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OLUMIANT- baricitinib tablet, film coated 
Eli Lilly and Company


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-BOXED WARNING

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WARNING: SERIOUS INFECTIONS, MALIGNANCY, AND THROMBOSIS

SERIOUS INFECTIONS

Patients treated with OLUMIANT are at risk for developing serious infections
that may lead to hospitalization or death [see Warnings and Precautions (5.1)
and Adverse Reactions (6.1)]. Most patients who developed these infections were
taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt OLUMIANT until the infection is
controlled.

Reported infections include:

 * Active tuberculosis, which may present with pulmonary or extrapulmonary
   disease. 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)].

MALIGNANCIES

Lymphoma and other malignancies have been observed in patients treated with
OLUMIANT [see Warnings and Precautions (5.2)].

THROMBOSIS

Thrombosis, including deep venous thrombosis and pulmonary embolism, has been
observed at an increased incidence in patients treated with OLUMIANT compared to
placebo. In addition, there were cases of arterial thrombosis. Many of these
adverse events were serious and some resulted in death. Patients with symptoms
of thrombosis should be promptly evaluated. [see Warnings and Precautions
(5.3)].

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+HIGHLIGHTS OF PRESCRIBING INFORMATION


HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use OLUMIANT
safely and effectively. See full prescribing information for OLUMIANT.
OLUMIANT (baricitinib) tablets, for oral use
Initial U.S. Approval: 2018


WARNING: SERIOUS INFECTIONS, MALIGNANCY, AND THROMBOSIS


SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING.

 * Serious infections leading to hospitalization or death, including
   tuberculosis and bacterial, invasive fungal, viral, and other opportunistic
   infections, have occurred in patients receiving OLUMIANT. If a serious
   infection develops, interrupt OLUMIANT until the infection is controlled.
   (5.1)
 * Prior to starting OLUMIANT, test for latent tuberculosis; if positive, start
   treatment for tuberculosis prior to starting OLUMIANT. Monitor all patients
   for active tuberculosis during treatment, even if initial tuberculosis test
   is negative. (5.1)
 * Lymphoma and other malignancies have been observed in patients treated with
   OLUMIANT. (5.2)
 * Thrombosis, including deep venous thrombosis, pulmonary embolism, and
   arterial thrombosis, some fatal, have occurred in patients treated with
   OLUMIANT. Patients with symptoms of thrombosis should be evaluated promptly.
   (5.3)


RECENT MAJOR CHANGES

Dosage and Administration: Dose Modifications in Patients with Renal or Hepatic
Impairment, Dose Modifications Due to Drug Interactions (2.4, 2.5) 10/2019
Warnings and Precautions, Hypersensitivity (5.7) 07/2020




INDICATIONS AND USAGE

OLUMIANT® is a Janus kinase (JAK) inhibitor indicated for the treatment of adult
patients with moderately to severely active rheumatoid arthritis who have had an
inadequate response to one or more TNF antagonist therapies. (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)




DOSAGE AND ADMINISTRATION

 * The recommended dose of OLUMIANT is 2 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, 5.5)
 * Moderate Renal Impairment: Reduce dose to 1 mg once daily. (2.4)








DOSAGE FORMS AND STRENGTHS

Tablets: 2 mg, 1 mg (3)


CONTRAINDICATIONS

None. (4)


WARNINGS AND PRECAUTIONS

 * Gastrointestinal Perforations: Use with caution in patients at risk. (5.4)
 * Laboratory Assessment: Monitor for changes in lymphocytes, neutrophils,
   hemoglobin, liver enzymes, and lipids. (5.5)
 * Vaccinations: Avoid use with live vaccines. (5.6)
 * Hypersensitivity: Serious reactions have been reported. (5.7)










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.





