Momelotinib

Momelotinib is an oral inhibitor of Janus kinases 1 and 2 (JAK1 and JAK2) that also inhibits activin A receptor type 1 (ACVR1, also called activin receptor-like kinase 2 or ALK-2). Myelofibrosis is a myeloproliferative neoplasm in which JAK signalling is constitutively active and dysregulated, which contributes to inflammation and to over-activity of ACVR1.

Mechanism of Action

• JAK1/JAK2 inhibition: momelotinib and its major circulating metabolite, M21, inhibit wild-type JAK1 and JAK2 and the mutant JAK2 V617F. These kinases activate STAT proteins that control gene transcription affecting inflammation, haematopoiesis and immune regulation. Both compounds act on JAK2 more strongly than on JAK3 and TYK2.
• ACVR1 inhibition: momelotinib and M21 also inhibit ACVR1 directly. This lowers liver hepcidin expression, increases iron availability and raises red blood cell production.
• Pharmacodynamic effects: in blood from patients with myelofibrosis, cytokine-induced STAT3 phosphorylation was inhibited most strongly 2 hours after a dose, and the effect lasted at least 6 hours. Circulating hepcidin fell quickly and stayed low throughout a 24-week study, with higher iron levels and haemoglobin.
• Active metabolite: M21 retains about 40% of the pharmacological activity of momelotinib.
• Other kinases: momelotinib and M21 may also inhibit further kinases, among them other JAK family members, IKK and IRAK1.

Pharmacokinetics

• Absorption: rapid, with peak plasma concentration within 3 hours of a dose. Exposure rises less than in proportion to dose, especially above 300 mg. At 200 mg once daily at steady state, mean Cmax was 479 ng/mL and AUCtau 3,288 ng×h/mL. Low-fat and high-fat meals raised Cmax (by 38% and 28%) and AUC (by 16% and 28%), which was not clinically meaningful.
• Distribution: about 91% bound to plasma proteins; the apparent volume of distribution at steady state is 984 L, indicating extensive tissue distribution.
• Metabolism: by several CYP enzymes (CYP3A4 36%, CYP2C8 19%, CYP2C19 19%, CYP2C9 17%, CYP1A2 9%). The active metabolite M21 is formed by CYP oxidation followed by aldehyde oxidase; the M21-to-momelotinib AUC ratio ranges from 1.4 to 2.1.
• Elimination: terminal half-life about 4 to 8 hours for momelotinib, and similar for M21; apparent total clearance 103 L/h. After a radiolabelled dose, 69% of the radioactivity appeared in the faeces (13% of the dose as unchanged momelotinib) and 28% in the urine (less than 1% as unchanged momelotinib).
• Special populations: the SmPC advises no dose adjustment for patients aged 65 years and older or for renal impairment above 15 mL/min, and a lower starting dose in severe hepatic impairment (see Administration and Dosage).

• Myelofibrosis with moderate to severe anaemia: treatment of disease-related splenomegaly or symptoms in adults with moderate to severe anaemia who have primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis and who are Janus kinase (JAK) inhibitor-naïve or have been treated with ruxolitinib.

• Hypersensitivity to momelotinib or to any of the excipients (SmPC section 6.1).
• Pregnancy.
• Breast-feeding.

The reactions below were identified in 448 patients who received Omjjara 200 mg daily for a median of 24 weeks in three randomised, active-controlled phase 3 studies in adults with myelofibrosis (MOMENTUM, SIMPLIFY-1 and SIMPLIFY-2). The most common were diarrhoea (23%), thrombocytopenia (21%), nausea (17%), headache (13%), dizziness (13%), fatigue (12%), asthenia (11%), abdominal pain (11%) and cough (10%). Thrombocytopenia was also the most common severe reaction (grade 3 or higher, 12%), the most common reason for stopping treatment (2.5%) and the most common reason for dose reduction or interruption (7%).

Very common (≥1/10): thrombocytopenia, dizziness, headache, cough, diarrhoea, abdominal pain, nausea, asthenia, fatigue.

Common (≥1/100 to <1/10): urinary tract infection, upper respiratory tract infection, pneumonia, nasopharyngitis, COVID-19, cystitis, bronchitis, oral herpes, sinusitis, herpes zoster, cellulitis, respiratory tract infection, sepsis, lower respiratory tract infection, oral candidiasis, skin infection, gastroenteritis, neutropenia, vitamin B1 deficiency, syncope, peripheral neuropathy, paraesthesia, blurred vision, vertigo, hypotension, haematoma, flushing, vomiting, constipation, rash, arthralgia, pain in extremity, pyrexia, increased alanine and aspartate aminotransferase, contusion.

