JAKAVI 15mg tablets medication leaflet

Jakavi 5 mg tablets

Jakavi 10 mg tablets

Jakavi 15 mg tablets

Jakavi 20 mg tablets

Jakavi 5 mg tablets

Each tablet contains 5 mg ruxolitinib (as phosphate).

Each tablet contains 71.45 mg lactose monohydrate.

Jakavi 10 mg tablets

Each tablet contains 10 mg ruxolitinib (as phosphate).

Each tablet contains 142.90 mg lactose monohydrate.

Jakavi 15 mg tablets

Each tablet contains 15 mg ruxolitinib (as phosphate).

Each tablet contains 214.35 mg lactose monohydrate.

Jakavi 20 mg tablets

Each tablet contains 20 mg ruxolitinib (as phosphate).

Each tablet contains 285.80 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Tablet.

Jakavi 5 mg tablets

Round curved white to almost white tablets of approximately 7.5 mm in diameter with “NVR”debossed on one side and “L5” debossed on the other side.

Jakavi 10 mg tablets

Round curved white to almost white tablets of approximately 9.3 mm in diameter with “NVR”debossed on one side and “L10” debossed on the other side.

Jakavi 15 mg tablets

Ovaloid curved white to almost white tablets of approximately 15.0 x 7.0 mm with “NVR” debossedon one side and “L15” debossed on the other side.

Jakavi 20 mg tablets

Elongated curved white to almost white tablets of approximately 16.5 x 7.4 mm with “NVR” debossedone one side and “L20” debossed on the other side.

Myelofibrosis (MF)

Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult patientswith primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia veramyelofibrosis or post essential thrombocythaemia myelofibrosis.

Polycythaemia vera (PV)

Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant to orintolerant of hydroxyurea.

Graft versus host disease (GvHD)

Acute GvHD

Jakavi is indicated for the treatment of adults and paediatric patients aged 28 days and older with acutegraft versus host disease who have inadequate response to corticosteroids or other systemic therapies(see section 5.1).

Chronic GvHD

Jakavi is indicated for the treatment of adults and paediatric patients aged 6 months and older withchronic graft versus host disease who have inadequate response to corticosteroids or other systemictherapies (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 beforeinitiating therapy with Jakavi.

Complete blood count, including a white blood cell count differential, should be monitored every 2 to4 weeks until Jakavi doses are stabilised, and then as clinically indicated (see section 4.4).

Myelofibrosis (MF)

The recommended starting dose of Jakavi in MF is based on platelet counts (see Table 1):

Table 1 Starting doses in myelofibrosis

Platelet count Starting dose

Greater than 200 000/mm3 20 mg twice daily100 000 to 200 000/mm3 15 mg twice daily75 000 to less than 100 000/mm3 10 mg twice daily50 000 to less than 75 000/mm3 5 mg twice daily

Polycythaemia vera (PV)

The recommended starting dose of Jakavi in PV is 10 mg twice daily.

Graft versus host disease (GvHD)

The recommended starting dose of Jakavi in acute and chronic GvHD is based on age (see Tables 2and 3):

Table 2 Starting doses in acute graft versus host disease

Age group Starting dose12 years old and above 10 mg twice daily6 years to less than 12 years old 5 mg twice daily28 days to less than 6 years old 8 mg/m2 twice daily

Table 3 Starting doses in chronic graft versus host disease

Age group Starting dose12 years old and above 10 mg twice daily6 years to less than 12 years old 5 mg twice daily6 months to less than 6 years old 8 mg/m2 twice daily

These starting doses in GvHD can be administered using either the tablet for patients who can swallowtablets whole or the oral solution.

Jakavi can be added to corticosteroids and/or calcineurin inhibitors (CNIs).

Doses may be titrated based on efficacy and safety.

Myelofibrosis and polycythaemia vera

If efficacy is considered insufficient and blood counts are adequate, doses may be increased by amaximum of 5 mg twice daily, up to the maximum dose of 25 mg twice daily.

The starting dose should not be increased within the first four weeks of treatment and thereafter nomore frequently than at 2-week intervals.

Treatment should be discontinued for platelet counts less than 50 000/mm3 or absolute neutrophilcounts less than 500/mm3. In PV, treatment should also be interrupted when haemoglobin is below8 g/dl. After recovery of blood counts above these levels, dosing may be re-started at 5 mg twice dailyand gradually increased based on careful monitoring of complete blood cell count, including a whiteblood cell count differential.

Dose reductions should be considered if the platelet count decreases during treatment as outlined in

Table 4, with the goal of avoiding dose interruptions for thrombocytopenia.

Table 4 Dosing recommendation for MF patients with thrombocytopenia

Dose at time of platelet decline25 mg 20 mg 15 mg 10 mg 5 mgtwice daily twice daily twice daily twice daily twice daily

Platelet count New dose20 mg 15 mg100 000 to <125 000/mm3 No change No change No changetwice daily twice daily10 mg 10 mg 10 mg75 000 to <100 000/mm3 No change No changetwice daily twice daily twice daily5 mg 5 mg 5 mg 5 mg50 000 to <75 000/mm3 No changetwice daily twice daily twice daily twice daily

Less than 50 000/mm3 Hold Hold Hold Hold Hold

In PV, dose reductions should also be considered if haemoglobin decreases below 12 g/dl and isrecommended if it decreases below 10 g/dl.

Graft versus host disease

Dose reductions and temporary interruptions of treatment may be needed in GvHD-patients withthrombocytopenia, neutropenia, or elevated total bilirubin after standard supportive therapy includinggrowth-factors, anti-infective therapies and transfusions. One dose level reduction step isrecommended (10 mg twice daily to 5 mg twice daily or 5 mg twice daily to 5 mg once daily). Inpatients who are unable to tolerate Jakavi at a dose of 5 mg once daily, treatment should beinterrupted. Detailed dosing recommendations are provided in Table 5.

Table 5 Dosing recommendations during ruxolitinib therapy for GvHD patients withthrombocytopenia, neutropenia or elevated total bilirubin

Laboratory parameter Dosing recommendation

Platelet count <20 000/mm3 Reduce Jakavi by one dose level. If platelet count≥20 000/mm3 within seven days, dose may be increased toinitial dose level, otherwise maintain reduced dose.

Platelet count <15 000/mm3 Hold Jakavi until platelet count ≥20 000/mm3, then resume atone lower dose level.

Absolute neutrophil count (ANC) Reduce Jakavi by one dose level. Resume at initial dose level≥500/mm3 to <750/mm3 if ANC >1 000/mm3.

Absolute neutrophil count Hold Jakavi until ANC >500/mm3, then resume at one lower<500/mm3 dose level. If ANC >1 000/mm3, dosing may resume at initialdose level.

Total bilirubin elevation not caused >3.0 to 5.0 x upper limit of normal (ULN): Continue Jakaviby GvHD (no liver GvHD) at one lower dose level until ≤3.0 x ULN.

>5.0 to 10.0 x ULN: Hold Jakavi up to 14 days until totalbilirubin ≤3.0 x ULN. If total bilirubin ≤3.0 x ULN dosingmay resume at current dose. If not ≤3.0 x ULN after 14 days,resume at one lower dose level.

>10.0 x ULN: Hold Jakavi until total bilirubin ≤3.0 x ULN,then resume at one lower dose level.

Total bilirubin elevation caused by >3.0 x ULN: Continue Jakavi at one lower dose level until

GvHD (liver GvHD) total bilirubin ≤3.0 x ULN.

Dose adjustment with concomitant strong CYP3A4 inhibitors or dual CYP2C9/3A4 inhibitors

When ruxolitinib is administered with strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and

CYP3A4 enzymes (e.g. fluconazole) the unit dose of ruxolitinib should be reduced by approximately50%, to be administered twice daily (see sections 4.4 and 4.5). The concomitant use of ruxolitinib withfluconazole doses greater than 200 mg daily should be avoided.

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

In patients with severe renal impairment (creatinine clearance less than 30 ml/min) the recommendedstarting dose based on platelet count for MF, PV and GvHD patients should be reduced byapproximately 50% to be administered twice daily. Patients should be carefully monitored with regardto safety and efficacy during ruxolitinib treatment (see section 4.4).

There are limited data to determine the best dosing options for patients with end-stage renal disease(ESRD) on haemodialysis. Pharmacokinetic/pharmacodynamic simulations based on available data inthis population suggest that the starting dose for MF patients with ESRD on haemodialysis is a singledose of 15 to 20 mg or two doses of 10 mg given 12 hours apart, to be administered post-dialysis andonly on the day of haemodialysis. A single dose of 15 mg is recommended for MF patients withplatelet count between 100 000/mm3 and 200 000/mm3. A single dose of 20 mg or two doses of 10 mggiven 12 hours apart is recommended for MF patients with platelet count of >200 000/mm3.

Subsequent doses (single administration or two doses of 10 mg given 12 hours apart) should beadministered only on haemodialysis days following each dialysis session.