DRUG INTERACTIONS

The recommended dose of OLUMIANT in patients taking strong Organic Anion
Transporter 3 (OAT3) inhibitors (e.g., probenecid) is 1 mg once daily. (2.5,
7.1)





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)

















See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 7/2020

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+FULL PRESCRIBING INFORMATION: CONTENTS*


FULL PRESCRIBING INFORMATION: CONTENTS*


WARNING: SERIOUS INFECTIONS, MALIGNANCY, AND THROMBOSIS


1 INDICATIONS AND USAGE


1.1 RHEUMATOID ARTHRITIS


2 DOSAGE AND ADMINISTRATION


2.1 DOSAGE IN RHEUMATOID ARTHRITIS


2.2 GENERAL CONSIDERATIONS FOR ADMINISTRATION


2.3 DOSE MODIFICATIONS DUE TO SERIOUS INFECTIONS AND CYTOPENIAS


2.4 DOSE MODIFICATIONS IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT


2.5 DOSE MODIFICATIONS DUE TO DRUG INTERACTIONS


3 DOSAGE FORMS AND STRENGTHS


4 CONTRAINDICATIONS


5 WARNINGS AND PRECAUTIONS


5.1 SERIOUS INFECTIONS


5.2 MALIGNANCY AND LYMPHOPROLIFERATIVE DISORDERS


5.3 THROMBOSIS


5.4 GASTROINTESTINAL PERFORATIONS


5.5 LABORATORY ABNORMALITIES


5.6 VACCINATIONS


5.7 HYPERSENSITIVITY


6 ADVERSE REACTIONS


6.1 CLINICAL TRIALS EXPERIENCE


6.2 POSTMARKETING EXPERIENCE


7 DRUG INTERACTIONS


7.1 STRONG OAT3 INHIBITORS


7.2 OTHER JAK INHIBITORS OR BIOLOGIC DMARDS


8 USE IN SPECIFIC POPULATIONS


8.1 PREGNANCY


8.2 LACTATION


8.4 PEDIATRIC USE


8.5 GERIATRIC USE


8.6 HEPATIC IMPAIRMENT


8.7 RENAL IMPAIRMENT


10 OVERDOSAGE


11 DESCRIPTION


12 CLINICAL PHARMACOLOGY


12.1 MECHANISM OF ACTION


12.2 PHARMACODYNAMICS


12.3 PHARMACOKINETICS


13 NONCLINICAL TOXICOLOGY


13.1 CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY


14 CLINICAL STUDIES


16 HOW SUPPLIED/STORAGE AND HANDLING


16.1 HOW SUPPLIED


16.2 STORAGE AND HANDLING


17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not
listed.

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+1 INDICATIONS AND USAGE


1 INDICATIONS AND USAGE


1.1 RHEUMATOID ARTHRITIS

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

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.

Hide


+2 DOSAGE AND ADMINISTRATION


2 DOSAGE AND ADMINISTRATION


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 (5.5)].
 * 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)].

Table 1: Dose Adjustments for Lymphopenia Low Absolute Lymphocyte Count (ALC)
Lab Value (cells/mm3) Recommendation ALC greater than or equal to 500 Maintain
dose ALC less than 500 Interrupt OLUMIANT until ALC greater than or equal to 500

Table 2: Dose Adjustments for Neutropenia Low Absolute Neutrophil Count (ANC)
Lab Value (cells/mm3) Recommendation ANC greater than or equal to 1000 Maintain
dose ANC less than 1000 Interrupt OLUMIANT until ANC greater than or equal to
1000

Table 3: Dose Adjustments for Anemia Low Hemoglobin Value Lab Value (g/dL)
Recommendation Greater than or equal to 8 Maintain dose Less than 8 Interrupt
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 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)].

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+3 DOSAGE FORMS AND STRENGTHS


3 DOSAGE FORMS AND STRENGTHS

OLUMIANT for oral administration is available as debossed, film-coated,
immediate-release tablets:

 * 1 mg tablet contains a recessed area on each face of the tablet surface, is
   very light pink, round, debossed with “Lilly” on one side and “1” on the
   other.
 * 2 mg tablet contains a recessed area on each face of the tablet surface, is
   light pink, oblong, debossed with “Lilly” on one side and “2” on the other.

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+4 CONTRAINDICATIONS


4 CONTRAINDICATIONS

None.

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+5 WARNINGS AND PRECAUTIONS


5 WARNINGS AND PRECAUTIONS


5.1 SERIOUS INFECTIONS

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive
fungal, viral, or other opportunistic pathogens have been reported in 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.

Tuberculosis

Evaluate 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 a history of latent or
active TB in whom an adequate course of treatment cannot be confirmed, and for
patients with a negative test for latent TB but who have risk factors for TB
infection. Consultation with a physician with expertise in the treatment of TB
is recommended to aid in the decision about whether initiating anti-TB therapy
is appropriate for an individual patient.

