Jakavi 5mg/ml oral solution

Jakavi is indicated for the treatment of patients aged 2 years and older with acute or chronic graft versus host disease who have inadequate response to corticosteroids (see section 5.1).

Jakavi treatment should only be initiated by a physician experienced in the administration of anti‑cancer medicinal products.

A complete blood cell count, including a white blood cell count differential, must be performed before initiating therapy with Jakavi.

Complete blood count, including a white blood cell count differential, should be monitored every 2 to 4 weeks until Jakavi doses are stabilised, and then as clinically indicated (see section 4.4).

Posology

The recommended starting dose of Jakavi in acute and chronic graft versus host disease (GvHD) is based on age (see Table 1):

Table 1 Starting doses in acute and chronic graft versus host disease

These starting doses in GvHD can be administered using either the tablet for patients at or above 6 years old who can swallow tablets or the oral solution.

The patient should drink water after taking the oral solution to ensure the medicinal product has been completely swallowed. If the patient is unable to swallow and has a nasogastric or gastric tube in situ, the Jakavi oral solution can be administered via a nasogastric or gastric feeding tube of size French 4 (or greater) and not exceeding 125 cm in length. The tube should be flushed with water after delivering the oral solution.

Volume of ruxolitinib to be administered when using a dose of 4 mg/m² is presented in Table 2.

Table 2 Volume of ruxolitinib oral solution (5 mg/ml) to be administered when using a dose of 4 mg/m²

Dose modifications

Doses may be titrated based on efficacy and safety.

Dose reductions and temporary interruptions of treatment may be needed in GvHD-patients with thrombocytopenia, neutropenia, or elevated total bilirubin after standard supportive therapy including growth-factors, anti-infective therapies and transfusions. The recommended starting dose for GvHD patients should be reduced by approximately 50% to be administered twice daily. In patients who are unable to tolerate Jakavi at the reduced dose level, treatment should be interrupted. Detailed dosing recommendations are provided in Table 3.

Table 3 Dosing recommendations for GvHD patients with thrombocytopenia, neutropenia, or elevated total bilirubin

Dose adjustment with concomitant strong CYP3A4 inhibitors or fluconazole

When ruxolitinib is administered with strong CYP3A4 inhibitors in MF and PV patients or dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole) in MF, PV or GvHD patients, the unit dose of ruxolitinib should be reduced by approximately 50%, to be administered twice daily (see section 4.5). The concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily should be avoided.

More frequent monitoring (e.g. twice a week) of haematology parameters and of clinical signs and symptoms of ruxolitinib‑related adverse drug reactions is recommended while on strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes.

Special populations

Renal impairment

No specific dose adjustment is needed in patients with mild or moderate renal impairment.

The recommended starting dose for GvHD patients with severe renal impairment (creatinine clearance less than 30 ml/min) should be reduced by approximately 50% to be administered twice daily. Patients should be carefully monitored with regard to safety and efficacy during ruxolitinib treatment.

There are no data for GvHD patients with end-stage renal disease (ESRD).

Hepatic impairment

Patients diagnosed with hepatic impairment while receiving ruxolitinib should have complete blood counts, including a white blood cell count differential, monitored at least every one to two weeks for the first 6 weeks after initiation of therapy with ruxolitinib and as clinically indicated thereafter once their liver function and blood counts have been stabilised. Ruxolitinib dose can be titrated to reduce the risk of cytopenia.

In patients with mild, moderate or severe hepatic impairment not related to GvHD, the starting dose of ruxolitinib should be reduced by 50% (see section 5.2).

In patients with GvHD liver involvement and an increase of total bilirubin to >3 x ULN, blood counts should be monitored more frequently for toxicity and a dose reduction by one dose level may be considered.

Paediatric population

The safety and efficacy of Jakavi in paediatric patients have been established in GvHD based on clinical studies (see section 5.1).

Treatment discontinuation

In GvHD, tapering of Jakavi may be considered in patients with a response and after having discontinued corticosteroids. A 50% dose reduction of Jakavi every two months is recommended. If signs or symptoms of GvHD reoccur during or after the taper of Jakavi, re-escalation of treatment should be considered.

Method of administration

Jakavi is to be taken orally, with or without food.

It is recommended that a healthcare professional discusses how to administer the prescribed daily dose of the oral solution with the patient or caregiver prior to administration of the first dose.

It is recommended that the dose of Jakavi is taken at a similar time every day, using the re-usable oral syringe provided.

If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose.

Jakavi can be administered via a nasogastric (NG) or gastric (G) feeding tube of size French 4 (or greater) and not exceeding 125 cm in length.

Instructions for preparation are provided in the instructions for use at the end of the leaflet.

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

Pregnancy and lactation.

Myelosuppression

Treatment with Jakavi can cause haematological adverse drug reactions, including thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood cell count differential, must be performed before initiating therapy with Jakavi.

Thrombocytopenia is generally reversible and is usually managed by reducing the dose or temporarily withholding Jakavi (see sections 4.2 and 4.8). However, platelet transfusions may be required as clinically indicated.

Patients developing anaemia may require blood transfusions. Dose modifications or interruption for patients developing anaemia may also need to be considered.

Patients with a haemoglobin level below 10.0 g/dl at the beginning of the treatment have a higher risk of developing a haemoglobin level below 8.0 g/dl during treatment compared to patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent monitoring of haematology parameters and of clinical signs and symptoms of Jakavi‑related adverse drug reactions is recommended for patients with baseline haemoglobin below 10.0 g/dl.

Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by temporarily withholding Jakavi (see sections 4.2 and 4.8).

Complete blood counts should be monitored as clinically indicated and dose adjusted as required (see sections 4.2 and 4.8).

Infections

Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred in patients treated with Jakavi. Patients should be assessed for the risk of developing serious infections. Physicians should carefully observe patients receiving Jakavi for signs and symptoms of infections and initiate appropriate treatment promptly. Treatment with Jakavi should not be started until active serious infections have resolved.

Tuberculosis has been reported in patients receiving Jakavi. Before starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. This can include medical history, possible previous contact with tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-gamma release assay, as applicable. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised.

Hepatitis B viral load (HBV-DNA titre) increases, with and without associated elevations in alanine aminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBV infections taking Jakavi. It is recommended to screen for HBV prior to commencing treatment with Jakavi. Patients with chronic HBV infection should be treated and monitored according to clinical guidelines.

Herpes zoster

Physicians should educate patients about early signs and symptoms of herpes zoster, advising that treatment should be sought as early as possible.

Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) has been reported with Jakavi treatment. Physicians should be particularly alert to symptoms suggestive of PML that patients may not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs occur, referral to a neurologist and appropriate diagnostic measures for PML should be considered. If PML is suspected, further dosing must be suspended until PML has been excluded.

