• Dosage & Indications:

Rheumatoid Arthritis:
Indicated for adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies

May be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs)

2 mg PO qDay

Alopecia Areata:
Indicated for adults with severe alopecia areata

2 mg PO qDay; increase to 4 mg qDay if inadequate response

With nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss, consider 4 mg qDay

Once adequate response achieved with 4 mg/day, decrease to 2 mg/day

COVID-19:
Indicated for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized adults who require supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)

4 mg PO qDay

Recommended treatment duration is 14 days or until hospital discharge, whichever comes first

*Dosage Modifications:

Absolute lymphocyte count (ALC)
RA or alopecia areata:
ALC ≥500 cells/mm3: Maintain dose
ALC <500 cells/mm3: Avoid initiation or interrupt dosing until ALC ≥500 cells/mm3

COVID-19:
ALC ≥200 cells/mm3: Maintain dose
ALC <200 cells/mm3: Avoid initiation or interrupt dosing until ALC ≥200 cells/mm3

Absolute neutrophil count (ANC)
RA or alopecia areata:
ANC ≥1000 cells/mm3: Maintain dose
ANC <1000 cells/mm3: Avoid initiation or interrupt dosing until ANC ≥1000 cells/mm3

COVID-19:
ANC ≥500 cells/mm3: Maintain dose
ANC <500 cells/mm3: Avoid initiation or interrupt dosing until ANC ≥500 cells/mm3

Anemia:
RA or alopecia areata
Hgb ≥8 g/dL: Maintain dose
Hgb <8 g/dL: Avoid initiation or interrupt dosing until Hgb ≥8 g/dL

Renal impairment
RA:
Mild (eGFR 60 to <90 mL/min/1.73 m2): No dose adjustment required
Moderate (eGFR 30 to <60 mL/min/1.73 m2): Decrease to 1 mg/day
Severe (eGFR <30 mL/min/1.73 m2): Not recommended (not studied)
Alopecia areata:
Mild (eGFR 60 to <90 mL/min/1.73 m2): No dose adjustment required
Moderate (eGFR 30 to <60 mL/min/1.73 m2): Reduce dose by 50%
Severe (eGFR <30 mL/min/1.73 m2): Not recommended
COVID-19:
Mild (eGFR 60 to <90 mL/min/1.73 m2): No dose adjustment
Moderate (eGFR 30 to <60 mL/min/1.73 m2): Decrease to 2 mg/day
Severe (eGFR 15 to <30 mL/min/1.73 m2): Decrease to 1 mg/day
eGFR <15 mL/min/1.73 m2, patients on dialysis, have end-stage renal disease, or have acute kidney injury: Not recommended

Hepatic impairment:
RA or alopecia areata
Interrupt if ALT/AST increased and drug-induced liver injury (DILI) suspected, until DILI diagnosis excluded
Mild or moderate: No dose adjustment required
Severe: Not recommended
COVID-19:
Interrupt if ALT/AST increased and DILI suspected, until DILI diagnosis excluded
Increased ALT/AST: Consider interruption until the diagnosis of drug-induced liver injury is excluded
Severe: Not studied; use only if benefits outweigh risks

Coadministration with strong organic anion transporter 3 (OAT3) inhibitors (eg, probenecid):
If recommended dose is 4 mg/day, reduce to 2 mg/day
If recommended dose is 2 mg/day, reduce to 1 mg/day
If recommended dose is 1 mg/day, consider discontinuing probenecid

*Dosing Considerations

Consider following evaluations before initiating:

1. Active and latent tuberculosis (TB) infection: Do not give to patients with active TB; if latent infection positive in patients with rheumatoid arthritis, consider treatment for TB before initiating.
2. Screen for viral hepatitis in accordance with clinical guidelines.
3. Baseline hepatic and renal function: Assess baseline values and monitor for laboratory changes; modify dosage based on hepatic and renal impairment, and laboratory abnormalities.

Complete blood cell count (CBC)

1. Assess baseline to determine whether treatment can be initiated.
2. Rheumatoid arthritis: Not recommended with ALC <500 cells/μL, ANC <1000 cells/μL, or hemoglobin level <8 g/dL.
3. COVID-19: Not recommended with ALC <200 cells/μL, ANC <500 cells/μL.
4. Monitor CBC during treatment and modify dosage as recommended.

RA or alopecia areata:

1. Avoid in patients with active, serious infection, including localized infections; if serious infection occurs, withhold treatment.
2. Update immunizations in agreement with current immunization guidelines before initiating.
3. Limitations of use: Not recommended for use in combination with other Janus kinase (JAK) inhibitors, biologic DMARDs, or with potent immunosuppressants (eg, azathioprine, cyclosporine).

