brepocitinib

5 WARNINGS AND PRECAUTIONS Serious Infections: Avoid use of LISRAYA during an active serious infection, including localized infections. ( 5.1 ) Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported. Discontinue LISRAYA if a clinically significant hypersensitivity reaction occurs. ( 5.6 ) Gastrointestinal (GI) Perforations: Monitor patients at risk for GI perforations and promptly evaluate patients with symptoms. ( 5.7 ) Hypoglycemia in Patients with Diabetes: Consider increased monitoring of blood glucose. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia. ( 5.8 ) Laboratory Abnormalities: Monitor lymphocyte counts, neutrophil counts, hemoglobin, liver enzymes, including GGT, and lipids during LISRAYA treatment. ( 5.9 ) Immunizations: Avoid use with live vaccines. ( 5.10 ) Embryofetal Toxicity: Based on animal studies, LISRAYA may cause fetal harm. Advise female patients of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.11 , 8.1 , 8.3 ) 5.1 Serious Infections LISRAYA increases the risk of infections, including serious bacterial, fungal, viral, and opportunistic infections that may lead to hospitalization or death. The most common serious infections reported with LISRAYA were pneumonia and sepsis [see Adverse Reactions ( 6.1 )]. Other reported infections with use of JAK inhibitors, including LISRAYA, were tuberculosis, which may present with pulmonary or extrapulmonary disease, invasive fungal infections which may present with disseminated rather than localized disease, bacterial infections, viral infections (including herpes zoster), and other infections due to opportunistic pathogens. Avoid use of LISRAYA in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating LISRAYA in patients: with chronic or recurrent infection who have been exposed to TB with a history of a serious or an opportunistic infection who have resided or traveled in areas of endemic TB or endemic mycoses; or with underlying conditions that may predispose them to infection. Closely monitor patients for signs and symptoms of infection during and after treatment with LISRAYA. If a patient develops a serious infection, including a serious opportunistic infection, interrupt LISRAYA treatment until the infection resolves or is adequately treated. In patients who develop a new infection during treatment with LISRAYA, promptly complete diagnostic testing, initiate appropriate antimicrobial therapy, and monitor the patients closely. LISRAYA may be resumed once the infection resolves or is adequately treated. Tuberculosis Evaluate and test patients for latent and active TB infection prior to and during administration of LISRAYA. If positive, treat for TB prior to LISRAYA treatment. Consider anti-TB therapy prior to initiation of LISRAYA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. 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, including patients who tested negative for latent TB infection prior to LISRAYA treatment, for signs and symptoms of active TB during LISRAYA treatment. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) were reported in patients who received LISRAYA. If a patient develops herpes zoster, consider interrupting LISRAYA until the episode resolves. Prior to initiating LISRAYA treatment, perform viral hepatitis screening in accordance with clinical guidelines. Monitor patients for viral hepatitis reactivation during therapy with LISRAYA. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA were excluded from clinical trials. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical trials. If hepatitis B virus DNA is detected during LISRAYA treatment, consult a liver specialist. LISRAYA is not recommended in patients with active hepatitis B or hepatitis C. 5.2 Mortality In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with rheumatoid arthritis (RA) 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers. Consider the benefits and risks for the individual patient prior to initiating or continuing LISRAYA treatment. LISRAYA is not approved for the treatment of RA. 5.3 Malignancy and Lymphoproliferative Disorders Malignancies were observed in clinical trials of LISRAYA. In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with RA, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]) and lymphomas were observed in patients 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 study, current or past smokers had an additional increased risk of overall malignancies. LISRAYA is not approved for the treatment of RA. Consider the benefits and risks for the individual patient prior to initiating or continuing LISRAYA treatment, particularly in patients with a known malignancy (other than a successfully treated NMSC) and patients who develop a malignancy during treatment with LISRAYA. Advise patients to limit exposure to ultraviolet (UV) light (natural or artificial) by wearing protective clothing and using a broad-spectrum sunscreen. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. 5.4 Major Adverse Cardiovascular Events Major adverse cardiovascular events (MACE), defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, were observed in patients treated with LISRAYA during clinical trials. In the dermatomyositis clinical trial, referred to as “Trial DM,” inclusive of open-label treatment, adjudicated MACE occurred in 3 patients (1.1 per 100 patient-years) treated with LISRAYA. In a large, randomized, postmarketing safety study of another JAK inhibitor in patients with RA 50 years of age and older with at least one cardiovascular risk factor, a higher rate of MACE 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. LISRAYA is not approved for the treatment of RA. Consider the benefits and risks for the individual patient prior to initiating or continuing LISRAYA treatment, 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 LISRAYA in patients who have experienced a myocardial infarction or stroke. 