Momelotinib dihydrochloride, a Janus Kinase (JAK) 1 and 2 and mutant JAK2V617F inhibitor, is an antineoplastic agent.1
Intermediate- and High-Risk Myelofibrosis
Momelotinib dihydrochloride is a kinase inhibitor indicated for the treatment of intermediate or high-risk myelofibrosis (MF), including primary MF or secondary MF (post-polycythemia vera and post-essential thrombocythemia), in adults with anemia.1 Momelotinib has been designated as an orphan drug by FDA for this use.2
The efficacy of momelotinib for the treatment of adults with intermediate-1, intermediate-2, or high-risk MF, including primary MF, post-polycythemia vera, or post-essential thrombocythemia, as defined by the Dynamic International Prognostic Scoring System or International Prognostic Scoring System for MF, was established in the MOMENTUM trial and in a subpopulation of adults with anemia in the SIMPLIFY-1 trial.1 All patients received a starting dosage of momelotinib 200 mg orally once daily.1 Eligible patients had a baseline platelet count of ≥25,000 cells/mm3 in the MOMENTUM trial and ≥50,000 cells/mm3 in the SIMPLIFY-1 trial.1
The MOMENTUM trial was a double-blind, randomized, active-controlled, phase 3 trial.1, 3 To be considered for inclusion, patients greater than 18 years of age were required to have a confirmed diagnosis of primary MF, or post-polycythemia vera or post-essential thrombocythemia MF, and were required to have been previously treated with a Janus Kinase (JAK) inhibitor for ≥90 days or for 28 days if therapy was complicated by 4 units or more red blood cells transfused in 8 weeks or Grade 3 or 4 adverse events.3 Patients were also required to be symptomatic (with a total symptom score [TSS] of 10 or more), anemic (hemoglobin <10 g/dL), have a platelet count >25,000 cells/m3, baseline splenomegaly, be classified as high-risk, intermediate-2 risk, or intermediate-1 risk, and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0—2.3 Patients were randomly assigned in a 2:1 ratio to either momelotinib 200 mg orally once daily with danazol placebo or danazol 300 mg orally twice daily with momelotinib placebo.1, 3 Patients who were receiving a JAK inhibitor at baseline were tapered over more than 1 week, then completed a non-treatment interval of at least 2 weeks beginning at least 7 days before the first day of baseline assessment.3 Patients were stratified by total symptom score (<22 or ≥22), spleen size (<12 cm or ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomization (0 units versus 1—4 units versus ≥5 units), and study site.3 Symptoms were measured using the Myelofibrosis Symptom Assessment Form diary, which captured core symptoms of fatigue, night sweats, itching, abdominal discomfort, pain under the ribs on the left side, feeling of fullness after beginning to eat, and bone pain.1 For each item, symptom scores ranging from 0 (absent) to 10 (worst imaginable) were added to create a TSS (maximum score of 70).1 The primary endpoint was the Myelofibrosis Symptom Assessment Form TSS response rate at week 24, defined as ≥50% reduction in mean TSS over the 28 days immediately before the end of week 24 as compared to baseline.3
A total of 195 patients (130 in the momelotinib group and 65 in the danazol group) were enrolled in the MOMENTUM trial.1, 3 The median age was 71 years (range, 38 to 96 years), with the majority of patients (79%) being 65 years of age or older.1, 3 The majority of patients were male (63%) and white (81%).1 Sixty-four percent of patients had primary MF, 19% had post-polycythemia vera MF, and 17% had post-essential thrombocythemia MF.1, 3 Five percent of patients had intermediate-1 risk, 57% had intermediate-2 risk, and 35% had high-risk disease.1, 3 Within the 8 weeks prior to treatment, 79% of patients had received red blood cell transfusions (median 4 units, interquartile range: 1—6).1 At baseline, 13% and 15% of patients were transfusion independent, defined as no red blood cell transfusions in the 12 weeks before the first dose