1.1 Rheumatoid Arthritis

OLUMIANT® (baricitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) blockers.

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.

2.1 Dosage in Rheumatoid Arthritis

The recommended dose of OLUMIANT is 2 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 8 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)].

2.3 Dose Modifications Due to Serious Infections and Cytopenias

If a patient develops a 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)].

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 1 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 3 (OAT3) inhibitors, such as probenecid, is 1 mg once daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

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 infection
• who have been exposed to tuberculosis
• with a history of a serious or an opportunistic infection
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with OLUMIANT. Interrupt OLUMIANT if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with OLUMIANT should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and OLUMIANT should be interrupted if the patient is not responding to therapy. Do not resume OLUMIANT until the infection is controlled.

5.2 Mortality

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OLUMIANT.

5.3 Malignancy and Lymphoproliferative Disorders

Malignancies were observed in clinical studies of OLUMIANT [see Adverse Reactions (6.1)].

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OLUMIANT, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

5.4 Major Adverse Cardiovascular Events

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OLUMIANT, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue OLUMIANT in patients that have experienced a myocardial infarction or stroke.

5.5 Thrombosis

Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with OLUMIANT compared to placebo. In addition, arterial thrombosis events in the extremities have been reported in clinical studies with OLUMIANT. Many of these adverse events were serious and some resulted in death. There was no clear relationship between platelet count elevations and thrombotic events. In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers.

If clinical features of DVT/PE or arterial thrombosis occur, patients should discontinue OLUMIANT and be evaluated promptly and treated appropriately. Avoid OLUMIANT in patients that may be at increased risk of thrombosis.

5.6 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 a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

5.7 Laboratory Abnormalities

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 a serious hypersensitivity reaction occurs, promptly discontinue OLUMIANT while evaluating the potential causes of the reaction [see Adverse Reactions (6.2)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

The following data include six randomized double-blind placebo-controlled studies (three Phase 2, three Phase 3) and a long-term extension study. All patients had moderately to severely active RA. Patients were randomized to placebo (1070 patients), OLUMIANT 2 mg (479 patients), or baricitinib 4 mg (997 patients).

Patients could be switched to baricitinib 4 mg from placebo or OLUMIANT 2 mg from as early as Week 12 depending on the study design. All patients initially randomized to placebo were switched to baricitinib 4 mg by Week 24.

During the 16-week treatment period, adverse events leading to discontinuation of treatment were reported by 35 patients (11.4 events per 100 patient-years) treated with placebo, 17 patients (12.1 events per 100 patient-years) with OLUMIANT 2 mg, and 40 patients (13.4 events per 100 patient-years) treated with baricitinib 4 mg.

During 0 to 52-week exposure, adverse events leading to discontinuation of treatment were reported by 31 patients (9.2 events per 100 patient-years) with OLUMIANT 2 mg, and 92 patients (10.2 events per 100 patient-years) treated with baricitinib 4 mg.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of OLUMIANT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Drug hypersensitivity (events such as rash, urticaria, and angioedema have been observed) [see Warnings and Precautions (5.9)].

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)].

8.1 Pregnancy

8.2 Lactation

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 3 studies, a 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 1 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)].

12.1 Mechanism of Action

Baricitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Baricitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.

JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In cell-free isolated enzyme assays, baricitinib had greater inhibitory potency at JAK1, JAK2 and TYK2 relative to JAK3. In human leukocytes, baricitinib inhibited cytokine induced STAT phosphorylation mediated by JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 with comparable potencies. However, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Following oral administration of OLUMIANT, peak plasma concentrations are reached approximately at 1 hour. A dose-proportional increase in systemic exposure was observed in the therapeutic dose range. The pharmacokinetics of baricitinib do not change over time. Steady-state concentrations are achieved in 2 to 3 days with minimal accumulation after once-daily administration.