The recommended starting dose for PV patients with ESRD on haemodialysis is a single dose of10 mg or two doses of 5 mg given 12 hours apart, to be administered post-dialysis and only on the dayof haemodialysis. These dose recommendations are based on simulations and any dose modification in

ESRD should be followed by careful monitoring of safety and efficacy in individual patients. No datais available for dosing patients who are undergoing peritoneal dialysis or continuous venovenoushaemofiltration (see section 5.2).

There are no data for GvHD patients with ESRD.

In MF patients with any hepatic impairment the recommended starting dose based on platelet countshould be reduced by approximately 50% to be administered twice daily. Subsequent doses should beadjusted based on careful monitoring of safety and efficacy. The recommended starting dose is 5 mgtwice daily for PV patients. Ruxolitinib dose can be titrated to reduce the risk of cytopenia (seesection 4.4).

In patients with mild, moderate or severe hepatic impairment not related to GvHD, the starting dose ofruxolitinib 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 countsshould be monitored more frequently for toxicity and a dose reduction by one dose level isrecommended.

No additional dose adjustments are recommended for elderly patients.

The safety and efficacy of Jakavi in children and adolescents aged up to 18 years with MF and PVhave not been established. No data are available (see section 5.1).

Treatment of MF and PV may be continued as long as the benefit-risk assessment remains positive.

However the treatment should be discontinued after 6 months if there has been no reduction in spleensize or improvement in symptoms since initiation of therapy.

It is recommended that, for patients who have demonstrated some degree of clinical improvement,ruxolitinib therapy be discontinued if they sustain an increase in their spleen length of 40% comparedwith baseline size (roughly equivalent to a 25% increase in spleen volume) and no longer havetangible improvement in disease-related symptoms.

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

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

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

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

Pregnancy and lactation.

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. Treatment should be discontinued in MFpatients with platelet count less than 50 000/mm3 or absoute neutrophil count less than 500/mm3 (seesection 4.2).

It has been observed that MF patients with low platelet counts (<200 000/mm3) at the start of therapyare more likely to develop thrombocytopenia during treatment.

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

Patients developing anaemia may require blood transfusions. Dose modifications or interruption forpatients 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 riskof developing a haemoglobin level below 8.0 g/dl during treatment compared to patients with a higherbaseline haemoglobin level (79.3% versus 30.1%). More frequent monitoring of haematologyparameters and of clinical signs and symptoms of Jakavi-related adverse drug reactions isrecommended for patients with baseline haemoglobin below 10.0 g/dl.

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

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

Serious bacterial, mycobacterial, fungal, viral and other opportunistic infections have occurred inpatients 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 infectionsand initiate appropriate treatment promptly. Treatment with Jakavi should not be started until activeserious infections have resolved.

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

Hepatitis B viral load (HBV-DNA titre) increases, with and without associated elevations in alanineaminotransferase and aspartate aminotransferase, have been reported in patients with chronic HBVinfections 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 clinicalguidelines.

Herpes zoster

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

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 anyof these new or worsening symptoms or signs, and if such symptoms/signs occur, referral to aneurologist 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 totalcholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol,and triglycerides. Lipid monitoring and treatment of dyslipidaemia according to clinical guidelines isrecommended.

Major adverse cardiac events (MACE)

In a large randomised active-controlled study of tofacitinib (another JAK inhibitor) in rheumatoidarthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, ahigher 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 patients65 years of age and older, patients who are current or past long-time smokers, and patients with ahistory of atherosclerotic cardiovascular disease or other cardiovascular risk factors.

Thrombosis

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

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported inpatients receiving Jakavi. In patients with MF and PV treated with Jakavi in clinical studies, the ratesof 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 patientshould 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 rheumatoidarthritis patients 50 years of age and older with at least one additional cardiovascular risk factor, ahigher 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 cellcarcinoma, have been reported in patients treated with ruxolitinib. Most of the MF and PV patients hadhistories of extended treatment with hydroxyurea and prior NMSC or pre-malignant skin lesions.

Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

The starting dose of Jakavi should be reduced in patients with severe renal impairment. For patientswith end-stage renal disease on haemodialysis the starting dose should be based on platelet counts for

MF patients, while the recommended starting dose is a single dose of 10 mg for PV patients (seesection 4.2). Subsequent doses (single dose of 20 mg or two doses of 10 mg given 12 hours apart in

MF patients; single dose of 10 mg or two doses of 5 mg given 12 hours apart in PV patients) should beadministered only on haemodialysis days following each dialysis session. Additional dosemodifications should be made with careful monitoring of safety and efficacy. In GvHD patients withsevere renal impairment, the starting dose of Jakavi should be reduced by approximately 50% (seesections 4.2 and 5.2).

The starting dose of Jakavi should be reduced by approximately 50% in MF and PV patients withhepatic impairment. Further dose modifications should be based on the safety and efficacy of themedicinal product. In GvHD patients with hepatic impairment not related to GvHD, the starting doseof Jakavi should be reduced by approximately 50% (see sections 4.2 and 5.2).

Patients diagnosed with hepatic impairment while receiving ruxolitinib should have complete bloodcounts, including a white blood cell count differential, monitored at least every one to two weeks forthe first 6 weeks after initiation of therapy with ruxolitinib and as clinically indicated thereafter oncetheir liver function and blood counts have been stabilised.

If Jakavi is to be co-administered with strong CYP3A4 inhibitors or dual inhibitors of CYP3A4 and

CYP2C9 enzymes (e.g. fluconazole), the unit dose of Jakavi should be reduced by approximately50%, to be administered twice daily (see sections 4.2 and 4.5).

More frequent monitoring (e.g. twice a week) of haematology parameters and of clinical signs andsymptoms of ruxolitinib-related adverse drug reactions is recommended while on strong CYP3A4inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes.

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

Withdrawal effects

Following interruption or discontinuation of Jakavi, symptoms of MF may return over a period ofapproximately one week. There have been cases of patients discontinuing Jakavi who experiencedsevere adverse events, particularly in the presence of acute intercurrent illness. It has not beenestablished whether abrupt discontinuation of Jakavi contributed to these events. Unless abruptdiscontinuation is required, gradual tapering of the dose of Jakavi may be considered, although theutility of the tapering is unproven.

Jakavi 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’.

Interaction studies have only been performed in adults.

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

Interactions resulting in dose reduction of ruxolitinib

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 CYP3A4inhibitor, ketoconazole, resulted in ruxolitinib Cmax 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 withconcurrent ketoconazole administration.

When administering ruxolitinib with strong CYP3A4 inhibitors the unit dose of ruxolitinib should bereduced by approximately 50%, to be administered twice daily.

Patients should be closely monitored (e.g. twice weekly) for cytopenias and dose titrated based onsafety 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 Cmax and AUC that were higher by 47% and232%, 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 withfluconazole 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 (seesection 4.2).

In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducerrifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after administrationof ruxolitinib alone. The exposure of ruxolitinib active metabolites was unchanged. Overall, theruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 induction resulted inminimal effect on the pharmacodynamics. However, this could be related to the high ruxolitinib doseresulting in pharmacodynamic effects near Emax. It is possible that in the individual patient, an increaseof 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 mgtwice daily for four days resulted in ruxolitinib Cmax 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 cytopeniaswhen 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 dabigatranetexilate, ciclosporin, rosuvastatin and potentially digoxin. Therapeutic drug monitoring (TDM) orclinical 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 thetime 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 isanticipated when combining them with ruxolitinib. Another study in healthy subjects indicated thatruxolitinib does not affect the pharmacokinetics of an oral contraceptive containing ethinylestradioland levonorgestrel. Therefore, it is not anticipated that the contraceptive efficacy of this combinationwill be compromised by co-administration of ruxolitinib.

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

Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was notobserved in rats or rabbits. However, the exposure margins compared to the highest clinical dose werelow and the results are therefore of limited relevance for humans (see section 5.3). The potential riskfor humans is unknown. As a precautionary measure, the use of Jakavi during pregnancy iscontraindicated (see section 4.3).

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 carriedout on an individual basis with careful counselling regarding potential risks to the foetus (seesection 5.3).

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

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

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

Myelofibrosis

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

Haematological adverse drug reactions (any Common Terminology Criteria for Adverse Events[CTCAE] grade) included anaemia (83.8%), thrombocytopenia (80.5%) and neutropenia (20.8%).

Anaemia, thrombocytopenia and neutropenia are dose-related effects.

The three most frequent non-haematological adverse drug reactions were bruising (33.3%), otherbleeding (including epistaxis, post-procedural haemorrhage and haematuria) (24.3%) and dizziness(21.9%).

The three most frequent non-haematological laboratory abnormalities identified as adverse reactionswere increased alanine aminotransferase (40.7%), increased aspartate aminotransferase (31.5%) andhypertriglyceridaemia (25.2%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4hypertriglyceridaemia or increased aspartate aminotransferase, nor CTCAE grade 4 increased alanineaminotransferase or hypercholesterolaemia were observed.

Discontinuation due to adverse events, regardless of causality, was observed in 30.0% of patients.

Polycythaemia vera

The most frequently reported adverse drug reactions were anaemia and increased alanineaminotransferase.

