4.1. Therapeutic indications

Omjjara is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients 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.

4.2. Posology and method of administration

Treatment should be initiated and monitored by physicians experienced in the use of anti-cancer medicinal products.

Posology

Omjjara should not be used in combination with other JAK inhibitors.

The recommended dose is 200 mg once daily.

Complete blood cell count and liver function tests must be performed before initiating treatment, periodically during treatment, and as clinically indicated (see section 4.4).

Dose modifications

Dose modifications should be considered for haematologic and non‑haematologic toxicities (table 1).

Table 1: Dose modifications for adverse reactions

Haematologic toxicities

Thrombocytopenia

Dose modificationa

Baseline platelet count

Platelet count

≥100 × 109/L

20 × 109/L to <50 × 109/L

Reduce daily dose by 50 mg from the last given dose

<20 × 109/L

Interrupt treatment until platelets recover to 50 × 109/L

Restart Omjjara at a daily dose of 50 mg below the last given doseb

≥50 × 109/L to <100 × 109/L

<20 × 109/L

Interrupt treatment until platelets recover to 50 × 109/L

Restart Omjjara at a daily dose of 50 mg below the last given doseb

<50 × 109/L

<20 × 109/L

Interrupt treatment until platelets recover to baseline

Restart Omjjara at a daily dose of 50 mg below the last given doseb

Neutropenia

Dose modificationa

ANC <0.5 × 109/L

Interrupt treatment until ANC ≥0.75 × 109/L

Restart Omjjara at a daily dose of 50 mg below the last given doseb

Non-haematologic toxicities

Hepatotoxicity

(unless other apparent causes)

Dose modificationa

ALT and/or AST >5 × ULN (or >5 × baseline, if baseline is abnormal) and/or total bilirubin >2 × ULN (or >2 × baseline, if baseline is abnormal)

Interrupt treatment until AST and ALT ≤2 × ULN or baseline and total bilirubin ≤1.5 × ULN or baseline

Restart Omjjara at a daily dose of 50 mg below the last given doseb

If reoccurrence of ALT or AST elevations >5 × ULN, permanently discontinue Omjjara

Other non-haematologic

Dose modificationa

Grade 3 or higherc

Grade 2 or higherc bleeding

Interrupt treatment until the toxicity resolves to Grade 1 or lower (or baseline)

Restart Omjjara at a daily dose of 50 mg below the last given doseb

ANC = absolute neutrophil count; ALT = alanine transaminase; AST = aspartate transaminase;

ULN = upper limit of normal.

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

b May reinitiate treatment at 100 mg if previously dosed at 100 mg.

c Graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).

Treatment with Omjjara should be discontinued in patients unable to tolerate 100 mg once daily.

Duration of use

Treatment may be continued for as long as the benefit-risk remains positive for patients, as assessed by the treating physician.

Missed dose

If a dose of Omjjara is missed, the next scheduled dose should be taken the following day. Two doses should not be taken at the same time to make up for the missed dose.

Special populations

Elderly

No dose adjustment is required for patients who are aged 65 years and older (see section 5.2).

Renal impairment

No dose adjustment is required for patients with renal impairment (>15 mL/min).

Omjjara has not been studied in patients with end-stage renal disease.

Hepatic impairment

No dose adjustment is recommended for patients with mild or moderate hepatic impairment (see section 4.4). The recommended starting dose of Omjjara is 150 mg once daily in patients with severe hepatic impairment (Child-Pugh Class C) (see section 5.2).

Paediatric population

The safety and efficacy of Omjjara in children and adolescents less than 18 years of age have not been established. No data are available.

Method of administration

Omjjara is for oral use only and can be taken with or without meals (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pregnancy and breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

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 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 4.5 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'.

4.5. Interaction with other medicinal products and other forms of interaction

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 Cmax by 29.4% and AUCinf 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 Cmax and decreased momelotinib AUCinf 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 (Cmax by 40.4% and AUCinf 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. 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 Cmax by 3.2-fold and AUC by 2.7-fold, which may increase the risk of adverse reactions of rosuvastatin. Tmax and t1/2 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 systemically acting hormonal contraceptives may be reduced (see sections 4.4 and 5.2).

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

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 (12%). The most common adverse reaction leading to discontinuation of Omjjara was thrombocytopenia (2.5%). 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

Not known: cannot be estimated from the available data

Table 2: Summary of adverse reactions reported in Phase 3 studies in adults with myelofibrosis

System organ class (SOC)

Adverse reaction

Frequency category

Infections and infestations

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

Common

COVID‑19 pneumonia

Uncommon

Blood and lymphatic system disorders

Thrombocytopeniaa

Very common

Neutropeniab

Common

Immune system disorders

Hypersensitivityc

Not known

Metabolism and nutrition disorders

Vitamin B1 deficiency

Common

Nervous system disorders

Dizziness, headache

Very common

Syncope, peripheral neuropathyd, paraesthesia

Common

Eye disorders

Blurred vision

Common

Ear and labyrinth disorders

Vertigo

Common

Vascular disorders

Hypotension, haematoma, flushing

Common

Respiratory, thoracic and mediastinal disorders

Cough

Very common

Gastrointestinal disorders

Diarrhoea, abdominal pain, nausea

Very common

Vomiting, constipation

Common

Skin and subcutaneous tissue disorders

Rashe

Common

Musculoskeletal and connective tissue disorders

Arthralgia, pain in extremity

Common

General disorders and administration site conditions

Asthenia, fatigue

Very common

Pyrexia

Common

Investigations

Alanine transaminase (ALT) increased, aspartate transaminase (AST) increased

Common

Injury, poisoning and procedural complications

Contusion

Common

a Thrombocytopenia includes platelet count decreased.

b Neutropenia includes neutrophil count decreased.

c Adverse drug reaction derived from post-marketing experience.

d Peripheral neuropathy includes peripheral sensory neuropathy, peripheral motor neuropathy, neuropathy peripheral, peripheral sensorimotor neuropathy, neuralgia, and polyneuropathy.

e Rash includes rash maculo‑papular, rash erythematous, drug eruption, rash follicular, rash macular, and rash pustular.

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.

Rash

Cases of rash (including erythema multiforme and a case of Toxic Epidermal Necrolysis [TEN]) requiring hospitalisation have been reported in the post‑marketing setting.

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 Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

If overdose is suspected, the patient should be monitored for any signs or symptoms of adverse reactions or effects, and appropriate standard of care measures should be instituted immediately. Further management should be as clinically indicated. Haemodialysis is not expected to enhance the elimination of momelotinib.