Lipid abnormalities/elevations

Treatment with Jakavi has been associated with increases in lipid parameters including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides. Lipid monitoring and treatment of dyslipidaemia according to clinical guidelines is recommended.

Major adverse cardiac events (MACE)

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years of age 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.

MACE have been reported in patients receiving Jakavi. Prior to initiating or continuing therapy with Jakavi, 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 a 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 of age 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 deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving Jakavi. In patients with MF and PV treated with Jakavi in clinical studies, the rates of thromboembolic events were similar in Jakavi and control-treated patients.

Prior to initiating or continuing therapy with Jakavi, 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 of age 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 Jakavi.

Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell carcinoma, have been reported in patients treated with ruxolitinib. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Special populations

Renal impairment

In GvHD patients with severe renal impairment, the starting dose of Jakavi should be reduced by approximately 50% (see sections 4.2 and 5.2).

Hepatic impairment

In GvHD patients with hepatic impairment not related to GvHD, the starting dose of Jakavi should be reduced by approximately 50% (see sections 4.2 and 5.2).

Interactions

If Jakavi is to be co‑administered with strong CYP3A4 inhibitors in MF and PV patients or dual inhibitors of CYP3A4 and CYP2C9 enzymes (e.g. fluconazole) in MF, PV and GvHD patients, the unit dose of Jakavi should be reduced by approximately 50%, to be administered twice daily (for monitoring frequency see sections 4.2 and 4.5).

The concomitant use of cytoreductive therapies with Jakavi was associated with manageable cytopenias (see section 4.2 for dose modifications during cytopenias).

Excipients

Propylene glycol

Jakavi contains 150 mg propylene glycol in each ml of oral solution.

Parahydroxybenzoate

This medicinal product contains methyl and propyl parahydroxybenzoate, which may cause allergic reactions (possibly delayed).

Interaction studies have only been performed in adults.

Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, medicinal products inhibiting these enzymes can give rise to increased ruxolitinib exposure.

Interactions resulting in dose reduction of ruxolitinib

CYP3A4 inhibitors

Strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole)

In healthy subjects co‑administration of ruxolitinib (10 mg single dose) with a strong CYP3A4 inhibitor, ketoconazole, resulted in ruxolitinib C_max and AUC that were higher by 33% and 91%, respectively, than with ruxolitinib alone. The half‑life was prolonged from 3.7 to 6.0 hours with concurrent ketoconazole administration.

When administering ruxolitinib with strong CYP3A4 inhibitors the unit dose of ruxolitinib should be reduced by approximately 50%, to be administered twice daily, except in GvHD patients. The effect of strong CYP3A4 inhibitors in patients with GvHD was not found to have a significant impact on any parameter in the population pharmacokinetic model.

Patients should be closely monitored (e.g. twice weekly) for cytopenias and dose titrated based on safety and efficacy (see section 4.2).

Dual CYP2C9 and CYP3A4 inhibitors

In healthy subjects co‑administration of ruxolitinib (10 mg single dose) with a dual CYP2C9 and CYP3A4 inhibitor, fluconazole, resulted in ruxolitinib C_max and AUC that were higher by 47% and 232%, respectively, than with ruxolitinib alone.

50% dose reduction should be considered when using medicinal products which are dual inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily.

Enzyme inducers

CYP3A4 inducers (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St.John's wort (Hypericum perforatum))

Patients should be closely monitored and the dose titrated based on safety and efficacy (see section 4.2).

In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducer rifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after administration of ruxolitinib alone. The exposure of ruxolitinib active metabolites was unchanged. Overall, the ruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 induction resulted in minimal effect on the pharmacodynamics. However, this could be related to the high ruxolitinib dose resulting in pharmacodynamic effects near E_max. It is possible that in the individual patient, an increase of the ruxolitinib dose is needed when initiating treatment with a strong enzyme inducer.

Other interactions to be considered affecting ruxolitinib

Mild or moderate CYP3A4 inhibitors (such as, but not limited to, ciprofloxacin, erythromycin, amprenavir, atazanavir, diltiazem, cimetidine)

In healthy subjects co‑administration of ruxolitinib (10 mg single dose) with erythromycin 500 mg twice daily for four days resulted in ruxolitinib C_max and AUC that were higher by 8% and 27%, respectively, than with ruxolitinib alone.

No dose adjustment is recommended when ruxolitinib is co‑administered with mild or moderate CYP3A4 inhibitors (e.g. erythromycin). However, patients should be closely monitored for cytopenias when initiating therapy with a moderate CYP3A4 inhibitor.

Effects of ruxolitinib on other medicinal products

Substances transported by P‑glycoprotein or other transporters

Ruxolitinib may inhibit P‑glycoprotein and breast cancer resistance protein (BCRP) in the intestine. This may result in increased sytemic exposure of substrates of these transporters, such as dabigatran etexilate, ciclosporin, rosuvastatin and potentially digoxin. Therapeutic drug monitoring (TDM) or clinical monitoring of the affected substance is advised.

It is possible that the potential inhibition of P‑gp and BCRP in the intestine can be minimised if the time between administrations is kept apart as long as possible.

A study in healthy subjects indicated that ruxolitinib did not inhibit the metabolism of the oral CYP3A4 substrate midazolam. Therefore, no increase in exposure of CYP3A4 substrates is anticipated when combining them with ruxolitinib. Another study in healthy subjects indicated that ruxolitinib does not affect the pharmacokinetics of an oral contraceptive containing ethinylestradiol and levonorgestrel. Therefore, it is not anticipated that the contraceptive efficacy of this combination will be compromised by co-administration of ruxolitinib.

Pregnancy

There are no data from the use of Jakavi in pregnant women.

Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was not observed in rats or rabbits. However, the exposure margins compared to the highest clinical dose were low and the results are therefore of limited relevance for humans (see section 5.3). The potential risk for humans is unknown. As a precautionary measure, the use of Jakavi during pregnancy is contraindicated (see section 4.3).

Women of childbearing potential/Contraception

Women of child‑bearing potential should use effective contraception during the treatment with Jakavi. In case pregnancy should occur during treatment with Jakavi, a risk/benefit evaluation must be carried out on an individual basis with careful counselling regarding potential risks to the foetus (see section 5.3).

Breast‑feeding

Jakavi must not be used during breast‑feeding (see section 4.3) and breast‑feeding should therefore be discontinued when treatment is started. It is unknown whether ruxolitinib and/or its metabolites are excreted in human milk. A risk to the breast‑fed child cannot be excluded. Available pharmacodynamic/toxicological data in animals have shown excretion of ruxolitinib and its metabolites in milk (see section 5.3).

Fertility

There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect on fertility was observed.

Jakavi has no or negligible sedating effect. However, patients who experience dizziness after the intake of Jakavi should refrain from driving or using machines.