Monitor patients for the development of signs and symptoms of TB, including
patients who tested negative for latent TB infection prior to initiating
therapy.

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes
zoster), were reported in clinical studies with OLUMIANT. If a patient develops
herpes zoster, interrupt OLUMIANT treatment until the episode resolves.

The impact of OLUMIANT on chronic viral hepatitis reactivation is unknown.
Patients with evidence of active hepatitis B or C infection were excluded from
clinical trials. Patients who were positive for hepatitis C antibody but
negative for hepatitis C virus RNA were permitted to enroll. Patients with
positive hepatitis B surface antibody and hepatitis B core antibody, without
hepatitis B surface antigen, were permitted to enroll; such patients should be
monitored for expression of hepatitis B virus (HBV) DNA. Should HBV DNA be
detected, consult with a hepatologist. Perform screening for viral hepatitis in
accordance with clinical guidelines before starting therapy with OLUMIANT.


5.2 MALIGNANCY AND LYMPHOPROLIFERATIVE DISORDERS

Consider the risks and benefits of OLUMIANT treatment prior to initiating
therapy in patients with a known malignancy other than a successfully treated
non-melanoma skin cancer (NMSC) or when considering continuing OLUMIANT in
patients who develop a malignancy. Malignancies were observed in clinical
studies of OLUMIANT [see Adverse Reactions (6.1)].

Non-melanoma skin cancers

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with
OLUMIANT. Periodic skin examination is recommended for patients who are at
increased risk for skin cancer.


5.3 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. OLUMIANT should be used
with caution in patients who may be at increased risk of thrombosis. If clinical
features of DVT/PE or arterial thrombosis occur, patients should be evaluated
promptly and treated appropriately.


5.4 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.


5.5 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 8 g/dL were reported in
OLUMIANT clinical trials. Avoid initiation or interrupt OLUMIANT treatment in
patients with hemoglobin less than 8 g/dL. Evaluate at baseline and thereafter
according to routine patient management. Adjust dosing based on hemoglobin
levels [see 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.


5.6 VACCINATIONS

Avoid use of live vaccines with OLUMIANT.

Update immunizations in agreement with current immunization guidelines prior to
initiating OLUMIANT therapy.


5.7 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)].

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+6 ADVERSE REACTIONS


6 ADVERSE REACTIONS


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.

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
2 mg, and 298 patients (100.1 events per 100 patient-years) treated with
baricitinib 4 mg.

During 0 to 52 week exposure, infections were reported by 200 patients (59.6
events per 100 patients-years) treated with OLUMIANT 2 mg, and 500 patients
(55.3 events per 100 patient-years) treated with baricitinib 4 mg.

In the 0 to 52 week exposure population, the most commonly reported infections
with OLUMIANT were viral upper respiratory tract infection, upper respiratory
tract infection, urinary tract infection, and bronchitis.

Serious Infections – During the 16-week treatment period, serious infections
were reported in 13 patients (4.2 events per 100 patient-years) treated with
placebo, 5 patients (3.6 events per 100 patient-years) treated with OLUMIANT
2 mg, and 11 patients (3.7 events per 100 patient-years) treated with
baricitinib 4 mg.

During 0 to 52 week exposure, serious infections were reported in 14 patients
(4.2 events per 100 patient-years) treated with OLUMIANT 2 mg and 32 patients
(3.5 events per 100 patient-years) treated with baricitinib 4 mg.

In the 0 to 52 week exposure population, the most commonly reported serious
infections with OLUMIANT were pneumonia, herpes zoster, and urinary tract
infection [see Warnings and Precautions (5.1)].

Tuberculosis – During the 16-week treatment period, no events of tuberculosis
were reported.

During 0 to 52 week exposure, events of tuberculosis were reported in 0 patients
treated with OLUMIANT 2 mg and 1 patient (0.1 per 100 patient-years) treated
with baricitinib 4 mg [see Warnings and Precautions (5.1)].

Cases of disseminated tuberculosis were also reported.

Opportunistic Infections (excluding tuberculosis) – During the 16-week treatment
period, opportunistic infections were reported in 2 patients (0.6 per 100
patient-years) treated with placebo, 0 patients treated with OLUMIANT 2 mg and
2 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg.

