Momelotinib

Momelotinib may inhibit organic cation transporter 1 (OCT1). The active metabolite of momelotinib, M21, may inhibit multidrug and toxic compound extrusion transporter 1 (MATE1). Momelotinib and M21 have not been evaluated for MATE2-K inhibition. Therefore, caution is advised when administering momelotinib with sensitive substrates of OCT1, MATE1 and MATE2-K (e.g., metformin).

Momelotinib is an inhibitor of BCRP in vitro. Co-administration of a single dose of rosuvastatin at 10 mg (a BCRP substrate) with multiple doses of momelotinib (200 mg once daily) increased rosuvastatin C_max by 3.2-fold and AUC by 2.7-fold, which may increase the risk of adverse reactions of rosuvastatin. T_max and t_1/2 of rosuvastatin remained unchanged. Momelotinib may increase exposure to other sensitive BCRP substrates, including sulfasalazine.

Momelotinib is a substrate of OATP1B1 and OATP1B3 transporters. Co-administration with a single dose of rifampicin, capturing the OATP1B1/1B3 inhibition effect, moderately increased momelotinib exposure (C_max by 40.4% and AUC_inf by 57.1%). Therefore, caution and monitoring for adverse reactions is advised with concomitant use of OATP1B1/1B3 inhibitors, including ciclosporin.

Momelotinib may induce CYP1A2 and CYP2B6 and may inhibit CYP2B6. Therefore, narrow therapeutic index or sensitive substrate medicinal products of CYP1A2 (e.g., theophylline, tizanidine) or CYP2B6 (e.g., cyclophosphamide) should be co-administered with momelotinib with caution.

Momelotinib may inhibit P-gp in the gut and increase exposure to P-gp substrates. Therefore, caution is advised when administering momelotinib with P-gp substrates with a narrow therapeutic index.

Multiple doses of rifampicin (600 mg daily for 7 days) decreased momelotinib C_max by 29.4% and AUC_inf by 46.1% when compared with momelotinib (200 mg single dose) plus rifampicin single‑dose (600 mg), to capture the induction effect of rifampicin. Co-administration of strong CYP3A4 inducers may lead to decreased momelotinib exposure and consequently a risk for reduced efficacy. Therefore, additional monitoring of the clinical signs and symptoms of myelofibrosis is recommended with concomitant use of momelotinib and strong CYP3A4 inducers (including but not limited to carbamazepine, phenobarbital, phenytoin, and St John’s wort [Hypericum perforatum]).

The recommended starting dose of momelotinib is 150 mg once daily in patients with severe hepatic impairment (Child-Pugh Class C).

Multiple doses of momelotinib had no influence on the exposure of midazolam, a sensitive CYP3A substrate. However, a risk for induction of other pregnane X receptor (PXR) regulated enzymes apart from CYP3A4 cannot be completely excluded and the effectiveness of concomitant administration of oral contraceptives may be reduced.

Major adverse cardiovascular events (MACE) have been reported in patients receiving Omjjara, however, a causal relationship has not been established. Prior to initiating or continuing therapy with Omjjara, the benefits and risks for the individual patient should be considered particularly in patients 65 years of age and older, patients who are current or past long-time smokers, and patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors.

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 JAK inhibitors, including momelotinib. The effect of momelotinib on viral replication in patients with chronic HBV infection is unknown. Patients with chronic HBV infection who receive momelotinib should have their chronic HBV infection treated and monitored according to clinical HBV guidelines.

There are no data from the use of momelotinib in pregnant women. Studies in animals have shown embryo-foetal toxicity at exposures lower than human exposure at the recommended dose. Based on its mechanism of action, momelotinib may cause foetal harm. As a JAK inhibitor, momelotinib has been shown to cause embryo-foetal mortality and teratogenicity in pregnant rats and rabbits at clinically-relevant exposures. Momelotinib is contraindicated during pregnancy. If momelotinib is used during pregnancy, or if the patient becomes pregnant while taking this medicinal product, the patient should discontinue treatment and be advised of the potential hazard to the foetus.

It is unknown whether momelotinib/metabolites are excreted in human milk. Momelotinib was present in rat pups following nursing from treated dams with adverse events in the offspring. A risk to the breast-fed child cannot be excluded. Momelotinib is contraindicated during breast-feeding.