Haematological adverse reactions (any CTCAE grade) included anaemia (61.8%), thrombocytopenia(25.0%) and neutropenia (5.3%). Anaemia and thrombocytopenia CTCAE grade 3 or 4 were reportedin 2.9% and 2.6% of the patients, respectively.

The three most frequent non-haematological adverse reactions were weight gain (20.3%), dizziness(19.4%) and headache (17.9%).

The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) identifiedas adverse reactions were increased alanine aminotransferase (45.3%), increased aspartateaminotransferase (42.6%), and hypercholesterolaemia (34.7%). No CTCAE grade 4 increased alanineaminotransferase or hypercholesterolaemia, and one CTCAE grade 4 increased aspartateaminotransferase were observed.

Discontinuation due to adverse events, regardless of causality, was observed in 19.4% of patients.

Acute GvHD

The most frequently reported adverse drug reactions in REACH2 (adult and adolescent patients) werethrombocytopenia, anaemia, neutropenia, increased alanine aminotransferase and increased aspartateaminotransferase. The most frequently reported adverse drug reactions in the pool of paediatricpatients (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 andadolescent patients) and in the pool of paediatric patients (REACH2 and REACH4) includedthrombocytopenia (85.2% and 55.1%), anaemia (75.0% and 70.8%) and neutropenia (65.1% and70.0%), respectively. Grade 3 anaemia was reported in 47.7% of patients in REACH2 and in 45.8% ofpatients in the paediatric pool. Grade 3 and 4 thrombocytopenia were reported in 31.3% and 47.7% ofpatients in REACH2 and in 14.6% and 22.4% of patients in the paediatric pool, respectively. Grade 3and 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 non-haematological adverse drug reactions in REACH2 (adult and adolescentpatients) 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% and9.8%), 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 aspartateaminotransferase (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 reportedin 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 in REACH3 (adult and adolescent patients) wereanaemia, hypercholesterolemia and increased aspartate aminotransferase. The most frequently reportedadverse drug reactions in the pool of paediatric patients (adolescents from REACH3 and paediatricpatients from REACH5) were neutropenia, hypercholesterolaemia and increased alanineaminotransferase.

Haematological laboratory abnormalities identified as adverse drug reactions in REACH3 (adult andadolescent 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 patientsin 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 4thrombocytopenia were reported in 5.9% and 10.7% of adult and adolescent patients in REACH3 andin 7.7% and 11.1% of patients in the paediatric pool, respectively.

The most frequent non-haematological adverse drug reactions in REACH3 (adult and adolescentpatients) 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 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 weregrade 1 and 2, however grade 3 laboratory abnormalities reported in the pool of paediatric patientsincluded 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.

The safety of Jakavi in MF patients was evaluated using the long-term follow-up data from twophase 3 studies (COMFORT-I and COMFORT-II) including data from patients initially randomised toruxolitinib (n=301) and patients who received ruxolitinib after crossing over from control treatments(n=156). The median exposure upon which the adverse drug reaction frequency categories for MFpatients are based was 30.5 months (range 0.3 to 68.1 months).

The safety of Jakavi in PV patients was evaluated using the long-term follow-up data from twophase 3 studies (RESPONSE, RESPONSE 2) including data from patients initially randomised toruxolitinib (n=184) and patients who received ruxolitinib after crossing over from control treatments(n=156). The median exposure upon which the adverse drug reaction frequency categories for PVpatients are based was 41.7 months (range 0.03 to 59.7 months).

The safety of Jakavi in acute GvHD patients was evaluated in the phase 3 study REACH2 and in thephase 2 study REACH4. REACH2 included data from 201 patients ≥12 years of age initiallyrandomised to Jakavi (n=152) and patients who received Jakavi after crossing over from the bestavailable therapy (BAT) arm (n=49). The median exposure upon which the adverse drug reactionfrequency categories were based was 8.9 weeks (range 0.3 to 66.1 weeks). In the pool of paediatricpatients ≥2 years of age (6 patients in REACH2 and 45 patients in REACH4), the median exposurewas 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 thephase 2 study REACH5. REACH3 included data from 226 patients ≥12 years of age initiallyrandomised 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 was41.4 weeks (range 0.7 to 127.3 weeks). In the pool of paediatric patients ≥2 years of age (10 patients in

REACH3 and 45 patients in REACH5), the median exposure was 57.1 weeks (range 2.1 to155.4 weeks).

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 ordisabling, grade 5=death.

Adverse drug reactions from clinical studies in MF and PV (Table 6) and in acute and chronic GvHD(Table 7) are listed by MedDRA system organ class. Within each system organ class, the adverse drugreactions are ranked by frequency, with the most frequent reactions first. In addition, thecorresponding frequency category for each adverse drug reaction is based on the followingconvention: 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 availabledata).

Table 6 Frequency category of adverse drug reactions reported in the phase 3 studies in MFand PV

Adverse drug reaction Frequency category for MF Frequency category for PVpatients patients

Urinary tract infectionsd Very common Very common

Herpes zosterd Very common Very common

Pneumonia Very common Common

Sepsis Common Uncommon

Tuberculosis Uncommon Not knowne

HBV reactivation Not knowne Uncommon

Blood and lymphatic system disordersa,d

Anaemiaa

CTCAEc grade 4 Very common Uncommon(<6.5g/dl)

CTCAEc grade 3 Very common Common(<8.0 - 6.5g/dl)

Any CTCAEc grade Very common Very common

Thrombocytopeniaa

CTCAEc grade 4 Common Uncommon(<25 000/mm3)

CTCAEc grade 3 Very common Common(50 000 - 25 000/mm3)

Any CTCAEc grade Very common Very common

Neutropeniaa

CTCAEc grade 4 Common Uncommon(<500/mm3)

CTCAEc grade 3 Common Uncommon(<1 000 - 500/mm3)

Any CTCAEc grade Very common Common

Pancytopeniaa,b Common Common

Bleeding (any bleeding Very common Very commonincluding intracranial, andgastrointestinal bleeding,bruising and other bleeding)

Bruising Very common Very common

Gastrointestinal bleeding Very common Common

Intracranial bleeding Common Uncommon

Other bleeding (including Very common Very commonepistaxis, post-proceduralhaemorrhage andhaematuria)

Hypercholesterolaemiaa Very common Very commonany CTCAEc grade

Hypertriglyceridaemiaa Very common Very commonany CTCAEc grade

Weight gain Very common Very common

Dizziness Very common Very common

Headache Very common Very common

Elevated lipase, any CTCAEc

Very common Very commongrade

Constipation Very common Very common

Flatulence Common Common

Increased alanineaminotransferasea

CTCAEc grade 3 Common Common(> 5x - 20 x ULN)

Any CTCAEc grade Very common Very common

Increased aspartateaminotransferasea

Any CTCAEc grade Very common Very common

Hypertension Very common Very commona Frequency is based on new or worsened laboratory abnormalities compared to baseline.b Pancytopenia is defined as haemoglobin level <100 g/l, platelet count <100x109/l, andneutrophil count <1.5x109/l (or low white blood cell count of grade 2 if neutrophil count ismissing), simultaneously in the same lab assessmentc Common Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild,grade 2 = moderate, grade 3 = severe, grade 4 = life-threateningd These adverse drug reactions are discussed in the text.e Adverse drug reaction derived from post-marketing experience

Upon discontinuation, MF patients may experience a return of MF symptoms such as fatigue, bonepain, fever, pruritus, night sweats, symptomatic splenomegaly and weight loss. In clinical studies in

MF the total symptom score for MF symptoms gradually returned to baseline value within 7 days afterdose discontinuation (see section 4.4).

Table 7 Frequency category of adverse drug reactions reported in clinical studies in GvHD

Acute GvHD Chronic Chronic GvHD

Acute GvHD(Paediatric GvHD (Paediatric(REACH2)pool) (REACH3) pool)

Frequency Frequency Frequency Frequency

Adverse drug reactioncategory category category category

CMV infections Very common Very common Common Common

CTCAE3 grade ≥3 Very common Common Common N/A5

Sepsis Very common Common -6 -6

CTCAE grade ≥34 Very common Common -6 -6

Urinary tract infections Very common Common Common Common

CTCAE grade ≥3 Common Common Common Common

BK virus infections -6 -6 Common Common

CTCAE grade ≥3 -6 -6 Uncommon N/A5

Thrombocytopenia1 Very common Very common Very common Very common

CTCAE grade 3 Very common Very common Common Common

CTCAE grade 4 Very common Very common Very common Very common

Anaemia1 Very common Very common Very common Very common

CTCAE grade 3 Very common Very common Very common Very common

Neutropenia1 Very common Very common Very common Very common

CTCAE grade 3 Very common Very common Common Very common

CTCAE grade 4 Very common Very common Common Very common

Pancytopenia1,2 Very common Very common -6 -6

Hypercholesterolaemia1 Very common Very common Very common Very common

CTCAE grade 3 Common N/A5 Common Common

CTCAE grade 4 Common N/A5 Uncommon Common

Weight gain -6 -6 Common Common

CTCAE grade ≥3 -6 -6 N/A5 Common

Headache Common Common Very common Very common

CTCAE grade ≥3 Uncommon N/A5 Common Common

Hypertension Very common Very common Very common Very common

CTCAE grade ≥3 Common Very common Common Common

Increased lipase1 -6 -6 Very common Very common

CTCAE grade 3 -6 -6 Common Common

CTCAE grade 4 -6 -6 Uncommon Common

Increased amylase1 -6 -6 Very common Very common

CTCAE grade 3 -6 -6 Common Common

CTCAE grade 4 -6 -6 Common N/A5

Nausea Very common Common -6 -6

CTCAE grade ≥3 Uncommon N/A5 -6 -6

Constipation -6 -6 Common Common

CTCAE grade ≥3 -6 -6 N/A5 N/A5

Increased alanine Very common Very common Very common Very commonaminotransferase1

