chills. shortness of breath. warm, red, or painful skin or sores on your body. feeling tired. muscle aches. blood in your phlegm. diarrhea or stomach pain. cough. weight loss. burning when you urinate or urinating more often than normal. Lymphoma and other cancers including skin cancers can happen in people taking OLUMIANT. People taking medicine in the class of medicines called Janus kinase (JAK) inhibitors have higher risk of certain cancers including lymphoma and lung cancer, especially if you are current or past smoker. Tell your healthcare provider if you have ever had any type of cancer. discomfort in the center of your chest that lasts for more than few minutes, or that goes away and comes back. severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw. pain or discomfort in your arms, back, neck, jaw, or stomach. shortness of breath with or without chest discomfort. breaking out in cold sweat. nausea or vomiting. feeling lightheaded. weakness in one part or on one side of your body. slurred speech. Tell your healthcare provider if you have had blood clots in the veins of your legs or lungs in the past.. Tell your healthcare provider right away if you have any signs and symptoms of blood clots during treatment with OLUMIANT, including: swelling, pain or tenderness in the leg, sudden unexplained chest pain, or shortness of breath. Tell your healthcare provider if you have had diverticulitis (inflammation in parts of the large intestine) or ulcers in your stomach or intestines. Some people taking OLUMIANT can get tears in their stomach or intestines. This happens most often in people who also take nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate.. Tell your healthcare provider right away if you have fever and stomach-area pain that does not go away, and change in your bowel habits. low lymphocyte counts. Lymphocytes are white blood cells that help the body fight off infections.. low neutrophil counts. Neutrophils are white blood cells that help the body fight off infections.. low red blood cell counts. This may mean that you have anemia, which may make you feel weak and tired. OLUMIANT is prescription medicine used to treat adults with moderately to severely active rheumatoid arthritis after treatment with or more medicines called tumor necrosis factor (TNF) blockers have been used, and did not work well enough or could not be tolerated.. It is not known if OLUMIANT is safe and effective in children.. See What is the most important information should know about OLUMIANT. have an infection.. are current or past smoker.. have had heart attack, other heart problems or stroke.. have kidney problems.. have liver problems.. have low red or white blood cell counts.. have recently received or are scheduled to receive vaccine. People who take OLUMIANT should not receive live vaccines.. have any stomach area (abdominal) pain or been diagnosed with diverticulitis or ulcers in your stomach or intestines.. are pregnant or plan to become pregnant. It is not known if OLUMIANT will harm an unborn baby.. are breastfeeding or plan to breastfeed. It is not known if OLUMIANT passes into your breast milk. You and your healthcare provider should decide if you will take OLUMIANT or breastfeed. You should not do both. a medicine called probenecid.. any other medicines to treat your rheumatoid arthritis. For example, you should not take tocilizumab (Actemra(R)), etanercept (Enbrel(R)), adalimumab (Humira(R)), infliximab (Remicade(R)), rituximab (Rituxan(R)), abatacept (Orencia(R)), anakinra (Kineret(R)), certolizumab pegol (Cimzia(R)), golimumab (Simponi(R)), tofacitinib (Xeljanz(R), Xeljanz(R) XR), sarilumab (Kevzara(R)), azathioprine or cyclosporine while you are taking OLUMIANT. Taking OLUMIANT with these medicines may increase your risk of infection. Take OLUMIANT exactly as your healthcare provider tells you to take it.. Take OLUMIANT time day with or without food.. upper respiratory tract infections (common cold, sinus infections). nausea. cold sores. shingles.

SPL UNCLASSIFIED SECTION.

