4.1. Therapeutic indications

Myelofibrosis (MF)

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

Polycythaemia vera (PV)

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

Graft versus host disease (GvHD)

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

4.2. Posology and method of administration

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

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

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

Posology

Starting dose

Myelofibrosis (MF)

The recommended starting dose of Jakavi in myelofibrosis (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 orally twice daily

100,000 to 200,000/mm3

15 mg orally twice daily

75,000 to less than 100,000/mm3

10 mg orally twice daily

50,000 to less than 75,000/mm3

5 mg orally twice daily

Polycythaemia vera (PV)

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

Graft versus host disease (GvHD)

The recommended starting dose of Jakavi in acute and chronic graft versus host disease (GvHD) is based on age (see Table 2):

Table 2 Starting doses in acute and chronic graft versus host disease

Age group

Starting dose

12 years old and above

10 mg orally twice daily

6 years to less than 12 years old

5 mg orally twice daily

2 years to less than 6 years old

4 mg/m2 orally twice daily

These starting doses in GvHD can be administered using either the tablet for patients at or above 6 years old who can swallow tablets or the oral solution for patients under 12 years old.

Dose modifications

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 a maximum 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 no more frequently than at 2‑week intervals.

Treatment should be discontinued for platelet counts less than 50,000/mm3 or absolute neutrophil counts less than 500/mm3. In PV, treatment should also be interrupted when haemoglobin is below 8 g/dl. After recovery of blood counts above these levels, dosing may be re-started at 5 mg twice daily and gradually increased based on careful monitoring of complete blood cell count, including a white blood cell count differential.

Dose reductions should be considered if the platelet count decreases during treatment as outlined in Table 3, with the goal of avoiding dose interruptions for thrombocytopenia.

Table 3 Dosing recommendation for thrombocytopenia

Dose at time of platelet decline

25 mgtwice daily

20 mgtwice daily

15 mgtwice daily

10 mgtwice daily

5 mgtwice daily

Platelet count

New dose

100,000 to <125,000/mm3

20 mgtwice daily

15 mgtwice daily

No change

No change

No change

75,000 to <100,000/mm3

10 mgtwice daily

10 mgtwice daily

10 mgtwice daily

No change

No change

50,000 to <75,000/mm3

5 mgtwice daily

5 mgtwice daily

5 mgtwice daily

5 mgtwice daily

No change

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 is recommended if it decreases below 10 g/dl.

Graft versus host disease

Dose reductions and temporary interruptions of treatment may be needed in GvHD-patients with thrombocytopenia, neutropenia, or elevated total bilirubin after standard supportive therapy including growth-factors, anti-infective therapies and transfusions. One dose level reduction step is recommended (10 mg twice daily to 5 mg twice daily or 5 mg twice daily to 5 mg once daily). In patients who are unable to tolerate Jakavi at a dose of 5 mg once daily, treatment should be interrupted. Detailed dosing recommendations are provided in Table 4.

Table 4 Dosing recommendations for GvHD patients with thrombocytopenia, 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 to initial dose level, otherwise maintain reduced dose.

Platelet count <15,000/mm3

Hold Jakavi until platelet count ≥20,000/mm3, then resume at one lower dose level.

Absolute neutrophil count (ANC) ≥500/mm3 to <750/mm3

Reduce Jakavi by one dose level. Resume at initial dose level if ANC >1,000/mm3.

Absolute neutrophil count <500/mm3

Hold Jakavi until ANC >500/mm3, then resume at one lower dose level. If ANC >1,000/mm3, dosing may resume at initial dose level.

Total bilirubin elevation, no liver GvHD

>3.0 to 5.0 x ULN: Continue Jakavi at one lower dose level until ≤3.0 x ULN.

>5.0 to 10.0 x ULN: Hold Jakavi up to 14 days until total bilirubin ≤3.0 x ULN. If total bilirubin ≤3.0 x ULN dosing may 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, liver GvHD

>3.0 x ULN: Continue Jakavi at one lower dose level until total bilirubin ≤3.0 x ULN.

