baricitinib

Baricitinib is a disease-modifying antirheumatic drug (DMARD) approved by the FDA to control inflammation in rheumatoid arthritis, alopecia areata, and COVID-19 in adults. It has emergency use authorization (EUA) to treat COVID-19 in children 2 years and above. Baricitinib is a synthetic small molecule drug made up of microscopic particles that can get inside a cell and alter intracellular functions.

Baricitinib belongs to JAK inhibitor class of medications, which works by blocking the activity of Janus kinase enzymes and their pro-inflammatory signaling pathways. Janus kinases are a group of intracellular enzymes known as protein tyrosine kinases which play an important role in stimulating immune function and blood cell production (hematopoiesis). Janus kinases transmit signals from the cellular membrane downstream within the cell to stimulate intracellular processes.

There are four types of Janus kinases, JAK1, JAK2, JAK3, and tyrosine kinase (TYK2). In response to signals arising from extracellular inflammatory proteins (cytokines) or growth factors, Janus kinases activate signal transducers and activators of transcription (STATs), which regulate gene expression and intracellular activity. By inhibiting Janus kinases, baricitinib interrupts the signaling and reduces JAK-mediated inflammation and immune response.

• Treatment with baricitinib can increase the risk of serious infections that can lead to hospitalization and death. Most patients with rheumatoid arthritis who developed infections were also receiving immunosuppressant drugs such as corticosteroids and methotrexate.
• Reported infections include:
  • Active tuberculosis: Do not administer baricitinib to patients with active tuberculosis. Test patients (except those with COVID-19) for latent tuberculosis and if found positive, start treatment for tuberculosis before initiating baricitinib treatment.
  • Invasive fungal infections, including candidiasis and pneumocystosis.
  • Bacterial, viral and other opportunistic infections.
• Consider the risks and benefits of treatment before starting baricitinib in patients with chronic or recurrent infection.
• Monitor patients for signs of infection during and after baricitinib treatment, including for possible development of tuberculosis in patients who tested negative for latent tuberculosis before starting treatment.
• If serious infection develops, interrupt baricitinib therapy until infection is controlled.
• Studies comparing another Janus inhibitor with tumor necrosis factor (TNF) blocker drugs in RA patients who are 50 years and older and with at least one cardiovascular risk, indicate that there is a higher risk for the following in patients treated with JAK inhibitors:
  • Major adverse cardiovascular events (MACE) including myocardial infarction (MI), stroke and cardiovascular death. Current and past smokers are at a greater risk for MACE. Discontinue baricitinib treatment in patients who have experienced stroke or MI.
  • Lymphoma and other malignancies (excluding nonmelanoma skin cancer). Current and past smokers have a greater risk. Consider risks and benefits of treatment before starting baricitinib in patients with malignancy.
  • Development of blood clot blocks in veins (deep vein thrombosis), arteries (arterial thrombosis) and lungs (pulmonary embolism). Monitor patients for symptoms, evaluate the patient, discontinue baricitinib and initiate appropriate treatment if thrombosis develops.
  • All-cause mortality including sudden cardiovascular death.
• Some patients have developed hypersensitivity reactions including rash, hives, angioedema and serious reactions. Discontinue baricitinib if the patient develops serious hypersensitivity reactions.
• Baricitinib may increase the risk for gastrointestinal perforation. Evaluate patients who develop new abdominal symptoms.
• Baricitinib treatment may increase the incidence of blood disorders including anemia, neutropenia and lymphopenia, blood lipids and elevated liver enzymes. Evaluate patients with elevated liver enzymes to identify the cause, and interrupt therapy if drug-injury is suspected, until this diagnosis is excluded. 
• COVID-19 treatment:
  • Monitor patients with COVID-19 for signs and symptoms of new infections during and after treatment with baricitinib.
  • There is limited information regarding baricitinib use in patients with COVID-19 and concomitant active serious infections. Consider risks and benefits before starting therapy.
  • If new infections develop, initiate diagnostic tests and appropriate treatment. If a patient is unresponsive to treatment, interrupt baricitinib therapy.
  • Screen for viral hepatitis in accordance with clinical guidelines before starting therapy. Impact of baricitinib therapy on chronic viral hepatitis reactivation is unknown.
  • Consider the risks and benefits of treatment before starting baricitinib in patients with chronic or recurrent infection, history of opportunistic infections, underlying conditions predisposing them to infection, or exposure to tuberculosis.
  • If a patient develops herpes zoster, interrupt therapy until the condition resolves.
• Avoid use of live vaccines during baricitinib treatment. Update immunizations in patients with rheumatoid arthritis or alopecia areata as per current guidelines before initiating therapy.

