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  • CLASSES

    Janus Associated Kinase (JAK) Inhibitors
    Other Specific Antirheumatics

    BOXED WARNING

    Corticosteroid therapy, diabetes mellitus, fungal infection, herpes infection, human immunodeficiency virus (HIV) infection, immunosuppression, infection, pulmonary disease, tuberculosis, viral infection

    Avoid the use of baricitinib in rheumatoid arthritis and alopecia areata patients with an active, serious or opportunistic infection, including localized infections. In patients with COVID-19 and concomitant active serious infections, data are limited; therefore, the risks and benefits of baricitinib treatment in COVID-19 patients with other concurrent infections should be considered. Serious and sometimes fatal bacterial infection, mycobacterial infection, invasive fungal infection, viral infection, or infections due to other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving baricitinib. The risks and benefits of treatment should be considered prior to initiating baricitinib in patients: 1) with chronic or recurrent infection; 2) who have been exposed to tuberculosis; 3) with a history of a serious or an opportunistic infection; 4) who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or 5) with underlying conditions that may predispose them to infection (e.g., diabetes mellitus, human immunodeficiency virus (HIV) infection, chronic pulmonary disease, low lymphocyte counts, and pre-existing immunosuppression). The most common serious infections reported with baricitinib included pneumonia, herpes zoster, and urinary tract infections. Among opportunistic infections, tuberculosis, cryptococcosis, acute histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, and BK virus were reported with baricitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppression agents such as methotrexate or corticosteroid therapy. Ask patients if they have lived or have traveled to the Ohio and Mississippi River valleys or the Southwest because of an increased chance of acquiring certain kinds of fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis. Viral reactivation, including cases of herpes infection reactivation (e.g., herpes zoster), were observed in clinical studies. If a patient develops herpes zoster, interrupt baricitinib therapy until the episode resolves. Carefully consider the risks and benefits of baricitinib before starting the drug in patients who have been exposed to tuberculosis (TB). Baricitinib should not be administered to patients with active tuberculosis. Patients, except those with COVID-19, should be evaluated and tested for latent TB infection prior to and per applicable guidelines during baricitinib administration. Consider anti-tuberculosis therapy before baricitinib administration in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Monitor patients for the development of signs and symptoms of tuberculosis in all patients during treatment. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with baricitinib. Therapy with baricitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with baricitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

    Lymphoma, new primary malignancy, skin cancer, tobacco smoking

    Baricitinib may increase the risk for a new primary malignancy. In a large, postmarketing, randomized safety clinical trial in rheumatoid arthritis patients 50 years of age and older with one or more CV risk factors, higher rates of cancer [excluding non-melanoma skin cancer (NMSC)] and lymphoma were observed with use of tofacitinib, another JAK inhibitor, compared to tumor necrosis factor (TNF) inhibitors. Baricitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions. A higher rate of lung cancer was also observed in patients with a history of current or past tobacco smoking treated with the JAK inhibitor compared to those treated with a TNF inhibitor. Patients with a history of current or past tobacco smoking were at also at an increased risk of overall cancers. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with risk factors such as smoking, those who develop malignancy, and those with a known malignancy other than successfully treated non-melanoma skin cancer (NMCS). Reserve baricitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. NMSCs have also been reported in patients treated with baricitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

    Cardiac disease, hypertension, mortality, myocardial infarction, stroke, thrombocytosis, thromboembolic disease, thromboembolism, thrombosis

    Avoid use of baricitinib in patients who are at an increased risk of thrombosis and thromboembolism, including those with thromboembolic disease. Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have been reported with baricitinib therapy. Many of these events were serious and some resulted in death. In COVID-19 patients, baricitinib has been associated with increases in platelet counts (thrombocytosis) and serious venous thrombosis, including PE. COVID-19 patients receiving baricitinib during clinical trials, were recommended or required to receive venous thromboembolism (VTE) prophylaxis unless a major contraindication was noted. In a large, postmarketing, randomized safety clinical trial in rheumatoid arthritis patients 50 years of age and older with one or more CV risk factors, higher rates of all-cause mortality (including sudden CV death), major adverse CV events (MACE; defined as CV death, non-fatal myocardial infarction (MI), and non-fatal stroke), and thrombosis (including DVT and PE) were observed in patients taking tofacitinib, another Janus kinase (JAK) inhibitor, compared to patients taking tumor necrosis factor (TNF) inhibitors. Many of the observed thrombotic events were serious and some resulted in death. Baricitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions. Current or past tobacco smokers have an additional increased risk of major CV adverse events. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with cardiovascular risk factors (e.g., cardiac disease, hypertension, previous myocardial infarction) or those who are current or past smokers. Reserve baricitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients of the potential increased risk for major adverse CV events and to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot. If a patient develops a thromboembolic event, discontinue the drug.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral Janus kinase (JAK) inhibitor, a target specific DMARD
    Used in adults with moderate-to-severe rheumatoid arthritis; used in adults with severe alopecia areata; used in hospitalized adults with COVID-19 who require supplemental oxygen, mechanical ventilation, or ECMO
    Serious infections, blood clots, and malignancy may occur; reserve for patients intolerant of 1 or more TNF inhibitors