Specific Populations

Effects of Body Weight, Gender, Race, and Age

Body weight, gender, race, ethnicity, and age did not have a clinically relevant effect on the PK (AUC and Cmax) of baricitinib (Figure 1). The mean effects of intrinsic factors on PK parameters (AUC and Cmax) were generally within the inter-subject PK variability of baricitinib. The inter-subject variabilities (% coefficients of variation) in AUC and Cmax of baricitinib are approximately 41% and 22%, respectively. [See Use in Specific Populations (8.5)].

Renal Impairment

Baricitinib systemic exposure in AUC was increased by 1.41-, 2.22-, 4.05- and 2.41-fold for mild, moderate, severe, and ESRD (with hemodialysis) renal impairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in Cmax were 1.16-, 1.46-, 1.40- and 0.88-fold, respectively (Figure 1) [see Use in Specific Populations (8.7)].

Hepatic Impairment

Baricitinib systemic exposure and Cmax increased by 1.19- and 1.08-fold for the moderate hepatic impairment group, respectively, compared to subjects with normal hepatic function (Figure 1) [see Use in Specific Populations (8.6)].

Figure 1: Impact of Intrinsic Factors on Baricitinib Pharmacokineticsa,b

a Reference values for weight, age, gender, and race comparisons are 70 kg, 54 years, male, and white, respectively; reference groups for renal and hepatic impairment are subjects with normal renal and hepatic function, respectively.

b Effects of renal and hepatic impairment on baricitinib exposure were summarized from dedicated renal and hepatic impairment studies, respectively. Effects of other intrinsic factors on baricitinib exposure were summarized from population PK analysis.

Drug Interactions

Potential for Baricitinib to Influence the PK of Other Drugs

In 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) 1 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 Drugsa

a Reference group is administration of concomitant drug alone.

Potential for Other Drugs to Influence the PK of Baricitinib

In vitro studies suggest that baricitinib is a 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 a substrate for OAT3, Pgp, BCRP and MATE2-K. In a 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 a 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 Baricitinibb

a Values are based on simulated studies.

b Reference group is administration of baricitinib alone.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of baricitinib was evaluated in Sprague-Dawley rats and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female rats that received baricitinib for 91 to 94 weeks at oral doses up to 8 or 25 mg/kg/day, respectively (approximately 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 7 of 19 (36.8%) drug-treated females with evidence of mating were not gravid compared to 1 of 19 (5.3%) control females. It could not be determined from the study design if these findings were attributable to toxicities in one sex or both. Fertility was unaffected in male and female rats at oral doses of 15 mg/kg and 25 mg/kg, respectively (approximately 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 5 mg/kg/day and were mated to males that received the same dose (approximately 8 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).

Dose-Ranging Studies

The dose-ranging studies I (NCT01185353) and II (NCT01469013) included a 12-week randomized comparison of baricitinib 1, 2, 4, and 8 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 1 and 2 mg daily and for baricitinib 4 and 8 mg daily, with the highest response for baricitinib 8 mg daily. In dose-ranging Study II, there was not a clear trend of dose response, with similar response rates for 1 mg and 4 mg and 2 mg and 8 mg.

Confirmatory Studies

The efficacy and safety of OLUMIANT 2 mg once daily was assessed in two confirmatory phase 3 trials. These trials were randomized, double-blind, multicenter studies in patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR)/European League Against Rheumatism 2010 criteria. Patients over 18 years of age were eligible if at least 6 tender and 6 swollen joints were present at baseline. The two studies (Studies III and IV) evaluated OLUMIANT 2 mg and baricitinib 4 mg.

Study III (NCT01721057) was a 24-week trial in 684 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to conventional DMARDs (cDMARDs). Patients received OLUMIANT 2 mg or 4 mg once daily or placebo added to existing background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Study IV (NCT01721044) was a 24-week trial in 527 patients with moderately to severely active rheumatoid arthritis who had an inadequate response or intolerance to 1 or more TNF inhibitor therapies with or without other biologic DMARDs (TNFi-IR). Patients received OLUMIANT 2 mg or baricitinib 4 mg once daily or placebo added to background cDMARD treatment. From Week 16, non-responding patients could be rescued to receive baricitinib 4 mg once daily. The primary endpoint was the proportion of patients who achieved an ACR20 response at Week 12.

