Momelotinib

1 INDICATIONS AND USAGE OJJAARA is indicated for the treatment of intermediate or high‑risk myelofibrosis (MF), including primary MF or secondary MF [post‑polycythemia vera (PV) and post‑essential thrombocythemia (ET)], in adults with anemia. OJJAARA is a kinase inhibitor indicated for the treatment of intermediate or high‑risk myelofibrosis (MF), including primary MF or secondary MF [post‑polycythemia vera (PV) and post‑essential thrombocythemia (ET)], in adults with anemia. ( 1 )

12.1 Mechanism of Action Momelotinib is an inhibitor of wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2 V617F , which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Momelotinib and its major human circulating metabolite, M21, have higher inhibitory activity for JAK2 compared to JAK3 and tyrosine kinase 2 (TYK2). Momelotinib and M21 additionally inhibit activin A receptor type 1 (ACVR1), also known as activin receptor like kinase 2 (ALK2), which produces subsequent inhibition of liver hepcidin expression and increased iron availability resulting in increased red blood cell production. MF is a myeloproliferative neoplasm associated with constitutive activation and dysregulated JAK signaling that contributes to inflammation and hyperactivation of ACVR1. JAK signaling recruits and activates STAT (signal transducers and activation of transcription) proteins resulting in nuclear localization and subsequent regulation of gene transcription.

