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Baricitinib

Class: Disease-modifying Antirheumatic Drugs
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: 1173900-33-8
Brands: Olumiant

Medically reviewed on Jun 25, 2018

Warning

WARNING: SERIOUS INFECTIONS, MALIGNANCY, AND THROMBOSIS1

See full prescribing information for complete boxed warning. 1

  • Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving baricitinib.1

  • If a serious infection develops, interrupt baricitinib until the infection is controlled. 1

  • Prior to starting baricitinib, perform a test for latent tuberculosis; if it is positive, start treatment for tuberculosis prior to starting baricitinib. 1

  • Monitor all patients for active tuberculosis during treatment, even if the initial latent tuberculosis test is negative. 1

  • Lymphoma and other malignancies have been observed in patients treated with baricitinib. 1

  • Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, some fatal, have occurred in patients treated with baricitinib. Patients with symptoms of thrombosis should be evaluated promptly. 1

Introduction

See also: Kevzara

Baricitinib is a disease-modifying antirheumatic drug (DMARD).

Uses for Baricitinib

Baricitinib has the following uses:

Baricitinib is a Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.1

Baricitinib has the following limitation of use:

Use of baricitinib in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.1

Baricitinib Dosage and Administration

General

Baricitinib is available in the following dosage form(s) and strength(s):

Tablets (not scored): 2 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage & Administration

The recommended dose of baricitinib is 2 mg once daily.1

Baricitinib may be used as monotherapy or in combination with methotrexate or other DMARDs.1

Anemia: Avoid initiation or interrupt baricitinib in patients with hemoglobin less than 8 g/dL.1

Lymphopenia: Avoid initiation or interrupt baricitinib in patients with an Absolute Lymphocyte Count less than 500 cells/mm3.1

Neutropenia: Avoid initiation or interrupt baricitinib in patients with an Absolute Neutrophil Count less than 1000 cells/mm3.1

Cautions for Baricitinib

Contraindications

None. 1

Warnings/Precautions

Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving baricitinib. The most common serious infections reported with baricitinib included pneumonia, herpes zoster, and urinary tract infection. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, esophageal candidiasis, pneumocystosis, acute histoplasmosis, cryptococcosis, cytomegalovirus, and BK virus were reported with baricitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. 1

Avoid use of baricitinib in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating baricitinib in patients: 1

  • with chronic or recurrent infection 1

  • who have been exposed to tuberculosis 1

  • with a history of a serious or an opportunistic infection 1

  • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or 1

  • with underlying conditions that may predispose them to infection. 1

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with baricitinib. Interrupt baricitinib 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, the patient should be closely monitored, and baricitinib should be interrupted if the patient is not responding to therapy. Do not resume baricitinib until the infection is controlled. 1

Tuberculosis

Evaluate and test patients for latent or active infection prior to administration of baricitinib. Patients with latent tuberculosis (TB) should be treated with standard antimycobacterial therapy before initiating baricitinib. 1

Baricitinib should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of baricitinib in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection. Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient. 1

Monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy. 1

Viral Reactivation

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies with baricitinib. If a patient develops herpes zoster, interrupt baricitinib treatment until the episode resolves. 1

The impact of baricitinib on chronic viral hepatitis reactivation is unknown. Patients with evidence of active hepatitis B or 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. Perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy with baricitinib. 1

Malignancy and Lymphoproliferative Disorders

Consider the risks and benefits of baricitinib treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing baricitinib in patients who develop a malignancy. Malignancies were observed in clinical studies of baricitinib. 1

Non-melanoma Skin Cancers

Non-melanoma skin cancers (NMSCs) have been reported in patients treated with baricitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. 1

Thrombosis

Thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with baricitinib compared to placebo. In addition, arterial thrombosis events in the extremities have been reported in clinical studies with baricitinib. Many of these adverse events were serious and some resulted in death. There was no clear relationship between platelet count elevations and thrombotic events. Baricitinib should be used with caution in patients who may be at increased risk of thrombosis. If clinical features of DVT/PE or arterial thrombosis occur, patients should be evaluated promptly and treated appropriately. 1

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical studies with baricitinib, although the role of JAK inhibition in these events is not known. 1

Baricitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation. 1

Laboratory Abnormalities

Neutropenia

Treatment with baricitinib was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3) compared to placebo.

Avoid initiation or interrupt baricitinib treatment in patients with an ANC less than 1000 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. For recommended dosage modifications based on ANC, consult the manufacturer's labeling.1

Lymphopenia

ALC less than 500 cells/mm3 were reported in baricitinib clinical trials. Lymphocyte counts less than the lower limit of normal were associated with infection in patients treated with baricitinib, but not placebo.

Avoid initiation or interrupt baricitinib treatment in patients with an ALC less than 500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management. For recommended dosage modifications based on ALC results, consult the manufacturer's labeling. 1

Anemia

Decreases in hemoglobin levels to less than 8 g/dL were reported in baricitinib clinical trials. Avoid initiation or interrupt baricitinib treatment in patients with hemoglobin less than 8 g/dL. Evaluate at baseline and thereafter according to routine patient management. For recommended dosage modifications based on hemoglobin results, consult the manufacturer's labeling.1

Liver Enzyme Elevations

Treatment with baricitinib was associated with increased incidence of liver enzyme elevation compared to placebo. Increases to greater than or equal to 5 times and greater than or equal to 10 time the upper limit of normal (ULN) were observed for both ALT and AST in patients in baricitinib clinical trials.

Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in ALT or AST are observed and drug-induced liver injury is suspected, interrupt baricitinib until this diagnosis is excluded. 1

Lipid Elevations

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 baricitinib initiation.