Clinical Response

The percentages of OLUMIANT-treated patients achieving ACR20, ACR50, and ACR70 responses, and Disease Activity Score (DAS28-CRP) <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 1 week with OLUMIANT 2 mg versus placebo.

In Study IV, the proportions of patients achieving DAS28-CRP <2.6 who had at least 3 active joints at the end of Week 24 were 18.2% and 10.5%, in the placebo and OLUMIANT 2 mg arms, respectively.

The effects of OLUMIANT treatment on the components of the ACR response criteria for Studies III and IV are shown in Table 7.

Figure 4: Percent of Patients Achieving ACR20

Physical Function Response

Improvement in physical function was measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). Patients receiving OLUMIANT 2 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 Outcomes

General health status was assessed by the Short Form health survey (SF-36). In Studies III and IV, compared to placebo, patients treated with OLUMIANT 2 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.

16.1 How Supplied

OLUMIANT for oral administration is available as debossed, film-coated, immediate-release tablets. Each tablet contains a recessed area on each face of the tablet surface.

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep out of reach of children.

Dosing

Alternate Administration

For patients who are unable to swallow whole tablets, alternate administration may be considered:

• Oral dispersion
• Gastrostomy tube (G tube)
• Nasogastric tube (NG tube)

Preparation for Alternate Administration

• Oral administration of dispersed tablets in water:
  For patients who are unable to swallow whole tablets, 1-mg, 2-mg, or 4-mg baricitinib tablet(s), or any combination of tablets necessary to achieve the desired dose up to 4-mg may be placed in a container with approximately 10 mL (5 mL minimum) of room temperature water, dispersed by gently swirling the tablet(s) and immediately taken orally. The container should be rinsed with an additional 10 mL (5 mL minimum) of room temperature water and the entire contents swallowed by the patient (see Table 2).
• Administration via gastrostomy feeding tube:
  For patients with a gastrostomy feeding tube, 1-mg, 2-mg, or 4-mg baricitinib tablet(s), or any combination of tablets necessary to achieve the desired dose up to 4-mg may be placed in a container with approximately 15 mL (10 mL minimum) of room temperature water and dispersed with gentle swirling. Ensure the tablet(s) are sufficiently dispersed to allow free passage through the tip of the syringe. Withdraw entire contents from the container into an appropriate syringe and immediately administer through the gastric feeding tube. Rinse container with approximately 15 mL (10 mL minimum) of room temperature water, withdraw the contents into the syringe, and administer through the tube (see Table 2).
• Administration via nasogastric feeding tube:
  For patients with an enteral feeding tube, 1-mg, 2-mg, or 4-mg baricitinib tablet(s), or a combination of tablets necessary to achieve the desired dose up to 4-mg may be placed into a container with approximately 30 mL of room temperature water and dispersed with gentle swirling. Ensure the tablet(s) are sufficiently dispersed to allow free passage through the tip of the syringe. Withdraw the entire contents from the container into an appropriate syringe and immediately administer through the enteral feeding tube. To avoid clogging of small diameter tubes (smaller than 12 Fr), the syringe can be held horizontally and shaken during administration. Rinse container with a sufficient amount (minimum of 15 mL) of room temperature water, withdraw the contents into the syringe, and administer through the tube (see Table 2).

Intact tablets are not hazardous. Tablets may be crushed to facilitate dispersion. It is not known if powder from the crushed tablets may constitute a reproductive hazard to the preparer. Use proper control measures (e.g., ventilated enclosure) or personal protective equipment (i.e., N95 respirator).

Dispersed tablets are stable in water for up to 4 hours.

Serious Infections

There is limited information regarding use of baricitinib in patients with COVID-19 and concomitant active serious infections.

