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Baricitinib

Class: Disease-modifying Antirheumatic Drugs
- JAK Inhibitor
- Janus Kinase Inhibitor
Chemical Name: 2-[1-ethylsulfonyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]azetidin-3-yl]acetonitrile
Molecular Formula: C16H17N7O2S
CAS Number: 1187594-09-7
Brands: Olumiant

Medically reviewed by Drugs.com on Aug 5, 2019. Written by ASHP.

Warning

    Serious Infections
  • Serious, sometimes fatal infections including tuberculosis (pulmonary or extrapulmonary disease), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections reported. (See Infectious Complications under Cautions.)

  • Carefully consider risks and benefits prior to initiating baricitinib therapy in patients with chronic or recurring infections.

  • Evaluate patients for latent tuberculosis infection prior to and periodically during treatment; if indicated, initiate appropriate antimycobacterial regimen prior to initiating baricitinib therapy.

  • Closely monitor patients for infection, including active tuberculosis in those with a negative test for latent tuberculosis, during and after treatment. If serious infection develops, interrupt baricitinib therapy until infection is controlled.

    Malignancies
  • Lymphoma and other malignancies reported. (See Malignancies and Lymphoproliferative Disorders under Cautions.)

    Thrombosis
  • Serious, sometimes fatal thromboembolic events, including DVT, PE, and arterial thrombosis, reported. Promptly evaluate patients with symptoms of thrombosis. (See Thromboembolic Events under Cautions.)

Introduction

Immunomodulating agent and disease-modifying antirheumatic drug (DMARD); Janus kinase (JAK) inhibitor.

Uses for Baricitinib

Rheumatoid Arthritis in Adults

Management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response to ≥1 tumor necrosis factor (TNF) blocking agents; can be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, sulfasalazine).

Concomitant use with other JAK inhibitors (e.g., tofacitinib) or biologic DMARDs, such as TNF blocking agents (e.g., adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), selective costimulation modulators (e.g., abatacept), and anti-interleukin-6-receptor monoclonal antibodies (e.g., sarilumab, tocilizumab), not recommended.

Concomitant use with potent immunosuppressive agents (e.g., azathioprine, cyclosporine) also not recommended.

Baricitinib Dosage and Administration

General

  • Do not initiate therapy in patients with absolute lymphocyte count <500/mm3, ANC <1000/mm3, or hemoglobin concentration <8 g/dL.

  • Evaluate patients for latent tuberculosis infection prior to initiation of therapy and consider appropriate antimycobacterial treatment if indicated. Do not use in patients with active tuberculosis or other serious active infection. (See Infectious Complications under Cautions.)

Concomitant Therapy

  • Do not use concomitantly with other JAK inhibitors, biologic DMARDs, or potent immunosuppressive agents. (See Rheumatoid Arthritis in Adults under Uses.)

Restricted Distribution

Obtain through specialty pharmacies. Consult the Olumiant website ([Web]) for specific ordering and availability information.

Administration

Oral Administration

Administer orally without regard to food.

Dosage

Adults

Rheumatoid Arthritis
Oral

2 mg once daily.

Treatment Interruption for Toxicity
Treatment Interruption for Infection

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

Treatment Interruption for Hematologic Toxicity

If absolute lymphocyte count <500/mm3, interrupt treatment until lymphocyte count ≥500/mm3, then resume baricitinib 2 mg daily.

If ANC <1000/mm3, interrupt treatment until ANC ≥1000/mm3, then resume baricitinib 2 mg daily.

If hemoglobin concentration <8 g/dL, interrupt treatment until hemoglobin concentration ≥8 g/dL, then resume baricitinib 2 mg daily.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: No dosage adjustment needed.

Severe hepatic impairment: Not studied; use not recommended.

Renal Impairment

Mild renal impairment: No dosage adjustment needed.

Moderate to severe renal impairment (eGFR <60 mL/minute per 1.73 m2): Use not recommended.