and a hemoglobin ≥8 g/dL, in the momelotinib and danazol groups, respectively.1 At baseline, the median hemoglobin was 8 g/dL, median platelet count was 96,000 cells/mm3, and median palpable spleen volume was 2,105 cm3 (range, 609—9,717 cm3).1 The baseline TSS score was 28 in the momelotinib group and 26 in the danazol group.1 At week 24, 25% of patients in the momelotinib group and 9% of patients in the danazol group reported a TSS reduction of 50% or more, for a total treatment difference of 15%.1, 3 The reported change in TSS from baseline was -9.4 versus -3.1 in the momelotinib and danazol groups, respectively.1 Transfusion independence was noted in 30% of patients who received momelotinib compared to 20% of patients who received danazol; 35% of patients who received momelotinib required no transfusions during the 24-week treatment period compared to 17% in the danazol group.1 A reduction in spleen volume by 25% or more was noted in 39% of patients in the momelotinib group versus 6% in the danazol group; a reduction of 35% or more in spleen volume was noted in 22% versus 3% of patients, respectively.1 Prior to the end of the 24-week trial, 27.7% of patients that received momelotinib and 41.5% of patients that received danazol discontinued treatment.1
After completion of the initial 24-week MOMENTUM trial, all patients initially randomized who remained in the study were transferred to an open-label extension study with momelotinib 200 mg orally once daily.1, 3, 4 Patients who were randomly assigned to the danazol group but who discontinued treatment before week 24 in the initial MOMENTUM trial could also receive open-label momelotinib.4 Continuing with the methodology of the initial MOMENTUM trial, the primary endpoint was Myelofibrosis Symptom Assessment Form TSS response rate for an additional 24 weeks (total duration 48 weeks).4 After week 48, patients receiving open-label momelotinib could enter an extended access study.4 A total of 134 patients (93 from the original momelotinib group and 41 from the original danazol group) entered the open-label extension study; a total of 94 patients completed 48 weeks of treatment with momelotinib.4 Among TSS-evaluable patients, 45% of the patients from the original momelotinib group and 50% of patients from the original danazol group were considered responders.4 TSS responders at any time during the open-label treatment period were 61% and 59% of evaluable patients in the momelotinib and danazol groups, respectively.4 TSS responders in both groups from the initial 24-week MOMENTUM trial maintained a TSS response; an additional 38% of non-responders in the original momelotinib group and 52% in the original danazol group became responders before week 48.4 All week 24 responders with a week 48 scan maintained spleen volumes below baseline.4 Hemoglobin improvements were also maintained through week 48.4 The safety of momelotinib during the open-label extension period was consistent with the initial 24-week trial; no new safety signals were identified.4
The SIMPLIFY-1 trial was a double-blind, randomized, active-controlled trial conducted in JAK inhibitor-naïve patients with high-risk, intermediate-2 risk, or symptomatic intermediate-1 risk MF.1, 5 To be considered for inclusion, patients greater than 18 years of age were required to have palpable splenomegaly (≥5 cm below the left costal margin), a confirmed diagnosis of primary MF, post-polycythemia vera or post-essential thrombocythemia MF, an ECOG performance status ≤2, and life expectancy >24 weeks.5 Patients with prior use of a JAK inhibitor, prior splenectomy, spleen irradiation <3 weeks before the first dose of study treatment, certain cancers (history or concurrent disease), uncontrolled intercurrent illness that would limit study compliance, or those who were eligible for allogeneic stem cell transplant were excluded.5 The study had a 24-week double-dummy treatment phase in which patients were randomized in a 1:1 ratio to either momelotinib 200 mg orally once daily or ruxolitinib 20 mg twice daily.5 After completion of the double-blind treatment phase, patients were eligible to receive momelotinib in an open-label phase.5 The primary endpoint was a reduction of ≥35% in spleen volume from baseline at week 24.5 The baseline characteristics and efficacy results provided for initial FDA approval of momelotinib were based on a subset of patients who had anemia, defined as a hemoglobin <10 g/dL at baseline.5