    COMMON BRAND NAMES

    OLUMIANT

    HOW SUPPLIED

    Baricitinib/OLUMIANT Oral Tab: 1mg, 2mg, 4mg

    DOSAGE & INDICATIONS

    For the treatment of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, in hospitalized patients requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
    NOTE: Prior to initiating treatment, obtain a baseline complete blood count (CBC), hepatic function, and renal function. Monitor patients for laboratory changes and modify dosage based on laboratory abnormalities.
    Oral dosage
    Adults

    4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend use of baricitinib with dexamethasone in patients on supplemental oxygen, including noninvasive ventilation, high-flow oxygen, mechanical ventilation, or ECMO.[65314]

    Children and Adolescents 9 to 17 years†

    4 mg PO once daily for a recommended duration of 14 days or until hospital discharge, whichever comes first. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The NIH COVID-19 treatment guidelines recommend consideration of the addition of baricitinib for patients requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO who do not have rapid (e.g., within 24 hours) improvement in oxygenation after initiation of dexamethasone. Remdesivir may be added for patients requiring high-flow oxygen or noninvasive ventilation.

    Children 2 to 8 years†

    2 mg PO once daily for a recommended duration of 14 days or until hospital discharge, whichever comes first. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The NIH COVID-19 treatment guidelines recommend consideration of the addition of baricitinib for patients requiring high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO who do not have rapid (e.g., within 24 hours) improvement in oxygenation after initiation of dexamethasone. Remdesivir may be added for patients requiring high-flow oxygen or noninvasive ventilation.

    For the treatment of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to 1 or more tumor necrosis factor (TNF) inhibitors.
    NOTE: Reserve baricitinib for patients who have an inadequate response or intolerance to 1 or more TNF inhibitors. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particularly in those who smoke, have cardiovascular risk factors, develop malignancy, or have a known malignancy other than successfully treated non-melanoma skin cancer (NMSC). A large randomized safety clinical trial with another JAK inhibitor, tofacitinib, showed an increased risk of malignancy, all-cause mortality (including sudden cardiac death), major adverse cardiovascular events (MACE; defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), and thrombosis (including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis), compared to tumor necrosis factor (TNF) inhibitors in patients with RA. Baricitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions.
    Oral dosage
    Adults

    2 mg PO once daily. May give with or without methotrexate or other non-biologic (conventional) disease-modifying antirheumatic drugs (DMARDs). Do not use in combination with other Janus kinase (JAK) inhibitors, biologic or targeted DMARDs, or potent immunosuppressants such as azathioprine and cyclosporine. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    For the treatment of severe alopecia areata.
    Oral dosage
    Adults

    2 mg PO once daily. May increase to 4 mg PO once daily if the response to treatment is inadequate. For patients with nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss, consider initiating treatment at 4 mg PO once daily. Once an adequate response is achieved, decrease to 2 mg PO once daily. Do not use in combination with other Janus kinase (JAK) inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

    MAXIMUM DOSAGE

    Adults

    2 mg/day PO for rheumatoid arthritis; 4 mg/day PO for alopecia areata; 4 mg/day PO for COVID-19.

    Geriatric

    2 mg/day PO for rheumatoid arthritis; 4 mg/day PO for alopecia areata; 4 mg/day PO for COVID-19.

    Adolescents

    Safety and efficacy have not been established; however, investigational doses of 4 mg/day PO have been used for COVID-19.

    Children

    Children 9 to 12 years: Safety and efficacy have not been established; investigational doses of 4 mg/day PO have been used for COVID-19.
    Children 2 to less than 9 years: Safety and efficacy have not been established; however, investigational doses of 2 mg/day PO have been used for COVID-19.
    Children less than 2 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage Adjustments for Rheumatoid Arthritis and Alopecia areata:
    Mild or moderate impairment: No dosage adjustments needed; however, if increases in alanine transaminase (ALT) or aspartate transaminase (AST) are observed and drug-induced liver injury is suspected, interrupt baricitinib until the diagnosis of drug-induced liver injury has been excluded.
    Severe impairment: Not recommended.
     
    Dosage Adjustments for COVID-19:
    Mild or moderate impairment: No dosage adjustments needed; however, if increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt baricitinib until the diagnosis of drug-induced liver injury has been excluded.
    Severe impairment: Administer only if the potential benefits outweigh the potential risks.

    Renal Impairment

    Dosage Adjustments for Rheumatoid Arthritis:
    eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment is needed.
    eGFR 30 to 59 mL/minute/1.73 m2: Reduce to 1 mg PO once daily.
    eGFR less than 30 mL/minute/1.73 m2: Use not recommended.
     
    Dosage Adjustments for Alopecia areata:
    eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment is needed.
    eGFR 30 to 59 mL/minute/1.73 m2: Reduce recommended dose by 50%.
    eGFR less than 30 mL/minute/1.73 m2: Use not recommended.
     