Geriatric Patients

No dosage adjustment needed based on age. Select dosage with caution because of possible age-related decrease in renal function.

Other Special Populations

Dosage adjustment based on body weight, ethnicity, or gender not required.

Cautions for Baricitinib

Contraindications

  • Manufacturer states none known.

Warnings/Precautions

Warnings

Infectious Complications

Serious, sometimes fatal infections (including pneumonia, urinary tract infection, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus infection, and BK virus infection) reported, particularly in patients receiving concomitant therapy with immunosuppressive agents (e.g., methotrexate, corticosteroids). Infections may be disseminated.

Do not initiate baricitinib in patients with serious active infections, including localized infections. Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses are endemic.

Closely monitor patients during and after treatment with baricitinib for the development of signs or symptoms of infection. If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient. If infection fails to respond to anti-infective therapy or if serious infection, opportunistic infection, or sepsis develops, interrupt baricitinib treatment until the infection is controlled.

Evaluate all patients for active or latent tuberculosis prior to and periodically during therapy. Do not use in patients with active tuberculosis. When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to baricitinib therapy. Consider initiation of antimycobacterial therapy prior to initiation of baricitinib in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis. Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.

Monitor all patients, including those with a negative test for latent tuberculosis, for active tuberculosis.

Viral reactivation, including herpes zoster reactivation, reported. If herpes zoster reactivation occurs, interrupt baricitinib treatment until the episode is resolved.

Effect on risk of reactivation of chronic viral hepatitis not known; patients with evidence of HBV or HCV infection were excluded from clinical trials. Screen all patients for viral hepatitis in accordance with current standards of care prior to baricitinib therapy. Patients testing positive for hepatitis C antibody but negative for HCV RNA may receive baricitinib. Patients testing positive for hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc) but negative for hepatitis B surface antigen (HBsAg) also may receive baricitinib but should be monitored for expression of HBV DNA; consultation with liver disease experts is recommended if HBV DNA is detected.

Malignancies and Lymphoproliferative Disorders

Lymphoma and other malignancies observed.

Consider risks and benefits of baricitinib prior to initiating therapy in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer) or when considering whether to continue baricitinib in patients who develop a malignancy.

Periodic dermatologic examinations recommended for patients at increased risk for skin cancer.

Thromboembolic Events

Serious, sometimes fatal thromboembolic events (e.g., DVT, PE, arterial thrombosis in the extremities) reported. Relationship between platelet count elevation and thromboembolic events not established. (See Hematologic Effects under Cautions.)

Use with caution in patients at increased risk of thrombosis. Promptly evaluate all patients with signs or symptoms suggestive of DVT, PE, or arterial thrombosis and initiate treatment as appropriate.

Other Warnings and Precautions

GI Perforation

GI perforation reported; role of JAK inhibition by baricitinib not known.

Use with caution in patients at increased risk for GI perforation (e.g., patients with history of diverticulitis). Promptly evaluate patients with new-onset abdominal symptoms for early identification of GI perforation.

Hematologic Effects

Possible lymphopenia, neutropenia, and anemia. May require interruption of baricitinib therapy (see Treatment Interruption for Hematologic Toxicity under Dosage and Administration).

Lymphocyte counts below the lower limit of normal associated with increased incidence of infections.

Dose-related increases in platelet count observed; relationship between platelet count elevation and thromboembolic events not established. (See Thromboembolic Events under Cautions.)

Do not initiate baricitinib in patients with lymphocyte count <500/mm3, ANC <1000/mm3, or hemoglobin concentration <8 g/dL.

Monitor lymphocyte count, ANC, and hemoglobin concentrations at baseline and periodically during treatment.

Hepatic Effects

Elevated hepatic enzyme concentrations reported.

Monitor liver function tests at baseline and periodically during treatment. In case of elevations, promptly evaluate patient for drug-induced hepatotoxicity. If drug-induced hepatic injury is suspected, interrupt baricitinib therapy until such diagnosis excluded.