During 0 to 52 week exposure, opportunistic infections were reported in 1
patient (0.3 per 100 patient-years) treated with OLUMIANT 2 mg and 5 patients
(0.6 per 100 patient-years) treated with baricitinib 4 mg [see Warnings and
Precautions (5.1)].

Malignancy – During the 16-week treatment period, malignancies excluding
non-melanoma skin cancers (NMSC) were reported in 0 patients treated with
placebo, 1 patient (0.7 per 100 patient-years) treated with OLUMIANT 2 mg, and 1
patient (0.3 per 100 patient-years) treated with baricitinib 4 mg.

During the 0 to 52 week treatment period, malignancies excluding NMSC were
reported in 2 patients (0.6 per 100 patient-years) treated with OLUMIANT 2 mg
and 6 patients (0.7 per 100 patient-years) treated with baricitinib 4 mg [see
Warnings and Precautions (5.2)].

Venous Thrombosis – During the 16-week treatment period, venous thromboses (deep
vein thrombosis or pulmonary embolism) were reported in 0 patients treated with
placebo, 0 patients treated with OLUMIANT 2 mg, and 5 patients (1.7 per 100
patient-years) treated with baricitinib 4 mg.

During the 0 to 52 week treatment period, venous thromboses were reported in 2
patients (0.6 per 100 patient-years) treated with OLUMIANT 2 mg and 7 patients
(0.8 per 100 patient-years) treated with baricitinib 4 mg.

Arterial Thrombosis – During the 16-week treatment period, arterial thromboses
were reported in 1 patient treated with placebo (0.3 per 100 patient-years), 2
patients (1.4 per 100 patient-years) treated with OLUMIANT 2 mg, and 2 patients
(0.7 per 100 patient-years) treated with baricitinib 4 mg.

During the 0 to 52 week treatment period, arterial thromboses were reported in 3
patients (0.9 per 100 patient-years) treated with OLUMIANT 2 mg and 3 patients
(0.3 per 100 patient-years) treated with baricitinib 4 mg.

Laboratory Abnormalities

Neutropenia – During the 16-week treatment period, neutrophil counts below
1000 cells/mm3 occurred in 0% of patients treated with placebo, 0.6% of patients
treated with OLUMIANT 2 mg, and 0.3% of patients treated with baricitinib 4 mg.
There were no neutrophil counts below 500 cells/mm3 observed in any treatment
group [see Warnings and Precautions (5.1, 5.5)].

Platelet Elevations – During the 16-week treatment period, increases in platelet
counts above 600,000 cells/mm3 occurred in 1.1% of patients treated with
placebo, 1.1% of patients treated with OLUMIANT 2 mg, and 2.0% of patients
treated with baricitinib 4 mg. Mean platelet count increased by 3000 cells/mm3
at 16 weeks in patients treated with placebo, by 15,000 cells/mm3 at 16 weeks in
patients treated with OLUMIANT 2 mg and by 23,000 cells/mm3 in patients treated
with baricitinib 4 mg.

Liver Enzyme Elevations – Events of increases in liver enzymes ≥3 times the ULN
were observed in patients treated with OLUMIANT [see Warnings and Precautions
(5.5)].

 * During the 16-week treatment period, ALT elevations ≥3 times the ULN occurred
   in 1.0% of patients treated with placebo, 1.7% of patients treated with
   OLUMIANT 2 mg, and 1.4% of patients treated with baricitinib 4 mg.
 * During the 16-week treatment period, AST elevations ≥3 times the ULN occurred
   in 0.8% of patients treated with placebo, 1.3% of patients treated with
   OLUMIANT 2 mg, and 0.8% of patients treated with baricitinib 4 mg.
 * In a phase 3 study of DMARD naive patients, during the 24-week treatment
   period, ALT and AST elevations ≥3 times the ULN occurred in 1.9% and 0% of
   patients treated with methotrexate monotherapy, 1.9% and 1.3% of patients
   treated with baricitinib 4 mg monotherapy, and 4.7% and 1.9% of patients
   treated with baricitinib 4 mg plus methotrexate.