CTCAE grade 3 Very common Very common Common Very common

CTCAE grade 4 Common N/A5 Uncommon Common

Increased aspartate Very common Very common Very common Very commonaminotransferase1

CTCAE grade 3 Common Common Common Very common

CTCAE grade 4 N/A5 N/A5 Uncommon N/A5

Increased blood creatine -6 -6 Very common Very commonphosphokinase1

CTCAE grade 3 -6 -6 Common N/A5

CTCAE grade 4 -6 -6 Common N/A5

Increased blood -6 -6 Very common Commoncreatinine1

CTCAE grade 3 -6 -6 Common N/A5

CTCAE grade 4 -6 -6 N/A5 N/A51 Frequency is based on new or worsened laboratory abnormalities compared to baseline.2 Pancytopenia is defined as haemoglobin level <100 g/l, platelet count <100 x 109/l, andneutrophil count <1.5 x 109/l (or low white blood cell count of grade 2 if neutrophil count ismissing), simultaneously in the same laboratory assessment.3 CTCAE Version 4.03.4 Grade ≥3 sepsis includes 20 (10%) grade 5 events in REACH2. There were no grade 5 eventsin the paediatric pool.5 Not applicable: no cases reported6 “-”: not an identified adverse drug reaction in this indication

Description of selected adverse drug reactions

In phase 3 clinical studies in MF, median time to onset of first CTCAE grade 2 or higher anaemia was1.5 months. One patient (0.3%) discontinued treatment because of anaemia.

In patients receiving ruxolitinib mean decreases in haemoglobin reached a nadir of approximately10 g/litre below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a newsteady state that was approximately 5 g/litre below baseline. This pattern was observed in patientsregardless of whether they had received transfusion during therapy.

In the randomised, placebo-controlled study COMFORT-I 60.6% of Jakavi-treated MF patients and37.7% of placebo-treated MF patients received red blood cell transfusions during randomisedtreatment. In the COMFORT-II study the rate of packed red blood cell transfusions was 53.4% in the

Jakavi arm and 41.1% in the best available therapy arm.

In the randomised period of the pivotal studies, anaemia was less frequent in PV patients than in MFpatients (40.8% versus 82.4%). In the PV population, the CTCAE grade 3 and 4 events were reportedin 2.7%, while in the MF patients the frequency was 42.56%.

In the phase 3 acute (REACH2) and chronic (REACH3) GvHD studies, anaemia (all grades) wasreported in 75.0% and 68.6% of patients, CTCAE grade 3 was reported in 47.7% and 14.8% ofpatients, respectively. In paediatric patients with acute and chronic GvHD, anaemia (all grades) wasreported in 70.8% and 49.1% of patients, CTCAE grade 3 was reported in 45.8% and 17.0% ofpatients, respectively.

In the phase 3 clinical studies in MF, in patients who developed grade 3 or 4 thrombocytopenia, themedian time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible withdose reduction or dose interruption. The median time to recovery of platelet counts above 50 000/mm3was 14 days. During the randomised period, platelet transfusions were administered to 4.7% ofpatients receiving ruxolitinib and to 4.0% of patients receiving control regimens. Discontinuation oftreatment because of thrombocytopenia occurred in 0.7% of patients receiving ruxolitinib and 0.9% ofpatients receiving control regimens. Patients with a platelet count of 100 000/mm3 to 200 000/mm3before starting ruxolitinib had a higher frequency of grade 3 or 4 thrombocytopenia compared topatients with platelet count >200 000/mm3 (64.2% versus 38.5%).

In the randomised period of the pivotal studies, the rate of patients experiencing thrombocytopeniawas lower in PV (16.8%) patients compared to MF (69.8%) patients. The frequency of severe (i.e.

CTCAE grade 3 and 4) thrombocytopenia was lower in PV (2.7%) than in MF (11.6%) patients.

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 (REACH3), grade 3 and 4thrombocytopenia 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.

In the phase 3 clinical studies in MF, in patients who developed grade 3 or 4 neutropenia, the mediantime to onset was 12 weeks. During the randomised period, dose holding or reductions due toneutropenia were reported in 1.0% of patients, and 0.3% of patients discontinued treatment because ofneutropenia.

In the randomised period of the phase 3 studies in PV patients, neutropenia was reported in 1.6% ofpatients exposed to ruxolitinib compared to 7% in reference treatments. In the ruxolitinib arm onepatient developed CTCAE grade 4 neutropenia. An extended follow-up of patients treated withruxolitinib showed 2 patients reporting CTCAE grade 4 neutropenia.

In the phase 3 acute GvHD study (REACH2), grade 3 and 4 neutropenia was observed in 17.9% and20.6% of patients, respectively. In the phase 3 chronic GvHD study (REACH3), grade 3 and 4neutropenia was lower (9.5% and 6.7%) than in acute GvHD. In paediatric patients, the frequency ofgrade 3 and 4 neutropenia was 32.0% and 22.0%, respectively, in acute GvHD and 17.3% and 11.1%,respectively, in chronic GvHD.

In the phase 3 pivotal studies in MF bleeding events (including intracranial and gastrointestinal,bruising and other bleeding events) were reported in 32.6% of patients exposed to ruxolitinib and23.2% of patients exposed to the reference treatments (placebo or best available therapy). Thefrequency of grade 3 to 4 events was similar for patients treated with ruxolitinib or referencetreatments (4.7% versus 3.1%). Most of the patients with bleeding events during the treatmentreported bruising (65.3%). Bruising events were more frequently reported in patients taking ruxolitinibcompared with the reference treatments (21.3% versus 11.6%). Intracranial bleeding was reported in1% of patients exposed to ruxolitinib and 0.9% exposed to reference treatments. Gastrointestinalbleeding was reported in 5.0% of patients exposed to ruxolitinib compared to 3.1% exposed toreference treatments. Other bleeding events (including events such as epistaxis, post-proceduralhaemorrhage and haematuria) were reported in 13.3% of patients treated with ruxolitinib and 10.3%treated with reference treatments.

During the long-term follow-up of phase 3 clinical studies in MF, the cumulative frequency ofbleeding events increased proportionally to the increase in the follow-up time. Bruising events werethe most frequently reported bleeding events (33.3%). Intracranial and gastrointestinal bleeding eventswere reported in 1.3% and 10.1% of patients respectively.

In the comparative period of phase 3 studies in PV patients, bleeding events (including intracranial andgastrointestinal, bruising and other bleeding events) were reported in 16.8% of patients treated withruxolitinib, 15.3% of patients receiving best available therapy in RESPONSE study and 12.0% ofpatients receiving best available therapy in RESPONSE 2 study. Bruising was reported in 10.3% ofpatients treated with ruxolitinib, 8.1% of patients receiving best available therapy in RESPONSEstudy and 2.7% of patients receiving best available therapy in RESPONSE 2 study. No intracranialbleeding or gastrointestinal haemorrhage events were reported in patients receiving ruxolitinib. Onepatient treated with ruxolitinib experienced a grade 3 bleeding event (post-procedural bleeding); nograde 4 bleeding was reported. Other bleeding events (including events such as epistaxis, post-procedural haemorrhage, gingival bleeding) were reported in 8.7% of patients treated with ruxolitinib,6.3% of patients treated with best available therapy in RESPONSE study and 6.7% of patients treatedwith best available therapy in RESPONSE 2 study.

During the long-term follow-up of phase 3 studies in PV, the cumulative frequency of bleeding eventsincreased proportionally to the increase in the follow-up time. Bruising events were the mostfrequently reported bleeding events (17.4%). Intracranial and gastrointestinal bleeding events werereported in 0.3% and 3.5% of patients respectively.

In the comparative period of the phase 3 acute GvHD study (REACH2), bleeding events were reportedin 25.0% and 22.0% of patients in the ruxolitinib and BAT arms respectively. The sub-groups ofbleeding events were generally similar between treatment arms: bruising events (5.9% in ruxolitinibvs. 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 nopatients 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). Nointracranial bleeding events were reported in paediatric patients.