Effects on Serum Lipids

Dose-related increases in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride concentrations reported. Ratio of LDL-cholesterol to HDL-cholesterol not substantially affected. Increases observed at 12 weeks of therapy and remained stable thereafter.

Measure lipid concentrations approximately 12 weeks after initiation of therapy. Manage dyslipidemia according to current standards of care.

Immunization

Avoid live vaccines. Update immunizations according to current administration guidelines prior to initiation of baricitinib.

Specific Populations

Pregnancy

No adequate data in pregnant women.

Skeletal malformations, reduced fetal body weight, and embryolethality observed in animal studies at exposures ≥20 times the exposure at the maximum recommended human dosage. No evidence of developmental toxicity at exposures 5–13 times the exposure at the maximum recommended human dosage.

Lactation

Distributed into milk in rats; not known whether baricitinib distributes into human milk, affects nursing infants, or affects milk production. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out. Select dosage with caution because of age-related decreases in renal function; consider monitoring renal function.

Hepatic Impairment

Systemic exposure not substantially affected by moderate hepatic impairment. Dosage adjustment not necessary for mild or moderate hepatic impairment.

Not studied in patients with severe hepatic impairment; use not recommended.

Renal Impairment

Dosage adjustment not necessary in patients with mild renal impairment.

Not recommended in patients with moderate to severe renal impairment (eGFR <60 mL/minute per 1.73 m2). (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Upper respiratory tract infection, nausea, herpes simplex, herpes zoster.

Interactions for Baricitinib

Substrate for organic anion transporter (OAT) 3, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug and toxin extrusion transporter (MATE) 2K in vitro.

Substrate for CYP3A4 in vitro; however, no clinically important pharmacokinetic interactions observed with index CYP3A inducers or inhibitors.

Does not inhibit or induce CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A in vitro. Also does not inhibit P-gp or organic anion transporting polypeptide (OATP) 1B1 in vitro.

Inhibits OAT1, OAT2, OAT3, organic cation transporter (OCT) 1, OCT2, OATP1B3, BCRP, MATE1, and MATE2K in vitro; however, clinically important changes in the pharmacokinetics of substrates of these transporters are unlikely.

Drugs Affecting Organic Anion Transport

Potent OAT3 inhibitors: Substantial increase in baricitinib exposure. Concomitant use not recommended.

Less-potent OAT3 inhibitors (i.e., less potent than probenecid): Clinically important pharmacokinetic interactions not expected. Dosage adjustment not required.

Immunosuppressive Agents

Possible increased risk of serious infection. Concomitant use with potent immunosuppressive agents not recommended.

Vaccines

Avoid live vaccines.

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles (e.g., fluconazole, ketoconazole)

No clinically important effect on pharmacokinetics of baricitinib

Dosage adjustment of baricitinib not necessary

Azathioprine

Possible increased risk of serious infection

Concomitant use not recommended

Contraceptives, oral

No clinically important effects on pharmacokinetics of ethinyl estradiol or levonorgestrel

Cyclosporine

Possible increased risk of serious infection

No clinically important effect on pharmacokinetics of baricitinib

Concomitant use not recommended

Diclofenac

Clinically important pharmacokinetic interactions not expected

No dosage adjustment required

Digoxin

No clinically important effect on pharmacokinetics of digoxin

Dosage adjustment of digoxin not necessary

DMARDs, biologic (e.g., TNF blocking agents)

Concomitant use not recommended

Ibuprofen

Clinically important pharmacokinetic interactions not expected

No dosage adjustment required

Methotrexate

No clinically important effect on pharmacokinetics of either drug

Dosage adjustments not necessary

Omeprazole

No clinically important effect on pharmacokinetics of baricitinib

Dosage adjustment of baricitinib not necessary

Probenecid

Approximately twofold increase in AUC of baricitinib

Concomitant use not recommended

Rifampin

No clinically important effect on pharmacokinetics of baricitinib

Dosage adjustment of baricitinib not necessary

Simvastatin

No clinically important effect on pharmacokinetics of simvastatin

Dosage adjustment of simvastatin not necessary

Baricitinib Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained approximately 1 hour following oral administration.