Lipid Elevations – In controlled clinical trials, OLUMIANT treatment was
associated with dose-related increases in lipid parameters including total
cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol. Elevations
were observed at 12 weeks and remained stable thereafter. During the 12-week
treatment period, changes in lipid parameters are summarized below:

 * Mean LDL cholesterol increased by 8 mg/dL in patients treated with OLUMIANT
   2 mg and by 14 mg/dL in patients treated with baricitinib 4 mg.
 * Mean HDL cholesterol increased by 7 mg/dL in patients treated with OLUMIANT
   2 mg and by 9 mg/dL in patients treated with baricitinib 4 mg.
 * The mean LDL/HDL ratio remained stable.
 * Mean triglycerides increased by 7 mg/dL in patients treated with OLUMIANT
   2 mg and by 15 mg/dL in patients treated with baricitinib 4 mg.

[See Warnings and Precautions (5.5)].

Creatine Phosphokinase (CPK) – OLUMIANT treatment was associated with increases
in CPK within one week of starting OLUMIANT and plateauing after 8 to 12 weeks.
At 16 weeks, the mean change in CPK for OLUMIANT 2 mg and baricitinib 4 mg was
37 IU/L and 52 IU/L, respectively.

Creatinine – In controlled clinical trials, dose-related increases in serum
creatinine were observed with OLUMIANT treatment. At 52 weeks, the mean increase
in serum creatinine was less than 0.1 mg/dL with baricitinib 4 mg. The clinical
significance of the observed serum creatinine increases is unknown.

Other Adverse Reactions

Other adverse reactions are summarized in Table 4.

Table 4: Adverse Reactions occurring in greater than or equal to 1% of OLUMIANT
2 mg and Baricitinib 4 mg Treated Patients in Placebo-Controlled Trials

a Includes acute sinusitis, acute tonsillitis, chronic tonsillitis,
epiglottitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis,
pharyngotonsillitis, rhinitis, sinobronchitis, sinusitis, tonsillitis,
tracheitis, and upper respiratory tract infection.

b Includes eczema herpeticum, genital herpes, herpes simplex, ophthalmic herpes
simplex, and oral herpes.

Events Weeks 0-16 Placebo OLUMIANT
2 mg Baricitinib
4 mg n=1070
(%) n=479
(%) n=997
(%) Upper respiratory tract infectionsa 11.7 16.3 14.7 Nausea 1.6 2.7 2.8 Herpes
simplexb 0.7 0.8 1.8 Herpes zoster 0.4 1.0 1.4

Additional adverse drug reactions occurring in fewer than 1% of patients: acne.


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 (5.7)].

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+7 DRUG INTERACTIONS


7 DRUG INTERACTIONS


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)].

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+8 USE IN SPECIFIC POPULATIONS


8 USE IN SPECIFIC POPULATIONS


8.1 PREGNANCY

Risk Summary

The limited human data on use of OLUMIANT in pregnant women are not sufficient
to inform a 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 5 and 13 times the exposure at the MRHD,
respectively. In a pre- and post-natal development study in pregnant female
rats, oral baricitinib administration at exposures approximately 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 T cells on post-natal day (PND) 35 with
evidence of recovery by PND 65, and developmental delays that might be
attributable to decreased body weight gain. No developmental toxicity was
observed at an exposure approximately 9 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 a background risk of
birth defect, loss, or other adverse outcomes. In the U.S. general population,
the estimated background risk of major birth defects and miscarriage in
clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryofetal development study in pregnant rats, dosed orally during the
period of organogenesis from gestation days 6 to 17, baricitinib was teratogenic
(skeletal malformations that consisted of bent limb bones and rib anomalies) at
exposures equal to or greater than approximately 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 5 times the MRHD (on
an AUC basis at a maternal oral dose of 2 mg/kg/day).

In an embryofetal development study in pregnant rabbits, dosed orally during the
period of organogenesis from gestation days 7 to 20, embryolethality, decreased
fetal body weights, and skeletal malformations (rib anomalies) were observed in
the presence of maternal toxicity at an exposure approximately 84 times the MRHD
(on an AUC basis at a maternal oral dose of 30 mg/kg/day). Embryolethality
consisted of increased post-implantation loss that was due to elevated
incidences of both early and late resorptions. No developmental toxicity was
observed in rabbits at an exposure approximately 12 times the MRHD (on an AUC
basis at a maternal oral dose of 10 mg/kg/day).