Uncommon (≥1/1,000 to <1/100): COVID-19 pneumonia.

Not known: hypersensitivity (reported after marketing).

Serious and fatal infections, severe thrombocytopenia and neutropenia, liver enzyme increases, and reports of cardiovascular events, thrombosis and malignancies are the main safety points (see Special Instructions).

Momelotinib is cleared by several CYP enzymes (CYP3A4 contributes most) and aldehyde oxidase, and it is a substrate of the uptake transporters OATP1B1 and OATP1B3. It also inhibits some transporters and enzymes.

• Strong CYP3A4 inducers (carbamazepine, phenobarbital, phenytoin, St John’s wort): can lower momelotinib exposure and efficacy; rifampicin 600 mg daily for 7 days lowered Cmax by 29.4% and AUC by 46.1% against a single rifampicin dose. Monitor the clinical signs and symptoms of myelofibrosis more closely. Rifampicin itself, which also inhibits OATP1B1/1B3, changed AUC by only 15.3% and can be given without a dose change.
• OATP1B1/1B3 inhibitors (including ciclosporin): a single dose of rifampicin raised momelotinib Cmax by 40.4% and AUC by 57.1%. Use with caution and monitor for adverse reactions.
• BCRP substrates: momelotinib inhibits BCRP. Rosuvastatin Cmax rose 3.2-fold and AUC 2.7-fold, and other sensitive BCRP substrates such as sulfasalazine may also rise. Monitor for adverse reactions.
• P-gp substrates with a narrow therapeutic index: momelotinib may inhibit P-gp in the gut; use with caution.
• OCT1, MATE1 and MATE2-K substrates (for example metformin): momelotinib and M21 may inhibit these transporters; use sensitive substrates with caution.
• CYP1A2 and CYP2B6 substrates: momelotinib may induce CYP1A2 and CYP2B6 and may inhibit CYP2B6. Use narrow-therapeutic-index or sensitive substrates of CYP1A2 (theophylline, tizanidine) or CYP2B6 (cyclophosphamide) with caution.
• Hormonal contraceptives: induction of other PXR-regulated enzymes cannot be excluded, so systemic hormonal contraceptives may be less effective; add a barrier method (see Special Instructions).
• Other JAK inhibitors: Omjjara must not be combined with them.
• Food: it can be taken with or without meals.

Treatment should be started and monitored by physicians experienced in the use of anti-cancer medicinal products. The tablets are taken by mouth, with or without meals. A complete blood count and liver function tests are required before starting, periodically during treatment and as clinically indicated.

Recommended Dose

• 200 mg once daily, continued for as long as the benefit-risk balance remains positive in the treating physician’s judgement.

Dose Modifications

Dose modification should be considered for haematological and non-haematological toxicity. Each reduction is 50 mg below the last given dose; doses may be raised again, up to the starting dose, as clinically appropriate, and a patient previously on 100 mg may restart at 100 mg. Treatment is discontinued in patients who cannot tolerate 100 mg once daily.

• Thrombocytopenia: with a baseline platelet count of 100 × 10⁹/L or more, a fall to 20 to below 50 × 10⁹/L calls for a 50 mg reduction of the daily dose. A fall below 20 × 10⁹/L (baseline 50 × 10⁹/L or more) means interrupting treatment until platelets recover to 50 × 10⁹/L, then restarting 50 mg lower. With a baseline below 50 × 10⁹/L and a fall below 20 × 10⁹/L, interrupt until platelets recover to baseline, then restart 50 mg lower.
• Neutropenia: absolute neutrophil count below 0.5 × 10⁹/L means interrupting until it is 0.75 × 10⁹/L or higher, then restarting 50 mg lower.
• Hepatotoxicity (unless another cause is apparent): ALT or AST above 5 times the upper limit of normal (or baseline, if abnormal) and/or total bilirubin above 2 times the upper limit (or baseline) means interrupting until AST and ALT are 2 times the upper limit or baseline or lower and bilirubin is 1.5 times the upper limit or baseline or lower, then restarting 50 mg lower. If ALT or AST above 5 times the upper limit recurs, stop permanently.
• Other non-haematological toxicity: grade 3 or higher toxicity, or grade 2 or higher bleeding, means interrupting until it resolves to grade 1 or lower (or baseline), then restarting 50 mg lower.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years and older.
• Renal impairment: no adjustment for renal impairment above 15 mL/min; not studied in end-stage renal disease.
• Hepatic impairment: no adjustment for mild or moderate impairment; the recommended starting dose in severe impairment (Child-Pugh C) is 150 mg once daily.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.

