OMJJARA Film-coated tablet Ref.[108272] Active ingredients: Momelotinib

Infections

Infections, including serious and fatal bacterial and viral infections (including COVID-19), have occurred in patients treated with Omjjara (see section 4.8). Omjjara should not be initiated in patients with active infections. Physicians should carefully observe patients receiving Omjjara for signs and symptoms of infection (including but not limited to fever, cough, diarrhoea, vomiting, nausea, and pain upon urination) and initiate appropriate treatment promptly.

Hepatitis B reactivation

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

Thrombocytopenia and neutropenia

New onset of severe (Grade ≥3) thrombocytopenia and neutropenia was observed in patients treated with Omjjara (see section 4.8). A complete blood count including platelet count should be obtained before initiating treatment with Omjjara, periodically during treatment, and as clinically indicated.

Dose interruption or reduction may be required (see section 4.2).

Hepatic monitoring

Liver function tests should be obtained before initiating treatment with Omjjara, periodically during treatment, and as clinically indicated. If increases in ALT, AST or bilirubin related to treatment are suspected, dose interruption or reduction may be required (see section 4.2).

Major adverse cardiovascular events (MACE)

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of MACE, defined as cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke, was observed with tofacitinib compared to tumour necrosis factor (TNF) inhibitors.

Events of 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.

Thrombosis

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose dependent higher rate of venous thromboembolic events (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE) was observed with tofacitinib compared to TNF inhibitors.

Events of DVT and PE have been reported in patients receiving Omjjara. However, a causal association has not been established. In patients with myelofibrosis treated with Omjjara in clinical trials, the rates of thromboembolic events were similar in Omjjara and control-treated patients. Prior to initiating or continuing therapy with Omjjara, the benefits and risks for the individual patient should be considered particularly in patients with cardiovascular risk factors (see also section 4.4 Major adverse cardiovascular events [MACE]).

Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

Second primary malignancies

In a large randomised active controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a higher rate of malignancies, particularly lung cancer, lymphoma and non-melanoma skin cancer (NMSC) was observed with tofacitinib compared to TNF inhibitors.

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including Omjjara. However, a causal association has not been established.

Interactions

Based on the potential of Omjjara to increase the plasma concentrations of certain medicinal products (e.g., sensitive breast cancer resistance protein [BCRP] substrates, such as rosuvastatin and sulfasalazine), patients should be monitored for adverse reactions with co-administration (see section 4.5).

Co-administration of strong cytochrome P450 (CYP) 3A4 inducers may lead to decreased exposure of Omjjara and consequently a risk for reduced efficacy. Therefore, additional monitoring of the clinical signs and symptoms of myelofibrosis is recommended with concomitant use of Omjjara and strong CYP3A4 inducers (including but not limited to carbamazepine, phenobarbital, phenytoin, and St John’s wort [Hypericum perforatum]) (see section 4.5).

Women of childbearing potential

Given uncertainties whether Omjjara may reduce the effectiveness of hormonal contraceptives, women using oral hormonal contraceptives should add a barrier method during treatment and for at least 1 week after the last dose of Omjjara (see sections 4.5 and 4.6).

Excipients with known effect

Omjjara contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Effect of other medicinal products on momelotinib

Momelotinib undergoes metabolism though multiple CYP enzymes (including CYP3A4, CYP2C8, CYP2C9, CYP2C19, and CYP1A2) and aldehyde oxidase, with CYP3A4 having the greatest contribution.

Strong CYP3A4 inducers

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]).

Multiple doses of rifampicin (600 mg daily for 7 days) did not change momelotinib C_max and decreased momelotinib AUC_inf by 15.3% when compared with momelotinib alone (200 mg single dose), capturing the combined effect of CYP3A4 induction and organic anion transporting peptide (OATP)1B1 and OATP1B3 inhibition. Momelotinib can be co-administered with rifampicin without a dose modification.

Transporters

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.

Effect of momelotinib on other medicinal products

Transporters

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 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.

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).

CYP450 substrates

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.

Hormonal contraceptives

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 (see sections 4.4 and 5.2).

Women of childbearing potential/Contraception

Women of childbearing potential should be advised to avoid becoming pregnant whilst receiving Omjjara. It is currently unknown whether Omjjara 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 Omjjara (see sections 4.4 and 4.5).

Pregnancy

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 (see section 5.3). Based on its mechanism of action, Omjjara may cause foetal harm. As a JAK inhibitor, Omjjara has been shown to cause embryo-foetal mortality and teratogenicity in pregnant rats and rabbits at clinically-relevant exposures. Omjjara is contraindicated during pregnancy (see section 4.3). If Omjjara 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.

Breast-feeding

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 (see section 5.3). A risk to the breast-fed child cannot be excluded. Omjjara is contraindicated during breast-feeding (see section 4.3).

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 (see section 5.3).

Omjjara 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 Omjjara should observe caution when driving or using machines (see section 4.8).

Summary of the safety profile

The safety of Omjjara, evaluated in three randomised, active-controlled, multicentre studies in adults with myelofibrosis (MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2), is presented below (table 2). Among patients treated with Omjjara 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 Omjjara 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 Omjjara during a median duration of 24 weeks during clinical trials (see section 5.1). 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

Table 2. 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 Omjjara experienced thrombocytopenia; 12% (54/448) of patients treated with Omjjara 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 Omjjara 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 Omjjara; 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 Omjjara in clinical trials.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.