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    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 use of baricitinib in patients with an active, serious infection, including localized infections. 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 should be evaluated and tested for latent or active 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. COVID-19 per Emergency Use Authorization (EUA): There are limited information regarding the use of baricitinib in patients with COVID-19 who also have other concurrent active serious infections. Avoid use of baricitinib in COVID-19 patients with known active TB infection. In patients with active serious infections other than COVID-19 or chronic/recurrent infections, consider whether the potential benefits of baricitinib therapy outweigh the potential risks.

    Lymphoma, new primary malignancy, skin cancer, tobacco smoking

    Baricitinib may increase the risk for a new primary malignancy. A large randomized safety clinical trial showed an increased risk of cancer with use of tofacitinib, another JAK inhibitor, compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis. 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 cancer (e.g., lymphomas, lung cancer) was also observed. Patients with a history of current or past tobacco smoking were at 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, thrombocytosis, thromboembolic disease, thromboembolism, thrombosis

    Use baricitinib with caution in patients with thromboembolic disease or who are at an increased risk of thrombosis and thromboembolism.[63229] Baricitinib may cause increases in platelet counts (thrombocytosis). Serious venous thrombosis, including PE, have been reported in COVID-19 patients treated with baricitinib. Venous thromboembolism (VTE) prophylaxis is recommended for hospitalized COVID-19 patients unless contraindicated. A large randomized safety clinical trial showed an increased risk of serious heart-related events such as heart attack or stroke, blood clots, and mortality with use of tofacitinib, another JAK inhibitor, compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis. Baricitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions. 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). Reserve baricitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients 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
    Serious infections and malignancy may occur; may cause increased risk of thrombosis; reserve use for patients intolerant to one or more TNF inhibitors

    COMMON BRAND NAMES

    OLUMIANT

    HOW SUPPLIED

    Baricitinib/OLUMIANT Oral Tab: 1mg, 2mg

    DOSAGE & INDICATIONS

    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) antagonists.
    Oral dosage
    Adults

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

    INVESTIGATIONAL USE: 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: Patients must have eGFR, aminotransferases (liver function tests), and complete blood count (CBC) with differential evaluated prior to first dose of baricitinib.
    Oral dosage
    Adults

    4 mg PO once daily for a recommended duration of 14 days or until hospital discharge, whichever comes first; optimal treatment duration unknown. The National Institutes of Health (NIH) COVID-19 treatment guidelines recommend the following regarding use of baricitinib: (1) recommended for use with dexamethasone (with or without remdesivir) in patients on noninvasive ventilation or high-flow oxygen IF there is evidence of clinical progression or increased markers of inflammation; (2) for patients on conventional oxygen supplementation, efficacy data are insufficient; however some Panel members support use in patients who don't yet require noninvasive ventilation or high-flow oxygen but are exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone.[65314]

    Children and Adolescents 9 years of age and older

    4 mg PO once daily for a recommended duration of 14 days or until hospital discharge, whichever comes first; optimal treatment duration unknown. The National Institutes of Health (NIH) COVID-19 treatment guidelines state there are insufficient data to recommend either for or against use in pediatric patients.[65314]

    Children 2 to less than 9 years

    2 mg PO once daily for a recommended duration of 14 days or until hospital discharge, whichever comes first; optimal treatment duration unknown. The National Institutes of Health (NIH) COVID-19 treatment guidelines state there are insufficient data to recommend either for or against use in pediatric patients.[65314]

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2 mg/day PO; investigational doses of 4 mg/day PO have been used for COVID-19.

    Geriatric

    2 mg/day PO; investigational doses of 4 mg/day PO have been used 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

    FDA-approved Hepatic Impairment Dosage Adjustments:
    Mild or moderate impairment: No dosage adjustments needed.
    Severe impairment: Not recommended.
     
    Dosage Adjustments for the treatment of COVID-19 per the Emergency Use Authorization (EUA):
    If increases in alanine transaminase (ALT) or aspartate transaminase (AST) occur and drug-induced liver injury is suspected, interrupt baricitinib until the diagnosis of drug-induced liver disease has been excluded.

    Renal Impairment

    FDA-approved Renal Impairment Dosage Adjustments:
    eGFR more than 60 mL/minute/1.73 m2: No dosage adjustment is needed.
    eGFR 30 to 60 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 the treatment of COVID-19 per the Emergency Use Authorization (EUA):
    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 less than 60 mL/minute/1.73 m2: Reduce to 2 mg PO once daily.
    eGFR 15 to less than 30 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 less than 60 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 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); however, the FDA has issued an Emergency Use Authorization which allows for baricitinib to be used to treat COVID-19 in hospitalized adult and pediatric patients 2 years and older 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 onset of the event.