    Dosage Adjustments for COVID-19:
    Adults, Adolescents, and Children 9 years and older
    eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment is needed.
    eGFR 30 to 59 mL/minute/1.73 m2: Reduce to 2 mg PO once daily.
    eGFR 15 to 29 mL/minute/1.73 m2: Reduce to 1 mg PO once daily.
    eGFR less than 15 mL/minute/1.73 m2: Use not recommended.
     
    Children 2 to less than 9 years
    eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment is needed.
    eGFR 30 to 59 mL/minute/1.73 m2: Reduce to 1 mg PO once daily.
    eGFR less than 30 mL/minute/1.73 m2: Use not recommended.
     
    Baricitinib is not recommended for use in patients who are on dialysis, have end-stage renal disease (ESRD) defined as eGFR less than 15 mL/minute/1.73 m2, or have acute kidney injury.

    ADMINISTRATION

     
    COVID-19 per the Emergency Use Authorization (EUA):
    NOTE: Baricitinib is not FDA-approved to treat coronavirus disease 2019 (COVID-19) in pediatric patients; however, the FDA has issued an Emergency Use Authorization which allows for baricitinib to be used to treat COVID-19 in hospitalized pediatric patients (ages, 2 to 17 years) requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). Under the EUA, health care providers are required to communicate to the patient, parent, or caregiver information consistent with the "Fact Sheet for Patients, Parents and Caregivers" prior to the patient receiving treatment; such information includes the following:
    The option to accept or refuse baricitinib
    The significant known and potential risks and benefits of baricitinib, and the extent to which such potential risks and benefits are unknown
    Available alternative treatments and the risks and benefits of those alternatives
     
    NOTE: If provision of this information delays treatment to the degree that would endanger the lives of patients, then the information must be provided as soon as practical following baricitinib administration.
     
    NOTE: Under the EUA, health care providers are required to report all medication errors and serious adverse events potentially related to baricitinib therapy within 7 calendar days from the health care provider's awareness of the event.

    Oral Administration
    Oral Solid Formulations

    Administer tablets with or without food.
    For a 1 mg dose when the 1 mg tablet is not available: A 2 mg tablet can be split using a tablet splitter that has a razor blade to administer half a 2 mg tablet once daily. The tablet should be split along the longest diameter. If the portions of the tablet are determined to be visually unequal, they should be discarded. Take care in storing the second tablet half to avoid breakage prior to the next dose.

    Extemporaneous Compounding-Oral

    For patients unable to swallow whole tablets, one of the following alternative administration methods may be used.
    Intact tablets are not hazardous; however, it is not known if powder from crushed tablets may constitute a reproductive hazard to the preparer. If tablets are crushed, use proper control measures (e.g., ventilated enclosure) or personal protective equipment (i.e., N95 respirator).
    Tablets dispersed in water are stable for up to 4 hours.
     
    Oral administration of dispersed tablets in water:
    Place the needed number of tablets to achieve a single dose (maximum 4 mg) into a container with approximately 10 mL (minimum 5 mL) of room temperature water. Either 1 mg, 2 mg, 4 mg, or a combination of tablets may be utilized to achieve the desired dose.
    Gently swirl the water to disperse the tablets and immediately drink. Tablets may be crushed to facilitate dispersion.
    Rinse the container with an additional 10 mL (minimum 5 mL) of room temperature water and swallow the entire contents.
     
    Administration via gastrostomy tube (G tube):
    Place the needed number of tablets to achieve a single dose (maximum 4 mg) into a container with approximately 15 mL (minimum 10 mL) of room temperature water. Either 1 mg, 2 mg, 4 mg, or a combination of tablets may be utilized to achieve the desired dose.
    Gently swirl the water to disperse the tablets and ensure that the tablets are sufficiently dispersed to allow free passage through the tip of the syringe. Tablets may be crushed to facilitate dispersion.
    Withdraw the entire contents from the container into an appropriate syringe and immediately administer into the gastric tube.
    Rinse container with 15 mL (minimum 10 mL) of room temperature water, withdraw entire contents into the syringe, and administer through the gastric tube.
     
    Administration via nasogastric tube (NG tube) or orogastric tube (OG tube):
    Place the needed number of tablets to achieve a single dose (maximum 4 mg) into a container with approximately 30 mL of room temperature water. Either 1 mg, 2 mg, 4 mg, or a combination of tablets may be utilized to achieve the desired dose.
    Gently swirl the water to disperse the tablets and ensure that the tablets are sufficiently dispersed to allow free passage through the tip of the syringe. Tablets may be crushed to facilitate dispersion.
    Withdraw the entire contents from the container into an appropriate syringe and immediately administer into the NG or OG tube.
    To avoid clogging of small diameter tubes (smaller than French size 12), the syringe may be held horizontally and shaken during administration.
    Rinse container with a sufficient amount of room temperature water (minimum 15 mL), withdraw entire contents into the syringe, and administer through the NG or OG tube.