Steady-state concentrations attained in 2–3 days following once-daily dosing, with minimal accumulation.

Absolute oral bioavailability is approximately 80%.

Food

High-fat meal delays time to peak plasma concentration by 0.5 hours and reduces AUC and peak plasma concentrations by 11 and 18%, respectively; not considered clinically important.

Special Populations

Mild, moderate, or severe renal impairment increased AUC by 1.41-, 2.22-, or 4.05-fold, respectively; in individuals with end-stage renal disease receiving hemodialysis, AUC increased by 2.41-fold.

Moderate hepatic impairment does not substantially increase AUC.

Age, gender, body weight, and race do not affect pharmacokinetics.

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.

Plasma Protein Binding

Approximately 50% bound to plasma proteins and 45% bound to serum proteins.

Elimination

Metabolism

Minimal metabolism; mediated by CYP3A4.

Elimination Route

Eliminated principally by renal filtration and active secretion.

Excreted as unchanged drug in urine (69%) and feces (15%). Approximately 6% of a dose eliminated as metabolites.

Half-life

Approximately 12 hours in patients with rheumatoid arthritis.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

  • Inhibits JAK1 and JAK2 and, to a lesser extent, tyrosine kinase 2 (TYK2) relative to JAK3. JAKs mediate signaling of cytokines and growth factors important for hematopoiesis and immune function.

  • Binding of cytokines to receptors on the cell surface activates pairing of JAKs (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2), which leads to phosphorylation and subsequent localization of signal transducer and activator of transcription (STAT) proteins to the nucleus and modulation of gene expression. Baricitinib prevents phosphorylation and activation of STATs.

  • Inhibits cytokine-induced STAT phosphorylation mediated by JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 combinations with comparable potencies; relevance of inhibition of specific JAKs to therapeutic efficacy not known.

  • Causes dose-dependent inhibition of IL-6-induced STAT3 phosphorylation in whole blood of healthy individuals. Maximal inhibition observed approximately 1 hour after dosing; activity returns to near baseline by 24 hours.

  • Mean serum IgG, IgM, and IgA concentrations decrease within 12 weeks of initiation of baricitinib (but generally remain within normal reference ranges) and remain stable throughout treatment. Decreases in C-reactive protein (CRP) concentrations observed as early as 1 week in patients with rheumatoid arthritis and are maintained throughout treatment.

Advice to Patients

  • Importance of advising patients about potential benefits and risks of baricitinib. Importance of patients reading the medication guide prior to initiation of therapy and each time the prescription is refilled.

  • Increased susceptibility to infection. Risk of herpes zoster, which may be serious. Importance of promptly informing clinicians if any signs or symptoms of infection (e.g., fever, sweating, chills, myalgia, cough, dyspnea, fatigue, diarrhea, dysuria, erythema) develop.

  • Risk of lymphoma and other malignancies.

  • Risk of thromboembolic events. Importance of contacting clinicians if symptoms of thromboembolism (e.g., shortness of breath; chest pain; swelling, pain, or tenderness in the leg) develop.

  • Risk of GI perforation. Importance of promptly notifying clinicians of persistent fever and abdominal pain or changes in bowel function.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or any history of cancer, thromboembolism, diverticulitis, gastric or intestinal ulcers, tuberculosis, HBV or HCV infection, or other chronic or recurring infections.

  • Importance of periodic laboratory monitoring.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution is restricted. (See Restricted Distribution under Dosage and Administration.)

Baricitinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2 mg

Olumiant

Lilly

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 5, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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