A total of 432 patients were enrolled in the SIMPLY-1 trial; 181 patients with anemia met the criteria for inclusion in the subset evaluation.1, 5 The median age was 68 years (range, 25 to 86 years); the majority of patients were aged 65 years and older (67%), male (59%), and white (81%).1 Sixty-three patients had primary MF, 13% had post-polycythemia vera MF, and 24% had post-essential thrombocythemia MF.1 Four percent of patients had intermediate-1 risk, 25% had intermediate-2 risk, and 71% had high-risk disease.1 At baseline, 29% and 44% of patients were transfusion independent in the groups treated with momelotinib or ruxolitinib, respectively.1 The baseline median hemoglobin was 8.8 mg/dL and the median platelet count was 193,000 cells/mm3.1 Mean palpable spleen length at baseline was 12 cm below the costal margin; the median spleen volume at baseline was 1,843 cm3.1 At week 24, 25% of patients treated with momelotinib achieved a TSS reduction of 50% compared to 35% of patients treated with ruxolitinib.1 Spleen volume reduction of 35% or more was noted in 31.4% versus 32.6% of patients treated with momelotinib versus ruxolitinib, respectively.1
The SIMPLIFY 2 trial was a randomized, open-label, phase 3 trial of momelotinib versus best available therapy in patients with symptomatic MF who had suboptimal responses or hematologic toxic effects with ruxolitinib.6 Patients with MF, a palpable spleen of at least 5 cm, and a history of previous ruxolitinib treatment for at least 28 days who either required red blood cell transfusions while on ruxolitinib or required dosage reductions with at least one Grade 3 hematologic toxicity (including thrombocytopenia, anemia, or bleeding) without grade 2 or greater peripheral neuropathy were included.6 Patients were randomized in a 2:1 ratio to either open-label momelotinib 200 mg orally once daily or best available therapy, which could include ruxolitinib, chemotherapy, steroids, no treatment, or other standard interventions, for 24 weeks.6 After the initial 24 weeks, patients continued to receive extended treatment with momelotinib.6 The primary endpoint was a reduction in spleen volume of at least 35% at 24 weeks as compared to baseline.6
A total of 156 patients were enrolled in the SIMPLIFY 2 trial: 104 in the momelotinib group and 52 in the best available treatment group.6 In the best available treatment group, 89% (46 patients) received ruxolitinib, 23% (12 patients) received hydroxyurea, and 12% (6 patients) received corticosteroids.6 Fourteen patients (27%) received a combination of ruxolitinib with additional therapies (most commonly hydroxyurea or corticosteroids).6 Approximately one-half of the patients in both groups (56% in the momelotinib group and 52% in the best available treatment group) were transfusion dependent at baseline; approximately one-third (31% in the momelotinib group and 37% in the ruxolitinib group) were transfusion independent.6 There were more patients in the momelotinib group that were transfusion independent than in the best available treatment group at week 24 (43% versus 21%, respectively).6 A reduction of at least 35% in spleen volume (the primary efficacy endpoint) was reported in 7 patients (7%) in the momelotinib group and 3 (6%) patients in the best available treatment group (p=0.90).6