Serious infections have occurred in patients receiving baricitinib:

• Avoid the use of baricitinib with known active tuberculosis.
• Consider if the potential benefits outweigh the potential risks of baricitinib treatment in patients with active serious infections other than COVID-19 or chronic / recurrent infections.

Thrombosis

In hospitalized patients with COVID-19, prophylaxis for VTE is recommended unless contraindicated. If clinical features of deep vein thrombosis/pulmonary embolism occur, patients should be evaluated promptly and treated appropriately.

Abnormal Laboratory Values

There is limited information regarding use of baricitinib in patients with COVID-19 and any of the following clinical findings:

• ANC <1000 cells/mm3
• ALC <200 cells/mm3
• Hemoglobin <8 g/dL

Evaluate at baseline and thereafter according to local patient management practice. Monitor closely when treating patients with abnormal baseline and post-baseline laboratory values.

See Table 1 for dosage adjustments for patients with abnormal renal, hematological and hepatic laboratory values. Manage patients according to routine clinical guidelines.

Vaccinations

Avoid use of live vaccines with baricitinib.

Hypersensitivity

If a serious hypersensitivity occurs, discontinue baricitinib while evaluating the potential causes of the reaction.

See Warnings and Precautions in the FDA approved full prescribing information for additional information on risks associated with longer-term treatment with baricitinib.

Serious Side Effects

Serious venous thrombosis, including pulmonary embolism, and serious infections have been observed in COVID-19 patients treated with baricitinib and are known adverse drug reactions of baricitinib.

Efficacy

ACTT-2 (Adaptive COVID-19 Treatment Trial 2) Study in Hospitalized Adults Diagnosed with COVID-19 Infection

A randomized, double-blind, placebo-controlled clinical trial (ACTT-2, NCT04401579) of hospitalized adults with confirmed SARS-CoV-2 infection compared treatment with baricitinib, a JAK inhibitor, plus remdesivir, an anti-viral (combination group; n=515) with placebo plus remdesivir (placebo group; n=518). Patients had to have laboratory-confirmed SARS-CoV-2 infection as well as at least one of the following to be enrolled in the trial: radiographic infiltrates by imaging, SpO2≤94% on room air, a requirement for supplemental oxygen, or a requirement for mechanical ventilation or ECMO. Patients treated with the combination received the following regimen:

• Baricitinib 4 mg once daily (orally) for 14 days or until hospital discharge
• Remdesivir 200 mg on Day 1 and 100 mg once daily (via intravenous infusion) on subsequent days for a total treatment duration of 10 days or until hospital discharge

For the overall population (N=1033 patients) at randomization, mean age was 55 years (with 30% of patients aged 65 or older); 63% of patients were male, 51% were Hispanic or Latino, 48% were White, 15% were Black or African American, and 10% were Asian; 14% did not require supplemental oxygen, 55% required supplemental oxygen, 21% required non-invasive ventilation or high-flow oxygen, and 11% required invasive mechanical ventilation or ECMO. The most common comorbidities were obesity (56%), hypertension (52%), and type 2 diabetes (37%). Demographics and disease characteristics were balanced across the combination group and the placebo group.

The primary endpoint, for the intent to treat population, was time to recovery within 29 days after randomization. Recovery was defined as being discharged from the hospital without limitations on activities, being discharged from the hospital with limitations on activities and/or requiring home oxygen or hospitalized but not requiring supplemental oxygen and no longer requiring medical care. The key secondary endpoint was clinical status on Day 15 assessed on an 8-point ordinal scale (OS) consisting of the following categories:

1. Not hospitalized, no limitations on activities [OS-1];
2. Not hospitalized, limitation on activities and/or requiring home oxygen [OS-2];
3. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care [OS-3];
4. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise) [OS 4];
5. Hospitalized, requiring supplemental oxygen [OS 5];
6. Hospitalized, on non-invasive ventilation or high-flow oxygen devices [OS 6];
7. Hospitalized, on invasive mechanical ventilation or ECMO [OS 7]; and
8. Death [OS 8]

For the overall population, the median time to recovery (defined as discharged from hospital or hospitalized but not requiring supplemental oxygen or ongoing medical care) was 7 days for baricitinib + remdesivir compared to 8 days for placebo + remdesivir [hazard ratio: 1.15 (95% CI 1.00, 1.31); p=0.047].