Summary of the safety profile

Acute GvHD

REACH 1

The most frequently reported adverse drug reactions were anaemia, thrombocytopenia, and neutropenia.

Hematological laboratory abnormalities identified as adverse drug reactions included anaemia (87.1%), thrombocytopenia (84.1%) and neutropenia (65.2%). Grade 3 anaemia was reported in 51.6% of patients (Grade 4 not applicable per CTCAE v4.03). Grade 3 and 4 thrombocytopenia were reported in 24.0% and 49.2% of patients, respectively.

The most frequent non-hematological adverse drug reactions were nausea (32.4%), sepsis (22.5%) and hypertension (22.5%).

The most frequent non-hematological laboratory abnormalities identified as adverse drug reactions were increased ALT (50.7%), increased AST (50.7%). The majority were of grade 1 and 2.

Discontinuation due to adverse events, regardless of causality, was observed in 32.4% of patients

REACH 2

The most frequently reported adverse drug reactions (>50%) in REACH2 (adult and adolescent patients) were thrombocytopenia, anaemia neutropenia, increased alanine aminotransferase and increased aspartate aminotransferase. The most frequently reported adverse drug reactions (>50%) in the pool of paediatric patients (adolescents from REACH2 and paediatric patients from REACH4) were anaemia, neutropenia, increased alanine aminotransferase, hypercholesterolaemia and thrombocytopenia.

Haematological laboratory abnormalities identified as adverse drug reactions in REACH2 (adult and adolescent patients) and in the pool of paediatric patients (REACH2 and REACH4) included thrombocytopenia (85.2% and 55.1%), anaemia (75.0% and 70.8%) and neutropenia (65.1% and 70.0%), respectively. Grade 3 anaemia was reported in 47.7% of patients in REACH 2 and in 45.8% of paediatric patients. Grade 3 and 4 thrombocytopenia were reported in 31.3% and 47.7% of patients in REACH2 and in 14.6% and 22.4% of patients in the paediatric pool, respectively. Grade 3 and 4 neutropenia were reported in 17.9% and 20.6% of patients in REACH2 and in 32.0% and 22.0% of patients in the paediatric pool, respectively.

The most frequent (>15%) non-haematological adverse drug reactions in REACH2 (adult and adolescent patients) and in the pool of paediatric patients (REACH2 and REACH4) were cytomegalovirus (CMV) infection (32.3% and 31.4%), sepsis (25.4% and 9.8%) urinary tract infections (17.9% and 9.8%), hypertension (13.4% and 17.6%) and nausea (16.4% and 3.9%), respectively.

The most frequent non-haematological laboratory abnormalities identified as adverse drug reactions in REACH2 (adult and adolescent patients) and in the pool of paediatric patients (REACH2 and REACH4) were increased alanine aminotransferase (54.9% and 63.3%), increased aspartate aminotransferase (52.3% and 50.0%) and hypercholesterolaemia (49.2% and 61.2%), respectively. The majority were of grade 1 and 2 however grade 3 increased alanine aminotransferase was reported in 17.6% of patients in REACH2 and 27.3% of patients in the paediatric pool.

Discontinuation due to adverse events, regardless of causality, was observed in 29.4% of patients in REACH2 and in 21.6% of patients in the paediatric pool.

Chronic GvHD

The most frequently reported adverse drug reactions (>50%) in REACH3 (adult and adolescent patients) were anaemia, hypercholesterolemia and increased aspartate aminotransferase. The most frequently reported adverse drug reactions (>50%) in the pool of paediatric patients (adolescents from REACH3 and paediatric patients from REACH5) were neutropenia, hypercholesterolaemia and increased alanine aminotransferase.

Haematological laboratory abnormalities identified as adverse drug reactions in REACH3 (adult and adolescent patients) and in the pool of paediatric patients (REACH3 and REACH5) included anaemia (68.6% and 49.1%), neutropenia (36.2% and 59.3%), and), thrombocytopenia (34.4% and 35.2%) respectively. Grade 3 anaemia was reported in 14.8% of patients in REACH3 and in 17.0% of patients in the paediatric pool. Grade 3 and 4 neutropenia were reported in 9.5% and 6.7% of patients in REACH3 and in 17.3% and 11.1% of patients in the paediatric pool, respectively. Grade 3 and 4 thrombocytopenia were reported in 5.9% and 10.7% of adult and adolescent patients in REACH3 and in 7.7% and 11.1% of patients in the paediatric pool, respectively.

The most frequent (>10%) non-haematological adverse drug reactions in REACH3 (adult and adolescent patients) and in the pool of paediatric patients (REACH3 and REACH5) were hypertension (15.0% and 14.5%) and, headache (10.2% and 18.2%), respectively.

The most frequent (>50%) non-haematological laboratory abnormalities identified as adverse drug reactions in REACH3 (adult and adolescent patients) and in the pool of paediatric patients (REACH3 and REACH5) were hypercholesterolaemia (52.3% and 54.9%), increased aspartate aminotransferase (52.2% and 45.5%) and increased alanine aminotransferase (43.1% and 50.9%). The majority were grade 1 and 2, however grade 3 laboratory abnormalities reported in the pool of paediatric patients included increased alanine aminotransferase (14.9%) and increased aspartate aminotransferase (11.5%).

Discontinuation due to adverse events, regardless of causality, was observed in 18.1% of patients in REACH3 and in 14.5% of patients in the paediatric pool.

Tabulated list of adverse drug reactions from clinical studies

The safety of Jakavi in acute GvHD patients was evaluated in the phase 2 study REACH1 and in the phase 2 study REACH4. , including data from 71 patients treated with Jakavi, and the phase 3 study REACH2, including data from 201 patients ≥12 years of age initially randomised to Jakavi (n=152) and patients who received Jakavi after crossing over from the best available therapy BAT arm (n=49). In REACH1, the median exposure upon which the adverse drug reaction frequency categories were based was 6.6 weeks (range 0.6 to 115.9 weeks). In REACH2, the median exposure was 8.9 weeks (range 0.3 to 66.1 weeks). In the pool of paediatric patients (REACH2 and REACH4), the median exposure was 16.7 weeks (range 1.1 to 48.9 weeks).

The safety of Jakavi in chronic GvHD patients was evaluated in the phase 3 study REACH3 and in the phase 2 study REACH5. REACH3, include data from 226 patients ≥12 years of age initially randomised to Jakavi (n=165) and patients who received Jakavi after crossing over from BAT (n=61). The median exposure upon which the adverse drug reaction frequency categories were based was 41.4 weeks (range 0.7 to 127.3 weeks). In the pool of paediatric patients (REACH3 and REACH5), the median exposure was 57.1 weeks (range 2.1 to 155.4 weeks).

See section 5.1 for details of dose administered in each study.