Missed Dose

If a dose is missed, take the next scheduled dose the following day. Never take two doses together to make up for a missed one.

Infections

Serious and fatal bacterial and viral infections, including COVID-19, have occurred. Omjjara should not be started in patients with active infections. Patients should be watched for signs and symptoms of infection (fever, cough, diarrhoea, vomiting, nausea, pain on urination) and treated promptly.

Hepatitis B Reactivation

Rises in hepatitis B viral load, with or without raised ALT or AST, have been reported in patients with chronic hepatitis B taking JAK inhibitors, including Omjjara. Its effect on viral replication is unknown. Patients with chronic hepatitis B should have the infection treated and monitored according to clinical guidelines.

Blood Counts and Liver Function

New severe (grade 3 or higher) thrombocytopenia and neutropenia occurred. A blood count with platelets and liver function tests are done before treatment, periodically during it and when clinically indicated. Dose interruption or reduction may be needed for low counts or suspected treatment-related increases in ALT, AST or bilirubin.

Cardiovascular Events and Thrombosis

In a large randomised study of another JAK inhibitor (tofacitinib) in rheumatoid arthritis patients aged 50 and over with at least one cardiovascular risk factor, major adverse cardiovascular events and, dose-dependently, venous thromboembolism occurred more often than with TNF inhibitors. Such events, including deep vein thrombosis and pulmonary embolism, have been reported with Omjjara, but a causal relationship has not been established, and in trials the rate of thromboembolic events was similar to controls. Before and during treatment the individual benefit and risk should be weighed, particularly in patients aged 65 or older, current or past long-term smokers, and those with atherosclerotic cardiovascular disease or other risk factors. Symptoms of thrombosis need prompt evaluation and treatment.

Second Primary Malignancies

In the same tofacitinib study, malignancies (particularly lung cancer, lymphoma and non-melanoma skin cancer) were more frequent than with TNF inhibitors. Lymphoma and other malignancies have been reported with JAK inhibitors, including Omjjara; a causal association has not been established.

Medicines That Interact

Patients taking sensitive BCRP substrates such as rosuvastatin and sulfasalazine should be monitored for adverse reactions. With strong CYP3A4 inducers, monitor the signs and symptoms of myelofibrosis for loss of efficacy (see Drug Interactions).

Pregnancy, Breastfeeding and Fertility

• Contraindication: Omjjara is contraindicated in pregnancy and during breast-feeding.
• Contraception: women of childbearing potential should avoid becoming pregnant. It is unknown whether Omjjara reduces the effect of systemic hormonal contraceptives, so these users should add a barrier method during treatment and for at least 1 week after the last dose.
• Pregnancy: there are no human data. Animal studies showed embryo-foetal toxicity at exposures below those in humans, and as a JAK inhibitor it caused embryo-foetal mortality and teratogenicity in rats and rabbits at clinically relevant exposures. If used in pregnancy, or if the patient becomes pregnant, treatment should stop and the patient should be told of the risk to the foetus.
• Breast-feeding: it is unknown whether momelotinib or its metabolites pass into human milk; momelotinib was present in rat pups nursed by treated dams, with adverse events, so a risk to the breast-fed child cannot be excluded.
• Fertility: no human data; momelotinib impaired fertility in male and female rats.

Lactose and Sodium

The tablets contain lactose monohydrate (50.8 mg, 76.1 mg and 101.5 mg in the 100 mg, 150 mg and 200 mg tablets). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them. Each tablet contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Omjjara may have a minor influence on the ability to drive and use machines. Patients who feel dizzy or have blurred vision after a dose should take care.

Store in the original bottle to protect from moisture. Do not remove the desiccant and do not swallow it. No special temperature storage conditions are required. Each carton holds one white high-density polyethylene bottle with a child-resistant cap and an induction-sealed liner, containing 30 film-coated tablets, a silica gel desiccant and a polyester coil.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Treatment is started and monitored by a physician experienced in the use of anti-cancer medicinal products. Omjjara tablets are taken at home, so the medicine is supplied to the patient or to the treating clinic on prescription.