Myeloproliferative disorders, including myelofibrosis, frequently occur as the result of a driver mutation in the JAK 2 signal transducer and activator of transcription (STAT) 5 signaling pathway.7, 9 Patients with low- or intermediate-risk myelofibrosis who lack significant symptoms may be managed with observation alone.9 However, if cytoreductive therapy is indicated in low- to intermediate-risk patients, hydroxyurea is often recommended as first-line treatment.9, 12 There is no current consensus on the management of splenomegaly in patients with MF before allogeneic stem cell transplantation.9 Historically, myelofibrosis-associated splenomegaly was treated with hydroxyurea; however, some experts currently recommend JAK inhibitors as first-line treatment in patients with intermediate or high-risk disease who are not eligible for allogeneic stem cell transplantation, in those who are unresponsive to or cannot tolerate hydroxyurea, and to reduce spleen size prior to allogeneic stem cell transplantation.9, 10, 11, 12
Momelotinib should be swallowed whole.1 Tablets should not be cut, crushed, or chewed.1
Momelotinib can be taken with or without food.1
If a dose of momelotinib is missed, the next scheduled dose should be taken the following day.1
Delay starting momelotinib until active infections have resolved.1
Store momelotinib at 20-25ºC; excursions are permitted to 15-30ºC.1 Momelotinib should be dispensed and stored in the original bottle to protect from moisture.1 The cap should be replaced securely each time after opening.1 Do not discard desiccant.1
Dosage of momelotinib dihydrochloride is expressed in terms of momelotinib.1
The recommended dosage of momelotinib is 200 mg orally once daily with or without food.1
Dosage Modifications for Toxicity
Dosage modifications of momelotinib are recommended for both hematologic and non-hematologic adverse reactions (see Tables 1 and 2).1 Discontinue momelotinib in patients who are unable to tolerate 100 mg once daily.1
Baseline Platelet Count | Current Platelet Count | Recommended Dosage Modificationa |
|---|---|---|
≥100,000 cells/mm3 | 20,000 cells/mm3 to <50,000 cells/mm3 | Reduce daily dosage by 50 mg from the last given dosage |
≥100,000 cells/mm3 | <20,000 cells/mm3 | Interrupt treatment until platelets recover to 50,000 cells/mm3 Restart momelotinib at a daily dosage of 50 mg below the last given dosageb |
≥50,000 cells/mm3to <100,000 cells/mm3 | <20,000 cells/mm3 | Interrupt treatment until platelets recover to 50,000 cells/mm3 Restart momelotinib at a daily dosage of 50 mg below the last given dosageb |
<50,000 cells/mm3 | <20,000 cells/mm3 | Interrupt treatment until platelets recover to baseline Restart momelotinib at a daily dosage of 50 mg below the last given dosageb |
aReinitiate or escalate treatment up to starting dosage as clinically appropriate.
bMay reinitiate treatment at 100 mg if previous dosage was 100 mg.
Adverse Reaction | Severity | Recommended Dosage Modificationa |
|---|---|---|
Neutropenia | Absolute neutrophil count <500 cells/mm3 | Interrupt treatment until absolute neutrophil count ≥750 cells/mm3 Restart momelotinib at a daily dosage of 50 mg below the last given dosageb |
Hepatotoxicity (unless other apparent etiology) | ALT and/or AST >5 times the upper limit of normal (ULN) (or >5 times baseline if baseline is abnormal) and/or total bilirubin >2 times the ULN (or >2 times baseline, if baseline is abnormal) | Interrupt treatment until AST and ALT ≤2 times the ULN or baselinec and total bilirubin ≤1.5 times the ULN or baselined Restart momelotinib at a daily dosage of 50 mg below the last given dosageb If reoccurrence of ALT or AST elevations >5 times the ULN, permanently discontinue momelotinib |
Other Non-Hematologic Toxicity | Grade 3 or highere | Interrupt treatment until toxicity resolves to Grade 1 or lower (or baseline) Restart momelotinib at a daily dosage of 50 mg below the last given dosageb |
aReinitiate or escalate treatment up to starting dosage as clinically appropriate.
bMay reinitiate treatment at 100 mg if previous dosage was 100 mg.
cIf baseline >2 times the ULN.
dIf baseline >1.5 times the ULN.
eGraded using the National Cancer Institute Common Terminology Criteria for Adverse Events.
