Momelotinib Dihydrochloride (Monograph)

Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

[Web]

Introduction

Janus Kinase (JAK) 1 and 2 and mutant JAK2^V617F inhibitor; antineoplastic agent.

Uses for Momelotinib Dihydrochloride

Intermediate- and High-Risk Myelofibrosis

Indicated for 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; designated as an orphan drug by the FDA for this use.

Patients with low- or intermediate-risk MF who lack significant symptoms may be managed with observation alone. However, if cytoreductive therapy is indicated in low- to intermediate-risk patients, hydroxyurea is often recommended as first-line treatment. Historically, MF-associated splenomegaly was treated with hydroxyurea; however, some experts recommend JAK inhibitors 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.

Momelotinib Dihydrochloride Dosage and Administration

General

Pretreatment Screening

• Obtain CBC with platelet and neutrophil counts.

• Obtain a hepatic function panel. Delay starting in uncontrolled acute or chronic liver disease until apparent causes investigated and treated as clinically indicated.

• In patients with hepatitis B virus infections, check hepatitis B serologies. If HBsAg and/or anti-HBc antibody is positive, consider consultation with a hepatologist regarding monitoring for reactivation versus prophylactic hepatitis B therapy.

• Assess the risks and benefits for major cardiovascular adverse events, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.

Patient Monitoring

• Obtain CBC with platelet and neutrophil counts periodically during treatment and as clinically indicated.

• Monitor hepatic function (including AST, ALT, and bilirubin) every month for first 6 months, then periodically as clinically indicated.

• Monitor for signs and symptoms of infection, including reactivation of hepatitis B, and initiate appropriate treatment promptly.

• Assess the risks and benefits for major cardiovascular adverse events while continuing therapy, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.

• Monitor for symptoms of major cardiovascular adverse events and evaluate and treat promptly.

• Monitor for the development of secondary malignancies, particularly in current or past smokers.

• Evaluate symptoms of thrombosis, including deep vein thrombosis and pulmonary embolism, and treat appropriately.

Administration

Swallow whole; do not cut, crush, or chew.

Can be taken with or without food.

If a dose is missed, next scheduled dose should be taken the following day.

Delay starting until active infections have resolved.

Dosage

Dosage of momelotinib dihydrochloride expressed in terms of momelotinib.

Adults

Myelofibrosis

Oral

200 mg once daily with or without food.

Dosage Modifications for Toxicity

Dosage modifications recommended for hematologic and non-hematologic adverse reactions (see Tables 1 and 2). Discontinue in patients unable to tolerate 100 mg once daily.

Reinitiate or escalate treatment up to starting dosage as clinically appropriate.

May reinitiate at 100 mg if previous dosage was 100 mg.

Reinitiate or escalate treatment up to starting dosage as clinically appropriate.

May reinitiate at 100 mg if previous dosage was 100 mg.

If baseline >2 times ULN.

If baseline >1.5 times ULN.

Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events.

Special Populations

Hepatic Impairment

Recommended starting dosage in severe hepatic impairment (Child-Pugh class C) is 150 mg orally once daily. No dosage adjustment recommended in mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Momelotinib Dihydrochloride

Contraindications

• None.

Warnings/Precautions

Risk of Infections

Serious, including fatal, infections (e.g., bacterial and viral, including COVID-19) reported. Delay starting momelotinib until active infections have resolved. Monitor patients for signs and symptoms of infection and initiate appropriate treatment promptly.

Hepatitis B viral load (hepatitis B viral-DNA titer) increases, with or without associated elevations in ALT or AST, reported in patients with chronic hepatitis B virus (HBV) infection taking JAK inhibitors, including momelotinib. The effect of momelotinib on viral replication in patients with chronic HBV infection unknown. In patients with HBV infections, check hepatitis B serologies prior to initiation. If HBsAg and/or anti-HBc antibody is positive, consider consultation with hepatologist regarding monitoring for reactivation versus prophylactic hepatitis B therapy. Patients with chronic HBV infection should have chronic HBV infection treated and monitored according to clinical HBV guidelines.

