Deuruxolitinib Phosphate

5 WARNINGS AND PRECAUTIONS Increased Risk of LEQSELVI-Associated Serious Adverse Reactions in CYP2C9 Poor Metabolizers or with Concomitant Use of Moderate or Strong CYP2C9 Inhibitors : LEQSELVI is contraindicated in patients who are CYP2C9 poor metabolizers or patients taking a moderate or strong CYP2C9 inhibitor. ( 5.6 ) Gastrointestinal Perforations: Monitor patients who may be at increased risk for gastrointestinal perforation. Evaluate promptly patients presenting with new onset abdominal symptoms. ( 5.7 ) Lipid Elevations, Anemia, Neutropenia, and Lymphopenia: Monitor for changes in lipids, hemoglobin, neutrophils, and lymphocytes. ( 5.8 ) Immunizations: Avoid use of live vaccines during or immediately prior to LEQSELVI treatment. ( 5.9 ) 5.1 Serious Infections Serious infections have been reported in subjects with alopecia areata receiving LEQSELVI [see Adverse Reactions ( 6.1 )] . Avoid use of LEQSELVI in patients with an active, serious infection including localized infections. Prior to LEQSELVI treatment, consider the risks and benefits in patients: with chronic or recurrent infection who have been exposed to tuberculosis with a history of a serious or opportunistic infection who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or with underlying conditions that may predispose them to infection Closely monitor patients for the development of signs and symptoms of infection during and after treatment with LEQSELVI. If the patient develops a serious infection, interrupt treatment with LEQSELVI until the infection resolves or is adequately treated. If a patient develops a new infection during treatment with LEQSELVI, initiate complete diagnostic testing appropriate for an immunocompromised patient and appropriate antimicrobial therapy. Tuberculosis Evaluate patients for latent and active tuberculosis (TB) infection prior to LEQSELVI treatment. LEQSELVI is not recommended for use in patients with active TB. Treat patients with latent TB before LEQSELVI treatment. Consider anti-TB therapy prior to LEQSELVI treatment in patients with previously untreated latent TB 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. Monitor patients receiving LEQSELVI for signs and symptoms of active TB during treatment, including patients who tested negative for latent TB infection prior to treatment. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were reported in clinical trials with LEQSELVI [see Adverse Reactions ( 6.1 )] . If a patient develops herpes zoster, consider interrupting LEQSELVI treatment until the episode resolves. The impact of LEQSELVI on chronic viral hepatitis reactivation is unknown. Subjects with positive results for hepatitis B surface antigens (HBsAg), antibodies to hepatitis B core antigens (anti-HBc), or hepatitis C virus (HCV) with detectable HCV RNA at screening were excluded from LEQSELVI clinical trials. Perform screening for viral hepatitis before treatment with LEQSELVI. LEQSELVI is not recommended for use in patients with active hepatitis B or hepatitis C (HCV RNA detected). If non-active hepatitis B infection is discovered, monitoring for reactivation or prophylactic treatment is recommended. Follow hepatitis B clinical guidelines or refer to a liver specialist. Hepatitis B viral load (HBV-DNA titer) increase, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, has been reported in subjects with chronic HBV infections receiving JAK inhibitors used to treat inflammatory conditions. The effect of LEQSELVI on viral replication in patients with chronic HBV infection is unknown. 5.2 Mortality In a large, randomized, postmarketing safety trial of another JAK inhibitor in rheumatoid arthritis (RA) subjects 50 years and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in subjects treated with the JAK inhibitor compared with TNF blockers. Consider the benefits and risks for the individual patient prior to and during treatment with LEQSELVI. 5.3 Malignancy and Lymphoproliferative Disorders Malignancies were observed in clinical trials of LEQSELVI [see Adverse Reactions 6.1 )] . In a large, randomized, postmarketing safety trial of another JAK inhibitor in subjects with RA, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in subjects treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in subjects treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this trial, current or past smokers had an additional increased risk of overall malignancies. Consider the benefits and risks for the individual patient prior to and during treatment with LEQSELVI, particularly in patients with a known malignancy (other than successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers. Non-melanoma skin cancers Non-melanoma skin cancers (NMSCs) have been reported in patients treated with LEQSELVI. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. 5.4 Major Adverse Cardiovascular Events (MACE) In a large, randomized, postmarketing safety trial of another JAK inhibitor in subjects with RA 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Consider the benefits and risks for the individual patient prior to and during treatment with LEQSELVI, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue LEQSELVI in patients that have experienced a myocardial infarction or stroke. 5.5 Thrombosis Thrombosis, including pulmonary embolism (PE), deep vein thrombosis (DVT) and cerebral venous sinus thrombosis (CVT) have been reported in clinical trials of deuruxolitinib [see Adverse Reactions ( 6.1 )] . There was no clear relationship between platelet count elevations and thrombotic events. Thrombosis, including DVT, PE, and arterial thrombosis have been reported in subjects receiving JAK inhibitors used to treat inflammatory conditions. Many of these adverse reactions were serious and some resulted in death. In a large, randomized, postmarketing safety trial of another JAK inhibitor in subjects with RA 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers. Avoid LEQSELVI in patients who may be at increased risk of thrombosis. If symptoms of thrombosis occur, discontinue LEQSELVI and evaluate and treat patients appropriately. 5.6 Increased Risk of LEQSELVI-Associated Serious Adverse Reactions in CYP2C9 Poor Metabolizers or with Concomitant Use of Moderate or Strong CYP2C9 Inhibitors Higher plasma concentrations of deuruxolitinib, which may increase the risk of LEQSELVI-associated serious adverse reactions such as thrombosis, may occur when LEQSELVI is used in patients who: Are CYP2C9 poor metabolizers [see Use in Specific Populations ( 8.8 ) and Clinical Pharmacology ( 12.5 )] . Are on a concomitant moderate or strong CYP2C9 inhibitor [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )] . Prior to LEQSELVI treatment, test patients for CYP2C9 variants to determine if they are poor metabolizers [see Dosage and Administration ( 2.1 )] . An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of LEQSELVI is not currently available. LEQSELVI is contraindicated in patients who are CYP2C9 poor metabolizers or patients who are on concomitant moderate or strong CYP2C9 inhibitors [see Contraindications ( 4 )] . 5.7 Gastrointestinal Perforations Gastrointestinal perforations have been reported in clinical trials with LEQSELVI. Monitor patients treated with LEQSELVI who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Evaluate promptly patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation. 5.8 Lipid Elevations, Anemia, Neutropenia, and Lymphopenia Perform a CBC prior to and periodically during treatment with LEQSELVI [see Dosage and Administration ( 2.1 )] . Lipid Elevations Treatment with LEQSELVI was associated with increases in triglycerides and total cholesterol, including HDL-C and LDL-C [see Adverse Reactions 6.1 )] . The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Perform assessment of lipid parameters at baseline and periodically during treatment with LEQSELVI. Manage patients according to clinical guidelines for hyperlipidemia. Anemia Treatment with LEQSELVI was associated with an increased incidence of anemia (hemoglobin less than 8 g/dL) compared to placebo [see Adverse Reactions ( 6.1 )] . Avoid or interrupt LEQSELVI treatment in patients with hemoglobin less than 8 g/dL [see Dosage and Administration ( 2.3 )] . Neutropenia Treatment with LEQSELVI was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm 3 ) compared to placebo [see Adverse Reactions ( 6.1 )] . Avoid or interrupt LEQSELVI treatment in patients with an ANC less than 1,000 cells/mm 3 [see Dosage and Administration ( 2.3 )] . Lymphopenia Treatment with LEQSELVI was associated with an increased incidence of lymphopenia (ALC less than 500 cells/mm 3 ) compared to placebo [see Adverse Reactions ( 6.1 )] . Avoid or interrupt LEQSELVI treatment in patients with an ALC less than 500 cells/mm 3 [see Dosage and Administration ( 2.3 )] . 5.9 Immunizations Prior to LEQSELVI treatment, complete all necessary immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in accordance with current immunization guidelines. Avoid use of live vaccines during or immediately prior to LEQSELVI treatment.