In a pre- and post-natal development study in pregnant female rats dosed orally
from gestation day 6 through lactation day 20, adverse findings observed in pups
included decreased survival from birth to post-natal day 4 (due to increased
stillbirths and early neonatal deaths), decreased birth weight, decreased body
weight gain during the pre-weaning phase, increased incidence of malrotated
forelimbs during the pre-weaning phase, and decreased cytotoxic T cells on PND
35 with recovery by PND 65 at exposures approximately 43 times the MRHD (on an
AUC basis at a maternal oral dose of 25 mg/kg/day). Developmental delays (that
may be secondary to decreased body weight gain) were observed in males and
females at exposures approximately 43 times the MRHD (on an AUC basis at a
maternal oral dose of 25 mg/kg/day). These findings included decreased forelimb
and hindlimb grip strengths, and delayed mean age of sexual maturity. No
developmental toxicity was observed in rats at an exposure approximately 9 times
the MRHD (on an AUC basis at a maternal oral dose of 5 mg/kg/day).


8.2 LACTATION

Risk Summary

No information is available on the presence of OLUMIANT in human milk, the
effects of the drug on the breastfed infant, or the effects of the drug on milk
production. Baricitinib is present in the milk of lactating rats. 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.

Data

A single oral dose of 25 mg/kg radiolabeled baricitinib was administered to
lactating female Sprague-Dawley rats on post-partum day 13. Drug exposure was
approximately 45-fold greater in milk than in plasma based on AUC0-t values.


8.4 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)].

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+10 OVERDOSAGE


10 OVERDOSAGE

Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days
have been administered in clinical trials without dose-limiting toxicity.
Pharmacokinetic data of a single dose of 40 mg in healthy volunteers indicate
that more than 90% of the administered dose is expected to be eliminated within
24 hours.

In case of an overdose, it is recommended that the patient should be monitored
for signs and symptoms of adverse reactions. Patients who develop adverse
reactions should receive appropriate treatment.

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+11 DESCRIPTION


11 DESCRIPTION

OLUMIANT (baricitinib) is a 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-yl}acetonitrile.
Baricitinib has an empirical formula of C16H17N7O2S and a molecular weight of
371.42. Baricitinib has the following structural formula:



OLUMIANT tablets contain a recessed area on each face of the tablet surface and
are available for oral administration as debossed, film-coated,
immediate-release tablets. The 1 mg tablet is very light pink, round, debossed
with “Lilly” on one side and “1” on the other. The 2 mg tablet is light pink,
oblong, debossed with "Lilly" on one side and “2” on the other.

Each tablet contains 1 or 2 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.

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+12 CLINICAL PHARMACOLOGY


12 CLINICAL PHARMACOLOGY


12.1 MECHANISM OF ACTION

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

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


12.2 PHARMACODYNAMICS

Baricitinib inhibition of IL-6 induced STAT3 phosphorylation – Baricitinib
administration resulted in a dose dependent inhibition of IL-6 induced STAT3
phosphorylation in whole blood from healthy subjects with maximal inhibition
observed approximately 1 hour after dosing, which returned to near baseline by
24 hours. Similar levels of inhibition were observed using either IL-6 or TPO as
the stimulus.

Immunoglobulins – Mean serum IgG, IgM, and IgA values decreased by 12 weeks
after starting treatment with OLUMIANT, and remained stable through at least
52 weeks. For most patients, changes in immunoglobulins occurred within the
normal reference range.

C-reactive protein – In patients with rheumatoid arthritis, decreases in serum
C-reactive protein (CRP) were observed as early as one week after starting
treatment with OLUMIANT and were maintained throughout dosing.

Cardiac Electrophysiology – At a dose 10 times the maximum recommended dose,
baricitinib does not prolong the QT interval to any clinically relevant extent.


12.3 PHARMACOKINETICS

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

Absorption – The absolute bioavailability of baricitinib is approximately 80%.
An assessment of food effects in healthy subjects showed that a high-fat meal
decreased the mean AUC and Cmax of baricitinib by approximately 11% and 18%,
respectively, and delayed the tmax by 0.5 hours. Administration with meals is
not associated with a clinically relevant effect on exposure. In clinical
studies, OLUMIANT was administered without regard to meals.

Distribution – After intravenous administration, the volume of distribution is
76 L, indicating distribution of baricitinib into tissues. Baricitinib is
approximately 50% bound to plasma proteins and 45% bound to serum proteins.
Baricitinib is a substrate of the Pgp, BCRP, OAT3 and MATE2-K transporters,
which play roles in drug distribution.