In the comparative period of the phase 3 chronic GvHD study (REACH3), bleeding events werereported in 11.5% and 14.6% of patients in the ruxolitinib and BAT arms respectively. The sub-groupsof bleeding events were generally similar between treatment arms: bruising events (4.2% in ruxolitinibvs. 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 eventswere epistaxis, haematochezia, haematoma, post-procedural haemorrhage, and skin haemorrhage(1.8% each). No intracranial bleeding events were reported in patients with chronic GvHD.

In the phase 3 pivotal studies in MF, grade 3 or 4 urinary tract infection was reported in 1.0% ofpatients, herpes zoster in 4.3% and tuberculosis in 1.0%. In phase 3 clinical studies sepsis was reportedin 3.0% of patients. An extended follow-up of patients treated with ruxolitinib showed no trendstowards an increase in the rate of sepsis over time.

In the randomised period of the phase 3 studies in PV patients, one (0.5%) CTCAE grade 3 and nograde 4 urinary tract infection was reported. The rate of herpes zoster was similar in PV (4.3%)patients and MF (4.0%) patients. There was one report of CTCAE grade 3 post-herpetic neuralgiaamongst the PV patients. Pneumonia was reported in 0.5% of patients treated with ruxolitinibcompared to 1.6% of patients in reference treatments. No patients in the ruxolitinib arm reportedsepsis or tuberculosis.

During long-term follow-up of phase 3 studies in PV, frequently reported infections were urinary tractinfections (11.8%), herpes zoster (14.7%) and pneumonia (7.1%). Sepsis was reported in 0.6% ofpatients. No patients reported tuberculosis in long-term follow-up.

In the phase 3 acute GvHD study (REACH2), during the comparative period, urinary tract infectionswere 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 theruxolitinib arm compared to 24.0% (grade ≥3, 10.0%) in the BAT arm. Sepsis events were reported in12.5% (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 3event. During extended follow-up of patients treated with ruxolitinib, urinary tract infections werereported 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; CMVcolitis, CMV enteritis and CMV gastrointestinal infection of any grade were reported in four, two andone 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 lowerfrequency in paediatric patients with acute GvHD (9.8% each) compared to adult and adolescentpatients. CMV infections were reported in 31.4% of paediatric patients (grade 3, 5.9%).

In the phase 3 chronic GvHD study (REACH3), during the comparative period, urinary tractinfections 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%) ofpatients in the ruxolitinib arm compared to 1.3% in the BAT arm. CMV infections were reported in9.1% (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 armcompared to 6.3% (grade ≥3, 5.7%) in the BAT arm. During extended follow-up of patients treatedwith 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 werereported in 8.8% (grade ≥3, 1.3%) and 3.5% (grade ≥3, 3.5%) of patients, respectively. In paediatricpatients with chronic GvHD, urinary tract infections were reported in 5.5% (grade 3, 1.8%) of patientsand BK virus infection was reported in 1.8% (no grade ≥3) of patients. CMV infections occurred in7.3% (no grade ≥3) of patients.

Elevated lipase

In the randomised period of the RESPONSE study, the worsening of lipase values was higher in theruxolitinib arm compared to the control arm, mainly due to the differences among grade 1 elevations(18.2% vs 8.1%). Grade ≥2 elevations were similar between treatment arms. In RESPONSE 2, thefrequencies were comparable between the ruxolitinib and the control arm (10.8% vs 8%). During long-term follow-up of phase 3 PV studies, 7.4% and 0.9% of patients reported grade 3 and grade 4elevation of lipase values. No concurrent signs and symptoms of pancreatitis with elevated lipasevalues were reported in these patients.

In phase 3 studies in MF, high lipase values were reported in 18.7% and 19.3% of patients in theruxolitinib arms compared to 16.6% and 14.0% in the control arms in COMFORT-I and COMFORT-

II studies, respectively. In patients with elevated lipase values, no concurrent signs and symptoms ofpancreatitis were reported.

In the comparative period of the phase 3 acute GvHD study (REACH2), new or worsened lipasevalues 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. Duringextended 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 wasreported 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 lipasevalues 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. Duringextended 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 lipasewas reported with lower frequency (20.4%, grade 3 and 4: 3.8% and 1.9%, respectively) in paediatricpatients.

Increased systolic blood pressure

In the phase 3 pivotal clinical studies in MF an increase in systolic blood pressure of 20 mmHg ormore from baseline was recorded in 31.5% of patients on at least one visit compared with 19.5% of thecontrol-treated patients. In COMFORT-I (MF patients) the mean increase from baseline in systolic BPwas 0 to 2 mmHg on ruxolitinib versus a decrease of 2 to 5 mmHg in the placebo arm. In COMFORT-

II mean values showed little difference between the ruxolitinib-treated and the control-treated MFpatients.

In the randomised period of the pivotal study in PV patients, the mean systolic blood pressureincreased by 0.65 mmHg in the ruxolitinib arm versus a decrease of 2 mmHg in the BAT arm.

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 profileobserved in paediatric patients who received treatment with ruxolitinib was similar to that observed inadult patients.

A total of 29 patients in study REACH2 and 25 patients in REACH3 aged >65 years and treated withruxolitinib were analysed for safety. Overall, no new safety concerns were identified and the safetyprofile in patients >65 years old is generally consistent with that of patients aged 18 to 65 years old.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Haemodialysis is not expected to enhance the elimination of ruxolitinib.

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

Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate thesignalling of a number of cytokines and growth factors that are important for haematopoiesis andimmune function.

MF and PV are myeloproliferative neoplasms known to be associated with dysregulated JAK1 and

JAK2 signalling. The basis for the dysregulation is believed to include high levels of circulatingcytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, andsilencing of negative regulatory mechanisms. MF patients exhibit dysregulated JAK signallingregardless of JAK2V617F mutation status. Activating mutations in JAK2 (V617F or exon 12) arefound in >95% of PV patients.

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

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

Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy subjects,

MF patients and PV patients. Ruxolitinib resulted in maximal inhibition of STAT3 phosphorylation2 hours after dosing which returned to near baseline by 8 hours in both healthy subjects and MFpatients, indicating no accumulation of either parent or active metabolites.

Baseline elevations in inflammatory markers associated with constitutional symptoms such as TNFα,

IL-6 and CRP in subjects with MF were decreased following treatment with ruxolitinib. MF patientsdid not become refractory to the pharmacodynamic effects of ruxolitinib treatment over time.

Similarly, patients with PV also presented with baseline elevations in inflammatory markers and thesemarkers were decreased following treatment with ruxolitinib.

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

Myelofibrosis

Two randomised phase 3 studies (COMFORT-I and COMFORT-II) were conducted in patients with

MF (primary MF, post-polycythaemia vera MF or post-essential thrombocythaemia MF). In bothstudies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category ofintermediate-2 or high risk based on the International Working Group (IWG) Consensus Criteria. Thestarting dose of Jakavi was based on platelet count. Patients with platelet counts ≤100 000/mm3 werenot eligible for enrolment in COMFORT studies but 69 patients were enrolled in the EXPAND study,a Phase Ib, open label, dose-finding study in patients with MF (primary MF, post-polycythaemia vera

MF or post-essential thrombocythaemia MF) and baseline platelet counts ≥50 000 and <100 000/mm3.

COMFORT-I was a double-blind, randomised, placebo-controlled study in 309 patients who wererefractory to or were not candidates for available therapy. The primary efficacy endpoint wasproportion of subjects achieving ≥35% reduction from baseline in spleen volume at week 24 asmeasured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT).

Secondary endpoints included duration of maintenance of a ≥35% reduction from baseline in spleenvolume, proportion of patients who had ≥50% reduction in total symptom score, changes in totalsymptom scores from baseline to week 24, as measured by the modified MF Symptom Assessment

Form (MFSAF) v2.0 diary, and overall survival.

COMFORT-II was an open-label, randomised study in 219 patients. Patients were randomised 2:1 toruxolitinib versus best available therapy. In the best available therapy arm, 47% of patients receivedhydroxyurea and 16% of patients received glucocorticoids. The primary efficacy endpoint wasproportion of patients achieving ≥35% reduction from baseline in spleen volume at week 48 asmeasured by MRI or CT.

Secondary endpoints included proportion of patients achieving a ≥35% reduction of spleen volumefrom baseline at week 24 and duration of maintenance of a ≥35% reduction from baseline spleenvolume.

In COMFORT-I and COMFORT-II, patient baseline demographics and disease characteristics werecomparable between the treatment arms.

Table 8 Percentage of patients with ≥35% reduction from baseline in spleen volume atweek 24 in COMFORT-I and at week 48 in COMFORT-II (ITT)

COMFORT-I COMFORT-II

Jakavi Placebo Jakavi Best available(N=155) (N=153) (N=144) therapy(N=72)

Time points Week 24 Week 48

Number (%) of subjects 65 (41.9) 1 (0.7) 41 (28.5) 0with spleen volumereduced by ≥35%95% confidence intervals 34.1, 50.1 0, 3.6 21.3, 36.6 0.0, 5.0p-value <0.0001 <0.0001

A significantly higher proportion of patients in the Jakavi group achieved ≥35% reduction frombaseline in spleen volume (Table 8) regardless of the presence or absence of the JAK2V617F mutation(Table 9) or the disease subtype (primary MF, post-polycythaemia vera MF, post-essentialthrombocythaemia MF).