Dose adjustment with concomitant strong CYP3A4 inhibitors or fluconazole

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

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

Special populations

Renal impairment

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

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

There are 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 in this population suggest that the starting dose for MF patients with ESRD on haemodialysis is a single dose of 15 to 20 mg or two doses of 10 mg given 12 hours apart, to be administered post-dialysis and only on the day of haemodialysis. A single dose of 15 mg is recommended for MF patients with platelet count between 100,000/mm3 and 200,000/mm3. A single dose of 20 mg or two doses of 10 mg given 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 be administered only on haemodialysis days following each dialysis session.

The recommended starting dose for PV patients with ESRD on haemodialysis is a single dose of 10 mg or two doses of 5 mg given 12 hours apart, to be administered post-dialysis and only on the day of 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 data is available for dosing patients who are undergoing peritoneal dialysis or continuous venovenous haemofiltration (see section 5.2).

There are no data for GvHD patients with ESRD.

Hepatic impairment

In MF patients with any hepatic impairment the recommended starting dose based on platelet count should be reduced by approximately 50% to be administered twice daily. Subsequent doses should be adjusted based on careful monitoring of safety and efficacy. The recommended starting dose is 5 mg twice daily for PV patients. Patients diagnosed with hepatic impairment while receiving ruxolitinib should have complete blood counts, including a white blood cell count differential, monitored at least every one to two weeks for the first 6 weeks after initiation of therapy with ruxolitinib and as clinically indicated thereafter once their liver function and blood counts have been stabilised. Ruxolitinib dose can be titrated to reduce the risk of cytopenia (see section 4.4).

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

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

Elderly patients (≥65 years)

No additional dose adjustments are recommended for elderly patients.

Paediatric population

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

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

Treatment discontinuation

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 spleen size 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% compared with baseline size (roughly equivalent to a 25% increase in spleen volume) and no longer have tangible improvement in disease‑related symptoms.

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

Method of administration

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

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

4.3. Contraindications

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

Pregnancy and lactation.

4.4. Special warnings and precautions for use

Myelosuppression

Treatment with Jakavi can cause haematological adverse drug reactions, including thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood cell count differential, must be performed before initiating therapy with Jakavi. Treatment should be interrupted in MF patients with platelet count less than 50,000/mm3 or absolute neutrophil count less than 500/mm3 (see section 4.2).

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

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

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

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

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

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

Infections

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

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

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

Herpes zoster

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

Progressive multifocal leukoencephalopathy

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

Lipid abnormalities/elevations

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

Major adverse cardiac events (MACE)

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

MACE have been reported in patients receiving Jakavi. Prior to initiating or continuing therapy with Jakavi, the benefits and risks for the individual patient should be considered particularly in patients 65 years of age and older, patients who are current or past long‑time smokers, and patients with a history of atherosclerotic cardiovascular disease or other cardiovascular risk factors.

Thrombosis

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

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving Jakavi. In patients with MF and PV treated with Jakavi in clinical studies, the rates of thromboembolic events were similar in Jakavi and control-treated patients.

Prior to initiating or continuing therapy with Jakavi, the benefits and risks for the individual patient should be considered, particularly in patients with cardiovascular risk factors (see also section 4.4 “Major adverse cardiovascular events (MACE)”) and additional risk factors for VTE such as history of VTE, major surgery, immobilisation, use of combined hormonal contraceptives or hormone replacement therapy, and inherited coagulation disorder.

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

Second primary malignancies

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

Lymphoma and other malignancies have been reported in patients receiving JAK inhibitors, including Jakavi.

Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell carcinoma, have been reported in patients treated with ruxolitinib. Most of the MF and PV patients had histories 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.

