LEQSELVI

1 INDICATIONS AND USAGE LEQSELVI™ is indicated for the treatment of adult patients with severe alopecia areata. Limitations of Use LEQSELVI is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine, or other potent immunosuppressants. LEQSELVI is a Janus kinase (JAK) inhibitor indicated for the treatment of adults with severe alopecia areata. ( 1 ) Limitations of Use: LEQSELVI is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants. ( 1 )

2 DOSAGE AND ADMINISTRATION For recommended testing, evaluations, and procedures prior to and during LEQSELVI treatment, see Full Prescribing Information. ( 2.1 ) Recommended dosage is 8 mg twice daily. ( 2.2 ) For treatment interruption for certain adverse reactions, see Full Prescribing Information. ( 2.3 ) 2.1 Recommended Evaluations and Immunizations Prior to and During Treatment Perform the following prior to treatment with LEQSELVI: CYP2C9 genotype determination: Test patients for CYP2C9 variants to determine CYP2C9 genotype. LEQSELVI is contraindicated in patients who are CYP2C9 poor metabolizers (patients with decreased cytochrome P450 (CYP) 2C9 function) [see Contraindications ( 4 )] . An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of LEQSELVI is not currently available. Evaluation for use of concomitant CYP2C9 inhibitors: LEQSELVI is contraindicated in patients taking moderate or strong CYP2C9 inhibitors [see Warnings and Precautions ( 5.6 )] . Active and latent tuberculosis (TB) evaluation: LEQSELVI treatment is not recommended in patients with active TB. For patients with latent TB or those with a negative latent TB test who are at high risk of TB, start preventive therapy for TB prior to LEQSELVI treatment [ see Warnings and Precautions ( 5.1 ) ]. Viral hepatitis screening in accordance with clinical guidelines: LEQSELVI treatment is not recommended in patients with active hepatitis B or hepatitis C. Hepatitis B infection screening: If hepatitis B infection is discovered, follow hepatitis B clinical guidelines, or refer to a liver specialist. Monitor patients for reactivation in accordance with clinical guidelines during treatment [ see Warnings and Precautions ( 5.1 ) ]. Complete blood count (CBC): LEQSELVI treatment is not recommended in patients with an absolute lymphocyte count (ALC) <500 cells/mm 3 absolute neutrophil count (ANC) <1,000 cells/mm 3 , or hemoglobin level <8 g/dl. Monitor complete blood counts periodically during treatment and modify dosage as recommended [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.8 )] . Complete any necessary immunizations, including herpes zoster vaccinations, according to current immunization guidelines prior to LEQSELVI treatment [see Warnings and Precautions ( 5.9 )] . 2.2 Recommended Dosage The recommended dosage of LEQSELVI for the treatment of severe alopecia areata is 8 mg orally twice daily, with or without food [see Clinical Pharmacology ( 12.3 )] . If a dose is missed, skip the missed dose and resume dosing at the next scheduled dose. 2.3 Treatment Interruption and Resumption Serious or Opportunistic Infections If a patient develops a serious or opportunistic infection, interrupt LEQSELVI treatment until the infection is controlled [see Warnings and Precautions ( 5.1 )] . Hematological Abnormalities Recommendations for LEQSELVI treatment interruption for hematologic abnormalities are described in Table 1 [see Warnings and Precautions ( 5.8 )] . Table 1: Recommendations for LEQSELVI Treatment Interruption for Hematologic Abnormalities and Resumption Laboratory Measure Interruption Criterion Resumption Criterion Absolute Lymphocyte Count (ALC) <500 cells/mm 3 ≥500 cells/mm 3 Absolute Neutrophil Count (ANC) <1000 cells/mm 3 ≥1000 cells/mm 3 Hemoglobin <8 g/dL ≥8 g/dL