In the clinical study programme the severity of adverse drug reactions was assessed based on the CTCAE, defining grade 1 mild, grade 2=moderate, grade 3=severe, grade 4=life‑threatening or disabling, grade 5=death.

Adverse drug reactions from clinical studies in acute and chronic GvHD (Table 4) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: 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); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 4 ADRs reported in studies Acute GvHD REACH 1 and Chronic GvHD REACH 3

The safety of JAKAVI in acute GvHD patients was also evaluated in the phase 3 study REACH2, including data from patients initially randomized to JAKAVI (n=152) and patients who received JAKAVI after crossing over from control treatment (n=49).

Table 5 ADRs reported in the supportive acute GvHD study REACH 2

The safety of JAKAVI in acute GvHD patients was also evaluated in the phase 3 study REACH2, including data from patients initially randomized to JAKAVI (n=152) and patients who received JAKAVI after crossing over from control treatment (n=49).

Table 6 Frequency category of adverse drug reactions reported in clinical studies in acute (REACH2, REACH4) and chronic (REACH3, REACH5) GvHD paediatric pool

Description of selected adverse drug reactions

Anaemia

In the acute GvHD studies REACH1, anaemia (all grades) was reported in 87.1% patients and CTCAE Grade 3 was reported in 51.6% patients.

In the phase 3 acute REACH 2 and chronic REACH 3 GvHD study, anaemia (all grades) was reported in 75.0% and 68.6% of patients, CTCAE Grade 3 was reported in 47.7% and 14.8% of patients, respectively.

In paediatric patients with acute and chronic GvHD, anaemia (all grades) was reported in 70.8% and 49.1% of patients, CTCAE grade 3 was reported in 45.8% and 17.0% of patients, respectively.

Thrombocytopenia

In the acute GvHD study (REACH1) Grade 3 and 4 thrombocytopenia was observed in 24.0% and 49.2% of patients, respectively. In the phase 3 acute GvHD study (REACH2) Grade 3 and 4 thrombocytopenia was observed in 31.3% and 47.7% of patients, respectively.

In the phase 3 chronic GvHD study (REACH 3), grade 3 and 4 thrombocytopenia was lower (5.9% and 10.7%) than in acute GvHD.

The frequency of grade 3 (14.6%) and 4 (22.4%) thrombocytopenia in paediatric patients with acute GvHD was lower than in REACH2. In paediatric patients with chronic GvHD, grade 3 and 4 thrombocytopenia was lower (7.7% and 11.1%) than in paediatric patients with acute GvHD.

Neutropenia

In the acute GvHD study (REACH1), Grade 3 and 4 neutropenia was observed in 29.2% and 15.9% of patients, respectively. In the acute GvHD study (REACH2), Grade 3 and 4 neutropenia was observed in 17.9% and 20.6% of patients, respectively.

In the phase 3 chronic GvHD study (REACH 3) grade 3 and 4 neutropenia was lower (9.5% and 6.7%) than in acute GvHD.

In paediatric patients, the frequency of grade 3 and 4 neutropenia was 32.0% and 22.0%, respectively, in acute GvHD and 17.3% and 11.1%, respectively, in chronic GvHD.

Bleeding

In the comparative period of the phase 3 acute GvHD study (REACH2), bleeding events were reported in 25.0% and 22.0% of patients in the ruxolitinib and BAT arms respectively. The sub-groups of bleeding events were generally similar between treatment arms: bruising events (5.9% in ruxolitinib vs. 6.7% in BAT arm), gastrointestinal events (9.2% vs. 6.7%) and other haemorrhage events (13.2% vs. 10.7%). Intracranial bleeding events were reported in 0.7% of patients in the BAT arm and in no patients in the ruxolitinib arm. In paediatric patients, the frequency of bleeding events was 23.5%. Events reported in ≥5% of patients were cystitis haemorrhagic and epistaxis (5.9% each). No intracranial bleeding events were reported in paediatric patients.

In the comparative period of the phase 3 chronic GvHD study (REACH3), bleeding events were reported in 11.5% and 14.6% of patients in the ruxolitinib and BAT arms respectively. The sub-groups of bleeding events were generally similar between treatment arms: bruising events (4.2% in ruxolitinib vs. 2.5% in BAT arm), gastrointestinal events (1.2% vs. 3.2%) and other haemorrhage events (6.7% vs. 10.1%). In paediatric patients, the frequency of bleeding events was 9.1%. The reported events were epistaxis, haematochezia, haematoma, post-procedural haemorrhage, and skin haemorrhage (1.8% each). No intracranial bleeding events were reported in patients with chronic GvHD.

Infections

In the phase 2 acute GvHD study (REACH1), Grade 3 CMV infections were reported in 8.5% (no Grade 4 event). CMV infection with organ involvement was seen in one patient who reported CMV chorioretinitis (grade 3).

Sepsis events including septic shock of any Grade were reported in 22.5% of patients.

In the phase 3 acute GvHD study (REACH 2), during the comparative period, urinary tract infections were reported in 9.9% (grade ≥3, 3.3%) of patients in the ruxolitinib arm compared to 10.7% (grade ≥3, 6.0%) in the BAT arm. CMV infections were reported in 28.3% (grade ≥3, 9.3%) of patients in the ruxolitinib arm compared to 24.0% (grade ≥3, 10.0%) in the BAT arm. Sepsis events were reported in 12.5% (grade ≥3, 11.1%) of patients in the ruxolitinib arm compared to 8.7% (grade ≥3, 6.0%) in the BAT arm. BK virus infection was reported only in the ruxolitinib arm in 3 patients with one grade 3 event. During extended follow-up of patients treated with ruxolitinib, urinary tract infections were reported in 17.9% (grade ≥3, 6.5%) of patients and CMV infections were reported in 32.3% (grade ≥3, 11.4%) of patients. CMV infection with organ involvement was seen in very few patients; CMV colitis, CMV enteritis and CMV gastrointestinal infection of any grade were reported in four, two and one patients, respectively.

Sepsis events including septic shock of any grade were reported in 25.4% (grade ≥3, 21.9%) of patients. Urinary tract infections and sepsis events were reported with lower frequency in paediatric patients with acute GvHD (9.8% each) compared to adult and adolescent patients. CMV infections were reported in 31.4% of paediatric patients (grade 3, 5.9%).