    STORAGE

    OLUMIANT:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Corticosteroid therapy, diabetes mellitus, fungal infection, herpes infection, human immunodeficiency virus (HIV) infection, immunosuppression, infection, pulmonary disease, tuberculosis, viral infection

    Avoid the use of baricitinib in rheumatoid arthritis and alopecia areata patients with an active, serious or opportunistic infection, including localized infections. In patients with COVID-19 and concomitant active serious infections, data are limited; therefore, the risks and benefits of baricitinib treatment in COVID-19 patients with other concurrent infections should be considered. Serious and sometimes fatal bacterial infection, mycobacterial infection, invasive fungal infection, viral infection, or infections due to other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving baricitinib. The risks and benefits of treatment should be considered prior to initiating baricitinib in patients: 1) with chronic or recurrent infection; 2) who have been exposed to tuberculosis; 3) with a history of a serious or an opportunistic infection; 4) who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or 5) with underlying conditions that may predispose them to infection (e.g., diabetes mellitus, human immunodeficiency virus (HIV) infection, chronic pulmonary disease, low lymphocyte counts, and pre-existing immunosuppression). The most common serious infections reported with baricitinib included pneumonia, herpes zoster, and urinary tract infections. Among opportunistic infections, tuberculosis, cryptococcosis, acute histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, and BK virus were reported with baricitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppression agents such as methotrexate or corticosteroid therapy. Ask patients if they have lived or have traveled to the Ohio and Mississippi River valleys or the Southwest because of an increased chance of acquiring certain kinds of fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis. Viral reactivation, including cases of herpes infection reactivation (e.g., herpes zoster), were observed in clinical studies. If a patient develops herpes zoster, interrupt baricitinib therapy until the episode resolves. Carefully consider the risks and benefits of baricitinib before starting the drug in patients who have been exposed to tuberculosis (TB). Baricitinib should not be administered to patients with active tuberculosis. Patients, except those with COVID-19, should be evaluated and tested for latent TB infection prior to and per applicable guidelines during baricitinib administration. Consider anti-tuberculosis therapy before baricitinib administration in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Monitor patients for the development of signs and symptoms of tuberculosis in all patients during treatment. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with baricitinib. Therapy with baricitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with baricitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

    Hepatic disease, hepatitis, hepatitis C infection

    Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with baricitinib. The impact of baricitinib on chronic viral hepatitis reactivation is unknown. Patients with evidence of active hepatitis B or hepatitis C infection were excluded from clinical trials. In clinical trials in patients with rheumatoid arthritis or alopecia areata, 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. Use baricitinib with caution in any other patient with hepatic disease or impairment. Increases in liver enzymes of 5-times and up to 10-times the upper limit of normal (ULN) were reported for both ALT and AST in clinical trials. Liver function tests (LFTs) should be evaluated at baseline and thereafter according to routine patient management. If increases in ALT or AST are seen and drug-induced liver toxicity is suspected, interrupt baricitinib treatment until drug-induced toxicity is excluded. Baricitinib is not recommended for rheumatoid arthritis or alopecia areata patients with severe hepatic impairment. For patients with COVID-19, baricitinib has not been studied in patients with severe hepatic impairment and should only be used if the potential benefit outweighs the potential risk.

    Neutropenia

    Determine neutrophil and lymphocyte counts before baricitinib initiation. Do not start the drug in rheumatoid arthritis or alopecia areata patients with an absolute lymphocyte count (ALC) less than 500 cells/mm3 or in patients with absolute neutrophil count (ANC) less than 1,000 cells/mm3. For COVID-19 patients, do not start the drug if the ALC is less than 200 cells/mm3 or the ANC is less than 500 cells/mm3. Baricitinib may cause lymphopenia and neutropenia. Monitor the ANC and ALC periodically during baricitinib treatment according to routine patient management. Interrupt treatment in rheumatoid arthritis and alopecia areata patients with an ANC less than 1,000 cells/mm3 or an ALC less than 500 cells/mm3 until the counts have recovered to amounts equal to or above these thresholds. Interrupt treatment in COVID-19 patients with an ANC less than 500 cells/mm3 or an ALC less than 200 cells/mm3 until the counts have recovered to amounts equal to or above these thresholds.[63229]

    Anemia

    Determine the hemoglobin concentration before baricitinib initiation, and do not start the drug in rheumatoid arthritis or alopecia areata patients with anemia defined as hemoglobin less than 8 grams/dL. Baricitinib may cause anemia. For patients who have hemoglobin 8 grams/dL or greater, monitor the hemoglobin concentration according to routine patient management. Treatment with baricitinib should be interrupted in patients who develop hemoglobin levels less than 8 grams/dL until the hemoglobin has recovered to 8 grams/dL or higher. There are limited data regarding the use of baricitinib in patients with COVID-19 and a hemoglobin less than 8 grams/dL.