Thrombocytopenia and Neutropenia

Momelotinib can cause thrombocytopenia and neutropenia. Assess CBC, including platelet and neutrophil counts, before initiating treatment and periodically during treatment as clinically indicated. Interrupt dosing or reduce the dosage for thrombocytopenia or neutropenia (see Tables 1 and 2).

Hepatotoxicity

Reversible drug-induced liver injury reported, including new or worsening elevations of ALT, AST, and total bilirubin. The median time to onset of any grade aminotransferase elevation was 2 months, with 75% of cases occurring within 4 months. Delay starting momelotinib in patients presenting with uncontrolled acute or chronic liver disease until apparent causes have been investigated and treated as clinically indicated. When initiating momelotinib, refer to manufacturer recommended dosing in hepatic impairment. Monitor liver function tests at baseline, every month for first 6 months, then periodically as clinically indicated. Modify dosage for increases in ALT, AST, or bilirubin suspected to be related to treatment (see Table 2).

Major Adverse Cardiovascular Events (MACE)

Another JAK inhibitor increased risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which momelotinib is not indicated. Consider risks and benefits prior to initiating or continuing therapy, particularly in current or past smokers and patients with other cardiovascular risk factors. Inform patients of symptoms of serious cardiovascular events and steps to take if they occur.

Thrombosis

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. Evaluate patients with symptoms of thrombosis and treat appropriately.

Malignancies

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. Current or past smokers are at increased risk. Consider benefits and risks prior to initiating or continuing therapy, particularly in patients with known malignancy (other than a successfully treated non-melanoma skin cancer), patients who develop a malignancy, and patients who are current or past smokers.

Specific Populations

Pregnancy

Insufficient evidence in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on animal studies, may cause embryo-fetal toxicity at exposures lower than expected exposure in patients receiving momelotinib 200 mg once daily. Momelotinib should only be used during pregnancy if expected benefits to the mother outweigh potential risks to fetus.

Lactation

No data on the presence of momelotinib or its metabolites in human milk, effects on breast-fed child, or effects on milk production. Unknown whether momelotinib distributed into human milk. Because of potential for serious adverse reactions in the breast-fed child, breastfeeding not recommended during treatment and for at least 1 week after last dose of momelotinib.

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.

Pediatric Use

Safety and effectiveness in pediatric patients not established.

Geriatric Use

No overall differences in safety or effectiveness observed between patients aged ≥65 years and younger adult patients.

Hepatic Impairment

Momelotinib is extensively metabolized. Exposure increases with severe hepatic impairment (Child-Pugh class C); dosage adjustments are recommended in severe hepatic impairment. No clinically significant changes in exposure observed in mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment.

Renal Impairment

No clinically significant differences in pharmacokinetics in renal impairment (eGFR 16.4 to above 120 mL/minute per 1.73 m2). Effect of end stage renal disease receiving dialysis is unknown.

Common Adverse Effects

Most common adverse effects (≥20%) include thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, nausea.

Drug Interactions

Metabolized by multiple CYP isoenzymes, including CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP1A2.

Organic anion transporter polypeptide (OATP) 1B1 and OATP1B3 substrate.

Breast cancer resistance protein (BCRP) inhibitor.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Metabolized by multiple CYP isoenzymes, including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%). Clinically important drug interactions with CYP3A4 inducers, inhibitors, and substrates were not observed.

Drugs Affecting or Affected by Transport Systems

Momelotinib is an OATP1B1 and OATP1B3 substrate. Concomitant use of an OATP1B1 or OATP1B3 inhibitor increases C_max and AUC, which may increase risk of adverse reactions with momelotinib. Monitor patients concomitantly receiving an OATP1B1/1B3 inhibitor for adverse reactions and consider momelotinib dose modifications.

Momelotinib may increase exposure of BCRP substrates, which may increase the risk of BCRP substrate adverse reactions. Dose adjustment of other BCRP substrates may be needed. Follow approved product information recommendations for other BCRP substrates.

Specific Drugs

Momelotinib Dihydrochloride Pharmacokinetics

Absorption

Bioavailability

Systemic exposure (C_max 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.

No clinically significant accumulation.