Patients assigned to baricitinib + remdesivir were more likely to have a better clinical status (according to an 8-point ordinal scale) at Day 15 compared to patients assigned to placebo + remdesivir [odds ratio: 1.26 (95% CI 1.01, 1.57); p=0.044].

The proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation by Day 29 was lower in baricitinib + remdesivir (23%) compared to placebo + remdesivir (28%) [odds ratio: 0.74 (95% CI 0.56, 0.99); p=0.039]. Patients who required non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation (including ECMO) at baseline needed to worsen by at least 1 point on an 8-point ordinal scale to progress.

The proportion of patients who died by Day 29 was 4.7% (24/515) for baricitinib + remdesivir vs. 7.1% (37/518) for placebo + remdesivir [Kaplan Meier estimated difference in Day 29 probability of mortality: -2.6% (95% CI -5.8%, 0.5%)].

COV-BARRIER Study in Hospitalized Adults Diagnosed with COVID-19 Infection

A randomized, double-blind, placebo-controlled clinical trial (COV-BARRIER, NCT04421027) of hospitalized adults with confirmed SARS-CoV-2 infection compared treatment with baricitinib 4mg once daily (n=764) with placebo (n=761). Patients could remain on background standard of care, as defined per local guidelines, including antimalarials, antivirals, corticosteroids, and/or azithromycin. The most frequently used therapies were:

• corticosteroids (79% of patients, mostly dexamethasone)
• remdesivir (19% of patients)

Patients had to have laboratory-confirmed SARS-CoV-2 infection, at least one instance of elevation in at least one inflammatory marker (CRP, D-dimer, LDH, ferritin), and at least one of the following to be enrolled in the trial: radiographic infiltrates by imaging, SpO2≤94% on room air, evidence of active COVID infection (with clinical symptoms including any of the following: fever, vomiting, diarrhea, dry cough, tachypnea defined as respiratory rate >24 breaths/min) or requirement for supplemental oxygen. Patients requiring invasive mechanical ventilation or ECMO at baseline were enrolled in a sub-study of COV-BARRIER that is ongoing.

For the overall population (N=1525 patients) at randomization, mean age was 58 years (with 33% of patients aged 65 or older); 63% of patients were male, 62% were White, 5% were Black or African American,12% were Asian; 12% did not require supplemental oxygen (OS 4), 63% required supplemental oxygen (OS 5), 24% required non-invasive ventilation or high-flow oxygen (OS 6). The most common comorbidities were hypertension (48%), obesity (33%), and type 2 diabetes (29%). Demographics and disease characteristics were balanced across the baricitinib and placebo groups.

The primary endpoint was the proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation within the first 28-days of the study. Patients who required non-invasive ventilation/high-flow oxygen at baseline needed to worsen by at least 1 point on an 8-point ordinal scale to progress. A key secondary endpoint was all-cause mortality by Day 28.

The estimated proportion of patients who died or progressed to non-invasive ventilation/high-flow oxygen or invasive mechanical ventilation was lower in patients treated with baricitinib (27.8%) compared to placebo (30.5%), but this effect was not statistically significant [odds ratio: 0.85 (95% CI 0.67, 1.08); p=0.180].

The proportion of patients who died by Day 28 was 8.1% (62/764) for baricitinib vs. 13.3% (101/761) for placebo [estimated difference in Day 28 probability of mortality = -4.9% (95% CI: -8.0%, -1.9%); hazard ratio = 0.56 (95% CI: 0.41, 0.77)].