• Interactions:

Contraindicated (1):
upadacitinib

Serious - Use Alternative (58):
abatacept
adalimumab
adenovirus types 4 and 7 live, oral
ado-trastuzumab emtansine
anakinra
axicabtagene ciloleucel
azathioprine
balsalazide
BCG vaccine live
brexucabtagene autoleucel
canakinumab
certolizumab pegol
ciltacabtagene autoleucel
cyclosporine
deferiprone
diflunisal
etanercept
ethacrynic acid
etrasimod
fingolimod
golimumab
idecabtagene vicleucel
infliximab
influenza virus vaccine quadrivalent, intranasal
irbesartan
ketorolac
lisocabtagene maraleucel
measles mumps and rubella vaccine, live
measles, mumps, rubella and varicella vaccine, live
meclofenamate
mefenamic acid
natalizumab
nateglinide
nitazoxanide
ocrelizumab
oxaprozin
penicillin G benzathine
pimecrolimus
pioglitazone
probenecid
rilonacept
rituximab
rituximab-hyaluronidase
rotavirus oral vaccine, live
siltuximab
smallpox (vaccinia) vaccine, live
tacrolimus
telmisartan
tisagenlecleucel
tocilizumab
tofacitinib
trastuzumab deruxtecan
typhoid vaccine live
valsartan
varicella virus vaccine live
vedolizumab
yellow fever vaccine
zoster vaccine live

Monitor Closely (7):
ifosfamide
mechlorethamine
pretomanid
trastuzumab
trastuzumab deruxtecan
ublituximab
vadadustat

Minor (0):

Adverse Effects:
>10%
RA
Upper respiratory tract infections (16.3%)
COVID-19
ALT ≥3 x ULN (18.1%)
AST ≥3 x ULN (11.8%)

• Adverse Effects:

>10%
RA
Upper respiratory tract infections (16.3%)
COVID-19
ALT ≥3 x ULN (18.1%)
AST ≥3 x ULN (11.8%)

1-10%
RA
Increased ALT/AST (1.3-4.7%)
Nausea (2.7-2.8%)
Platelet elevations (1-2%)
Herpes zoster infection (1-1.4%)
Herpes simplex infection (0.8-1.4%)
COVID-19
*Reported incidence less than placebo
Thrombocytosis >600,000 cells/mm3 (7.9%)
CPK >5 x ULN (4.5%)*
Neutropenia <1000 cells/mm3 (2.2%)
Deep vein thrombosis (1.5%)
Pulmonary embolism (1.5%)
Urinary tract infection (1.5%)

<1%
RA
Acne (<1%)
Neutropenia (0.3%)

Postmarketing Reports
Immune system disorders: Drug hypersensitivity (eg, rash, urticaria, angioedema)

Warnings:

• Contraindications:

None

• Cautions:

Hypersensitivity reactions (eg, angioedema, urticaria, rash) observed, including serious reactions; if serious hypersensitivity reaction occurs, promptly discontinue therapy while evaluating potential causes

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

If clinical features of DVT/PE or arterial thrombosis occur, patients should discontinue therapy and be evaluated promptly and treated appropriately; avoid this drug in patients that may be at increased risk of thrombosis

Malignancies were observed in clinical studies; non-melanoma skin cancers reported; periodic skin examination is recommended for patients who are at increased risk for skin cancer

Consider benefits and risks for individual patient prior to initiating or continuing therapy with this drug, 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

Higher rate for all-cause mortality and for MACE (defined as CV death, myocardial infarction, and stroke) reported with another JAK inhibitor compared with TNF blockers in patients who have RA and ≥1 CV risk

Increased incidence of thrombosis, including DVT and PE, observed compared with placebo; avoid therapy in patients who may be at increased risk of thrombosis

Gastrointestinal perforations reported in clinical studies with this drug; monitor therapy in patients who may be at increased risk for gastrointestinal perforation (eg, patients with a history of diverticulitis); evaluate promptly patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation

May increase incidence of neutropenia, lymphopenia, anemia, or elevated LFTs or lipids; monitor laboratory values at baseline and periodically during treatment

Promptly investigate cause of liver enzyme elevation recommended to identify potential cases of drug-induced liver injury; interrupt therapy if increased ALT or AST observed and drug-induced liver injury is suspected, until this diagnosis is excluded

• Infection risk:

