Ojjaara

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 )

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.

4 CONTRAINDICATIONS None. None. ( 4 )

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 Administration ( 2.3 )] . Monitor liver tests at baseline, every month for 6 months during treatment, then periodically as clinically indicated. If increases in ALT, AST or bilirubin related to treatment are suspected, modify OJJAARA dosage based upon Table 1 [see Dosage and Administration ( 2.4 )] . 5.4 Severe Cutaneous Adverse Reactions (SCARs) Severe cutaneous adverse reactions, including toxic epidermal necrolysis (TEN), have been observed in some patients treated with OJJAARA. If signs or symptoms of severe cutaneous reactions occur, interrupt OJJAARA until the etiology of the reaction has been determined. Consider early consultation with a dermatologist for evaluation and management. If etiology is considered to be associated with OJJAARA, permanently discontinue and do not reintroduce OJJAARA in patients who have experienced SCARs or other life ‑ threatening cutaneous reactions during OJJAARA treatment. 5.5 Major Adverse Cardiovascular Events (MACE) Another JAK inhibitor increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke [compared with those treated with tumor necrosis factor (TNF) blockers] in patients with rheumatoid arthritis, a condition for which OJJAARA is not indicated. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OJJAARA, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Inform patients receiving OJJAARA of the symptoms of serious cardiovascular events and the steps to take if they occur. 5.6 Thrombosis Another JAK inhibitor increased the risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared with those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which OJJAARA is not indicated. Evaluate patients with symptoms of thrombosis and treat appropriately. 5.7 Malignancies Another JAK inhibitor increased the risk of lymphoma and other malignancies excluding nonmelanoma skin cancer (NMSC) (compared with those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which OJJAARA is not indicated. Current or past smokers were at increased risk. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with OJJAARA, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers. 5.8 Symptom Exacerbation Following Interruption or Discontinuation of Treatment Following discontinuation of JAK inhibitors, including OJJAARA, signs and symptoms from myeloproliferative neoplasms may flare. Some patients with MF have experienced one or more of the following after discontinuing JAK inhibitors: fever, respiratory distress, hypotension, disseminated intravascular coagulation, or multi‑organ failure. If one or more of these signs and symptoms occur after discontinuation of OJJAARA, evaluate for and treat any intercurrent illness and consider restarting OJJAARA. Instruct patients not to interrupt or discontinue therapy without consulting their healthcare provider. When discontinuing or interrupting therapy for reasons other than potentially life-threatening toxicities, consider tapering the dose of OJJAARA gradually rather than discontinuing abruptly.

7 DRUG INTERACTIONS • Organic Anion Transporting Polypeptide (OATP)1B1/B3 inhibitors: Monitor for adverse reactions. ( 7.1 ) • Breast Cancer Resistance Protein (BCRP) substrates: Reduce rosuvastatin (BCRP substrate) dosage. Follow approved product information recommendations for other BCRP substrates. ( 7.2 ) 7.1 Effect of Other Drugs on OJJAARA Organic Anion Transporting Polypeptide (OATP)1B1/B3 Inhibitors Momelotinib is an OATP1B1/B3 substrate. Concomitant use with an OATP1B1/B3 inhibitor increases momelotinib maximal concentrations (C max ) and area under the concentration‑time curve (AUC), which may increase the risk of adverse reactions with OJJAARA [see Clinical Pharmacology ( 12.3 )] . Monitor patients concomitantly receiving an OATP1B1/B3 inhibitor for adverse reactions and consider OJJAARA dose modifications [see Dosage and Administration ( 2.4 )] . 7.2 Effect of OJJAARA on Other Drugs Breast Cancer Resistance Protein (BCRP) Substrates Momelotinib is a BCRP inhibitor. OJJAARA may increase exposure of BCRP substrates , which may increase the risk of BCRP substrate adverse reactions [see Clinical Pharmacology ( 12.3 )] . When administered concomitantly with OJJAARA, initiate rosuvastatin (BCRP substrate) at 5 mg and do not increase to more than 10 mg once daily. Dose adjustment of other BCRP substrates may also be needed. Follow approved product information recommendations for other BCRP substrates.