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. …

4 CONTRAINDICATIONS LEQSELVI is contraindicated in patients who: Are CYP2C9 poor metabolizers [see Warnings and Precautions ( 5.6 )] . Are on concomitant moderate or strong CYP2C9 inhibitors [see Warnings and Precautions ( 5.6 )] . LEQSELVI is contraindicated in patients: Who are CYP2C9 poor metabolizers. ( 4 ) Using moderate or strong CYP2C9 inhibitors. ( 4 )

7 DRUG INTERACTIONS Effect of Other Drugs on LEQSELVI Strong CYP3A and moderate or strong CYP2C9 inducers: Avoid concomitant use of LEQSELVI with strong CYP3A and moderate or strong CYP2C9 inducers. Deuruxolitinib is a CYP2C9 and CYP3A substrate. Concomitant use with a strong CYP3A and moderate or strong CYP2C9 inducer decreases deuruxolitinib exposure (C max and AUC), which may reduce LEQSELVI efficacy [see Clinical Pharmacology ( 12.3 )] . Moderate or strong CYP2C9 inhibitors: LEQSELVI is contraindicated in patients taking moderate or strong CYP2C9 inhibitors [see Contraindications ( 4 )] . Deuruxolitinib is a CYP2C9 substrate. Concomitant use with a moderate or strong CYP2C9 inhibitor is estimated to increase deuruxolitinib exposure (C max and AUC), which may increase the risk of LEQSELVI serious adverse reactions such as thrombosis [see Clinical Pharmacology ( 12.3 )] . Strong CYP3A4 and moderate or strong CYP2C9 inducers: Avoid concomitant use. ( 7 ) Moderate or strong CYP2C9 inhibitors: Contraindicated. ( 7 )

8.1 Pregnancy Risk Summary Based on the findings from animal reproduction studies, deuruxolitinib may cause fetal harm during pregnancy. Available data from pregnancies reported in clinical trials with LEQSELVI are not sufficient to evaluate for a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of deuruxolitinib to pregnant rats during the period of organogenesis at a dose 4.8 times the maximum recommended human dose (MRHD) resulted in reduced fetal weight and increased skeletal malformation. Oral administration of deuruxolitinib to pregnant rabbits during the period of organogenesis at a dose 0.3 times the MRHD resulted in maternal toxicity, reduced fetal weight, and increased post-implantation loss. Oral administration of deuruxolitinib to pregnant rats during pregnancy and lactation periods at a dose 5 times the MRHD resulted in maternal toxicity, decreased pup survival, and adverse effects on postnatal development (see Data ) . Advise pregnant women of the potential risk to a fetus. The background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies carry some risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects is 2 to 4% of the general population and miscarriage occurs in 15 to 20% of clinically recognized pregnancies. Data Animal Data In an embryo-fetal development study, deuruxolitinib was administered to pregnant rats during the period of organogenesis at oral doses of 15, 30, and 60 mg/kg/day. Reduced fetal weight and increased fetal skeletal malformation were noted at 60 mg/kg/day (4.8 times the MRHD based on AUC comparison) with no maternal toxicity. No embryo-fetal toxicity was observed at doses up to 30 mg/kg/day (equivalent to MRHD based on AUC comparison). In another embryo-fetal development study, deuruxolitinib was administered to pregnant rabbits during the period of organogenesis at oral doses of 6, 30, and 60 mg/kg/day. Reduced fetal weight and increased post-implantation loss were noted at 60 mg/kg/day (0.3 times the MRHD based on AUC comparison), at which maternal toxicity was observed. No embryo-fetal toxicity was noted at doses up to 30 mg/kg/day (0.05 times the MRHD based on AUC comparison). In a pre- and postnatal development study in rats, deuruxolitinib was administered to pregnant rats during pregnancy and lactation periods at oral doses of 15, 30, and 75 mg/kg/day. Decreases in liveborn pups and pup survival, decreased pup activity and lower pup body weights, and adverse effects on reproductive outcome in the second generation females (decreased corpora lutea, implantation, and number of live embryos, and increased resorption and post-implantation loss) were noted at 75 mg/kg/day (5 times the MRHD based on AUC comparison), at which maternal toxicity was also observed. No adverse effects on pre- and postnatal development were noted at doses up to 30 mg/kg/day (0.8 times the MRHD based on AUC comparison).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections [see Warnings and Precautions ( 5.1 )] Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions ( 5.3 )] Thrombosis [see Warnings and Precautions ( 5.5 )] Gastrointestinal perforations [see Warnings and Precautions ( 5.7 )] Lipid Elevations, Anemia, Neutropenia and Lymphopenia [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (≥1%) are: headache, acne, nasopharyngitis, blood creatine phosphokinase increased, hyperlipidemia, fatigue, weight increased, lymphopenia, thrombocytosis, anemia, skin and soft tissue infections, neutropenia, and herpes. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of LEQSELVI was evaluated in three randomized, placebo-controlled clinical trials (including a dose-ranging trial), two open-label trials, and two long-term extension trials in adult subjects with severe alopecia areata. These subjects had at least 50% scalp hair loss as measured by the Severity of Alopecia Tool (SALT) for more than six months. A total of 1,730 subjects with alopecia areata were treated across all trials, representing 1,962.9 patient-years of exposure. There were 974 subjects who were exposed to either LEQSELVI 8 mg or deuruxolitinib 12 mg for at least 1 year and 104 subjects who were exposed for at least 3 years. Deuruxolitinib 12 mg is not approved. Among 1,020 subjects enrolled in the placebo-controlled clinical trials, 640 subjects received LEQSELVI 8 mg twice daily, 380 subjects received deuruxolitinib 12 mg twice daily and 299 subjects received placebo twice daily for up to 24 weeks [see Clinical Studies ( 14 )] . Adverse Reactions occurring at ≥1% in the LEQSELVI 8 mg or deuruxolitinib 12 mg twice daily group and at a higher rate than in the placebo group are presented in Table 2 . A total of 20 (3.1%) of subjects treated with LEQSELVI 8 mg were discontinued from the trials due to adverse reactions. Table 2: Adverse Reactions Reported in ≥1% of Subjects with Alopecia Areata Treated with LEQSELVI 8 mg Twice Daily or Deuruxolitinib 12 mg Twice Daily (and More Frequently than Placebo) in Placebo-Controlled Trials Over 24-Weeks a. %-study size adjusted percentages. b. Acne includes: acne, dermatitis acneiform, and acne pustular. c. Hyperlipidemia includes: blood cholesterol increased, low density lipoprotein increased, blood triglycerides increased, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, and dyslipidaemia. d. Fatigue includes: fatigue, asthenia, hypersomnia, somnolence, and lethargy. e. Skin and soft issue infections includes: folliculitis, impetigo, skin infection, subcutaneous abscess, furuncle, paronychia, and pustule. f. Anemia includes: anemia, hematocrit decreased, hemoglobin decreased, iron deficiency anemia, and red blood cell count decreased. g. Neutropenia includes: neutropenia and neutrophil count decreased. h. Thrombocytosis includes: thrombocytosis and platelet count increased. i. Herpes includes: oral herpes, herpes simplex, genital herpes simplex, and nasal herpes. Placebo N = 299 n (%) a LEQSELVI 8 mg twice daily N = 640 n (%) a Deuruxolitinib 12 mg twice daily N = 380 n (%) a Acne b 13 (4.3) 66 (10.0) 52 (12.6) Headache 30 (9.4) 83 (12.4) 44 (10.5) Nasopharyngitis 21 (6.7) 54 (8.1) 33 (7.7) Blood creatine phosphokinase increased 7 (2.2) 35 (5.3) 27 (7.4) Hyperlipidemia c 10 (3.1) 30 (4.4) 19 (5.2) Fatigue d 12 (3.9) 26 (3.9) 20 (4.9) Skin and soft tissue infections e 2 (0.8) 11 (1.6) 15 (4.0) Anemia f 3 (…