The recommended starting dosage of momelotinib for patients with severe hepatic impairment (Child-Pugh class C) is 150 mg orally once daily.1 No dosage adjustment is recommended for patients with mild or moderate hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Serious, including fatal, infections (e.g., bacterial and viral, including COVID-19) occurred in 13% of patients treated with momelotinib.1 Infections regardless of grade occurred in 38% of patients treated with momelotinib.1 Delay starting momelotinib until active infections have resolved.1 Monitor patients receiving momelotinib for signs and symptoms of infection and initiate appropriate treatment promptly.1
Hepatitis B viral load (hepatitis B viral-DNA titer) increases, with or without associated elevations in ALT or AST, have been reported in patients with chronic hepatitis B virus (HBV) infection taking Janus Kinase (JAK) inhibitors, including momelotinib.1 The effect of momelotinib on viral replication in patients with chronic HBV infection is unknown.1 In patients with HBV infections, check hepatitis B serologies prior to starting momelotinib.1 If HBsAg and/or anti-HBc antibody is positive, consider consultation with a hepatologist regarding monitoring for reactivation versus prophylactic hepatitis B therapy.1 Patients with chronic HBV infection who receive momelotinib should have their chronic HBV infection treated and monitored according to clinical HBV guidelines.1
Thrombocytopenia and Neutropenia
Momelotinib can cause thrombocytopenia and neutropenia.1 New or worsening thrombocytopenia, with platelet counts less than 50,000 cells/mm3, was observed in 20% of patients treated with momelotinib.1 Eight percent of patients treated with momelotinib had baseline platelet counts less than 50,000 cells/mm3.1 Severe neutropenia, with an absolute neutrophil count (ANC) less than 500 cells/mm3, was observed in 2% of patients treated with momelotinib.1
Assess complete blood count (CBC), including platelet and neutrophil counts, before initiating treatment and periodically during treatment with momelotinib as clinically indicated.1 Interrupt dosing or reduce the dosage for thrombocytopenia or neutropenia according to manufacturer recommendations (see Tables 1 and 2).1
Two of the 993 patients with myelofibrosis who received at least 1 dose of momelotinib in clinical trials experienced reversible drug-induced liver injury.1 Overall, new or worsening elevations of ALT and AST (all grades) occurred in 23% and 24%, respectively, of patients treated with momelotinib; Grade 3 and 4 aminotransferase elevations occurred in 1% and 0.5% of patients, respectively.1 New or worsening elevations of total bilirubin occurred in 16% of patients treated with momelotinib.1 All total bilirubin elevations were Grades 1 and 2.1 The median time to onset of any grade aminotransferase elevation was 2 months, with 75% of cases occurring within 4 months.1
Delay starting momelotinib in patients presenting with uncontrolled acute or chronic liver disease until apparent causes have been investigated and treated as clinically indicated.1 When initiating momelotinib, refer to manufacturer recommended dosing in patients with hepatic impairment.1
Monitor liver function tests at baseline, every month for 6 months during treatment, then periodically as clinically indicated.1 If increases in ALT, AST, or bilirubin related to treatment are suspected, modify momelotinib dosage according to manufacturer recommendations (see Tables 1 and 2).1
Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions, including toxic epidermal necrolysis (TEN), have been reported with momelotinib therapy.1 If signs or symptoms of severe cutaneous reactions occur, momelotinib therapy should be interrupted until the cause of the reaction is determined.1 Early consultation with a dermatologist should be considered.1
Momelotinib should be permanently discontinued if the reaction is considered to be related to therapy.1 Reintroduction of momelotinib therapy should not occur in patients who have experienced severe cutaneous adverse reactions or other life-threatening cutaneous reactions during treatment.1
Major Adverse Cardiovascular Events (MACE)
Another JAK inhibitor increased the risk of major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, and stroke (compared to those treated with tumor necrosis factor [TNF] blockers) in patients with rheumatoid arthritis, a condition for which momelotinib is not indicated.1 Consider the risks and benefits for the individual patient prior to initiating or continuing therapy with momelotinib, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.1 Inform patients receiving momelotinib of the symptoms of serious cardiovascular events and the steps to take if they occur.1