2 DOSAGE AND ADMINISTRATION • Recommended dosage: 200 mg orally once daily with or without food. ( 2.1 ) • Severe hepatic impairment (Child-Pugh Class C): Reduce the starting dose to 150 mg orally once daily. ( 2.3 ) 2.1 Recommended Dosage The recommended dosage of OJJAARA is 200 mg orally once daily. OJJAARA may be taken with or without food. Swallow OJJAARA tablets whole. Do not cut, crush, or chew tablets. If a dose of OJJAARA is missed, the next scheduled dose should be taken the following day. 2.2 Laboratory Monitoring for Safety Obtain the following blood tests prior to starting treatment with OJJAARA, periodically during treatment, and as clinically indicated: • Complete blood count (CBC) with platelets [see Warnings and Precautions ( 5.2 )] • Hepatic panel [see Warnings and Precautions ( 5.3 )] 2.3 Dosage Modification for Hepatic Impairment The recommended starting dosage in patients with severe hepatic impairment (Child‑Pugh Class C) is 150 mg orally once daily [see Use in Specific Populations ( 8.6 )] . No dose adjustment is recommended for patients with mild or moderate hepatic impairment. 2.4 Dosage Modification for Adverse Reactions Manage hematologic and non‑hematologic adverse reactions as described in Table 1 . Table 1: Dose Modifications for OJJAARA-Related Adverse Reactions ALT = alanine transaminase; AST = aspartate transaminase; ULN = upper limit of normal. a Reinitiate or escalate treatment up to starting dosage as clinically appropriate. b May reinitiate treatment at 100 mg if previously dosed at 100 mg. c If baseline >2 × ULN. d If baseline >1.5 × ULN. e Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events per (CTCAE). Thrombocytopenia Dose Modification a Baseline Platelet Count Platelet Count ≥100 × 10 9 /L 20 × 10 9 /L to <50 × 10 9 /L Reduce daily dose by 50 mg from the last given dose. <20 × 10 9 /L Interrupt treatment until platelets recover to 50 × 10 9 /L. Restart OJJAARA at a daily dose of 50 mg below the last given dose. b ≥50 × 10 9 /L to <100 × 10 9 /L <20 × 10 9 /L Interrupt treatment until platelets recover to 50 × 10 9 /L. Restart OJJAARA at a daily dose of 50 mg below the last given dose. b <50 × 10 9 /L <20 × 10 9 /L Interrupt treatment until platelets recover to baseline. Restart OJJAARA at a daily dose of 50 mg below the last given dose. b Neutropenia Dose Modification a Absolute neutrophil count (ANC) <0.5 × 10 9 /L Interrupt treatment until ANC ≥0.75 × 10 9 /L. Restart OJJAARA at a daily dose of 50 mg below the last given dose. b Hepatotoxicity (unless other apparent causes) Dose Modification a ALT and/or AST >5 × ULN (or >5 × baseline, if baseline is abnormal) and/or total bilirubin >2 × ULN (or >2 × baseline, if baseline is abnormal) Interrupt treatment until AST and ALT ≤2 × ULN or baseline c and total bilirubin ≤1.5 × ULN or baseline. d Restart OJJAARA at a daily dose of 50 mg below the last given dose. b If reoccurrence of ALT or AST elevations >5 × ULN, permanently discontinue OJJAARA. Other Non ‑ Hematologic Dose Modification a Grade 3 or higher e Interrupt treatment until the toxicity resolves to Grade 1 or lower (or baseline). Restart OJJAARA at a daily dose of 50 mg below the last given dose. b Discontinue OJJAARA in patients unable to tolerate 100 mg once daily.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Risk of Infections and Hepatitis B Reactivation [see Warnings and Precautions ( 5.1 )] • Thrombocytopenia and Neutropenia [see Warnings and Precautions ( 5.2 )] • Hepatotoxicity [see Warnings and Precautions ( 5.3 )] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.4 )] • Major Adverse Cardiovascular Events [see Warnings and Precautions ( 5.5 )] • Thrombosis [see Warnings and Precautions ( 5.6 )] • Malignancies [see Warnings and Precautions ( 5.7 )] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment [see Warnings and Precautions ( 5.8 )] The most common adverse reactions (≥20% in either study) are thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OJJAARA was evaluated in 215 patients in 2 clinical trials (MOMENTUM and SIMPLIFY‑1 anemic subgroup [hemoglobin (Hb) <10 g/dL]) [see Clinical Studies ( 14 )] . MOMENTUM Patients in the MOMENTUM trial had been previously treated with a JAK inhibitor and were randomly assigned 2:1 to receive double‑blind OJJAARA 200 mg orally once daily (n = 130) or danazol 300 mg orally twice daily (n = 65) for 24 weeks, after which they were eligible to receive open‑label OJJAARA in an extended treatment phase. Among patients who received OJJAARA, 72% were exposed for 24 weeks or longer and 52% were exposed for 48 weeks or longer [see Clinical Studies ( 14 )] . Serious adverse reactions occurred in 35% of patients who received OJJAARA during the randomized treatment period of the MOMENTUM trial; the most common serious adverse reactions (≥2%) included bacterial infection (8%), viral infection (5%), hemorrhage (4%), acute kidney injury (3%), pneumonia (3%), pyrexia (3%), thrombosis (3%), syncope (2%), thrombocytopenia (2%), and renal and urinary tract infection (2%). Fatal adverse reactions occurred in 12% of patients who received OJJAARA; the most common (≥2%) fatal adverse reaction was viral infection (5%). Permanent discontinuation of OJJAARA due to an adverse reaction occurred in 18% of patients during the randomized treatment period of the MOMENTUM trial. Adverse reactions that resulted in permanent discontinuation (≥2%) included viral infection (2%) and thrombocytopenia (2%). Dosage reduction or treatment interruption due to an adverse reaction occurred in 34% of patients. Adverse reactions requiring dosage reduction and/or treatment interruption (≥2%) included thrombocytopenia (13%), bacterial infection (2%), diarrhea (2%), and neutropenia (2%). Among the 130 patients treated with OJJAARA during the randomized treatment period of MOMENTUM, the most common adverse reactions (≥20%) were thrombocytopenia, diarrhea, hemorrhage, and fatigue ( Table 2 ). Table 2: Adverse Reactions Occurring in ≥5% of Patients Receiving OJJAARA during Randomized Treatment in MOMENTUM a Study was not designed to evaluate meaningful comparisons of the incidence of adverse reactions across treatment groups. b Adverse reactions graded using CTCAE v.5. c Grouped term includes other related terms. d Excludes opportunistic infections. Adverse Reaction OJJAARA n = 130 Danazol a n = 65 All Grades b % Grade ≥3 % All Grades % Grade ≥3 % Thrombocytopenia c 28 22 17 12 Diarrhea c 22 0 9 2 Hemorrhage c 22 2 18 8 Fatigue c 21 2 20 5 Nausea c 16 2 9 3 Bacterial infection c,d 15 8 18 8 Abdominal pain c 13 1 18 3 Viral infection c,d 12 5 3 0 Pruritus c 11 2 11 0 Elevated liver enzymes c 1