In the phase 3 chronic GvHD study (REACH 3), during the comparative period, urinary tract infections were reported in 8.5% (grade ≥3, 1.2%) of patients in the ruxolitinib arm compared to 6.3% (grade ≥3, 1.3%) in the BAT arm. BK virus infection was reported in 5.5% (grade ≥3, 0.6%) of patients in the ruxolitinib arm compared to 1.3% in the BAT arm. CMV infections were reported in 9.1% (grade ≥3, 1.8%) of patients in the ruxolitinib arm compared to 10.8% (grade ≥3, 1.9%) in the BAT arm. Sepsis events were reported in 2.4% (grade ≥3, 2.4%) of patients in the ruxolitinib arm compared to 6.3% (grade ≥3, 5.7%) in the BAT arm. During extended follow-up of patients treated with ruxolitinib, urinary tract infections and BK virus infections were reported in 9.3% (grade ≥3, 1.3%) and 4.9% (grade ≥3, 0.4%) of patients, respectively. CMV infections and sepsis events were reported in 8.8% (grade ≥3, 1.3%) and 3.5% (grade ≥3, 3.5%) of patients, respectively. In paediatric patients with chronic GvHD, urinary tract infections were reported in 5.5% (grade 3, 1.8%) of patients and BK virus infection was reported in 1.8% (no grade ≥3) of patients. CMV infections occurred in 7.3% (no grade ≥3) of patients.

Elevated lipase

In the comparative period of the phase 3 acute GvHD study (REACH2), new or worsened lipase values were reported in 19.7% of patients in the ruxolitinib arm compared to 12.5% in the BAT arm; corresponding grade 3 (3.1% vs 5.1%) and grade 4 (0% vs 0.8%) increases were similar. During extended follow-up of patients treated with ruxolitinib, increased lipase values were reported in 32.2% of patients; grade 3 and 4 were reported in 8.7% and 2.2% of patients respectively. Elevated lipase was reported in 20.4% of paediatric patients (grade 3 and 4: 8.5% and 4.1%, respectively).

In the comparative period of the phase 3 chronic GvHD study (REACH3), new or worsened lipase values were reported in 32.1% of patients in the ruxolitinib arm compared to 23.5% in the BAT arm; corresponding grade 3 (10.6% vs 6.2%) and grade 4 (0.6% vs 0%) increases were similar. During extended follow-up of patients treated with ruxolitinib, increased lipase values were reported in 35.9% of patients; grade 3 and 4 were observed in 9.5% and 0.4% of patients, respectively. Elevated lipase was reported with lower frequency (20.4%, grade 3 and 4: 3.8% and 1.9%, respectively) in paediatric patients.

Paediatric patients

A total of 106 patients aged 2 to <18 years with GvHD were analysed for safety: 51 patients (45 patients in REACH4 and 6 patients in REACH2) in acute GvHD studies and 55 patients (45 patients in REACH5 and 10 patients in REACH3) in the chronic GvHD studies. The safety profile observed in paediatric patients who received treatment with ruxolitinib was similar to that observed in adult patients.

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

There is no known antidote for overdoses with Jakavi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anaemia and thrombocytopenia. Appropriate supportive treatment should be given.

Haemodialysis is not expected to enhance the elimination of ruxolitinib.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EJ01

Mechanism of action

Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC₅₀ values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function.

Ruxolitinib inhibits JAK‑STAT signalling and cell proliferation of cytokine‑dependent cellular models of haematological malignancies, as well as of Ba/F3 cells rendered cytokine‑independent by expressing the JAK2V617F mutated protein, with IC₅₀ ranging from 80‑320 nM.

JAK-STAT signalling pathways play a role in regulating the development, proliferation, and activation of several immune cell types important for GvHD pathogenesis.

Pharmacodynamic effects

In a thorough QT study in healthy subjects, there was no indication of a QT/QTc prolonging effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, indicating that ruxolitinib has no effect on cardiac repolarisation.

Clinical efficacy and safety

Acute graft-versus-host disease

In REACH-1, 71 patients (≥ 12 years) with grade II to IV corticosteroid-refractory acute GvHD (Mount Sinai Acute GvHD International Consortium (MAGIC) criteria) received open-label Jakavi at a dose of 5 mg twice daily. Corticosteroid refractoriness was determined when patients had progression after at least 3 days, failed to achieve a response after 7 days or failed corticosteroid taper.

Participants began oral administration of ruxolitinib at 5 mg BID; if hematologic parameters were stable and no treatment-related toxicity was observed after the first 3 days of treatment, the dose could be increased to 10 mg BID.

In addition to Jakavi, patients could have received standard allogeneic stem cell transplantation supportive care including anti-infective medicinal products and transfusion support.

At baseline, acute GvHD was grade II in 31.0%, Grade III in 46.5%, and Grade IV in 22.5%. Approximately half of the participants (52.1%) had at least 2 organs involved at baseline with distribution across the lower GI tract (71.8%), skin (50.7%), upper GI tract (31.0%), and liver (22.5%).71.8% had lower GI-tract and skin (50.7% involvement). Majority (80.3%) of them had peripheral blood stem cell (PBSC) transplants and from identical HLA-matched donors (63.4%).

The median time since alloSCT was 74.0 days, and the median time since acute GvHD diagnosis was 17.0 days. The median duration of study treatment as of the final analysis data cut-off date (05-Jun-2019) was 46.0 days, and 18 patients (25.4%) received ruxolitinib for more than 180 days.

The median age of participants was 58 years (range: 18-73 years), 49.3% were males and 50.7% were females, and 93.0% of participants were white/Caucasian. Approximately 60.6% of the participants had baseline ECOG performance status of 2 or higher, with 25.4% at 3 or higher.

All 71 participants had received prior systemic therapy with corticosteroids for the treatment of GVHD. The median duration of prior corticosteroid exposure was 16.0 days, and the median average daily dose of corticosteroids at the start of study treatment was 156.25 mg/day. In addition to prior corticosteroid treatment, 23.9% of participants had received calcineurin inhibitors, with or without methotrexate). The most common reasons for discontinuation of the most recent prior acute GVHD therapy were PD and lack of efficacy.

The primary endpoint of REACH1 was the overall response rate (ORR) on Day 28, defined as the proportion of patients in each arm with a complete response (CR), very good partial response (VGPR) or a partial response (PR) as per the CIBMTR modifications to the IBMTR response index.

The REACH 1 study achieved the predetermined threshold for a positive study outcome (lower limit of the 95% CI for Day 28 ORR ≥ 40%). Forty participants (56.3% [95% CI: 44.0, 68.1]) demonstrated a response at Day 28, including 19 participants (26.8%) who achieved a CR, 6 participants who achieved a VGPR (8.5%) and 15 participants who achieved a PR (21.1%). Of the participants who had a response on Day 28, 19 of 40 participants had a CR (26.8%). The best ORR, defined as the proportion of participants demonstrating a response at any timepoint, was 76.1% (95% CI: 64.5, 85.4). The majority of participants (62.0%) achieved their first response within the first 14 days of treatment, with a median time to first response of 8 days; all first responses were achieved before Day 56.