Another JAK inhibitor increased the risk of thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombus (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which momelotinib is not indicated.1
Evaluate patients with symptoms of thrombosis and treat appropriately.1
Another JAK inhibitor increased the risk of lymphoma and other malignancies excluding non-melanoma skin cancer (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which momelotinib is not indicated.1 Current or past smokers were at increased risk.1
Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with momelotinib, particularly in patients with a known malignancy (other than a successfully treated non-melanoma skin cancer), patients who develop a malignancy, and patients who are current or past smokers.1
Symptom Exacerbation Following Interruption or Discontinuation of Treatment
Following discontinuation of momelotinib, signs and symptoms from myeloproliferative neoplasms may flare including fever, respiratory distress, hypotension, disseminated intravascular coagulation, or multi-organ failure.1
If one or more of these signs and symptoms occur after momelotinib discontinuation, clinicians should evaluate for and treat any intercurrent illness and consider resumption of momelotinib.1 Patients should be advised not to interrupt or discontinue therapy without consulting their clinician.1 When discontinuing or interrupting therapy for reasons other than potentially life-threatening toxicities, clinicians should consider tapering momelotinib gradually rather than discontinuing abruptly.1
There is insufficient evidence with momelotinib in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 Based on findings from animal studies conducted in rats and rabbits, momelotinib may cause embryo-fetal toxicity at exposures lower than the expected exposure in patients receiving momelotinib 200 mg once daily.1 Momelotinib should only be used during pregnancy if the expected benefits to the mother outweigh the potential risks to the fetus.1
In an embryo-fetal development study, pregnant rats received momelotinib 2, 6, or 12 mg/kg per day orally during the period of organogenesis (Gestation Day 6 to 17).1 Embryo-fetal toxicity, including embryonic death, soft tissue abnormalities, skeletal variations, and lower mean fetal body weights, was observed at a dosage of 12 mg/kg (in the presence of maternal toxicity).1 Skeletal variations were observed (in the absence of maternal toxicity) at 6 mg/kg per day at exposures 3.5 times the exposure at the recommended human dosage of 200 mg once daily based on the combined momelotinib and M21 (a major human metabolite) AUC.1 No developmental toxicity was observed at 2 mg/kg per day at exposures equivalent to the recommended dose (based on combined momelotinib and M21 AUC).1 In a pre- and post-natal development study, pregnant rats received momelotinib from organogenesis through lactation (Gestation Day 6 to lactation Day 20).1 Decreased pup body weights and embryo-lethality were observed in the dams administered 6 and 12 mg/kg per day.1 Pup survival was significantly reduced in the 12 mg/kg per day group from birth to Day 4 of lactation.1 Momelotinib exposure in dams at 6 and 12 mg/kg were approximately 2 times the exposure at the recommended dose (based on combined momelotinib and M21 AUC).1 The exposure of dams at the No Observed Effect Level dose of 2 mg/kg per day was less than the exposure at the recommended dosage (based on combined momelotinib and M21 AUC).1
In an embryo-fetal development study, pregnant rabbits received momelotinib at 7.5, 30, or 60 mg/kg per day orally during the period of organogenesis (Gestation Day 7 to 20).1 Momelotinib was associated with maternal toxicity at 60 mg/kg per 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).1 No developmental toxicity was observed at the lower dosages tested in rabbits.1
There are no data on the presence of momelotinib or its metabolites in human milk, the effects on the breast-fed child, or the effects on milk production.1 It is not known whether momelotinib is distributed into human milk.1 Because of the potential for serious adverse reactions in the breast-fed child, patients should not breast-feed during treatment with momelotinib and for at least 1 week after the last dose of momelotinib.1