5 WARNINGS AND PRECAUTIONS • Risk of Infections: Do not initiate OJJAARA in patients with an active infection. Monitor for signs and symptoms of infection, including reactivation of hepatitis B, and initiate appropriate treatment promptly. ( 5.1 ) • Thrombocytopenia and Neutropenia: Manage by dose reduction or interruption. ( 5.2 ) • Hepatotoxicity: Obtain liver tests before initiation of and periodically throughout treatment with OJJAARA. ( 5.3 ) • Severe Cutaneous Adverse Reactions (SCARs): Monitor for signs and symptoms, and interrupt OJJAARA until etiology of reaction has been determined. ( 5.4 ) • Major Adverse Cardiovascular Events (MACE): Monitor for symptoms, evaluate and treat promptly. ( 5.5 ) • Thrombosis: Evaluate and treat symptoms of thrombosis promptly. ( 5.6 ) • Malignancies: Monitor for development of secondary malignancies, particularly in current or past smokers. ( 5.7 ) • Symptom Exacerbation Following Interruption or Discontinuation of Treatment: Manage with supportive care and consider restarting OJJAARA. ( 5.8 ) 5.1 Risk of Infections Serious (including fatal) infections (e.g., bacterial and viral, including COVID‑19) occurred in 13% of patients treated with OJJAARA. Infections regardless of grade occurred in 38% of patients treated with OJJAARA [see Adverse Reactions ( 6.1 )] . Delay starting therapy with OJJAARA until active infections have resolved. Monitor patients receiving OJJAARA for signs and symptoms of infection and initiate appropriate treatment promptly. Hepatitis B Reactivation Hepatitis B viral load (HBV‑DNA titer) increases, with or without associated elevations in alanine transaminase (ALT) or aspartate transaminase (AST), have been reported in patients with chronic hepatitis B virus (HBV) infection taking Janus Kinase (JAK) inhibitors, including OJJAARA. The effect of OJJAARA on viral replication in patients with chronic HBV infection is unknown. In patients with HBV infections, check hepatitis B serologies prior to starting OJJAARA. If HBsAg and/or anti‑HBc antibody is positive, consider consultation with a hepatologist regarding monitoring for reactivation versus prophylactic hepatitis B therapy. Patients with chronic HBV infection who receive OJJAARA should have their chronic HBV infection treated and monitored according to clinical HBV guidelines. 5.2 Thrombocytopenia and Neutropenia OJJAARA can cause thrombocytopenia and neutropenia [see Adverse Reactions ( 6.1 )] . New or worsening thrombocytopenia, with platelet count less than 50 × 10 9 /L, was observed in 20% of patients treated with OJJAARA. Eight percent of patients treated with OJJAARA had baseline platelet counts less than 50 × 10 9 /L. Severe neutropenia, absolute neutrophil count (ANC) less than 0.5 × 10 9 /L, was observed in 2% of patients treated with OJJAARA. Assess CBCs, including platelet and neutrophil counts, before initiating treatment and periodically during treatment as clinically indicated. Interrupt dosing or reduce the dose for thrombocytopenia or neutropenia [see Dosage and Administration ( 2.4 )] . 5.3 Hepatotoxicity Two of the 993 patients with MF who received at least one dose of OJJAARA in clinical trials experienced reversible drug‑induced liver injury. Overall, new or worsening elevations of ALT and AST (all grades) occurred in 23% and 24%, respectively, of patients treated with OJJAARA; Grade 3 and 4 transaminase elevations occurred in 1% and 0.5% of patients, respectively. New or worsening elevations of total bilirubin occurred in 16% of patients treated with OJJAARA. All total bilirubin elevations were Grades 1‑2. The median time to onset of any grade transaminase elevation was 2 months, with 75% of cases occurring within 4 months. Delay starting therapy in patients presenting with uncontrolled acute and chronic liver disease until apparent causes have been investigated and treated as clinically indicated. When initiating OJJAARA, refer to dosing in patients with hepatic impairment [see Dosage and Ad

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE There is no known antidote for overdose with OJJAARA. If overdose is suspected, the patient should be monitored for signs or symptoms of adverse reactions or effects, and appropriate supportive treatment should be instituted immediately. Further management should be as clinically indicated. Hemodialysis is not expected to enhance the elimination of momelotinib. Consider contacting the Poison Help line (1‑800‑222‑1222) or a medical toxicologist for additional overdose management recommendations.