Onset

T_max (steady state): 2 hours post dose.

Effect of Food

No clinically significant differences observed following administration of high-fat (800 kcal, 50% fat) or low-fat (400 kcal, 20% fat) meal in healthy subjects.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

Approximately 91%.

Elimination

Metabolism

Metabolized by multiple CYP isoenzymes, including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%).

M21 is active human metabolite with approximately 40% of pharmacological activity of parent drug. M21 is formed by CYP followed by aldehyde oxidase metabolism of momelotinib.

Mean M21:momelotinib ratio for AUC: 1.4 to 2.1.

Elimination Route

Eliminated in feces (69%, 13% unchanged) and urine (28%, <1% unchanged).

Approximately 12% excreted in urine as M21 metabolite.

Half-life

4 to 8 hours.

Special Populations

No clinically significant differences in pharmacokinetics 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. Effect of end stage renal disease receiving dialysis on pharmacokinetics not known. C_max increased by 13% and AUC increased by 97% in severe hepatic impairment (Child-Pugh class C). M21 metabolite C_maxdecreased by 76% and AUC decreased by 48% in severe hepatic impairment (Child-Pugh class C).

Stability

Storage

Oral

Tablets, film-coated

Store at 20-25°C; excursions permitted to 15-30°C. Dispense and store in original bottle to protect from moisture. Replace cap securely each time after opening. Do not discard desiccant.

Actions

• Inhibitor of wild type JAK 1 and 2 and mutant JAK2^V617F, which contribute to signaling of cytokines and growth factors important for hematopoiesis and immune function.

• Momelotinib and major metabolite (M21) have higher inhibitor activity for JAK2 compared to JAK3 and tyrosine kinase 2.

• 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.

• Myelofibrosis 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 signal transducers and activation of transcription proteins resulting in nuclear localization and subsequent regulation of gene transcription.

• Momelotinib inhibited STAT3 phosphorylation in whole blood and was associated with an acute and sustained reduction in circulating hepcidin in patients with myelofibrosis.

Advice to Patients

• Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information).

• Advise patients that momelotinib should be swallowed whole with or without food. Tablets should not be cut, crushed, or chewed. Advise patients that if a dose of momelotinib is missed, the next scheduled dose should be taken the following day. Advise patients to store momelotinib in the original bottle with the desiccant to protect from moisture and to replace the cap securely each time after opening.

• Advise patients that momelotinib can increase the risk of infections, including COVID-19. Advise patients to promptly contact their clinician with any signs and symptoms of infection.

• Advise patient to inform their clinician if they have a history of HBV infection. Inform patients with a history of HBV infections that hepatitis B serologies should be obtained prior to starting momelotinib. Inform patients that based on the results of these tests, consultation with a hepatologist regarding monitoring for reactivation versus prophylactic hepatitis B therapy may be advised.

• Advise patients on the risk of thrombocytopenia and neutropenia while receiving momelotinib. Inform patients that monitoring of CBC, including platelet and neutrophil counts, is recommended before and during treatment with momelotinib.

• Advise patients on the risk of hepatic toxicity. Inform patients that monitoring of hepatic function is recommended before and during treatment with momelotinib.

• 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 females and females of reproductive potential of the potential risk of momelotinib to a fetus. Advise females to inform their clinician of a known or suspected pregnancy. 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.

• Because of the potential for serious adverse reactions in the breast-fed child, advise patients that breastfeeding is not recommended during treatment with momelotinib and for at least 1 week after the last dose of momelotinib.

• Advise patients that events of deep vein thrombosis and pulmonary embolism 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 inform their clinician about any signs or symptoms of deep vein thrombosis or pulmonary embolism.

• Advise patients that major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular death, have been reported in clinical studies with other JAK inhibitors used to treat rheumatoid arthritis, a condition for which momelotinib is not indicated. Advise patients, particularly those that are current or past smokers and patients with other cardiovascular risk factors, to monitor for signs and symptoms of cardiovascular events and to report them promptly to their clinician.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

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.

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 is obtained through designated specialty distributors and pharmacies. Contact manufacturer or consult the momelotinib website ([Web]) for specific availability information.

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