Momelotinib was present in rat pups following nursing from treated dams with adverse effects observed in the offspring.1 In a pre- and post-natal development study, momelotinib was administered orally to rats during the lactation period.1 The drug was detected in the plasma of nursing pups, which adversely affected pup survival.1
Females and Males of Reproductive Potential
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 momelotinib.1
Safety and effectiveness of momelotinib in pediatric patients have not been established.1
There were 275 patients aged 65 years and older in the clinical studies for myelofibrosis.1 Of the total number of momelotinib-treated patients in these studies, 75% (163 out of 216 patients) were aged 65 years and older, and 29% (63 out of 216 patients) were aged 75 years and older.1 No overall differences in safety or effectiveness of momelotinib have been observed between patients aged 65 years and older and younger adult patients.1
Momelotinib is extensively metabolized.1 Momelotinib exposure increased with severe hepatic impairment (Child-Pugh class C); dosage adjustments are recommended in patients with severe hepatic impairment.1 No clinically significant changes in momelotinib exposure were observed in subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.1 No dosage adjustment is recommended for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.1
There are no clinically significant differences in pharmacokinetics in renal impairment (eGFR 16.4 to above 120 mL/minute per 1.73 m2).1 The effect of end stage renal disease receiving dialysis is unknown.1
The most common adverse effects of momelotinib (≥20% of patients) reported in clinical studies include thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.1
Momelotinib is metabolized by multiple cytochrome P-450 (CYP) isoenzymes, including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%).1
Momelotinib is an organic anion transporter polypeptide (OATP) 1B1 and OATP1B3 substrate.1
Momelotinib is a breast cancer resistance protein (BCRP) inhibitor.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Momelotinib is metabolized by multiple cytochrome P-450 (CYP) isoenzymes, including CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP1A2.1 No clinically significant differences in momelotinib and M21 metabolite pharmacokinetics were observed when used concomitantly with multiple-dose rifampin (a strong CYP3A4 inducer) or with ritonavir (a strong CYP3A4 inhibitor).1 No clinically significant differences in the pharmacokinetics of midazolam (a CYP3A4 substrate) were observed when used concomitantly with momelotinib.1
Drugs Affecting or Affected by Transport Systems
Momelotinib is an OATP1B1 and OATP1B3 substrate.1 Concomitant use of an OATP1B1 or OATP1B3 inhibitor increases momelotinib maximum concentrations (Cmax) and AUC, which may increase the risk of adverse reactions with momelotinib.1 Momelotinib Cmax increased by 40% and AUC increased by 57% following concomitant use with a single dose of rifampin (an OATP1B1/1B3 inhibitor); the M21 metabolite Cmax increased by 6% and AUC increased by 12%.1 Monitor patients concomitantly receiving an OATP1B1/1B3 inhibitor for adverse reactions and consider momelotinib dosage modifications.1
Momelotinib is a BCRP inhibitor.1 Momelotinib may increase exposure of BCRP substrates, which may increase the risk of BCRP substrate adverse reactions.1 The Cmax and AUC of rosuvastatin (a BCRP substrate) increased 220% and 170%, respectively, when a single dose of 10 mg was concomitantly administered with multiple doses of momelotinib.1 When administered concomitantly with momelotinib, initiate rosuvastatin at 5 mg and do not increase to more than 10 mg once daily.1 Dosage adjustment of other BCRP substrates may also be needed.1 Follow approved product information recommendations for other BCRP substrates.1
Drugs Affecting Gastric Acidity
No clinically significant differences in momelotinib and M21 metabolite pharmacokinetics were observed when used concomitantly with omeprazole.1
Momelotinib is an inhibitor of wild type Janus Kinase (JAK) 1 and 2 and mutant JAK2V617F, which contribute to signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function.1 Momelotinib and its major human circulating metabolite, M21, have higher inhibitor activity for JAK2 compared to JAK3 and tyrosine kinase 2.1 Momelotinib and M21 additionally inhibit activin A receptor type 1 (ACVR1), also known as activin receptor like kinase 2, which produces subsequent inhibition of liver hepcidin expression and increased iron availability resulting in increased red blood cell production.1 Myelofibrosis is a myeloproliferative neoplasm associated with constitutive activation and dysregulated JAK signaling that contributes to inflammation and hyperactivation of ACVR1.1 JAK signaling recruits and activates signal transducers and activation of transcription (STAT) proteins resulting in nuclear localization and subsequent regulation of gene transcription.1 Momelotinib inhibited STAT3 phosphorylation in whole blood and was associated with an acute and sustained reduction in circulating hepcidin in patients with myelofibrosis.1