Table 9 Percentage of patients with ≥35% reduction from baseline in spleen volume by JAKmutation status (safety set)

COMFORT-I COMFORT-II

Jakavi Placebo Jakavi Best availabletherapy

JAK Positive Negative Positive Negative Positive Negative Positive Negativemutation (N=113) (N=40) (N=121) (N=27) (N=110) (N=35) (N=49) (N=20)status n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%)

Number 54 11 1 0 36 5 0 0(%) of (47.8) (27.5) (0.8) (32.7) (14.3)subjectswithspleenvolumereduced by≥35%

Time point After 24 weeks After 48 weeks

The probability of maintaining spleen response (≥35% reduction) to Jakavi for at least 24 weeks was89% in COMFORT-I and 87% in COMFORT-II; 52% maintained spleen responses for at least48 weeks in COMFORT-II.

In COMFORT-I, 45.9% subjects in the Jakavi group achieved a ≥50% improvement from baseline inthe week 24 total symptom score (measured using MFSAF diary v2.0), as compared to 5.3% in theplacebo group (p<0.0001 using chi-square test). The mean change in the global health status atweek 24, as measured by EORTC QLQ C30 was +12.3 for Jakavi and -3.4 for placebo (p<0.0001).

In COMFORT-I, after a median follow-up of 34.3 months, the death rate in patients randomised to theruxolitinib arm was 27.1% versus 35.1% in patients randomised to placebo; HR 0.687; 95% CI 0.459,1.029; p=0.0668.

In COMFORT-I, after a median follow-up of 61.7 months, the death rate in patients randomised to theruxolitinib arm was 44.5% (69 of 155 patients) versus 53.2% (82 of 154) in patients randomised toplacebo. There was a 31% reduction in the risk of death in the ruxolitinib arm as compared to placebo(HR 0.69; 95% CI 0.50, 0.96; p=0.025).

In COMFORT-II, after a median follow-up of 34.7 months, the death rate in patients randomised toruxolitinib was 19.9% versus 30.1% in patients randomised to best available treatment (BAT); HR0.48; 95% CI 0.28, 0.85; p=0.009. In both studies, the lower death rates noted in the ruxolitinib armwere predominantly driven by the results obtained in the post polycythaemia vera and post essentialthrombocythaemia subgroups.

In COMFORT-II, after a median follow-up of 55.9 months, the death rate in patients randomised tothe ruxolitinib arm was 40.4% (59 of 146 patients) versus 47.9% (35 of 73 patients) in patientsrandomized to best available therapy (BAT). There was a 33% reduction in risk of death in theruxolitinib arm compared to the BAT arm (HR 0.67; 95% CI 0.44, 1.02; p=0.062).

Polycythaemia vera

A randomised, open-label, active-controlled phase 3 study (RESPONSE) was conducted in222 patients with PV who were resistant to or intolerant of hydroxyurea defined based on the

European LeukemiaNet (ELN) international working group published criteria. 110 patients wererandomised to the ruxolitinib arm and 112 patients to the BAT arm. The starting dose of Jakavi was10 mg twice daily. Doses were then adjusted in individual patients based on tolerability and efficacywith a maximum dose of 25 mg twice daily. BAT was selected by the investigator on a patient-by-patient basis and included hydroxyurea (59.5%), interferon/pegylated interferon (11.7%), anagrelide(7.2%), pipobroman (1.8%) and observation (15.3%).

Baseline demographics and disease characteristics were comparable between the two treatments arms.

The median age was 60 years (range 33 to 90 years). Patients in the ruxolitinib arm had PV diagnosisfor a median of 8.2 years and had previously received hydroxyurea for a median of approximately3 years. Most patients (>80%) had received at least two phlebotomies in the last 24 weeks prior toscreening. Comparative data regarding long-term survival and incidence of disease complications ismissing.

The primary composite endpoint was the proportion of patients achieving both an absence ofphlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volume from baseline atweek 32. Phlebotomy eligibility was defined as a confirmed HCT of >45%, i.e. at least 3 percentagepoints higher than the HCT obtained at baseline or a confirmed HCT of >48%, depending on whichwas lower. Key secondary endpoints included the proportion of patients who achieved the primaryendpoint and remained free from progression at week 48, as well as the proportion of patientsachieving complete haematological remission at week 32.

The study met its primary objective and a higher proportion of patients in the Jakavi group achievedthe primary composite endpoint and each of its individual components. Significantly more patientstreated with Jakavi (23%) achieved a primary response (p<0.0001) compared to BAT (0.9%).

Haematocrit control was achieved in 60% of patients in the Jakavi arm compared to 18.8% in the BATarm and a ≥35% reduction in spleen volume was achieved in 40% of patients in the Jakavi armcompared to 0.9% in the BAT arm (Figure 1).

Both key secondary endpoints were also met. The proportion of patients achieving a completehaematological remission was 23.6% on Jakavi compared to 8.0% on BAT (p=0.0013) and theproportion of patients achieving a durable primary response at week 48 was 20% on Jakavi and 0.9%on BAT (p<0.0001).

Figure 1 Patients achieving the primary endpoint and components of the primary endpoint atweek 32

P value: < .0001 Individual components of primary70 Odds ratio (ruxolitinib/BAT) response at week 32and 95% CI:

60 32.67 (5.04, 1337) .RUX.BAT1 1

Primary composite endpoint at ≥35% reduction in spleen Haematocrit control withoutweek 32 volume phlebotomy

Symptom burden was assessed using the MPN-SAF total symptom score (TSS) electronic patientdiary, which consisted of 14 questions. At week 32, 49% and 64% of patients treated with ruxolitinibachieved a ≥50% reduction in TSS-14 and TSS-5, respectively, compared to only 5% and 11% ofpatients on BAT.

Treatment benefit perception was measured by the Patient Global Impression of Change (PGIC)questionnaire. 66% of patients treated with ruxolitinib compared to 19% treated with BAT reported animprovement as early as four weeks after beginning treatment. Improvement in perception oftreatment benefit was also higher in patients treated with ruxolitinib at week 32 (78% versus 33%).

Additional analyses from the RESPONSE study to assess durability of response were conducted atweek 80 and week 256 following randomisation. Out of 25 patients who had achieved primaryresponse at week 32, 3 patients had progressed by week 80 and 6 patients by week 256. Theprobability to have maintained a response from week 32 up to week 80 and week 256 was 92% and74%, respectively (see Table 10).

Table 10 Durability of primary response in the RESPONSE study

Week 32 Week 80 Week 256

Primary response 25/110 (23%) n/a n/aachieved at week 32*n/N (%)

Patients maintaining n/a 22/25 19/25primary response

Probability of n/a 92% 74%maintaining primaryresponse

* According to the primary response composite endpoint criteria: absence ofphlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volumefrom baseline.

n/a: not applicable

A second randomised, open label, active-controlled phase 3b study (RESPONSE 2) was conducted in149 PV patients who were resistant to, or intolerant of, hydroxyurea but without palpable

Percentage e of patientssplenomegaly. The primary endpoint defined as the proportion of patients achieving HCT control(absence of phlebotomy eligibility) at week 28 was met (62.2% in the Jakavi arm versus 18.7% in the

BAT arm). The key secondary endpoint defined as the proportion of patients achieving completehaematological remission at week 28 was also met (23.0% in the Jakavi arm versus 5.3% in the BATarm).

Graft-versus-host disease

Two randomised phase 3, open-label, multi-centre studies investigated Jakavi in patients 12 years ofage and older with acute GvHD (REACH2) and chronic GvHD (REACH3) after allogeneichaematopoietic stem cell transplantation (alloSCT) and insufficient response to corticosteroids and/orother systemic therapies. The starting dose of Jakavi was 10 mg twice daily.

Acute graft-versus-host disease

In REACH2, 309 patients with grade II to IV corticosteroid-refractory, acute GvHD were randomised1:1 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, failedto achieve a response after 7 days or failed corticosteroid taper.

BAT was selected by the investigator on a patient-by-patient basis and included anti-thymocyteglobulin (ATG), extracorporeal photopheresis (ECP), mesenchymal stromal cells (MSC), low dosemethotrexate (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 celltransplantation supportive care including anti-infective medicinal products and transfusion support.

Ruxolitinib was added to continued use of corticosteroids and/or calcineurin inhibitors (CNIs) such ascyclosporine or tacrolimus and/or topical or inhaled corticosteroid therapies per institutionalguidelines.

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

Patients on BAT could cross over to ruxolitinib after day 28 if they met the following criteria:

* Failed to meet the primary endpoint response definition (complete response [CR] or partialresponse [PR]) at day 28; OR

* Lost the response thereafter and met criteria for progression, mixed response, or no response,necessitating new additional systemic immunosuppressive treatment for acute GvHD, AND

* Did not have signs/symptoms of chronic GvHD.