    Lymphoma, new primary malignancy, skin cancer, tobacco smoking

    Baricitinib may increase the risk for a new primary malignancy. In a large, postmarketing, randomized safety clinical trial in rheumatoid arthritis patients 50 years of age and older with one or more CV risk factors, higher rates of cancer [excluding non-melanoma skin cancer (NMSC)] and lymphoma were observed with use of tofacitinib, another JAK inhibitor, compared to tumor necrosis factor (TNF) inhibitors. Baricitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions. A higher rate of lung cancer was also observed in patients with a history of current or past tobacco smoking treated with the JAK inhibitor compared to those treated with a TNF inhibitor. Patients with a history of current or past tobacco smoking were at also at an increased risk of overall cancers. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with risk factors such as smoking, those who develop malignancy, and those with a known malignancy other than successfully treated non-melanoma skin cancer (NMCS). Reserve baricitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. NMSCs have also been reported in patients treated with baricitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

    Cardiac disease, hypertension, mortality, myocardial infarction, stroke, thrombocytosis, thromboembolic disease, thromboembolism, thrombosis

    Avoid use of baricitinib in patients who are at an increased risk of thrombosis and thromboembolism, including those with thromboembolic disease. Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have been reported with baricitinib therapy. Many of these events were serious and some resulted in death. In COVID-19 patients, baricitinib has been associated with increases in platelet counts (thrombocytosis) and serious venous thrombosis, including PE. COVID-19 patients receiving baricitinib during clinical trials, were recommended or required to receive venous thromboembolism (VTE) prophylaxis unless a major contraindication was noted. In a large, postmarketing, randomized safety clinical trial in rheumatoid arthritis patients 50 years of age and older with one or more CV risk factors, higher rates of all-cause mortality (including sudden CV death), major adverse CV events (MACE; defined as CV death, non-fatal myocardial infarction (MI), and non-fatal stroke), and thrombosis (including DVT and PE) were observed in patients taking tofacitinib, another Janus kinase (JAK) inhibitor, compared to patients taking tumor necrosis factor (TNF) inhibitors. Many of the observed thrombotic events were serious and some resulted in death. Baricitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions. Current or past tobacco smokers have an additional increased risk of major CV adverse events. Consider the benefits and risks for the individual patient before initiation or continuation of therapy, particular in those with cardiovascular risk factors (e.g., cardiac disease, hypertension, previous myocardial infarction) or those who are current or past smokers. Reserve baricitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients of the potential increased risk for major adverse CV events and to seek emergency medical attention if they experience signs and symptoms of a heart attack, stroke, or blood clot. If a patient develops a thromboembolic event, discontinue the drug.

    Dialysis, renal disease, renal failure, renal impairment

    Use baricitinib with caution in patients with renal impairment. Dosage reductions are recommended in patients with an estimated glomerular filtration rate (eGFR) less than 60 mL/minute/1.73 m2. For rheumatoid arthritis and alopecia areata patients, treatment with baricitinib is not recommended in patients with severe renal impairment or renal failure (i.e., eGFR less than 30 mL/minute/1.73 m2). For adult COVID-19 patients, baricitinib is not recommended in patients who have end-stage renal disease (ESRD, eGFR less than 15 mL/minute/1.73 m2), are on dialysis, or who have acute kidney injury. COVID-19 per the Emergency Use Authorization (EUA): The eGFR must be obtained prior to administration of the first baricitinib dose. Baricitinib is not recommended in pediatric COVID-19 patients on dialysis, who have end-stage renal disease (ESRD, eGFR less than 15 mL/minute/1.73 m2), or who have acute kidney injury. Dosage reductions are recommended in pediatric patients 2 years and older with an eGFR of 30 to 59 mL/minute/1.73 m2. In pediatric patients 9 years and older with an eGFR of 15 to 29 mL/minute/1.73 m2, reduced dose baricitinib should only be used if the potential benefit outweighs the potential risk. Baricitinib therapy is not recommended in pediatric patients 2 years to less than 9 years with an eGFR less than 30 mL/minute/1.73 m2.

    Vaccination

    Update immunizations in agreement with current immunization guidelines prior to initiating baricitinib therapy in patients with rheumatoid arthritis or alopecia areata. Patients who are taking baricitinib should not receive vaccination with live vaccines. These patients may receive non-live vaccines during baricitinib therapy. The interval between live vaccinations and the initiation of baricitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

    Diverticulitis, GI perforation

    Cautious use of baricitinib is advised for patients who may be at increased risk for gastrointestinal (GI) perforation (e.g., patients with a history of diverticulitis). GI perforation has been noted among baricitinib recipients. Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of GI perforation.

    Hypercholesterolemia, hyperlipidemia

    Use baricitinib with caution in patients with hyperlipidemia or hypercholesterolemia. Treatment with baricitinib 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 initiation of baricitinib therapy in patients with rheumatoid arthritis or alopecia areata. Manage patients according to clinical guidelines for the management of hyperlipidemia.