Common side effects of baricitinib include:

COVID-19 treatment

• Increase in blood levels of liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
• High platelet count in blood (thrombocytosis)
• Pneumonia
• Blood clot block in the lungs (pulmonary embolism)
• Deep vein thrombosis (DVT)
• Septic shock
• Urinary tract infection
• Tuberculosis

RA and alopecia areata treatment

• Infections
• Upper respiratory tract infection
• Lower respiratory tract infection
• Urinary tract infection
• Genital Candida infection (candidiasis)
• Herpes zoster infection
• Fungal skin infection
• Pimples/zits (acne vulgaris)
• Inflammation of hair follicles (folliculitis)
• Headache
• Abdominal pain
• Nausea
• Excessive fatty substances in blood (hyperlipidemia)
• Weight gain
• Elevated liver enzymes including ALT, AST, and gamma-glutamyl transferase (GGT)
• Increase in creatine phosphokinase level in blood
• Low red blood cell count (anemia)
• Low neutrophil immune cell count (neutropenia)
• Blood clot block in an artery (arterial thrombosis)
• Low count of lymphocytes (lymphocytopenia)
• Malignant lymphoma (B-cell)
• Malignant tissue growth (neoplasm)

Other less common side effects of baricitinib include (any indication):

• Increase in HDL and LDL cholesterol levels
• Increase in triglycerides
• Increase in serum creatinine
• Esophageal candidiasis
• Gastrointestinal perforation
• Infections including:
  • Viral infection
  • BK virus
  • Cytomegalovirus disease
  • Cryptococcosis
  • Histoplasmosis
  • Candidiasis
  • Fungal infection
  • Mycobacterium infection
  • Opportunistic infection
  • Lung infection from Pneumocystis genus of fungus
• Reactivation of viral disease (COVID-19)
• Lung carcinoma
• Skin carcinoma
• Thrombosis
• Acute heart attack (myocardial infarction)
• Cerebrovascular accident
• Hypersensitivity reactions
• Swelling under the skin and mucous membranes (angioedema)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Tablet

• 1 mg
• 2 mg
• 4 mg

Adult:

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 orally once daily

Alopecia Areata

• Indicated for adults with severe alopecia areata
• 2 mg orally once daily; increase to 4 mg once daily if inadequate response
• With nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss, consider 4 mg once daily
• 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 orally once daily
• 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 or above: Maintain dose
  • ALC below 500 cells/mm3: Avoid initiation or interrupt dosing until ALC 500 cells/mm3 or higher
• ?COVID-19
  • ALC 200 cells/mm3 or above: Maintain dose
  • ALC below 200 cells/mm3: Avoid initiation or interrupt dosing until ALC 200 cells/mm3 or higher

Absolute neutrophil count (ANC)

• RA or alopecia areata
  • ANC 1000 cells/mm3 or above: Maintain dose
  • ANC below 1000 cells/mm3: Avoid initiation or interrupt dosing until ANC 1000 cells/mm3 or higher
• COVID-19
  • ANC 500 cells/mm3 or above: Maintain dose
  • ANC below 500 cells/mm3: Avoid initiation or interrupt dosing until ANC 500 cells/mm3 or higher

Anemia

• RA or alopecia areata
  • Hgb 8 g/dL or above: Maintain dose
  • Hgb below 8 g/dL: Avoid initiation or interrupt dosing until Hgb 8 g/dL or higher

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 below 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 below 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 below 30 mL/min/1.73 m2): Decrease to 1 mg/day
  • eGFR below 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 (e.g., 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

• 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
• Screen for viral hepatitis in accordance with clinical guidelines
• 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)

• Assess baseline to determine whether treatment can be initiated
• Rheumatoid arthritis: Not recommended with ALC below 500 cells/microliter, ANC below 1000 cells/microliter, or hemoglobin level below 8 g/dL
• COVID-19: Not recommended with ALC below 200 cells/microliter, ANC below 500 cells/microliter
• Monitor CBC during treatment and modify dosage as recommended

RA or alopecia areata

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

Pediatric:

COVID-19 (EUA)

• November 19, 2020: Emergency use authorization (EUA) issued by the FDA for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients aged 2 to 18 years who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)
• Children below 2 years: Not authorized
• Children 2 to 9 years: 2 mg orally once daily
• Children 9 to 18 years: 4 mg orally once daily
• Recommended treatment duration is 14 days or until hospital discharge, whichever comes first; optimal treatment duration unknown

Dosage Modifications

Absolute lymphocyte count (ALC)