Table 7 Day-28 Overall response rate

The REACH2 study evaluated 309 patients with grade II to IV corticosteroid-refractory, acute GvHD were randomised 1:1 to Jakavi or BAT. Patients were stratified by severity of acute GvHD at the time of randomisation. Corticosteroid refractoriness was determined when patients had progression after at least 3 days, failed to achieve a response after 7 days or failed corticosteroid taper.

Jakavi was administered orally twice per day at a dose of 10 mg bid.

BAT was selected by the investigator on a patient-by-patient basis and included anti-thymocyte globulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), etanercept, or infliximab.

In addition to Jakavi or BAT, patients could have received standard allogeneic stem cell transplantation supportive care including anti-infective medicinal products and transfusion support. as well as standard acute GvHD prophylaxis and treatment medicinal products initiated before randomisation including systemic corticosteroids and calcineurin inhibitors (CNIs) such as cyclosporine or tacrolimus. Topical or inhaled corticosteroid therapies were allowed to be continued per institutional guidelines.

Patients randomised to the BAT arm were allowed to cross over to the Jakavi arm after the day 28 visit, if they did not demonstrate complete or partial response at Day 28. Tapering of Jakavi was allowed after the day 56 visit for patients with treatment response.

The safety data derived from the REACH 2 study is presented above in section 4.8.

Chronic graft-versus-host disease

In REACH3, 329 patients with moderate or severe corticosteroid-refractory, chronic GVHD were randomised 1:1 to Jakavi or BAT. Patients were stratified by severity of chronic GVHD at the time of randomisation. Corticosteroid refractoriness was determined when patients had lack of response or disease progression after 7 days, or had disease persistence for 4 weeks or failed corticosteroid taper twice.

BAT was selected by the investigator on a patient-by-patient basis and included extracorporeal photopheresis (ECP), low dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib, or ibrutinib.

Patients were allowed to have received allogeneic stem cell transplantation (SCT) from any donor source and with any conditioning regimen. In addition to Jakavi or BAT, patients could have received standard allogeneic SCT supportive care including anti-infective medicinal products and transfusion support. Continued use of corticosteroids and CNIs such as cyclosporine or tacrolimus and topical or inhaled corticosteroid therapies were allowed per institutional guidelines.

Patients who received one prior systemic treatment other than corticosteroids and CNIs for chronic GvHD were eligible for inclusion in the study. In addition to corticosteroids and CNIs, prior systemic medicinal product for chronic GvHD was allowed to continue only if used for chronic GvHD prophylaxis (i.e. started before the chronic GvHD diagnosis) as per common medical practice.

Patients on BAT not achieving partial response or better, could cross over to ruxolitinib on cycle 7 day 1 and thereafter.

Tapering of Jakavi was allowed after the cycle 7 day 1 visit.

Baseline demographics and disease characteristics were balanced between the two treatment arms. The median age was 49 years (range 12 to 76 years). The study included 3.6% adolescent, 61.1% male and 75.4% white patients. The majority of enrolled patients had malignant underlying disease.

The severity at diagnosis of corticosteroid-refractory chronic GVHD was balanced between the two treatment arms, with 41% and 45% moderate, and 59% and 55% severe, in the Jakavi and the BAT arms, respectively.

The reasons for patients' insufficient response to corticosteroids in the Jakavi and BAT arm were i) a lack of response or disease progression after corticosteroid treatment for at least 7 days at 1 mg/kg/day of prednisone equivalents (37.6% and 44.5%, respectively), ii) disease persistence after 4 weeks at 0.5 mg/kg/day (35.2% and 25.6%), or iii) corticosteroid dependency (27.3% and 29.9%, respectively).

Among all patients, 73% and 45% had skin and lung involvement in the Jakavi arm, compared to 69% and 41% in the BAT arm.

The most frequently used prior systemic chronic GVHD therapies were corticosteroids only (43% in the Jakavi arm and 49% in the BAT arm) and corticosteroids+CNIs (41% patients in the Jakavi arm and 42% in the BAT arm).

The primary endpoint was the ORR on day 1 of cycle 7, defined as the proportion of patients in each arm with a CR or a PR without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response based on investigator assessment per National Institute of Health (NIH) criteria.

Key secondary endpoints were failure free survival (FFS) and proportion of patients with improvement of the modified Lee symptoms score (mLSS) at cycle 7 day 1. FFS, a composite time to event endpoint, incorporated the earliest of the following events: i) relapse or recurrence of underlying disease or death due to underlying disease, ii) non-relapse mortality, or iii) addition or initiation of another systemic therapy for chronic GVHD.

REACH3 met its primary objective. At the time of primary analysis (data cut-off data: 08-May-2020), the ORR at week 24 was higher in the Jakavi arm (49.7%) compared to the BAT arm (25.6%). There was a statistically significant difference between the treatment arms (stratified Cochrane-Mantel-Haenszel test p<0.0001, one-sided, OR: 2.99; 95% CI: 1.86, 4.80). Results are presented in Table 13.

Among the non-responders at cycle 7 day 1 in the Jakavi and BAT arms, 2.4% and 12.8% had disease progression, respectively.

Table 8 Overall response rate at cycle 7 day 1 in REACH3

The key secondary endpoint, FFS, demonstrated a statistically significant 63% risk reduction of Jakavi versus BAT (HR: 0.370; 95% CI: 0.268, 0.510, p<0.0001). Prior to crossover, the 5-months FFS probability (95% CI) was 78.1% (70.9%, 83.7%) and 62.7% (54.6%, 69.7%) for the Jakavi and BAT arms, respectively. The 6-months FFS probability (95% CI) was 74.9% (67.5%, 80.9%) and 44.5% (36.5%, 52.1%) for the Jakavi and BAT arms, respectively. At 6-months, the majority of FFS events were “addition or initiation of another systemic therapy for chronic GvVHD” (probability of that event was 13.5% and 48.5% for the Jakavi and BAT arms, respectively). Results for “relapse of underlying disease” and non-relapse mortality (NRM) were 2.46% vs 2.57% and 9.19% vs 4.46%, in the Jakavi and the BAT arms, respectively. No difference of cumulative incidences between treatment arms was observed when focusing on NRM only.

The rate of responders as per improvement of ≥7 points of total symptom score (TSS) from baseline of the mLSS showed a statistically significant difference (p=0.0011) between the Jakavi (24.2%) and BAT arms (11.0%).

Paediatric population

The Medicines and Healthcare Products Regulatory Agency has waived the obligation to submit the results of studies with Jakavi in all subsets of the paediatric population for the treatment of MF and PV. In GvHD paediatric patients (12 years of age and older), the safety and efficacy of Jakavi are supported by evidence from the studies REACH1, REACH2 and REACH3 and from the open label single arm phase 2 studies REACH4 and REACH5 (see section 4.2 for information on paediatric use).