    Geriatric

    During clinical trials, no overall differences in safety or effectiveness were noted between geriatric and younger adult patients receiving baricitinib for rheumatoid arthritis. However, greater sensitivity of some older individuals cannot be ruled out. Baricitinib is extensively excreted by the kidney, and the risk of adverse reactions may be greater for patients with impaired renal function. Geriatric patients are more likely to have decreased renal function; therefore, cautious dose selection and monitoring of renal function may be warranted in geriatric patients.

    Pregnancy

    Available data from clinical trials and postmarketing case reports regarding use of baricitinib during human pregnancy are insufficient to inform a drug-associated risk for major birth defects, miscarriages, or other adverse maternal or fetal outcomes. There are no human data on chronic baricitinib exposure throughout pregnancy; therefore, the risks and benefits with chronic use of the drug should be considered. When deciding whether to use the drug in pregnant patients with rheumatoid arthritis, consider that published data suggest increased disease activity is associated with risk of developing adverse pregnancy outcomes, including preterm delivery (before 37 weeks gestation), low birth weight (less than 2,500 grams) infants, and small for gestational age at birth. Based on finding from animal studies, exposure to baricitinib during pregnancy may cause fetal harm. In embryofetal development studies, oral administration to rats and rabbits at exposures at least 11- and 46-times the maximum recommended human dose (MRHD) of 4 mg per day, respectively, resulted in reduced fetal body weights, increased embryolethality (rabbits only), and dose-related increases in skeletal malformations. Developmental toxicity was not observed in pregnant rats and rabbits treated with baricitinib at approximately 2- and 7-times the MRHD, respectively. In a pre- and post-development study in pregnant rats, oral baricitinib administration at exposures approximately 24-times the MRHD resulted in a reduction in pup viability, decreased fetal birth weight, reduced fetal body weight gain, decreased cytotoxic T cells on post-natal day 35 with no evidence of recovery by day 65, and developmental delays that might be attributable to decreased body weight gain. No developmental toxicity was observed at exposures approximately 5-times the MRHD.[63229] The National Institutes of Health (NIH) states that there are limited data available on the use of Janus kinase (JAK) inhibitors, such as baricitinib, during pregnancy in patients with COVID-19. Among 33 reported cases of JAK inhibitor use during pregnancy in patients with non-COVID-19 indications (e.g., ulcerative colitis, rheumatoid arthritis, psoriasis), the outcomes were similar to those of the general population. However, because of the small molecular size, JAK inhibitors are likely to pass through the placenta; thus, fetal risk cannot be ruled out. The decision to administer baricitinib to a pregnant patient with COVID-19 must be shared between the patient and their healthcare providers, and potential maternal benefit and fetal risks must be considered. Consider pregnancy planning and contraception requirements for patients of childbearing potential. Report drug exposures during pregnancy to the manufacturer at 1-800-545-5979.

    Breast-feeding

    Due to the potential for serious adverse reactions in a nursing infant, breast-feeding is not recommended during baricitinib therapy and for 4 days after the last dose (approximately 5 to 6 elimination half-lives). No data are available on the presence of baricitinib in human milk, the effects of the drug on the breast-fed infant, or the effects on milk production. Baricitinib is present in the milk of lactating rats; the clinical relevance of this to human lactation is not known. Etanercept and infliximab may be potential alternatives to consider during breast-feeding. However, assessment of indication and patient-specific factors should be performed before considering an alternative agent.

    Children, infants

    The safety and efficacy of baricitinib in infants, children, and adolescents under the age of 18 years have not been established.

    Angioedema, serious hypersensitivity reactions or anaphylaxis

    Angioedema, urticaria, and rash have been reported with baricitinib therapy and may be a result of serious hypersensitivity reactions or anaphylaxis. Promptly discontinue baricitinib therapy if a serious hypersensitivity reaction is suspected.

    ADVERSE REACTIONS

    Severe

    thromboembolism / Delayed / 0.6-0.9
    thrombosis / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    stroke / Early / Incidence not known
    GI perforation / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    lymphoma / Delayed / Incidence not known
    skin cancer / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 1.1-18.1
    thrombocytosis / Delayed / 1.1-7.9
    neutropenia / Delayed / 0-2.2
    anemia / Delayed / 0-1.3
    lymphopenia / Delayed / 0-1.0
    cystitis / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    tracheitis / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known