1.1 Rheumatoid Arthritis. OLUMIANT(R) (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.Limitation 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.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store at 20 to 25C (68 to 77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Keep out of reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Hepatic Impairment: OLUMIANT is not recommended in patients with severe hepatic impairment. (2.4, 8.6)Renal Impairment: OLUMIANT is not recommended in patients with severe renal impairment. (2.4, 8.7). Hepatic Impairment: OLUMIANT is not recommended in patients with severe hepatic impairment. (2.4, 8.6). Renal Impairment: OLUMIANT is not recommended in patients with severe renal impairment. (2.4, 8.7). 8.1 Pregnancy. Risk SummaryThe limited human data on use of OLUMIANT in pregnant women are not sufficient to inform drug-associated risk for major birth defects or miscarriage. In animal embryo-fetal development studies, oral baricitinib administration to pregnant rats and rabbits at exposures equal to and greater than approximately 20 and 84 times the maximum recommended human dose (MRHD), 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 and 13 times the exposure at the MRHD, respectively. In pre- and post-natal development study in pregnant female rats, oral baricitinib administration at exposures approximately 43 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 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 times the exposure at the MRHD [see Animal Data].The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have 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.. Data. Animal DataIn an embryofetal development study in pregnant rats, dosed orally during the period of organogenesis from gestation days to 17, baricitinib was teratogenic (skeletal malformations that consisted of bent limb bones and rib anomalies) at exposures equal to or greater than approximately 20 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 times the MRHD (on an AUC basis at maternal oral dose of mg/kg/day).In an embryofetal development study in pregnant rabbits, dosed orally during the period of organogenesis from gestation days to 20, embryolethality, decreased fetal body weights, and skeletal malformations (rib anomalies) were observed in the presence of maternal toxicity at an exposure approximately 84 times the MRHD (on an AUC basis at 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 12 times the MRHD (on an AUC basis at maternal oral dose of 10 mg/kg/day).In pre- and post-natal development study in pregnant female rats dosed orally from gestation day through lactation day 20, adverse findings observed in pups included decreased survival from birth to post-natal day (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 cells on PND 35 with recovery by PND 65 at exposures approximately 43 times the MRHD (on an AUC basis at 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 43 times the MRHD (on an AUC basis at 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 times the MRHD (on an AUC basis at maternal oral dose of mg/kg/day).. 8.2 Lactation. Risk SummaryNo 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. Due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. Because of the potential for serious adverse reactions in nursing infants, advise an OLUMIANT-treated woman not to breastfeed.. DataA 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.. 8.4 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 four phase studies, total of 537 rheumatoid arthritis patients were 65 years of age and older, including 71 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)].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 elderly 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 Dosing and Administration (2.4)].. 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 severe hepatic impairment and is therefore not recommended [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].. 8.7 Renal Impairment. Renal function was found to significantly affect baricitinib exposure. The recommended dose of OLUMIANT in patients with moderate renal impairment (estimated glomerular filtration rate (GFR) between 30 and 60 mL/min/1.73 m2) is mg once daily. OLUMIANT is not recommended for use in patients with severe renal impairment (estimated GFR of less than 30 mL/min/1.73 m2) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Gastrointestinal Perforations: Use with caution in patients at risk. (5.6)Laboratory Assessment: Monitor for changes in lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. (5.7)Vaccinations: Avoid use with live vaccines. (5.8)Hypersensitivity: Serious reactions have been reported. (5.9). Gastrointestinal Perforations: Use with caution in patients at risk. (5.6). Laboratory Assessment: Monitor for changes in lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. (5.7). Vaccinations: Avoid use with live vaccines. (5.8). Hypersensitivity: Serious reactions have been reported. (5.9). 5.1 Serious Infections. Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients 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 infectionwho have been exposed to tuberculosiswith history of serious or an opportunistic infectionwho have resided or traveled in areas of endemic tuberculosis or endemic mycoses; orwith underlying conditions that may predispose them to infection.Closely monitor patients for the development of signs and symptoms of infection during and after treatment with OLUMIANT. Interrupt OLUMIANT if patient develops serious infection, an opportunistic infection, or sepsis. patient who develops 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.. with chronic or recurrent infection. who have been exposed to tuberculosis. with history of 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.. TuberculosisEvaluate and test patients for latent or active infection prior to administration of OLUMIANT. Patients with latent tuberculosis (TB) should be treated with standard antimycobacterial therapy before initiating OLUMIANT.OLUMIANT should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of OLUMIANT in patients with history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with negative test for latent TB but who have risk factors for TB infection. Consultation with 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.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 ReactivationViral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies with OLUMIANT. If 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 or infection were excluded from clinical trials. Patients who were positive for hepatitis antibody but negative for hepatitis virus RNA were permitted to enroll. Patients with positive hepatitis surface antibody and hepatitis core antibody, without hepatitis surface antigen, were permitted to enroll; such patients should be monitored for expression of hepatitis virus (HBV) DNA. Should HBV DNA be detected, consult with hepatologist. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with OLUMIANT.. 5.2 Mortality. In 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 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 large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, 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. higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. 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 known malignancy (other than successfully treated NMSC), patients who develop malignancy, and patients who are current or past smokers. Non-melanoma skin cancersNon-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 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 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 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 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 Gastrointestinal Perforations. Events of gastrointestinal perforation have been reported in clinical studies with OLUMIANT, although the role of JAK inhibition in these events is not known.OLUMIANT should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.. 5.7 Laboratory Abnormalities. Neutropenia- Treatment with OLUMIANT was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3) compared to placebo. Avoid initiation or interrupt OLUMIANT treatment in patients with an ANC less than 1000 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. Adjust dosing based on ANC [see Dosage and Administration (2.3) 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.Avoid initiation or interrupt OLUMIANT treatment in patients with an ALC less than 500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. Adjust dosing based on ALC [see Dosage and Administration (2.3)].. Anemia- Decreases in hemoglobin levels to less than g/dL were reported in OLUMIANT clinical trials. Avoid initiation or interrupt OLUMIANT treatment in patients with hemoglobin less than g/dL. Evaluate at baseline and thereafter according to routine patient management. Adjust dosing based on hemoglobin levels [see Dosage and Administration (2.3)].. 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 [see Adverse Reactions (6.1)].Manage patients according to clinical guidelines for the management of hyperlipidemia.. 5.8 Vaccinations. Avoid use of live vaccines with OLUMIANT.Update immunizations in agreement with current immunization guidelines prior to initiating OLUMIANT therapy.. 5.9 Hypersensitivity. Reactions such as angioedema, urticaria, and rash that may reflect drug hypersensitivity have been observed in patients receiving OLUMIANT, including serious reactions. If serious hypersensitivity reaction occurs, promptly discontinue OLUMIANT while evaluating the potential causes of the reaction [see Adverse Reactions (6.2)].

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. ContraceptionBased 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.