    Oral Administration
    Oral Solid Formulations

    Administer tablets with or without food.

    Extemporaneous Compounding-Oral

    COVID-19 per the Emergency Use Authorization (EUA):
    Proper control measure, such as a ventilated enclosure, or personal protective equipment (i.e., N95 respirator) should be used in the preparation of extemporaneous oral formulations; it is unknown whether the powder from crushed tablets constitute a reproductive hazard.
     
    Oral administration of dispersed tablets in water:
    For patients unable to swallow whole tablets.
    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, 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 container with 10 mL (minimum 5 mL) of room temperature water and swallow the entire contents.
    Tablets dispersed in water are stable for 4 hours.
     
    Administration via gastrostomy feeding 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, 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.
    Tablets dispersed in water are stable for 4 hours.
     
    Administration via nasogastric feeding tube (NG 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, 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 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 tube.
    Tablets dispersed in water are stable for 4 hours.

    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 use of baricitinib in patients with an active, serious infection, including localized infections. 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 should be evaluated and tested for latent or active 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. COVID-19 per Emergency Use Authorization (EUA): There are limited information regarding the use of baricitinib in patients with COVID-19 who also have other concurrent active serious infections. Avoid use of baricitinib in COVID-19 patients with known active TB infection. In patients with active serious infections other than COVID-19 or chronic/recurrent infections, consider whether the potential benefits of baricitinib therapy outweigh the potential risks.

    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. 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. Baricitinib is not recommended for patients with severe hepatic 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. COVID-19 per the Emergency Use Authorization (EUA): LFTs must be obtained prior to administration of the first baricitinib dose. Baricitinib has not been studied in patients with severe liver impairment and should only be administered to this patient population if the potential benefit outweighs the potential risk. It is not known whether dosage adjustments are needed in patients with severe liver impairment. If increases in ALT or AST occur and drug-induced liver injury is suspected, interrupt baricitinib treatment until the diagnosis of drug-induced liver injury is excluded.

    Neutropenia

    Determine neutrophil and lymphocyte counts before baricitinib initiation. Do not start the drug in 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. Baricitinib may cause lymphopenia and neutropenia. Monitor the ANC and ALC periodically during baricitinib treatment according to routine patient management. Interrupt treatment in 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.[63229] COVID-19 per the Emergency Use Authorization (EUA): Complete blood count (CBC) with differential must be obtained prior to administration of the first baricitinib dose. There are limited data regarding the use of baricitinib in patients with COVID-19 and an ANC less than 1,000 cells/mm3 or ALC less than 200 cells/mm3. The EUA states that no dosage adjustments are needed in COVID-19 patients for an ANC of 500 cells/mm3 or more. For an ANC less than 500 cells/mm3, consider a delay or interruption in baricitinib therapy until ANC is 500 cells/mm3 or more. Also, no dosage adjustments are needed in COVID-19 patients for an ALC of 200 cells/mm3 or more. For an ALC less than 200 cells/mm3, consider a delay or interruption in baricitinib therapy until ALC is 200 cells/mm3 or more.

    Anemia

    Determine the hemoglobin concentration before baricitinib initiation, and do not start the drug in 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. COVID-19 per the Emergency Use Authorization (EUA): Complete blood count (CBC) with differential must be obtained prior to administration of the first baricitinib dose. 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. A large randomized safety clinical trial showed an increased risk of cancer with use of tofacitinib, another JAK inhibitor, compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis. 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 cancer (e.g., lymphomas, lung cancer) was also observed. Patients with a history of current or past tobacco smoking were at 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, thrombocytosis, thromboembolic disease, thromboembolism, thrombosis

    Use baricitinib with caution in patients with thromboembolic disease or who are at an increased risk of thrombosis and thromboembolism.[63229] Baricitinib may cause increases in platelet counts (thrombocytosis). Serious venous thrombosis, including PE, have been reported in COVID-19 patients treated with baricitinib. Venous thromboembolism (VTE) prophylaxis is recommended for hospitalized COVID-19 patients unless contraindicated. A large randomized safety clinical trial showed an increased risk of serious heart-related events such as heart attack or stroke, blood clots, and mortality with use of tofacitinib, another JAK inhibitor, compared to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis. Baricitinib has not been studied in similar trials; however, the risks may be similar for all JAK inhibitors used for inflammatory conditions. 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). Reserve baricitinib for patients who have an inadequate response or intolerance to one or more TNF inhibitors. Advise patients 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 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) of 30 to 60 mL/minute/1.73 m2. Baricitinib is not recommended in patients with renal failure or an eGFR less than 30 mL/minute/1.73 m2. 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 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 adult and pediatric patients 2 years and older with an eGFR of 30 to less than 60 mL/minute/1.73 m2. In adult and pediatric patients 9 years and older with an eGFR of 15 to less than 30 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. 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, although the role of baricitinib in these events is not known. 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 in all patients should be performed approximately 12 weeks following initiation of baricitinib therapy. 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. 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