Safety

In placebo-controlled COVID-19 clinical trials, ACTT-2 and COV-BARRIER, for up to 29 days, 1257 patients received at least one dose of baricitinib 4 mg once daily, and 1261 patients received placebo, for up to 14 days or hospital discharge, whichever occurred first. Data on deaths, serious adverse events (SAEs), AEs leading to discontinuation, and infections are summarized in Table 3.

Of the known adverse drug reactions of baricitinib in clinical trials of other indications, Table 4 summarizes the observed frequencies of adverse reactions occurring in ≥ 1% of patients during the first 29 days of studies ACTT-2 and COV-BARRIER.

How Supplied

Baricitinib for oral administration is available as debossed, film-coated, immediate-release tablets. Each tablet contains a recessed area on each face of the tablet surface.

Under this EUA, baricitinib is supplied in 30 count bottles as follows:

• OLUMIANT (baricitinib) tablet 1 mg (NDC 0002-4732-30)
• OLUMIANT (baricitinib) tablet 2 mg (NDC 0002-4182-30), and
• baricitinib tablet 4 mg (NDC 0002-6885-30)

Storage and Handling

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Keep out of reach of children.

MANDATORY REQUIREMENTS FOR BARICITINIB ADMINISTRATION UNDER EMERGENCY USE AUTHORIZATION

In order to mitigate the risks of using this approved product for an unapproved use under EUA and to optimize the potential benefit of baricitinib, the following items are required. Use of baricitinib under this EUA is limited to the following (all requirements must be met):

1. Treatment of coronavirus disease 2019 (COVID-19) in hospitalized adults and pediatric patients 2 years of age or older requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or ECMO.
2. As the healthcare provider, communicate to your patient or parent/caregiver information consistent with the “Fact Sheet for Patients, Parents and Caregivers” prior to the patient receiving baricitinib. Healthcare providers (to the extent practicable given the circumstances of the emergency) must document in the patient's medical record that the patient/caregiver has been:
   1. Given the “Fact Sheet for Patients, Parents and Caregivers”,
   2. Informed of alternatives to receiving authorized baricitinib, and
   3. Informed that baricitinib is an approved drug that is authorized for the unapproved use under this Emergency Use Authorization.
3. Patients must have an eGFR, aminotransferases, and CBC with differential determined prior to first administration of baricitinib.
4. The prescribing healthcare provider and/or the provider's designee are/is responsible for mandatory reporting of all medication errors and all serious adverse events* potentially related to baricitinib treatment within 7 calendar days from the onset of the event. The reports should include unique identifiers and the words “Baricitinib treatment under Emergency Use Authorization (EUA)” in the description section of the report.
   • Submit adverse event reports to FDA MedWatch using one of the following methods:
     • Complete and submit the report online:
       www.fda.gov/medwatch/report.htm, or
     • Complete and submit a postage-paid Form FDA 3500
       (https://www.fda.gov/media/76299/download) and return by:
       • Mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787, or
       • Fax (1-800-FDA-0178), or
     • Call 1-800-FDA-1088 to request a reporting form.
     • Submitted reports should include in the field name, “Describe Event, Problem, or Product Use/Medication Error” the statement “Baricitinib use for COVID-19 under Emergency Use Authorization (EUA).”

   *Serious Adverse Events are defined as:

   • death;
   • a life-threatening adverse event;
   • inpatient hospitalization or prolongation of existing hospitalization;
   • a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions;
   • a congenital anomaly/birth defect;
   • a medical or surgical intervention to prevent death, a life-threatening event, hospitalization, disability, or congenital anomaly.
5. The prescribing healthcare provider and/or the provider's designee are/is to provide mandatory responses to requests from FDA for information about adverse events and medication errors following receipt of baricitinib.
6. OTHER REPORTING REQUIREMENTS
   Report adverse events or medication errors to Lilly at:
   1-855-LillyC19 (1-855-545-5921)

In addition, please provide a copy of all FDA MedWatch forms to:

Eli Lilly and Company, Global Patient Safety

Fax: 1-317-277-0853

E-mail: mailindata_gsmtindy@lilly.com