Momelotinib

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 )

100 mg round tablet – brown with an underlined “M” debossed on one side and “100” on the other side. 150 mg triangular tablet – brown with an underlined “M” debossed on one side and “150” on the other side. 200 mg capsule‑shaped tablet – brown with an underlined “M” debossed on one side and “200” on the other side. Tablets: 100 mg, 150 mg, 200 mg. ( 3 )

None. None. ( 4 )

• 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.

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. […]

• 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.

• Pregnancy: May cause fetal harm. ( 8.1 )
• Lactation: Advise not to breastfeed. ( 8.2 )

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).

8.2 Lactation Risk Summary There are no data on the presence of momelotinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. It is not known whether OJJAARA is excreted in human milk. Momelotinib was present in rat pups following nursing from treated dams with adverse effects observed in the offspring. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in a breastfed child, patients should not breastfeed during treatment with OJJAARA, and for at least 1 week after the last dose of OJJAARA. Data Animal Data: In a pre- and post‑natal development study, momelotinib was administered orally to rats during the lactation period; the drug was detected in plasma of nursing pups, which adversely affected pup survival.

8.3 Females and Males of Reproductive Potential Contraception Advise females of reproductive potential who are not pregnant to use highly effective contraception during therapy and for at least 1 week after the last dose of OJJAARA.

8.4 Pediatric Use The safety and effectiveness of OJJAARA in pediatric patients have not been established.

8.5 Geriatric Use There were 275 patients aged 65 years and older in the clinical studies for MF [see Clinical Studies ( 14 )] . Of the total number of OJJAARA‑treated patients in these studies, 163/216 (75%) were aged 65 years and older, and 63/216 (29%) were aged 75 years and older. No overall differences in safety or effectiveness of OJJAARA have been observed between patients aged 65 years and older and younger adult patients.

8.6 Hepatic Impairment The recommended starting dose of OJJAARA in patients with severe hepatic impairment (Child‑Pugh C) is 150 mg orally once daily [see Dosage and Administration ( 2.3 )] . No dose modification is recommended for patients with mild hepatic impairment (Child‑Pugh A) or moderate hepatic impairment (Child‑Pugh B). Momelotinib is extensively metabolized [see Clinical Pharmacology ( 12.3 )] . Momelotinib exposure increased with severe hepatic impairment (Child‑Pugh C). No clinically significant changes in momelotinib exposure were observed in subjects with mild hepatic impairment (Child‑Pugh A) or moderate hepatic impairment (Child‑Pugh B) [see Clinical Pharmacology ( 12.3 )] .

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.