    Mild

    infection / Delayed / 14.8-21.3
    headache / Early / 5.5-6.6
    acne vulgaris / Delayed / 0-5.9
    acneiform rash / Delayed / 0-5.9
    abdominal pain / Early / 0-3.8
    nausea / Early / 0-2.7
    folliculitis / Delayed / 1.4-2.2
    fatigue / Early / 0.8-2.2
    weight gain / Delayed / 0.9-1.6
    sinusitis / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    laryngitis / Delayed / Incidence not known
    influenza / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Abatacept: (Major) Concomitant use of baricitinib with biologic DMARDs, such as abatacept, is not recommended because of the possibility of additive immunosuppression and increased infection risk. There is insufficient experience to assess the safety and efficacy of this combination. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Adalimumab: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Anakinra: (Major) Concomitant use of baricitinib with biologic DMARDs, such as anakinra, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Azathioprine: (Major) Concomitant use of baricitinib with azathioprine is not recommended because of the possibility of additive immunosuppression and increased infection risk. There is insufficient experience to assess the safety and efficacy of this combination. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Bacillus Calmette-Guerin Vaccine, BCG: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Canakinumab: (Major) Concomitant use of baricitinib with biologic DMARDs, such as canakinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk.
    Certolizumab pegol: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Cyclosporine: (Major) Concomitant use of baricitinib with cyclosporine is not recommended because of the possibility of additive immunosuppression and increased infection risk. There is insufficient experience to assess the safety and efficacy of this combination. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Etanercept: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Golimumab: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Infliximab: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Intranasal Influenza Vaccine: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Leflunomide: (Moderate) Monitor for increased baricitinib effects if administered with leflunomide as baricitinib exposure may increase; a baricitinib dose reduction may be necessary. Baricitinib is an OAT3 substrate; leflunomide is an OAT3 inhibitor.
    Live Vaccines: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Measles/Mumps/Rubella Vaccines, MMR: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Probenecid: (Major) Reduce the recommended baricitinib dose by half in patients receiving concomitant therapy with probenecid. If the recommended dose is 4 mg daily, reduce to 2 mg daily. If the recommended dose is 2 mg daily, reduce to 1 mg daily. If the recommended dose is 1 mg daily, consider discontinuing probenecid. Coadministration of baricitinib and probenecid results in increased baricitinib exposure. In a drug interaction study, administration of probenecid increased baricitinib exposure by 2-fold. Baricitinib is an OAT3 substrate and probenecid is a strong OAT3 inhibitor.
    Probenecid; Colchicine: (Major) Reduce the recommended baricitinib dose by half in patients receiving concomitant therapy with probenecid. If the recommended dose is 4 mg daily, reduce to 2 mg daily. If the recommended dose is 2 mg daily, reduce to 1 mg daily. If the recommended dose is 1 mg daily, consider discontinuing probenecid. Coadministration of baricitinib and probenecid results in increased baricitinib exposure. In a drug interaction study, administration of probenecid increased baricitinib exposure by 2-fold. Baricitinib is an OAT3 substrate and probenecid is a strong OAT3 inhibitor.
    Rituximab: (Major) Concomitant use of baricitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Rituximab; Hyaluronidase: (Major) Concomitant use of baricitinib with biologic DMARDs, such as rituximab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Rotavirus Vaccine: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Rubella Virus Vaccine Live: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Sarilumab: (Major) Avoid the concomitant use of sarilumab with other biological DMARDs such as baricitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Secukinumab: (Major) Concomitant use of baricitinib with biologic DMARDs, such as secukinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Smallpox Vaccine, Vaccinia Vaccine: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Teriflunomide: (Moderate) Monitor for increased baricitinib effects if administered with teriflunomide as baricitinib exposure may increase; a baricitinib dose reduction may be necessary. Baricitinib is an OAT3 substrate; teriflunomide is an OAT3 inhibitor.
    Tocilizumab: (Major) Avoid the concomitant use of tocilizumab with other biological DMARDs such as baricitinib; coadministration has not been studied and may result in additive immunosuppression and increased risk of infection.
    Tofacitinib: (Major) Concomitant use of baricitinib with tofacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk.
    Tumor Necrosis Factor modifiers: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tumor necrosis factor (TNF) modifiers, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Typhoid Vaccine: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Upadacitinib: (Major) Concomitant use of baricitinib with upadacitinib is not recommended because of the duplication of the mechanism of action (both are Janus kinase inhibitors, also known as JAK inhibitors) and the possibility of increased immunosuppression and increased infection risk. Both drugs are known to cause elevations in hepatic enzymes and gastrointestinal perforation, and a possibility for increased thrombotic risk.
    Ustekinumab: (Major) Concomitant use of baricitinib with biologic DMARDs, such as ustekinumab, is not recommended because of the possibility of additive immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.
    Varicella-Zoster Virus Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
    Yellow Fever Vaccine, Live: (Major) Do not administer live virus vaccines to patients taking baricitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during baricitinib receipt. Before baricitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.