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 10 2 9 3 Pyrexia c 10 2 8 0 Cough c 8 0 5 0 Paresthesia c 8 1 2 0 Dizziness c 8 2 2 0 Vomiting c 8 1 0 0 Rash c 6 0 11 0 Renal and urinary tract infection c,d 6 2 11 5 Arrhythmia c 5 1 6 2 Neutropenia 5 5 3 3 SIMPLIFY‑1 Patients in the SIMPLIFY‑1 trial were JAK inhibitor naïve and randomly assigned 1:1 to receive double‑blind OJJAARA 200 mg orally once daily (n = 215) or ruxolitinib 5 to 20 mg orally twice daily (n = 217). Upon completion of the double‑blind treatment phase, all patients were eligible to receive OJJAARA during the open‑label phase. The safety of OJJAARA was evaluated in the population of patients with MF who were anemic at study entry. SIMPLIFY‑1 enrolled 180 anemic patients who received OJJAARA (n = 85) or ruxolitinib (n = 95). Among these anemic patients who received OJJAARA, 78% were exposed for 24 weeks or longer and 61% were exposed for 48 weeks or longer [see Clinical Studies ( 14 )] . Serious adverse reactions occurred in 28% of the anemic patients who received OJJAARA during the randomized treatment period of the SIMPLIFY‑1 trial; the most common serious adverse reactions (≥2%) included bacterial infection (7%), pneumonia (6%), heart failure (4%) arrhythmia (2%), and respiratory failure (2%). A fatal adverse reaction (bacterial infection) occurred in 1 patient who received OJJAARA. Permanent discontinuation of OJJAARA due to an adverse reaction occurred in 19% of the anemic patients during the randomized treatment period of the SIMPLIFY‑1 trial. Adverse reactions that resulted in permanent discontinuation of OJJAARA (≥2%) included bacterial infection (2%), dizziness (2%), fatigue (2%), hypotension (2%), and thrombocytopenia (2%). Dosage reductions or treatment interruptions of OJJAARA due to an adverse reaction occurred in 21% of patients. Adverse reactions requiring dosage reduction and/or treatment interruption (≥2%) were thrombocytopenia (8%), pneumonia (4%), bacterial infection (2%), abdominal pain (2%), elevated liver enzymes (2%), and hypotension (2%). Among the 85 anemic patients treated with OJJAARA during the randomized treatment period of SIMPLIFY‑1, the most common adverse reactions (≥20%) were dizziness, fatigue, bacterial infection, hemorrhage, thrombocytopenia, diarrhea, and nausea ( Table 3 ). Table 3: Adverse Reactions Occurring in ≥5% of Anemic Patients Receiving OJJAARA during Randomized Treatment in SIMPLIFY-1 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.4.03. c Grouped term includes other related terms. d Excludes opportunistic infections. Adverse Reactions OJJAARA n = 85 Baseline Hb <10 g/dL Ruxolitinib a n = 95 Baseline Hb <10 g/dL All Grades b % Grade ≥3 % All Grades % Grade ≥3 % Dizziness c 24 1 15 2 Fatigue c 22 0 25 1 Bacterial infection c,d 21 8 12 2 Hemorrhage c 21 1 18 2 Thrombocytopenia c 21 11 34 6 Diarrhea c 20 1 20 1 Nausea c 20 0 3 1 Abdominal pain c 18 1 14 1 Cough c 14 0 11 0 Hypotension c 14 2 0 0 Pain in extremity 12 0 5 0 Pyrexia c 12 1 11 0 Rash c 12 0 3 0 Renal and urinary tract infection c,d 12 1 4 0 Elevated liver enzymes c 11 4 9 0 Headache c 11 0 16 0 Peripheral edema 11 0 8 0 Arrhythmia c 8 2 2 1 Paresthesia c 8 0 3 0 Pneumonia c 8 8 5 3 Vomiting c 8 0 5 0 Back pain 7 1 2 0 Viral infection c,d 6 0 13 2 Vitamin B1 deficiency 6 0 7 0 Other Adverse Reactions Clinically relevant adverse reactions occurring in <5% of anemic patients in the MOMENTUM and SIMPLIFY‑1 studies include: Eye Disorders: Blurred vision. Infections and Infestations: Fungal infection (excludes opportunistic infections). Musculoskeletal and Connective Tissue Disorders: Arthralgia. Nervous System Disorders: Neuralgia, peripheral neuropathy, peripheral motor neuropathy, polyneuropathy, syncope. Vascular Disorders: Flushing. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of OJJAARA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: Hypersensitivity. Skin and Subcutaneous Tissue Disorders: Erythema multiforme, toxic epidermal necrolysis (TEN).

8.1 Pregnancy Risk Summary Available data on the use of OJJAARA in pregnant women are insufficient to determine whether there is a drug‑associated risk for major birth defects or miscarriage. Based on animal reproduction studies conducted in rats and rabbits, momelotinib may cause embryo‑fetal toxicity at exposures lower than the expected exposure in patients receiving 200 mg once daily (see Data) . OJJAARA should only be used during pregnancy if the expected benefits to the mother outweigh the potential risks to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data: In an embryofetal development study, pregnant rats received momelotinib 2, 6 or 12 mg/kg/day orally, during the period of organogenesis (Gestation Day 6 to 17). Embryo‑fetal toxicity (embryonic death, soft tissue anomalies, skeletal variations, and lower mean fetal body weights) was observed at 12 mg/kg (in the presence of maternal toxicity). Skeletal variations were observed (in the absence of maternal toxicity) at 6 mg/kg/day at exposures 3.5 times the exposure at the recommended human dose of 200 mg daily based on combined momelotinib and M21 (a major human metabolite) AUC. No developmental toxicity was observed at 2 mg/kg/day at exposures equivalent to the recommended dose (based on combined momelotinib and M21 AUC). In an embryofetal developmental study, pregnant rabbits received momelotinib at 7.5, 30 or 60 mg/kg/day orally during the period of organogenesis (Gestation Day 7 to 20). Momelotinib was associated with maternal toxicity at 60 mg/kg/day, which resulted in reduced mean fetal weight, delayed bone ossification, and an abortion at less than the exposure at the recommended dose (based on combined momelotinib and M21 AUC). No developmental toxicity was observed at lower doses tested in rabbits. In a pre- and post‑natal development study, pregnant rats received momelotinib 2, 6 or 12 mg/kg/day orally from organogenesis through lactation (Gestation Day 6 to lactation Day 20). Decreased pup body weights and embryo‑lethality were observed in the dams administered 6 and 12 mg/kg/day. Pup survival was significantly reduced in the 12 mg/kg/day group from birth to Day 4 of lactation. Momelotinib exposure in dams at 12 mg/kg and 6 mg/kg were approximately 2 times the exposure at the recommended dose (based on combined momelotinib and M21 AUC). The exposure in dams at the No Observed Adverse Effect Level (NOAEL) dose of 2 mg/kg was less than the exposure at the recommended dose (based on combined momelotinib and M21 AUC).