• ?COVID-19
  • ALC 200 cells/mm3 or above: Maintain dose
  • ALC below 200 cells/mm3: Avoid initiation or interrupt dosing until ALC 200 cells/mm3 or higher

Absolute neutrophil count (ANC)

• COVID-19
  • ANC 500 cells/mm3 or above: Maintain dose
  • ANC below 500 cells/mm3: Avoid initiation or interrupt dosing until ANC 500 cells/mm3 or higher

Renal impairment

• COVID-19 (2-9 years)
  • eGFR 60 mL/min/1.73 m2 or above: No dose adjustment
  • eGFR 30 to 60 mL/min/1.73 m2: Decrease to 1 mg/day
  • eGFR 15 to 30 mL/min/1.73 m2: Not recommended
  • eGFR below 15 mL/min/1.73 m2, patients on dialysis, have end-stage renal disease, or have acute kidney injury: Not recommended
• COVID-19 (≥9 years)
  • eGFR 60 mL/min/1.73 m2 or above: No dose adjustment
  • eGFR 30 to 60 mL/min/1.73 m2: Decrease to 2 mg/day
  • eGFR 15 to 30 mL/min/1.73 m2: Decrease to 1 mg/day
  • eGFR below 15 mL/min/1.73 m2, patients on dialysis, have end-stage renal disease, or have acute kidney injury: Not recommended

Hepatic impairment

• COVID-19
  • Increased ALT/AST: Consider interruption until the diagnosis of drug-induced liver injury is excluded
  • Severe: Not studied; use only if benefits outweigh the risks

Coadministration with strong organic anion transporter 3 (OAT3) inhibitors (e.g., probenecid)

• COVID-19
  • 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

COVID-19

• Evaluate baseline eGFR, liver enzymes, and CBC count to determine treatment suitability and dose
• Closely monitor patients with abnormal baseline and post-baseline laboratory values
• Not recommended with known active TB
• Data are limited in patients receiving systemic corticosteroids
• Has not been studied in combination with other JAK inhibitors or with biologic DMARDs (biologic treatments targeting cytokines, B-cells, or T-cells)
• EUA for patients hospitalized or in ACS
  • Authorized for emergency use to treat certain hospitalized patients with COVID-19
  • Authorization clarifies that individuals determined as being appropriate for acute inpatient hospitalization and who are admitted or transferred to an alternate care site (ACS) that can provide acute care that is comparable to general inpatient hospital care are within the terms and conditions of the EUA
  • An ACS is intended to provide additional hospital surge capacity and capability for communities overwhelmed by patients with COVID-19

Overdose

• No toxicity has been observed in clinical trials of baricitinib with administration of single doses of up to 40 mg and multiple doses of up to 20 mg daily for 10 days.
• Studies 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 overdose, patients should be monitored and appropriate symptomatic and supportive treatment administered.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Severe interactions of baricitinib include:
  • upadacitinib
• Baricitinib has serious interactions with at least 58 different drugs.
• Moderate interactions of baricitinib include:
  • ifosfamide
  • mechlorethamine
  • trastuzumab
  • trastuzumab deruxtecan
• Baricitinib has no mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There is insufficient data to determine drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes with baricitinib exposure during pregnancy.
• Animal reproductive studies indicate baricitinib can cause fetal harm. There are no human data on chronic use of baricitinib throughout pregnancy.
• Make a decision to use baricitinib after weighing the benefits and risks of using baricitinib during pregnancy, the mother’s clinical need, and risks to the mother and fetus from the drug and the underlying condition.
• Women of reproductive potential should practice effective contraception during treatment with baricitinib. Women planning pregnancy should discontinue baricitinib one month before conception.
• It is not known if baricitinib is present in human breast milk, but studies show it is excreted in rat milk. There is no information on baricitinib’s effects on milk production or on the breastfed infant.
• Avoid breastfeeding during baricitinib treatment and for 4 days after the last dose because of the potential for serious adverse reactions in the breastfed infant.
• Data collection to monitor pregnancy and infant outcomes following exposure to baricitinib is ongoing. Patients exposed to baricitinib during pregnancy are encouraged to notify the manufacturer Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979).

• Take baricitinib exactly as prescribed.
• Notify your healthcare provider immediately if you develop:
  • Signs and symptoms of new infection, or activation of latent tuberculosis or viral hepatitis
  • Symptoms of cardiovascular disease
  • Abdominal symptoms
  • Hypersensitivity reactions.
• Store baricitinib safely out of reach of children
• In case of overdose, seek medical help or contact Poison Control.