Manage patients according to clinical guidelines for the management of hyperlipidemia. 1

Vaccinations

Avoid use of live vaccines with baricitinib. 1

Update immunizations in agreement with current immunization guidelines prior to initiating baricitinib therapy. 1

Specific Populations

Pregnancy

Risk Summary: The limited human data on use of baricitinib in pregnant women are not sufficient to inform a drug-associated risk for major birth defects or miscarriage. In animal embryo-fetal development studies, oral baricitinib administration to pregnant rats and rabbits at exposures equal to and greater than approximately 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. No developmental toxicity was observed in pregnant rats and rabbits treated with oral baricitinib during organogenesis at approximately 5 and 13 times the exposure at the MRHD, respectively. In a pre- and post-natal development study in pregnant female rats, oral baricitinib administration at exposures approximately 43 times the MRHD resulted in reduction in pup viability (increased incidence of stillborn pups and early neonatal deaths), decreased fetal birth weight, reduced fetal body weight gain, decreased cytotoxic T cells on post-natal day (PND) 35 with evidence of recovery by PND 65, and developmental delays that might be attributable to decreased body weight gain. No developmental toxicity was observed at an exposure approximately 9 times the exposure at the MRHD. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 1

Animal Data: In an embryofetal development study in pregnant rats dosed orally during the period of organogenesis from gestation days 6 to 17, baricitinib was teratogenic (skeletal malformations that consisted of bent limb bones and rib anomalies) at exposures equal to or greater than approximately 20 times the MRHD (on an AUC basis at maternal oral doses of 10 mg/kg/day and higher). No developmental toxicity was observed in rats at an exposure approximately 5 times the MRHD (on an AUC basis at a maternal oral dose of 2 mg/kg/day). In an embryofetal development study in pregnant rabbits dosed orally during the period of organogenesis from gestation days 7 to 20, embryolethality, decreased fetal body weights, and skeletal malformations (rib anomalies) were observed in the presence of maternal toxicity at an exposure approximately 84 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both early and late resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 12 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day). In a pre- and post-natal development study in pregnant female rats dosed orally from gestation day 6 through lactation day 20, adverse findings observed in pups included decreased survival from birth to post-natal day 4 (due to increased stillbirths and early neonatal deaths), decreased birth weight, decreased body weight gain during the pre-weaning phase, increased incidence of malrotated forelimbs during the pre-weaning phase, and decreased cytotoxic T cells on PND 35 with recovery by PND 65 at exposures approximately 43 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Developmental delays (that may be secondary to decreased body weight gain) were observed in males and females at exposures approximately 43 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). These findings included decreased forelimb and hindlimb grip strengths, and delayed mean age of sexual maturity. No developmental toxicity was observed in rats at an exposure approximately 9 times the MRHD (on an AUC basis at a maternal oral dose of 5 mg/kg/day).1

Lactation

No information is available on the presence of baricitinib in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Baricitinib is present in the milk of lactating rats. Due to species-specific differences in lactation physiology, the clinical relevance of these data are not clear. Because of the potential for serious adverse reactions in nursing infants, advise an baricitinib-treated woman not to breastfeed. 1

A single oral dose of 25 mg/kg radiolabeled baricitinib was administered to lactating female Sprague-Dawley rats on post-partum day 13. Drug exposure was approximately 45-fold greater in milk than in plasma based on AUC0-t values. 1

Pediatric Use

The safety and effectiveness of baricitinib in pediatric patients have not been established. 1

Geriatric Use

Of the 3100 patients treated in the four phase 3 studies, a total of 537 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 1

Baricitinib is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.1

Hepatic Impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment. The use of baricitinib has not been studied in patients with severe hepatic impairment and is therefore not recommended. 1

Renal Impairment

Renal function was found to significantly affect baricitinib exposure. Baricitinib is not recommended for use in patients with estimated GFR of less than 60 mL/min/1.73 m2 . 1

Common Adverse Effects

Adverse reactions (greater than or equal to 1%) include: upper respiratory tract infections, nausea, herpes simplex, and herpes zoster.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Baricitinib is not recommended in patients taking strong organic anion transporter 3 (OAT3) inhibitors (e.g., probenecid).1

Actions

Mechanism of Action

Baricitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Baricitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. 1

JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In cell-free isolated enzyme assays, baricitinib had greater inhibitory potency at JAK1, JAK2 and TYK2 relative to JAK3. In human leukocytes, baricitinib inhibited cytokine induced STAT phosphorylation mediated by JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 with comparable potencies. However, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. 1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide). 1

Patient Counseling

Advise patients of the potential benefits and risks of baricitinib. 1

Infections

Inform patients that they may be more likely to develop infections when taking baricitinib. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of an infection. 1

Advise patients that the risk of herpes zoster is increased in patients treated with baricitinib and some cases can be serious. 1

Malignancies and Lymphoproliferative Disorders

Inform patients that baricitinib may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking baricitinib. Instruct patients to inform their healthcare provider if they have ever had any type of cancer. 1

Thrombosis

Advise patients that events of DVT and PE have been reported in clinical studies with baricitinib. Instruct patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE. 1

Laboratory Abnormalities

Inform patients that baricitinib may affect certain lab tests, and that blood tests are required before and during baricitinib treatment. 1

Lactation

Advise a woman not to breastfeed during treatment with baricitinib. 1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

Baricitinib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

2 mg

Olumiant

Eli Lilly and Company

AHFS Drug Information. © Copyright 2018, Selected Revisions June 25, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Eli Lilly and Company. Olumiant (baricitinib) ORAL prescribing information. 2018 May. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=866e9f35-9035-4581-a4b1-75a621ab55cf

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