Acute graft versus host disease

In REACH4, 45 paediatric patients with grade II-IV acute GvHD were treated with Jakavi added to corticosteroids to assess the safety, efficacy and pharmacokinetics of Jakavi. Patients were enrolled into 4 groups based on age (Group 1 [age ≥12 years to <18 years, N=18], Group 2 [age ≥6 years to <12 years, N=12], Group 3 [age ≥2 years to <6 years N=15] and Group 4 [age ≥28 days to <2 years N=0]). The doses used in each group are listed in Table 12 and patients were treated for 24 weeks or until discontinuation. Jakavi was administered as either a 5 mg tablet or a capsule/oral solution for paediatric patients <12 years.

Patients were allowed to have received prior systemic treatment for acute GvHD or had treatment naive acute GvHD. In addition to Jakavi, patients could have received standard allogeneic stem cell transplantation supportive care including anti-infective medicinal products and transfusion support. Continued use of systemic corticosteroids, CNI (cyclosporine or tacrolimus) and/or topical corticosteroid therapies were allowed per institutional guidelines.

Tapering of Jakavi was allowed after the day 56 visit.

Male and female patients accounted for 62.2% (n=28) and for 37.8% (n=17) patients, respectively. Overall, 27 patients (60.0%) had underlying malignancy, most frequently leukaemia (26 patients, 57.8%). Among the 45 paediatric patients enrolled in REACH4, 13 (28.9%) had treatment naïve acute GvHD and 32 (71.1%) had steroid refractory (SR)-acute GvHD. At baseline 64.4% of patients had grade II, 26.7% had grade III and 8.9% had grade IV aGvHD.

The overall response rate (ORR) at day 28 (primary efficacy endpoint) in REACH4 was 84.4% (90% CI: 72.8, 92.5) in all patients with CR in 48.9% of patients and PR in 35.6% of patients. In terms of pre-treatment status, the ORR at day 28 was 90.6% in SR-patients and 69.2% in treatment-naïve patients.

Rate of durable ORR at day 56 (measured by the proportion of patients who achieve a CR or PR at day 28 and maintain a CR or PR at day 56) was 66.7% in all REACH4 patients, 68.8% in SR-patients and 61.5% in treatment-naïve patients.

In REACH2, responses were observed at day 28 in 4 out of 5 adolescent patients with acute GvHD (3 had CR and 1 had PR) in the ruxolitinib arm and in 3 out of 4 adolescent patients (all had CR) in the BAT arm.

Overall response rate from all ruxolitinib paediatric patients (adolescents from REACH2 and paediatric patients from REACH4) are presented in Table 14.

Table 9 Overall response rate (ORR) at day 28 in acute GvHD paediatric patients

Chronic graft versus host disease

In REACH5, 45 paediatric patients with moderate or severe chronic GvHD were treated with Jakavi added to corticosteroids to assess safety, efficacy and pharmacokinetics of Jakavi treatment. Patients were enrolled into 4 groups based on age (Group 1 [age ≥12 years to <18 years, N=22], Group 2 [age ≥6 years to <12 years, N=16], Group 3 [age ≥2 years to <6 years, N=7] and Group 4 [age ≥28 days to <2 years, N=0]). The doses used in each group are listed in Table 13 and patients were treated for 39 cycles/156 weeks or until discontinuation. Jakavi was administered as either a 5 mg tablet or an oral solution for paediatric patients <12 years.

Patients were allowed to have received prior systemic therapy for chronic GvHD or had treatment-naive chronic GvHD. In addition to Jakavi, patients could have received standard allogeneic stem cell transplantation supportive care including anti-infective medicinal products and transfusion support. Continued use of topical corticosteroid therapies were allowed per institutional guidelines

Tapering of Jakavi was allowed after the cycle 7 day 1 visit.

Male and female patients accounted for 64.4% (n=29) and for 35.6% (n=16) of patients, respectively. with 30 patients (66.7%) with pre-transplant disease history of underlying malignancy, most frequently leukaemia (27 patients, 60%).

Among the 45 paediatric patients enrolled in REACH5, 17 (37.8%) were treatment-naïve chronic GvHD patients and 28 (62.2%) were SR-chronic GvHD patients. The disease was severe in 62.2% of patients and moderate in 37.8% of patients. Thirty-one (68.9%) patients had skin involvement, eighteen (40%) had mouth involvement, and fourteen (31.1%) had lung involvement.

The ORR at cycle 7 day 1 (primary efficacy endpoint) was 40% (90% CI: 27.7, 53.3) in REACH5 paediatric patients, 39.3% in SR-patients and 41.2% in treatment-naïve patients.

The best overall response (BOR) defined as the proportion of patients who achieved overall response (CR or PR) at any time up to cycle 7 day 1 or up to the start of additional systemic therapy for chronic GvHD was 82.2% (90% CI: 70.2, 90.8) in REACH5 paediatric patients.

In REACH3, responses were observed at cycle 7 day 1 in 3 out of 4 adolescent patients with chronic GvHD (all had PR) in the ruxolitinib arm and in 2 out of 8 adolescent patients (both had PR) in the BAT arm.

Overall response rate from all ruxolitinib paediatric patients (adolescent from REACH3 and paediatric patients from REACH5) are presented in Table 15.

Table 10 Overall response rate (ORR) at cycle 7 day 1 in chronic GvHD paediatric patients

Absorption

Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high permeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib is rapidly absorbed after oral administration with maximal plasma concentration (C_max) achieved approximately 1 hour post‑dose. Based on a human mass balance study, oral absorption of ruxolitinib, as ruxolitinib or metabolites formed under first‑pass, is 95% or greater. Mean ruxolitinib C_max and total exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. There was no clinically relevant change in the pharmacokinetics of ruxolitinib upon administration with a high‑fat meal. The mean C_max was moderately decreased (24%) while the mean AUC was nearly unchanged (4% increase) on dosing with a high‑fat meal.

Distribution

The mean volume of distribution at steady state is approximately67.5 litres in adolescent and adult acute GvHD patients and 60.9 litres in adolescent and adult chronic GvHD patients. The mean volume of distribution at steady state is approximately 30 litres in paediatric patients with acute or chronic GvHD and with a body surface area (BSA) below 1. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro is approximately 97%, mostly to albumin. A whole body autoradiography study in rats has shown that ruxolitinib does not penetrate the blood‑brain barrier.

Biotransformation

Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from CYP2C9. Parent compound is the predominant entity in human plasma, representing approximately 60% of the drug‑related material in circulation. Two major and active metabolites are present in plasma representing 25% and 11% of parent AUC. These metabolites have one half to one fifth of the parent JAK‑related pharmacological activity. The sum total of all active metabolites contributes to 18% of the overall pharmacodynamics of ruxolitinib. At clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6 or CYP3A4 based on in vitro studies. In vitro data indicate that ruxolitinib may inhibit P‑gp and BCRP.