Elimination – 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 a substrate of OAT3, Pgp, BCRP and MATE2-K from in vitro studies. In a
clinical pharmacology study, approximately 75% of the administered dose was
eliminated in the urine, while about 20% of the dose was eliminated in the
feces. Baricitinib was excreted predominately as unchanged drug in urine (69%)
and feces (15%).

Specific Populations

Effects of Body Weight, Gender, Race, and Age

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

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+13 NONCLINICAL TOXICOLOGY


13 NONCLINICAL TOXICOLOGY


13.1 CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

The carcinogenic potential of baricitinib was evaluated in Sprague-Dawley rats
and Tg.rasH2 mice. No evidence of tumorigenicity was observed in male or female
rats that received baricitinib for 91 to 94 weeks at oral doses up to 8 or
25 mg/kg/day, respectively (approximately 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).

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+14 CLINICAL STUDIES


14 CLINICAL STUDIES

The OLUMIANT clinical development program included two dose-ranging trials and
four confirmatory phase 3 trials. Although other doses have been studied, the
recommended dose of OLUMIANT is 2 mg once daily.

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.

Table 5: Proportion of Patients with ACR20 Response at Week 12 in Dose-Ranging
Studies % ACR20 Responders Dose-Ranging Study Placebo Baricitinib
1 mg daily Baricitinib
2 mg daily Baricitinib
4 mg daily Baricitinib
8 mg daily I (N=301) 41 57 54 75 78 II (N=145) 31 67 83 67 88

Confirmatory Studies

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

Table 6: Clinical Responsea

a 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 Patients cDMARD-IR TNFi-IR Study III Study IV Placebo + cDMARDs

OLUMIANT
2 mg/day + cDMARDs

∆ (95% CI)b Placebo + cDMARDs

OLUMIANT
2 mg/day + cDMARDs

∆ (95% CI)b N 228 229 176 174 ACR 20 Week 12
% 39 66
27 (18, 35) 27 49
22 (12, 32) Week 24
% 42 61
19 (10, 28) 27 45
18 (8, 27) ACR 50 Week 12
% 13 34
21 (13, 28) 8 20
12 (5, 19) Week 24
% 21 41
20 (12, 28) 13 23
10 (2, 18) ACR 70 Week 12
% 3 18
15 (9, 20) 2 13
11 (5, 16) Week 24
% 8 25
17 (11, 24) 3 13
10 (4, 16) DAS28-CRP<2.6 Week 12
% 9 26
(10, 24) 4 11
(2, 12) Week 24
% 11 31
(13, 27) 6 11
(-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

a 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; 8 categories: dressing and grooming, arising, eating, walking,
hygiene, reach, grip, and activities.

cDMARD-IR TNFi-IR Study III Study IV Placebo
+ cDMARDs OLUMIANT
2 mg/day
+ cDMARDs Placebo
+ cDMARDs OLUMIANT
2 mg/day
+ cDMARDs N 228 229 176 174 Number of Tender Joints (0-68) Baseline 24 (15) 24
(14) 28 (16) 31 (16) Week 12 15 (14) 11 (13) 20 (16) 19 (18) Number of Swollen
Joints (0-66) Baseline 13 (7) 14 (9) 17 (11) 19 (12) Week 12 8 (8) 5 (6) 12 (10)
10 (12) Painb Baseline 57 (23) 60 (21) 65 (19) 62 (22) Week 12 43 (24) 34 (25)
55 (25) 46 (28) Patient Global Assessmentb Baseline 60 (21) 62 (20) 66 (19) 67
(19) Week 12 44 (23) 36 (25) 56 (25) 46 (26) Physician Global Assessmentb
Baseline 62 (17) 64 (17) 67 (19) 67 (17) Week 12 41 (24) 33 (22) 50 (26) 36 (24)
Disability Index (HAQ-DI)c Baseline 1.50 (0.60) 1.51 (0.62) 1.78 (0.57) 1.71
(0.55) Week 12 1.17 (0.62) 0.96 (0.69) 1.59 (0.68) 1.31 (0.72) hsCRP (mg/L)
Baseline 17.7 (20.4) 18.2 (21.5) 20.6 (25.3) 19.9 (22.5) Week 12 17.2 (19.3) 8.6
(14.6) 19.9 (23.0) 13.5 (20.1)

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.