In patients with COVID-19, monitor for signs and symptoms of new infections during and after treatment; there is limited information regarding use in patients with COVID-19 and concomitant active serious infections; risks and benefits of treatment in COVID-19 patients with other concurrent infections should be considered
Serious and sometimes fatal infections may develop owing to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens reported; may cause reactivation of latent TB or viral infections
In patients with rheumatoid arthritis or alopecia areata, closely monitor for development of signs and symptoms of infection during and after treatment; interrupt therapy in patients with rheumatoid arthritis or alopecia areata, if patient develops a serious infection, an opportunistic infection, or sepsis
Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy; unknown impact on chronic viral hepatitis reactivation
Consider risks and benefits before initiating in patients with chronic or recurrent infection, history of serious or opportunistic infection, underlying conditions predisposing them to infection, or patients who have been exposed to tuberculosis or have resided or traveled in areas of endemic tuberculosis or mycoses
Consider TB therapy for patients with a negative test for latent TB but who have risk factors for TB infection; consultation with a physician with expertise in TB recommended to aid in decision about whether initiating anti-TB therapy is appropriate
Test patients with rheumatoid arthritis or alopecia areata for latent tuberculosis; patients with rheumatoid arthritis or alopecia areata and latent tuberculosis (TB) should be treated with standard antimycobacterial therapy before initiating therapy
Consider anti-TB therapy prior to initiation of treatment 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 recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient
If a new infection develops during treatment, promptly initiate diagnostic tests appropriate for an immunocompromised patient; if necessary, initiate appropriate antimicrobial therapy and closely monitor; interrupt baricitinib therapy if patient unresponsive to treatment; do not resume therapy until infection is controlled
If herpes zoster occurs, interrupt treatment until episode resolves

• Drug interaction overview:

Avoid use of live vaccines; update immunizations in agreement with current immunization guidelines before initiating
Coadministration with strong OAT3 inhibitors may increase baricitinib systemic exposure; dosage modification recommended

• Pregnancy & Lactation:

Pregnancy
Report pregnancies to Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979)

Based on findings from animal reproduction studies, therapy may cause fetal harm during pregnancy; available data from clinical trials and postmarketing reports of exposure in pregnancy are insufficient to inform a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes

There are no human data on chronic baricitinib exposure throughout pregnancy; there are risks to mother and the fetus associated with rheumatoid arthritis in pregnancy; consider risks and benefits with chronic use during pregnancy

Published data suggest that increased disease activity is associated with risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis; adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth

Based on animal studies, therapy may cause fetal harm when administered during pregnancy; consider pregnancy planning and prevention for females of reproductive potential

Animal studies:
In animal embryo-fetal development studies, oral baricitinib administration to pregnant rats and rabbits at exposures equal to and greater than ~20 and 84 times the maximum recommended human dose (MRHD), respectively, resulted in reduced fetal body weights, increased embryo lethality (rabbits only), and dose-related increases in skeletal malformations

Lactation:
Unknown if distributed in human breast milk

Baricitinib is present in the milk of lactating rats

Owing 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 women with rheumatoid arthritis not to breastfeed while taking baricitinib

Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.

• Pharmacology:

Mechanism of Action
Janus kinases (JAKs) pathways inhibitor; JAK consists of a group of intracellular tyrosine kinases that transmit signals from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoieses 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

Absorption
Absolute bioavailability: 80%

Peak plasma time: 1 hr

Steady-state achieved: 2-3 days

Distribution
Protein bound: 50% to plasma proteins and 45% to serum proteins

Vd: 76 L

Substrate of the P-gp, BCRP, OAT3 and MATE2-K transporters, which play roles in drug distribution

Metabolism
~6% of the orally administered baricitinib dose is identified as metabolites (3 from urine and 1 from feces), with CYP3A4 identified as the main metabolizing enzyme

No metabolites of baricitinib were quantifiable in plasma

Elimination
Half-life: 12 hr

Total body clearance: 8.9 L/hr

Excretion: 75% (69% unchanged) urine; 20% (15% unchanged) feces

• Administration:

Oral Administration
May take with or without food

Unable to swallow whole tablet
Oral:

1. Disperse tablet(s) for required dose in container with ~10 mL (5 mL minimum) of room temperature water by gently swirling contents; take immediately
2. Rinse container with an additional 5-10 mL of water and administer entire contents to patient

Gastrostomy feeding tube:

1. Disperse tablet(s) for required dose in container with ~15 mL (10 mL minimum) of room temperature water by gently swirling contents; ensure tablets are sufficiently dispersed to flow through syringe tip
2. Withdraw entire contents from container into an appropriate syringe and immediately administer through gastric tube
3. Rinse container with an additional 10-15 mL of water, withdraw entire content into syringe and administer to patient

Nasogastric or orogastric feeding tube:

1. Disperse tablet(s) for required dose in container with ~30 mL of room temperature water by gently swirling contents; ensure tablets are sufficiently dispersed to flow through syringe tip
2. Withdraw entire contents from container into an appropriate syringe and immediately administer through nasogastric tube
3. To avoid clogging small diameter tubes (<12 Fr), the syringe can be held horizontally and shaken during administration
4. Rinse container with enough (minimum of 15 mL) room temperature water, withdraw contents into syringe, and administer through nasogastric tube

• Storage:

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

Dispersed tablets in water: Stable for up to 4 hr

Handling
Intact tablet: Not hazardous
Crushed tablets: Unknown if powder may constitute a reproductive hazard to preparer; use proper control measures (eg, ventilated enclosure) or personal protective equipment (ie, N95 respirator).