Elimination

Ruxolitinib is mainly eliminated through metabolism. The mean elimination half‑life of ruxolitinib is approximately 3 hours. Following a single oral dose of [¹⁴C]‑labelled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism, with 74% of radioactivity excreted in urine and 22% via faeces. Unchanged parent substance accounted for less than 1% of the excreted total radioactivity.

Linearity/non‑linearity

Dose proportionality was demonstrated in the single and multiple dose studies.

Population pharmacokinetics

In a population pharmacokinetic evaluation, clearance was 10.4 l/h in adolescent and adult patients with acute GvHD and 7.8 l/h in adolescent and adult patients with chronic GvHD, with a 49% inter‑subject variability. In paediatric patients with acute or chronic GvHD and with a BSA below 1, clearance was between 6.5 and 7 l/h. No relationship was apparent between oral clearance and gender, patient age or race, based on a population pharmacokinetic evaluation in GvHD patients.

At a dose of 10 mg twice daily, exposure was increased in GvHD patients with a low body surface area (BSA). In subjects with a BSA of 1 m², 1.25 m² and 1.5 m², the predicted mean exposure (AUC) was respectively 31%, 22% and 12% higher than the typical adult (1.79 m²).

Special populations

Effects of age, gender or race

Based on studies in healthy subjects, no relevant differences in ruxolitinib pharmacokinetics were observed with regard to gender and race.

Population pharmacokinetics

In a population pharmacokinetic evaluation, clearance was 10.4 l/h in adolescent and adult patients with acute GvHD and 7.8 l/h in in adolescent and adult patients with chronic GvHD, with a 49% inter‑subject variability. In paediatric patients with acute or chronic GvHD and with a BSA below 1, clearance was between 6.5 and 7 l/h. No relationship was apparent between oral clearance and gender, patient age or race, based on a population pharmacokinetic evaluation in GvHD patients.

At a dose of 10 mg twice daily, exposure was increased in GvHD patients with a low body surface area (BSA). In subjects with a BSA of 1 m², 1.25 m² and 1.5 m², the predicted mean exposure (AUC) was respectively 31%, 22% and 12% higher than the typical adult (1.79 m²).

Paediatric population

As in adult patients with GvHD, ruxolitinib was rapidly absorbed after oral administration in paediatric patients with GvHD. Dosing in children between 6 and 11 years old at 5 mg twice daily and children between 2 and 5 years old at 4 mg/m² twice daily achieved comparable exposure to a dose of 10 mg twice daily in adolescents and adults, confirming the exposure matching approach implemented as part of the extrapolation assumption.

Based on a pooled population pharmacokinetic analysis in paediatric patients with acute or chronic GvHD, clearance of ruxolitinib decreased with decreasing BSA. After correcting for the BSA effect, other demographic factors such as age, body weight and body mass index did not have clinically significant effects on the exposure of ruxolitinib.

Renal impairment

Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and urinary creatinine. Following a single ruxolitinib dose of 25 mg, the exposure of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites tended to increase with increasing severity of renal impairment, and were most markedly increased in the subjects with severe renal impairment. It is unknown whether the increased metabolite exposure is of safety concern. A dose modification is recommended in patients with severe renal impairment.

Hepatic impairment

Following a single ruxolitinib dose of 25 mg in patients with varying degrees of hepatic impairment, the mean AUC for ruxolitinib was increased in patients with mild, moderate and severe hepatic impairment by 87%, 28% and 65%, respectively, compared to patients with normal hepatic function. There was no clear relationship between AUC and the degree of hepatic impairment based on Child‑Pugh scores. The terminal elimination half‑life was prolonged in patients with hepatic impairment compared to healthy controls (4.1 to 5.0 hours versus 2.8 hours). A dose reduction of approximately 50% is recommended for MF and PV patients with hepatic impairment (see section 4.2).

In GvHD patients with hepatic impairment not related to GvHD, the starting dose of ruxolitinib should be reduced by 50%.

Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity studies and in a carcinogenicity study. Target organs associated with the pharmacological action of ruxolitinib in repeated dose studies include bone marrow, peripheral blood and lymphoid tissues. Infections generally associated with immunosuppression were noted in dogs. Adverse decreases in blood pressure along with increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute volume was noted in a respiratory study in rats. The margins (based on unbound C_max) at the non‑adverse level in the dog and rat studies were 15.7‑fold and 10.4‑fold greater, respectively, than the maximum human recommended dose of 25 mg twice daily. No effects were noted in an evaluation of the neuropharmacological effects of ruxolitinib.

In juvenile rat studies, administration of ruxolitinib resulted in effects on growth and bone measures. Reduced bone growth was observed at doses ≥5 mg/kg/day when treatment started on postnatal day 7 (comparable to human newborn) and at ≥15 mg/kg/day when treatment started on postnatal days 14 or 21 (comparable to human infant, 1–3 years). Fractures and early termination of rats were observed at doses ≥30 mg/kg/day when treatment was started on postnatal day 7. Based on unbound AUC, the exposure at the NOAEL (no observed adverse effect level) in juvenile rats treated as early as postnatal day 7 was 0.3‑fold that of adult patients at 25 mg twice daily, while reduced bone growth and fractures occurred at exposures that were 1.5- and 13-fold that of adult patients at 25 mg twice daily, respectively. The effects were generally more severe when administration was initiated earlier in the postnatal period. Other than bone development, the effects of ruxolitinib in juvenile rats were similar to those in adult rats. Juvenile rats are more sensitive than adult rats to ruxolitinib toxicity.

Ruxolitinib decreased foetal weight and increased post‑implantation loss in animal studies. There was no evidence of a teratogenic effect in rats and rabbits. However, the exposure margins compared to the highest clinical dose were low and the results are therefore of limited relevance for humans. No effects were noted on fertility. In a pre‑ and post‑natal development study, a slightly prolonged gestation period, reduced number of implantation sites, and reduced number of pups delivered were observed. In the pups, decreased mean initial body weights and short period of decreased mean body weight gain were observed. In lactating rats, ruxolitinib and/or its metabolites were excreted into the milk with a concentration that was 13‑fold higher than the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic. Ruxolitinib was not carcinogenic in the Tg.rasH2 transgenic mouse model.

Propylene glycol (E 1520)

Citric acid anhydrous

Methyl parahydroxybenzoate (E 218)

Propyl parahydroxybenzoate (E 216)

Sucralose (E 955)

Strawberry dry flavour

Nitrogen

Purified water

Not applicable.

18 months

Store in a refrigerator (2°C – 8°C). Do not freeze.

After opening use within 60 days.

Jakavi oral solution is available in 70 ml amber glass bottles with a white polypropylene child-resistant screw cap closure. Packs containing one bottle of 60 ml oral solution, two 1 ml oral syringes and one press-in bottle adapter.

No special requirements.