Momelotinib (Monograph)

Brand name: Ojjaara
Drug class: Antineoplastic Agents

Introduction

Momelotinib dihydrochloride, a kinase inhibitor, is an antineoplastic agent.

Uses for Momelotinib

Momelotinib dihydrochloride has the following uses:

Momelotinib dihydrochloride 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.

Momelotinib Dosage and Administration

General

Momelotinib dihydrochloride is available in the following dosage form(s) and strength(s):

Tablets: 100 mg, 150 mg, or 200 mg of momelotinib.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

Recommended dosage: 200 mg orally once daily with or without food. Swallow tablets whole; do not cut, crush, or chew the tablets.
In patients with severe hepatic impairment (Child-Pugh Class C), reduce the starting dose to 150 mg orally once daily.
Dosage modifications may be required for hematologic and non-hematologic adverse reactions. See Full Prescribing Information for additional instructions.

Cautions for Momelotinib

Contraindications

None.

Warnings/Precautions

Risk of Infections

Serious (including fatal) infections (e.g., bacterial and viral, including COVID-19) occurred in 13% of patients treated with momelotinib. Infections regardless of grade occurred in 38% of patients treated with the drug. Delay starting therapy with momelotinib until active infections have resolved. Monitor patients receiving momelotinib for signs and symptoms of infection and initiate appropriate treatment promptly.

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 momelotinib. The effect of momelotinib on viral replication in patients with chronic HBV infection is unknown. In patients with HBV infections, check hepatitis B serologies prior to starting momelotinib. 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 momelotinib should have their chronic HBV infection treated and monitored according to clinical HBV guidelines.

Thrombocytopenia and Neutropenia

Momelotinib can cause thrombocytopenia and neutropenia.

New or worsening thrombocytopenia, with platelet count less than 50 × 10⁹/L, was observed in 20% of patients treated with momelotinib. Eight percent of patients treated with the drug had baseline platelet counts less than 50 × 10⁹/L.

Severe neutropenia, absolute neutrophil count (ANC) less than 0.5 × 10⁹/L, was observed in 2% of patients treated with momelotinib.

Assess complete blood counts (CBC), 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.

Hepatotoxicity

Two of the 993 patients with myelofibrosis (MF) who received at least one dose of momelotinib 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 momelotinib; 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 the drug. 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 momelotinib, refer to dosing in patients with hepatic impairment.

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 momelotinib dosage.

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 momelotinib is not indicated.

Consider the benefits and risks 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. Inform patients receiving momelotinib of the symptoms of serious cardiovascular events and the steps to take if they occur.

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 momelotinib is not indicated.

Evaluate patients with symptoms of thrombosis and treat appropriately.

Malignancies

Another JAK inhibitor increased the risk of lymphoma and other malignancies excluding nonmelanoma skin cancer (compared with those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which momelotinib 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 momelotinib, particularly in patients with a known malignancy (other than a successfully treated nonmelanoma skin cancer), patients who develop a malignancy, and patients who are current or past smokers.

Specific Populations

Pregnancy

Available data on the use of momelotinib 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. Momelotinib 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.

Lactation

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 momelotinib 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 momelotinib, and for at least 1 week after the last dose of the drug.

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.

Pediatric Use

The safety and effectiveness of momelotinib in pediatric patients have not been established.

Geriatric Use

There were 275 patients 65 years of age and older in the clinical studies for myelofibrosis (MF). Of the total number of momelotinib-treated patients in these studies, 163/216 (75%) were 65 years of age and older, and 63/216 (29%) were 75 years of age and older. No overall differences in safety or effectiveness of momelotinib have been observed between patients 65 years of age and older and younger adult patients.

Hepatic Impairment

The recommended starting dose of momelotinib in patients with severe hepatic impairment (Child-Pugh C) is 150 mg orally once daily. No dosage modification is recommended for patients with mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B).

Momelotinib is extensively metabolized. Drug 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).

Common Adverse Effects

The most common adverse reactions (≥20%) are thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Organic Anion Transporting Polypeptide (OATP)1B1/B3 inhibitors: Monitor for adverse reactions.
Breast Cancer Resistance Protein (BCRP) substrates: Reduce rosuvastatin (BCRP substrate) dosage. Follow approved product information recommendations for other BCRP substrates.

Actions

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. Myelofibrosis (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.

Advice to Patients

Advise the patient to read the FDA approved patient labeling.
Inform patients that momelotinib can increase the risk of infections (including COVID-19) and instruct them to promptly report to their healthcare provider any signs and symptoms of infection.
Inform patients that momelotinib can cause thrombocytopenia and neutropenia, and of the need to monitor complete blood count, including platelet and neutrophil counts, before and during treatment. Advise patients to observe for and report any bleeding to their healthcare provider.
Inform patients that momelotinib can cause hepatotoxicity, and of the need to monitor liver blood tests before and during treatment.
Advise patients that events of MACE including myocardial infarction, stroke, and cardiovascular death have been reported in clinical studies with another JAK inhibitor used to treat rheumatoid arthritis, a condition for which momelotinib is not indicated. Advise patients, especially current or past smokers and patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events and to report them to their healthcare provider.
Advise patients that events of deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which momelotinib is not indicated. Advise patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE.
Advise patients, especially current or past smokers, that lymphoma and other malignancies (excluding non-melanoma skin cancers) have been reported in clinical studies with another JAK inhibitor used to treat rheumatoid arthritis, a condition for which momelotinib is not indicated.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their prescriber of a known or suspected pregnancy.
Advise females of reproductive potential who are not pregnant to use highly effective contraception during therapy and for 1 week after the last dose of momelotinib.
Advise patients not to breastfeed during treatment with momelotinib and for at least 1 week after the last dose.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

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 Dihydrochloride
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