5.5 Thrombosis Thromboses, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including LISRAYA. Many of these adverse reactions were serious and some resulted in death. In a large, randomized, postmarketing safety study of another JAK inhibitor in patients 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. LISRAYA is not approved for the treatment of RA. Avoid LISRAYA in patients who may be at increased risk of thrombosis. If a patient develops symptoms of thrombosis, discontinue LISRAYA, promptly evaluate, and appropriately treat. 5.6 Hypersensitivity Reactions Hypersensitivity reactions were reported in patients who received LISRAYA. Some events were serious. If a clinically significant hypersensitivity reaction occurs, discontinue LISRAYA, and institute appropriate therapy. 5.7 Gastrointestinal Perforations Gastrointestinal perforation has been reported in patients treated with JAK inhibitors, including LISRAYA. Monitor LISRAYA-treated patients who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis and those taking concomitant drugs that increases the risk for gastrointestinal perforation, including NSAIDs or corticosteroids). If a patient presents with new onset abdominal pain during LISRAYA treatment, promptly evaluate for gastrointestinal perforation. 5.8 Hypoglycemia in Patients with Diabetes LISRAYA may cause hypoglycemia in patients with diabetes. Hypoglycemia, including severe hypoglycemia, has been reported following initiation of JAK inhibitors in patients with diabetes. During treatment with LISRAYA, consider increased monitoring of blood glucose as clinically indicated in patients with diabetes. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia. 5.9 Laboratory Abnormalities Neutropenia Treatment with LISRAYA was associated with an increased incidence of neutropenia (i.e., ANC less than 1,000 cells/mm 3 ). Evaluate neutrophil counts at baseline and thereafter according to routine patient management. Avoid LISRAYA initiation, and interrupt LISRAYA treatment in patients with a low neutrophil count (i.e., ANC less than 1,000 cells/mm 3 ) [see Dosage and Administration ( 2.1 )]. Lymphopenia ALC less than 500 cells/mm 3 were reported in patients who received LISRAYA. Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid LISRAYA initiation or interrupt LISRAYA treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm 3 ) [see Dosage and Administration ( 2.1 )]. Anemia Decreases in hemoglobin levels less than 8 g/dL were reported in LISRAYA-treated patients in clinical trials. Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid LISRAYA initiation or interrupt LISRAYA treatment in patients with a low hemoglobin level (i.e., less than 8 g/dL) [see Dosage and Administration ( 2.1 )] . Lipids Treatment with LISRAYA was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol [see Adverse Reactions ( 6.1 )] . The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined. Assess lipid parameters approximately 12 weeks after initiation of LISRAYA treatment. Manage patients according to clinical guidelines for hyperlipidemia. Liver Enzyme Elevations Treatment with LISRAYA was associated with increased incidence of liver enzyme elevations compared to treatment with placebo. Evaluate liver enzymes, including AST, ALT, and gamma-glutamyl transferase (GGT), at baseline and according to routine patient management thereafter. In patients with dermatomyositis, elevations in AST and ALT may reflect underlying dermatomyositis disease activity, and therefore, it is important to obtain GGT. Promptly evaluate the cause of liver enzyme elevation to identify potential cases of drug-induced liver injury (DILI). If increases in ALT or AST are observed during routine patient management and DILI is suspected, interrupt LISRAYA treatment until DILI is excluded. 5.10 Immunizations Avoid use of live vaccines immediately prior to and during LISRAYA treatment. Prior to initiating LISRAYA treatment, update immunizations, including prophylactic varicella zoster or herpes zoster vaccinations, according to current immunization guidelines. 5.11 Embryofetal Toxicity Based on findings in animal studies, LISRAYA may cause fetal harm when administered to a pregnant woman. Administration of brepocitinib to pregnant rats and rabbits at exposures 1.6 and 3 times the exposure at the maximum recommended human dose (MRHD), respectively, during organogenesis resulted in fetal skeletal malformations and increased post-implantation loss. Verify the pregnancy status of females of reproductive potential prior to starting treatment. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LISRAYA and for 3 days following the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

4 CONTRAINDICATIONS LISRAYA is contraindicated in patients with a history of hypersensitivity reactions to brepocitinib or any of the excipients in LISRAYA [see Warnings and Precautions ( 5.6 )] . LISRAYA is contraindicated in patients with a history of hypersensitivity reactions to brepocitinib or any of the excipients in LISRAYA. ( 4 )

10 OVERDOSAGE There is no specific antidote for overdose with LISRAYA. If an overdose of LISRAYA occurs, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for overdose management recommendations.