Tapering of Jakavi was allowed after the day 56 visit for patients with treatment response.

Baseline demographics and disease characteristics were balanced between the two treatment arms. Themedian age was 54 years (range 12 to 73 years). The study included 2.9% adolescent, 59.2% male and68.9% white patients. The majority of enrolled patients had malignant underlying disease.

The severity of acute GvHD was grade II in 34% and 34%, grade III in 46% and 47%, and grade IV in20% and 19% of the Jakavi and BAT arms, respectively.

The reasons for patients’ insufficient response to corticosteroids in the Jakavi and BAT arms were i)failure in achieving a response after 7 days of corticosteroid treatment (46.8% and 40.6%,respectively), ii) failure of corticosteroid taper (30.5% and 31.6%, respectively) or iii) diseaseprogression after 3 days of treatment (22.7% and 27.7%, respectively).

Among all patients, the most common organs involved in acute GvHD were skin (54.0%) and lowergastrointestinal tract (68.3%). More patients in the Jakavi arm had acute GvHD involving skin(60.4%) and liver (23.4%), compared to the BAT arm (skin: 47.7% and liver: 16.1%).

The most frequently used prior systemic acute GvHD therapies were corticosteroids+CNIs (49.4% inthe Jakavi arm and 49.0% in the BAT arm).

The primary endpoint was the overall response rate (ORR) on day 28, defined as the proportion ofpatients in each arm with a complete response (CR) or a partial response (PR) without the requirementof additional systemic therapies for an earlier progression, mixed response or non-response based oninvestigator assessment following the criteria by Harris et al. (2016).

The key secondary endpoint was the proportion of patients who achieved a CR or PR at day 28 andmaintained a CR or PR at day 56.

REACH2 met its primary objective. ORR at day 28 of treatment was higher in the Jakavi arm (62.3%)compared to the BAT arm (39.4%). There was a statistically significant difference between thetreatment arms (stratified Cochrane-Mantel-Haenszel test p<0.0001, two-sided, OR: 2.64; 95% CI:

1.65, 4.22).

There was also a higher proportion of complete responders in the Jakavi arm (34.4%) compared to

BAT arm (19.4%).

Day-28 ORR was 76% for grade II GvHD, 56% for grade III GvHD, and 53% for grade IV GvHD inthe Jakavi arm, and 51% for grade II GvHD, 38% for grade III GvHD, and 23% for grade IV GvHD inthe BAT arm.

Among the non-responders at day 28 in the Jakavi and BAT arms, 2.6% and 8.4% had diseaseprogression, respectively.

Overall results are presented in Table 11.

Table 11 Overall response rate at day 28 in REACH2

Jakavi BAT

N=154 N=155n (%) 95% CI n (%) 95% CI

Overall response 96 (62.3) 54.2, 70.0 61 (39.4) 31.6, 47.5

OR (95% CI) 2.64 (1.65, 4.22)p-value (2-sided) p <0.0001

Complete response 53 (34.4) 30 (19.4)

Partial response 43 (27.9) 31 (20.0)

The study met its key secondary endpoint based on the primary data analysis. Durable ORR at day 56was 39.6% (95% CI: 31.8, 47.8) in the Jakavi arm and 21.9% (95% CI: 15.7, 29.3) in the BAT arm.

There was a statistically significant difference between the two treatment arms (OR: 2.38; 95% CI:

1.43, 3.94; p=0.0007). The proportion of patients with a CR was 26.6% in the Jakavi arm versus16.1% in the BAT arm. Overall, 49 patients (31.6%) originally randomised to the BAT arm crossedover to the Jakavi arm.

Chronic graft-versus-host disease

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

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

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

Continued use of corticosteroids and CNIs such as cyclosporine or tacrolimus and topical or inhaledcorticosteroid therapies were allowed per institutional guidelines.

Patients who received one prior systemic treatment other than corticosteroids and/or CNI for chronic

GvHD were eligible for inclusion in the study. In addition to corticosteroids and CNI, prior systemicmedicinal product for chronic GvHD was allowed to continue only if used for chronic GvHDprophylaxis (i.e. started before the chronic GvHD diagnosis) as per common medical practice.

Patients on BAT could cross over to ruxolitinib on day 169 and thereafter due to disease progression,mixed response, or unchanged response, due to toxicity to BAT, or due to chronic GvHD flare.

Efficacy in patients that transition from active acute GvHD to chronic GvHD without tapering offcorticosteroids and any systemic treatment is unknown. Efficacy in acute or chronic GvHD after donorlymphocyte infusion (DLI) and in patients who did not tolerate steroid treatment is unknown.

Tapering of Jakavi was allowed after the day 169 visit.

Baseline demographics and disease characteristics were balanced between the two treatment arms. Themedian age was 49 years (range 12 to 76 years). The study included 3.6% adolescent, 61.1% male and75.4% white patients. The majority of enrolled patients had malignant underlying disease.

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

Patients’ insufficient response to corticosteroids in the Jakavi and BAT arm were characterised by i) alack of response or disease progression after corticosteroid treatment for at least 7 days at 1 mg/kg/dayof prednisone equivalents (37.6% and 44.5%, respectively), ii) disease persistence after 4 weeks at0.5 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% inthe Jakavi arm and 49% in the BAT arm) and corticosteroids+CNIs (41% patients in the Jakavi armand 42% in the BAT arm).

The primary endpoint was the ORR on day 169, defined as the proportion of patients in each arm witha 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 Institutes of Health(NIH) criteria.

A key secondary endpoint was failure free survival (FFS), a composite time to event endpoint,incorporating the earliest of the following events: i) relapse or recurrence of underlying disease ordeath due to underlying disease, ii) non-relapse mortality, or iii) addition or initiation of anothersystemic therapy for chronic GvHD.

REACH3 met its primary objective. At the time of primary analysis (data cut-off date: 08-May-2020),the ORR at week 24 was higher in the Jakavi arm (49.7%) compared to the BAT arm (25.6%). Therewas a statistically significant difference between the treatment arms (stratified Cochrane-Mantel-

Haenszel test p<0.0001, two-sided, OR: 2.99; 95% CI: 1.86, pct. 4.80). Results are presented in Table 12.

Among the non-responders at day 169 in the Jakavi and BAT arms, 2.4% and 12.8% had diseaseprogression, respectively.

Table 12 Overall response rate at day 169 in REACH3

Jakavi BAT

N=165 N=164n (%) 95% CI n (%) 95% CI

Overall response 82 (49.7) 41.8, 57.6 42 (25.6) 19.1, 33.0

OR (95% CI) 2.99 (1.86, pct. 4.80)p-value (2-sided) p<0.0001

Complete response 11 (6.7) 5 (3.0)

Partial response 71 (43.0) 37 (22.6)

The key secondary endpoint, FFS, demonstrated a statistically significant 63% risk reduction of Jakaviversus BAT (HR: 0.370; 95% CI: 0.268, 0.510, p<0.0001). At 6-months, the majority of FFS eventswere “addition or initiation of another systemic therapy for cGvHD” (probability of that event was13.4% vs 48.5% for the Jakavi and the BAT arms, respectively). Results for “relapse of underlyingdisease” and non-relapse mortality (NRM) were 2.46% vs 2.57% and 9.19% vs 4.46%, in the Jakaviand the BAT arms, respectively. No difference of cumulative incidences between treatment arms wasobserved when focusing on NRM only.

The European Medicines Agency has waived the obligation to submit the results of studies with Jakaviin all subsets of the paediatric population for the treatment of MF and PV. In GvHD paediatric patientsabove 2 years of age, the safety and efficacy of Jakavi are supported by evidence from the randomisedphase 3 studies REACH2 and REACH3 and from the open-label, single-arm phase 2 studies REACH4and REACH5 (see section 4.2 for information on paediatric use). The single-arm design does notisolate the contribution of ruxolitinib to overall efficacy.

Acute graft versus host disease

In REACH4, 45 paediatric patients with grade II to IV acute GvHD were treated with Jakavi andcorticosteroids +/- CNIs to assess the safety, efficacy and pharmacokinetics of Jakavi. Patients wereenrolled into 4 groups based on age (Group 1 [≥12 years to <18 years, N=18], Group 2 [≥6 years to<12 years, N=12], Group 3 [≥2 years to <6 years, N=15] and Group 4 [≥28 days to <2 years, N=0]).

The doses tested were 10 mg twice daily for Group 1, 5 mg twice daily for Group 2 and 4 mg/m2 twicedaily for Group 3 and patients were treated for 24 weeks or until discontinuation. Jakavi wasadministered as either a 5 mg tablet or a capsule/oral solution for paediatric patients <12 years.