Women of childbearing potential/Contraception

Women of childbearing potential should be advised to avoid becoming pregnant whilst receiving momelotinib. It is currently unknown whether momelotinib may reduce the effectiveness of systemically acting hormonal contraceptives, therefore women using systemically acting hormonal contraceptives should add a barrier method during treatment and for at least 1 week after the last dose of momelotinib.

Fertility

There are no data on the effects of momelotinib on human male or female fertility. In animal studies, momelotinib impaired fertility in male and female rats.

Momelotinib may have a minor influence on the ability to drive and use machines, dizziness or blurred vision may occur. Patients who experience dizziness or blurred vision after taking momelotinib should observe caution when driving or using machines.

Summary of the safety profile

The safety of momelotinib, evaluated in three randomised, active-controlled, multicentre studies in adults with myelofibrosis (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), is presented below (table). Among patients treated with momelotinib 200 mg daily in the randomised treatment period of the clinical trials (n=448), the most common adverse reactions were diarrhoea (23%), thrombocytopenia (21%), nausea (17%), headache (13%), dizziness (13%), fatigue (12%), asthenia (11%), abdominal pain (11%), and cough (10%).

The most common severe adverse reaction (≥ Grade 3) was thrombocytopenia (11%). The most common adverse reaction leading to discontinuation of momelotinib was thrombocytopenia (2%). The most common adverse reaction requiring dosage reduction and/or treatment interruption was thrombocytopenia (7%).

Tabulated list of adverse reactions

The following adverse reactions have been identified in 448 patients exposed to momelotinib during a median duration of 24 weeks during clinical trials. Adverse reactions are listed by MedDRA system organ classification (SOC) and by frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as:

Very common: ≥1/10
Common: ≥1/100 to <1/10
Uncommon: ≥1/1 000 to <1/100
Rare: ≥1/10 000 to <1/1 000

Summary of adverse reactions reported in Phase 3 studies in adults with myelofibrosis:

^a Thrombocytopenia includes platelet count decreased.
^b Neutropenia includes neutrophil count decreased. c Peripheral neuropathy includes peripheral sensory neuropathy, peripheral motor neuropathy, neuropathy peripheral, peripheral sensorimotor neuropathy, neuralgia, and polyneuropathy.

Description of selected adverse reactions

Infections

In the three randomised clinical trials, the most common infections were urinary tract infection (6%), upper respiratory tract infection (4.9%), pneumonia (3.6%), nasopharyngitis (2.9%), COVID-19 (2.7%), cystitis (2.7%), bronchitis (2.5%), and oral herpes (2.5%). The majority of infections were mild or moderate; the most frequently reported severe (≥ Grade 3) infections were pneumonia, sepsis, urinary tract infection, cellulitis, COVID-19 pneumonia, COVID-19, herpes zoster, cystitis, and skin infection. The proportion of patients discontinuing treatment due to an infection was 2% (9/448). Fatal infections were reported in 2.2% (10/448) of patients (most frequently reported COVID-19 and COVID-19 pneumonia).

Thrombocytopenia

In the three randomised clinical trials, 21% (94/448) of patients treated with momelotinib experienced thrombocytopenia; 12% (54/448) of patients treated with momelotinib experienced severe thrombocytopenia (≥ Grade 3). The proportion of patients discontinuing treatment due to thrombocytopenia was 2.5% (11/448).

Peripheral neuropathy

In the three randomised clinical trials, 8.7% (39/448) of patients treated with momelotinib experienced peripheral neuropathy. The majority of cases were mild or moderate, while one of the 39 cases was severe (≥ Grade 3). The proportion of patients discontinuing treatment due to peripheral neuropathy was 0.7% (3/448).

Elevated ALT/AST

In the three randomised clinical trials, new or worsening elevations of ALT and AST (all grades) occurred in 20% (88/448) and 20% (90/448), respectively, of patients treated with momelotinib; Grade 3 and 4 transaminase elevations occurred in 1.1% (5/448) and 0.2% (1/448) of patients, respectively. Reversible drug-induced liver injury has been reported in patients with myelofibrosis treated with momelotinib in clinical trials.