Momelotinib maximum concentrations (Cmax) and AUC increase proportionally from 100 to 300 mg (0.5 to 1.5 times the recommended dosage) but less than dose-proportional at dosages from 400 to 800 mg.1 There is no clinically significant accumulation.1 The median time to Cmax (Tmax) at steady state is 2 hours post dose.1 No clinically significant differences in momelotinib were observed following administration of either a high-fat (800 kcal, 50% fat) or low-fat (400 kcal, 20% fat) meal in healthy subjects.1 Momelotinib plasma protein binding is approximately 91% in healthy volunteers.1 The elimination half-life of momelotinib and the M21 metabolite is 4 to 8 hours.1 Momelotinib is metabolized by multiple cytochrome P-450 (CYP) isoenzymes, including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%).1 M21 is an active human metabolite that has approximately 40% of the pharmacological activity of the parent drug.1 M21 is formed by CYP followed by aldehyde oxidase metabolism of momelotinib.1 The mean M21 to momelotinib ratio for AUC ranged from 1.4 to 2.1.1 Following a single oral dose of radiolabeled momelotinib, 69% (13% unchanged) of radioactivity was excreted in feces and 28% (<1% unchanged) in urine.1 Approximately 12% of the administered dose was excreted in the urine as M21.1 No clinically significant differences in momelotinib and M21 pharmacokinetics were observed based on age (range, 28 to 92 years of age), race, sex, weight (range, 34-138 kg), renal impairment, or mild or moderate hepatic impairment.1 The effect of end stage renal disease receiving dialysis on momelotinib pharmacokinetics is not known.1 Momelotinib Cmax increased by 13% and AUC increased by 97% in subjects with severe hepatic impairment (Child-Pugh class C).1 The M21 metabolite Cmax decreased by 76% and AUC decreased by 48% in subjects with severe hepatic impairment (Child-Pugh class C).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Momelotinib is obtained through designated specialty distributors and pharmacies. Contact manufacturer or consult the momelotinib website ([Web]) for specific availability information.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 100 mg (of momelotinib) | Ojjaara® | GlaxoSmithKline |
150 mg (of momelotinib) | Ojjaara® | GlaxoSmithKline | ||
200 mg (of momelotinib) | Ojjaara® | GlaxoSmithKline |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. GlaxoSmithKline. Ojjaara® (momelotinib) oral tablets prescribing information. Durham, NC; 2026 May
2. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. [Web]
3. Verstovsek S, Gerds AT, Vannucchi AM, et al; MOMENTUM Study Investigators. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023; 401(10373):269-280.
4. Gerds AT, Verstovsek S, Vannucchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an udpated analysis of an international, double-blind, randomised phase 3 study. Lancet Haematol. 2023; 10(9):e735-e746.
5. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus Kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017; 35(34):3844-3850.
6. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018; 5(2):e73-e81.
7. Shantzer L, Berger K, Pu JJ. Primary myelofibrosis and its targeted therapy. Ann Hematol. 2017; 96(4):531-535.
8. Tremblay D, Mascarenhas J. Next generation therapeutics for the tretament of myelofibrosis. Cells. 2021; 10(5):1034.
9. Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from the European LeukemiaNet. Leukemia. 2018; 32(5):1057-1069.
10. Kröger N, Bacigalupo A, Barbui T, et al. Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EMBT/ELN International Working Group. Lancet Haematol. 2024; 11(1):e62-e74.
11. Vannucchi AM, Barbui T, Cervantes F, et al; ESCO Guidelines Committee. Philadelphia chromosome-negative chronic myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v85-99.
12. Polverelli N, Hernández-Boluda JC, Czerw T, et al. Splenomegaly in patients with primary or secondary myelofibrosis who are candidates for allogeneic hematopoietic cell transplantation: a Position Paper on behalf of the Chronic Malignancies Working Party of the EBMT. Lancet Haematol. 2023; 10(1):e59-e70.