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+16 HOW SUPPLIED/STORAGE AND HANDLING


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 a recessed area on each face of
the tablet surface.

OLUMIANT Tablets 1 mg 2 mg Color Very Light Pink Light Pink Shape Round Oblong
Identification Lilly Lilly 1 2 NDC Codes: Bottle of 30 0002-4732-30 0002-4182-30


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.

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+17 PATIENT COUNSELING INFORMATION


17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Patient Counseling

Advise patients of the potential benefits and risks of OLUMIANT.

Infections

Inform 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 Disorders

Inform 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 (5.2)].

Thrombosis

Advise 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 a DVT or PE [see Warnings and Precautions
(5.3)].

Laboratory Abnormalities

Inform patients that OLUMIANT may affect certain lab tests, and that blood tests
are required before and during OLUMIANT treatment [see Warnings and Precautions
(5.5)].

Lactation

Advise a woman not to breastfeed during treatment with OLUMIANT [see Use in
Specific Populations (8.2)].

Literature revised: 07/2020

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA
www.olumiant.com
Copyright © 2018, 2020, Eli Lilly and Company. All rights reserved.

OLM-0004-USPI-20200708

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-MEDICATION GUIDE

This Medication Guide has been approved by the U.S. Food and Drug Administration

Revised: 07/2020

MEDICATION GUIDE
OLUMIANT® (O-loo-me-ant)
(baricitinib)
tablets, for oral use

What is the most important information I should know about OLUMIANT?
OLUMIANT may cause serious side effects, including:
1. Serious infections.
OLUMIANT is a 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 a 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 a weak immune system. People
   with these conditions have a higher chance for infections.
 * have TB or have been in close contact with someone with TB.
 * have had hepatitis B 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

After 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. 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. Tell your healthcare provider if you have ever had any type of
   cancer.
   

3. 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.

 * 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.
   

4. 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 a change in your bowel habits.
   

5. 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 a 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.
6. 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 OLUMIANT?

 * OLUMIANT is a prescription medicine used to treat adult patients with
   moderately to severely active rheumatoid arthritis after treatment with at
   least one other medicine called a Tumor Necrosis Factor (TNF) antagonist has
   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 I should know about OLUMIANT?”
 * have an infection.
 * have kidney problems.
 * have liver problems.
 * have low red or white blood cell counts.
 * have recently received or are scheduled to receive a 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®), etanercept (Enbrel®), adalimumab
   (Humira®), infliximab (Remicade®), rituximab (Rituxan®), abatacept
   (Orencia®), anakinra (Kineret®), certolizumab pegol (Cimzia®), golimumab
   (Simponi®), tofacitinib (Xeljanz®, Xeljanz® XR), sarilumab (Kevzara®),
   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 a list of them to show your healthcare
provider and pharmacist when you get a new medicine. How should I take OLUMIANT?

 * Take OLUMIANT exactly as your healthcare provider tells you to take it.
 * Take OLUMIANT 1 time a day with or without food.

What are the possible side effects of OLUMIANT?
OLUMIANT can cause serious side effects including:


See “What is the most important information I should know about OLUMIANT?”

Common side effects of OLUMIANT include (these are not all of the possible side
effects of OLUMIANT):
 * upper respiratory tract infections (common cold, sinus infections)
 * nausea

 * cold sores
 * shingles
   

Call your doctor for medical advice about side effects. You may report side
effects to FDA at 1-800-FDA-1088. How should I store OLUMIANT?
Store OLUMIANT at room temperature between 68°F to 77°F (20°C to 25°C).
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 a
Medication Guide. Do not use OLUMIANT for a 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
OLUMIANT?
Active ingredient: baricitinib
Inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol,
microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol,
polyvinyl alcohol, talc, titanium dioxide.
OLUMIANT is a registered trademark of Eli Lilly and Company.
Marketed by: Lilly USA, LLC Indianapolis, IN 46285, USA
Copyright © 2018, 2020, 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-0002-MG-20200708

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Revised: 7/2020
Document Id: 5efe615c-e3b3-4c37-95c8-4895a8451ec0
34391-3
Set id: 866e9f35-9035-4581-a4b1-75a621ab55cf
Version: 9
Effective Time: 20200708
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