    Sufficient data are not available to inform a drug-associated risk for major birth defects or miscarriage with the use of baricitinib during human pregnancy. In embryofetal animal studies, oral administration to rats and rabbits at exposures greater than 20 and 84 times the maximum recommended human dose (MRHD), respectively, resulted in reduced fetal body weights, increased embryolethality (rabbits only), and dose-related increases in skeletal malformations. Developmental toxicity was not observed in pregnant rats and rabbits treated with baricitinib at approximately 5 and 13 times the MRHD, respectively. In a pre- and post-development study in pregnant rats, oral baricitinib administration at exposures approximately 43 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 9 times the MRHD.[63229] COVID-19 per Emergency Use Authorization (EUA): Baricitinib should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and fetus. The NIH states that there is limited data available on the use of janus kinase (JAK) inhibitors, such as baricitinib, during pregnancy. Among 33 reported cases of JAK 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. Risks of use should be balanced against potential benefits.

    Breast-feeding

    Because of the potential for serious adverse reactions in a nursing infant, breast-feeding during baricitinib therapy is not recommended. 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
    pulmonary embolism / Delayed / Incidence not known
    thrombosis / Delayed / 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 / 1.3-1.7
    thrombocytosis / Delayed / 1.1-1.1
    neutropenia / Delayed / 0.6-0.6
    tracheitis / Delayed / Incidence not known
    candidiasis / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    lymphopenia / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known

    Mild

    infection / Delayed / 16.3-16.3
    nausea / Early / 2.7-2.7
    acne vulgaris / Delayed / 0-1.0
    laryngitis / Delayed / Incidence not known
    rhinitis / Early / Incidence not known
    sinusitis / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    abdominal pain / 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 dose of baricitinib to 1 mg/day PO in patients receiving concomitant therapy with probenecid. For COVID-19 patients receiving baricitinib 4 mg/day PO, reduce dose to 2 mg/day PO. For COVID-19 patients receiving baricitinib 2 mg/day PO, reduce dose to 1 mg/day PO. For COVID-19 patients receiving baricitinib 1 mg/day PO, consider discontinuing probenecid. Coadministration of baricitinib and probenecid may result in increased baricitinib exposure. Baricitinib is an OAT3 substrate and probenecid is a strong OAT3 inhibitor. In a drug interaction study, administration of probenecid increased baricitinib exposure by 2-fold.
    Probenecid; Colchicine: (Major) Reduce the dose of baricitinib to 1 mg/day PO in patients receiving concomitant therapy with probenecid. For COVID-19 patients receiving baricitinib 4 mg/day PO, reduce dose to 2 mg/day PO. For COVID-19 patients receiving baricitinib 2 mg/day PO, reduce dose to 1 mg/day PO. For COVID-19 patients receiving baricitinib 1 mg/day PO, consider discontinuing probenecid. Coadministration of baricitinib and probenecid may result in increased baricitinib exposure. Baricitinib is an OAT3 substrate and probenecid is a strong OAT3 inhibitor. In a drug interaction study, administration of probenecid increased baricitinib exposure by 2-fold.
    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

    Sufficient data are not available to inform a drug-associated risk for major birth defects or miscarriage with the use of baricitinib during human pregnancy. In embryofetal animal studies, oral administration to rats and rabbits at exposures greater than 20 and 84 times the maximum recommended human dose (MRHD), respectively, resulted in reduced fetal body weights, increased embryolethality (rabbits only), and dose-related increases in skeletal malformations. Developmental toxicity was not observed in pregnant rats and rabbits treated with baricitinib at approximately 5 and 13 times the MRHD, respectively. In a pre- and post-development study in pregnant rats, oral baricitinib administration at exposures approximately 43 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 9 times the MRHD.[63229] COVID-19 per Emergency Use Authorization (EUA): Baricitinib should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and fetus. The NIH states that there is limited data available on the use of janus kinase (JAK) inhibitors, such as baricitinib, during pregnancy. Among 33 reported cases of JAK 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. Risks of use should be balanced against potential benefits.

    Because of the potential for serious adverse reactions in a nursing infant, breast-feeding during baricitinib therapy is not recommended. 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 hours in patients with rheumatoid arthritis (RA).[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.