    PREGNANCY AND LACTATION

    Pregnancy

    Available data from clinical trials and postmarketing case reports regarding use of baricitinib during human pregnancy are insufficient to inform a drug-associated risk for major birth defects, miscarriages, or other adverse maternal or fetal outcomes. There are no human data on chronic baricitinib exposure throughout pregnancy; therefore, the risks and benefits with chronic use of the drug should be considered. When deciding whether to use the drug in pregnant patients with rheumatoid arthritis, consider that published data suggest increased disease activity is associated with risk of developing adverse pregnancy outcomes, including preterm delivery (before 37 weeks gestation), low birth weight (less than 2,500 grams) infants, and small for gestational age at birth. Based on finding from animal studies, exposure to baricitinib during pregnancy may cause fetal harm. In embryofetal development studies, oral administration to rats and rabbits at exposures at least 11- and 46-times the maximum recommended human dose (MRHD) of 4 mg per day, respectively, resulted in reduced fetal body weights, increased embryolethality (rabbits only), and dose-related increases in skeletal malformations. Developmental toxicity was not observed in pregnant rats and rabbits treated with baricitinib at approximately 2- and 7-times the MRHD, respectively. In a pre- and post-development study in pregnant rats, oral baricitinib administration at exposures approximately 24-times the MRHD resulted in a reduction in pup viability, decreased fetal birth weight, reduced fetal body weight gain, decreased cytotoxic T cells on post-natal day 35 with no evidence of recovery by day 65, and developmental delays that might be attributable to decreased body weight gain. No developmental toxicity was observed at exposures approximately 5-times the MRHD.[63229] The National Institutes of Health (NIH) states that there are limited data available on the use of Janus kinase (JAK) inhibitors, such as baricitinib, during pregnancy in patients with COVID-19. Among 33 reported cases of JAK inhibitor use during pregnancy in patients with non-COVID-19 indications (e.g., ulcerative colitis, rheumatoid arthritis, psoriasis), the outcomes were similar to those of the general population. However, because of the small molecular size, JAK inhibitors are likely to pass through the placenta; thus, fetal risk cannot be ruled out. The decision to administer baricitinib to a pregnant patient with COVID-19 must be shared between the patient and their healthcare providers, and potential maternal benefit and fetal risks must be considered. Consider pregnancy planning and contraception requirements for patients of childbearing potential. Report drug exposures during pregnancy to the manufacturer at 1-800-545-5979.

    Due to the potential for serious adverse reactions in a nursing infant, breast-feeding is not recommended during baricitinib therapy and for 4 days after the last dose (approximately 5 to 6 elimination half-lives). No data are available on the presence of baricitinib in human milk, the effects of the drug on the breast-fed infant, or the effects on milk production. Baricitinib is present in the milk of lactating rats; the clinical relevance of this to human lactation is not known. Etanercept and infliximab may be potential alternatives to consider during breast-feeding. However, assessment of indication and patient-specific factors should be performed before considering an alternative agent.

    MECHANISM OF ACTION

    Baricitinib is an oral Janus kinase (JAK) inhibitor. Janus kinases are intracellular enzymes that transmit signals arising from cytokine or growth factor receptor interactions on the cellular membrane to influence cellular processes of immune cell function and hematopoiesis. JAK-mediated signaling is pivotal in immune activation, as cytokine receptors are expressed on most immune cells. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription proteins (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. Cytokine signaling is transmitted through pairing of JAKs such as JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, and JAK2/TYK2. Baricitinib has greater affinity for JAK1, JAK2, and TYK2, relative to JAK3. In human leukocytes, baricitinib inhibits cytokine-induced STAT phosphorylation mediated by JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 with comparable potencies. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.[63229]

    PHARMACOKINETICS

    Baricitinib is administered orally. After intravenous administration, the volume of distribution is 76 L, indicating the distribution of baricitinib into tissues. Plasma and serum protein bindings are approximately 50% and 45%, respectively. Approximately 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. 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 is predominately excreted as unchanged drug in the urine (69%) and feces (15%). The elimination half-life is approximately 12 to 16 hours in patients with rheumatoid arthritis (RA) and alopecia areata. In COVID-19 patients who are intubated and have baricitinib administered via nasogastric (NG) or orogastric (OG) tube, the total body clearance and half-life of baricitinib is 14.2 L/hour and 10.8 hours, respectively.[63229]
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP3A4, OAT3, P-glycoprotein (P-gp), BCRP, and MATE2-K
    In vitro studies indicate that baricitinib is a substrate of CYP3A4, OAT3, P-gp, BCRP, and MATE2-K. In clinical pharmacology studies, coadministration with ketoconazole (a strong CYP3A4) did not have an effect on the pharmacokinetics of baricitinib. In addition, no clinically meaningful effects on baricitinib pharmacokinetics when it was coadministered with fluconazole (CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampin (a strong CYP3A4 inducer). Coadministration with probenecid (a strong OAT3 inhibitor) resulted in an approximately 2-fold increase in baricitinib exposure. Coadministration with OAT3 inhibitors with less inhibition potential (i.e., ibuprofen and diclofenac) had minimal effect on baricitinib exposure. No clinically meaningful effect on the pharmacokinetics of baricitinib was noted with the coadministration of cyclosporine (a P-gp and BCRP inhibitor). In vitro data indicate baricitinib inhibits OAT1, OAT2, OAT3, OCT1, OCT2, OAT1B3, BCRP, and MATE1 and MATE2-K, but clinically meaningful changes in the pharmacokinetics of drugs that are substrates for these transporters are unlikely.[63229]

    Oral Route

    The absolute oral bioavailability of baricitinib is approximately 80%. In clinical trials, baricitinib was administered without regard to meals. Administration with meals is not associated with a clinically relevant effect on exposure. Peak plasma concentrations of baricitinib after oral administration were reached within 1 hour, and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady-state concentrations are achieved in 2 to 3 days with negligible accumulation.