Patients were enrolled with either steroid-refractory or treatment-naïve disease status. Patients wereconsidered steroid refractory as per institutional criteria or per physician decision in case institutionalcriteria were not available and were permitted to have received no more than one additional priorsystemic treatment for acute GvHD in addition to corticosteroids. Patients were considered treatmentnaïve if they had not received any prior systemic treatment for acute GvHD (except for a maximum72 hours prior systemic corticosteroid therapy of methylprednisolone or equivalent after the onset ofacute GvHD). In addition to Jakavi, patients were treated with systemic corticosteroids and/or CNI(cyclosporine or tacrolimus) and topical corticosteroid therapies were also allowed per institutionalguidelines. In REACH4, 40 patients (88.9%) received concomitant CNIs. Patients could also havereceived standard allogeneic stem cell transplantation supportive care including anti-infectivemedicinal products and transfusion support. Jakavi was to be discontinued in case of lack of responseto acute GvHD treatment at day 28.

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) of 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 acute GvHD. At baseline 64.4% of patients had grade II,26.7% had grade III and 8.9% had grade IV acute GvHD.

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 ofpre-treatment status, the ORR at day 28 was 90.6% in steroid refractory (SR) patients.

Rate of durable ORR at day 56 (key secondary endpoint) measured by the proportion of patients whoachieved a CR or PR at day 28 and maintained a CR or PR at day 56 was 66.7% in all REACH4patients, and 68.8% in SR patients.

Chronic graft versus host disease

In REACH5, 45 paediatric patients with moderate or severe chronic GvHD were treated with Jakaviand corticosteroids +/- CNIs to assess safety, efficacy and pharmacokinetics of Jakavi treatment.

Patients were enrolled into 4 groups based on age (Group 1 [≥12 years to <18 years, N=22], Group 2[≥6 years to <12 years, N=16], Group 3 [≥2 years to <6 years, N=7] and Group 4 [≥28 days to<2 years, N=0]). The doses tested were 10 mg twice daily for Group 1, 5 mg twice daily for Group 2and 4 mg/m2 twice daily for Group 3 and patients were treated for 39 cycles/156 weeks or untildiscontinuation. Jakavi was administered as either a 5 mg tablet or an oral solution for paediatricpatients <12 years.

Patients were enrolled with either steroid-refractory or treatment-naïve disease status. Patients wereconsidered steroid refractory as per institutional criteria or per physician decision in case institutionalcriteria were not available and were permitted to have received additional prior systemic treatment forchronic GvHD in addition to corticosteroids. Patients were considered treatment naïve if they had notreceived any prior systemic treatment for chronic GvHD (except for a maximum 72 hours priorsystemic corticosteroid therapy of methylprednisolone or equivalent after the onset of chronic GvHD).

In addition to Jakavi, patients continued use of systemic corticosteroids and/or CNI (cyclosporine ortacrolimus) and topical corticosteroid therapies were also allowed per institutional guidelines. In

REACH5, 23 patients (51.1%) received concomitant CNIs. Patients could also have received standardallogeneic stem cell transplantation supportive care including anti-infective medicinal products andtransfusion support. Jakavi was to be discontinued in case of lack of response to chronic GvHDtreatment day 169.

Tapering of Jakavi was allowed after the day 169 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 frequentlyleukaemia (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% ofpatients 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 day 169 (primary efficacy endpoint) was 40% (90% CI: 27.7, 53.3) in all REACH5paediatric patients, and 39.3% in SR patients.

Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with highpermeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib israpidly absorbed after oral administration with maximal plasma concentration (Cmax) achievedapproximately 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 Cmax and totalexposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. There was noclinically relevant change in the pharmacokinetics of ruxolitinib upon administration with a high-fatmeal. The mean Cmax was moderately decreased (24%) while the mean AUC was nearly unchanged(4% increase) on dosing with a high-fat meal.

The mean volume of distribution at steady state is approximately 75 litres in MF and PV patients,67.5 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 paediatricpatients with acute or chronic GvHD and with a body surface area (BSA) below 1 m2. At clinicallyrelevant 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 notpenetrate the blood-brain barrier.

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 thedrug-related material in circulation. Two major and active metabolites are present in plasmarepresenting 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% ofthe overall pharmacodynamics of ruxolitinib. At clinically relevant concentrations, ruxolitinib does notinhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potentinducer of CYP1A2, CYP2B6 or CYP3A4 based on in vitro studies. In vitro data indicate thatruxolitinib may inhibit P-gp and BCRP.

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

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

Effects of age, gender or race

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

In a population pharmacokinetic evaluation in MF patients, no relationship was apparent between oralclearance and patient age or race. The predicted oral clearance was 17.7 l/h in women and 22.1 l/h inmen, with 39% inter-subject variability in MF patients. Clearance was 12.7 l/h in PV patients, with a42% inter-subject variability and no relationship was apparent between oral clearance and gender,patient age or race, based on a population pharmacokinetic evaluation in PV patients. Clearance was10.4 l/h in adolescent and adult patients with acute GvHD and 7.8 l/h in adolescent and adult patientswith chronic GvHD, with a 49% inter-subject variability. In paediatric patients with acute or chronic

GvHD and with a BSA below 1 m2, clearance was between 6.5 and 7 l/h. No relationship was apparentbetween oral clearance and gender, patient age or race, based on a population pharmacokineticevaluation in GvHD patients. At a dose of 10 mg twice daily, exposure was increased in GvHDpatients with a low BSA. In subjects with a BSA of 1 m2, 1.25 m2 and 1.5 m2, the predicted meanexposure (AUC) was respectively 31%, 22% and 12% higher than the typical adult (1.79 m2).

The pharmacokinetics of Jakavi in paediatric patients <18 years old with MF and PV have not beenestablished.

As in adult patients with GvHD, ruxolitinib was rapidly absorbed after oral administration inpaediatric patients with GvHD. Dosing in children between 6 and 11 years old at 5 mg twice dailyachieved comparable exposure to a dose of 10 mg twice daily in adolescents and adults with acute andchronic GvHD, confirming the exposure matching approach implemented as part of the extrapolationassumption. In children between 2 and 5 years old with acute and chronic GvHD, the exposurematching approach suggested a dose of 8 mg/m2 twice daily.

Ruxolitinib has not been evaluated in paediatric patients with acute or chronic GvHD below the age of2 years, therefore modelling which accounts for age-related aspects in younger patients has been usedto predict the exposure in these patients, based on the data from adult patients.

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 clinicallysignificant effects on the exposure of ruxolitinib.

Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and urinarycreatinine. Following a single ruxolitinib dose of 25 mg, the exposure of ruxolitinib was similar insubjects 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 renalimpairment, and were most markedly increased in the subjects with severe renal impairment. It isunknown whether the increased metabolite exposure is of safety concern. A dose modification isrecommended in patients with severe renal impairment and end-stage renal disease (see section 4.2).

Dosing only on dialysis days reduces the metabolite exposure, but also the pharmacodynamic effect,especially on the days between dialysis.

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 hepaticimpairment 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 impairmentcompared to healthy controls (4.1 to 5.0 hours versus 2.8 hours). A dose reduction of approximately50% 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 shouldbe reduced by 50%.

Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity andreproductive toxicity studies and in a carcinogenicity study. Target organs associated with thepharmacological action of ruxolitinib in repeated dose studies include bone marrow, peripheral bloodand 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 telemetrystudy, and an adverse decrease in minute volume was noted in a respiratory study in rats. The margins(based on unbound Cmax) 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. Noeffects 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 or21 (comparable to human infant, 1-3 years). Fractures and early termination of rats were observed atdoses ≥30 mg/kg/day when treatment was started on postnatal day 7. Based on unbound AUC, theexposure at the NOAEL (no observed adverse effect level) in juvenile rats treated as early as postnatalday 7 was 0.3-fold that of adult patients at 25 mg twice daily, while reduced bone growth and fracturesoccurred 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 thepostnatal period. Other than bone development, the effects of ruxolitinib in juvenile rats were similarto 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 wasno evidence of a teratogenic effect in rats and rabbits. However, the exposure margins compared to thehighest clinical dose were low and the results are therefore of limited relevance for humans. No effectswere noted on fertility. In a pre- and post-natal development study, a slightly prolonged gestationperiod, reduced number of implantation sites, and reduced number of pups delivered were observed. Inthe pups, decreased mean initial body weights and short period of decreased mean body weight gainwere observed. In lactating rats, ruxolitinib and/or its metabolites were excreted into the milk with aconcentration that was 13-fold higher than the maternal plasma concentration. Ruxolitinib was notmutagenic or clastogenic. Ruxolitinib was not carcinogenic in the Tg.rasH2 transgenic mouse model.

Cellulose, microcrystalline

Magnesium stearate

Silica, colloidal anhydrous

Sodium starch glycolate (Type A)

Povidone K30

Hydroxypropylcellulose 300 to 600 cps

Lactose monohydrate

Not applicable.

3 years

Do not store above 30°C.

PVC/PE/PVDC/aluminium blister packs containing 14 or 56 tablets or multipacks containing 168(3 packs of 56) tablets.

Not all pack sizes or types may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Jakavi 5 mg tablets

EU/1/12/773/004-006

Jakavi 10 mg tablets

EU/1/12/773/014-016

Jakavi 15 mg tablets

EU/1/12/773/007-009

Jakavi 20 mg tablets

EU/1/12/773/010-012

Date of first authorisation: 23 August 2012

Date of latest renewal: 24 April 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu