Deuruxolitinib

12.1 Mechanism of Action Deuruxolitinib is a Janus kinase (JAK) inhibitor. JAKs mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. In an in vitro kinase activity assay, deuruxolitinib had greater inhibitory potency for JAK1, JAK2 and TYK2 relative to JAK3. The relevance of inhibition of JAK enzymes to therapeutic effectiveness is not currently known.

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

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 (1.0) 18 (2.6) 16 (3.4) Weight increased 4 (1.4) 19 (2.9) 10 (2.5) Neutropenia g 3 (0.7) 10 (1.4) 10 (2.8) Lymphopenia 2 (0.6) 2 (0.3) 7 (2.0) Thrombocytosis h 0 18 (2.7) 6 (1.6) Herpes i 2 (0.6) 8 (1.2) 6 (1.6) Additional adverse drug reactions occurring in fewer than 1% of subjects: herpes zoster, lipase increased, and candidiasis. A total of 868 subjects in the long-term extension trials received treatment with LEQSELVI 8 mg twice daily and 991 subjects received treatment with deuruxolitinib 12 mg twice daily for 52 weeks. In two open-label extension trials up to 3 years, 829 subjects received treatment with LEQSELVI 8 mg twice daily, and 1066 subjects received treatment with deuruxolitinib 12 mg twice daily. Specific Adverse Reactions (0-52 weeks) All Infections During the 24-week treatment period, infections were reported in 97 subjects (88.0 per 100 patient-years) treated with placebo, 222 subjects (101.5 per 100 patient-years) treated with LEQSELVI 8 mg twice daily and 153 subjec

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 )