Special populations

Renal impairment

The starting dose of Jakavi should be reduced in patients with severe renal impairment. For patients with 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 (see section 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 be administered only on haemodialysis days following each dialysis session. Additional dose modifications should be made with careful monitoring of safety and efficacy. In GvHD patients with severe renal impairment, the starting dose of Jakavi should be reduced by approximately 50% (see sections 4.2 and 5.2).

Hepatic impairment

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

Interactions

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

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

Withdrawal effects

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

Excipients

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

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

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

Interaction studies have only been performed in adults.

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

Interactions resulting in dose reduction of ruxolitinib

CYP3A4 inhibitors

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

In healthy subjects co‑administration of ruxolitinib (10 mg single dose) with a strong CYP3A4 inhibitor, ketoconazole, resulted in ruxolitinib 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 with concurrent ketoconazole administration.

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

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

Dual CYP2C9 and CYP3A4 inhibitors

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

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

Enzyme inducers

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

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

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

Other interactions to be considered affecting ruxolitinib

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

In healthy subjects co‑administration of ruxolitinib (10 mg single dose) with erythromycin 500 mg twice daily for four days resulted in ruxolitinib 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 cytopenias when initiating therapy with a moderate CYP3A4 inhibitor.

Effects of ruxolitinib on other medicinal products

Substances transported by P‑glycoprotein or other transporters

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

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

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

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

Women of childbearing potential/Contraception

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

Breast‑feeding

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

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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%), other bleeding (including epistaxis, post‑procedural haemorrhage and haematuria) (24.3%) and dizziness (21.9%).

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

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 reported in 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) identified as adverse reactions were increased alanine aminotransferase (45.3%), increased aspartate aminotransferase (42.6%), and hypercholesterolaemia (34.7%). No CTCAE grade 4 increased alanine aminotransferase or hypercholesterolaemia, and one CTCAE grade 4 increased aspartate aminotransferase were observed.

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

Acute GvHD

REACH 1

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

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

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

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

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

REACH 2

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

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

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

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

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

Chronic GvHD

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

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

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

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

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

Paediatric patients:

A total of 20 patients aged 12 to <18 years with GvHD were analysed for safety: 9 patients (5 in the ruxolitinib arm and 4 in the best available treatment [BAT] arm) in the study REACH2 and 11 patients (4 in the ruxolitinib arm and 7 in the BAT arm) in the study REACH3. Based on the similar exposure observed in adolescents and adults, the safety of ruxolitinib at the recommended dose of 10 mg twice daily is similar in frequency and severity.

Tabulated list of adverse drug reactions from clinical studies

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

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

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

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

Adverse drug reactions from clinical studies in MF and PV (Table 5) and in acute and chronic GvHD (Table 6) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 5 Frequency category of adverse drug reactions reported in the phase 3 studies in MF and PV

Adverse drug reaction

Frequency category for MF patients

Frequency category for PV patients

Infections and infestations

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

(<6.5g/dl)

Very common

Uncommon

CTCAEc grade 3

(<8.0 – 6.5g/dl)

Very common

Common

Any CTCAEc grade

Very common

Very common

Thrombocytopeniaa

CTCAEc grade 4

(<25,000/mm3)

Common

Uncommon

CTCAEc grade 3

(50,000 – 25,000/mm3)

Very common

Common

Any CTCAEc grade

Very common

Very common

Neutropeniaa

CTCAEc grade 4

(<500/mm3)

Common

Uncommon

CTCAEc grade 3

(<1,000 – 500/mm3)

Common

Uncommon

Any CTCAEc grade

Very common

Common

Pancytopeniaa,b

Common

Common

Bleeding (any bleeding including intracranial, and gastrointestinal bleeding, bruising and other bleeding)

Very common

Very common

Bruising

Very common

Very common

Gastrointestinal bleeding

Very common

Common

Intracranial bleeding

Common

Uncommon

Other bleeding (including epistaxis, post‑procedural haemorrhage and haematuria)

Very common

Very common

Metabolism and nutrition disorders

Hypercholesterolaemiaa any CTCAEc grade

Very common

Very common

Hypertriglyceridaemiaa any CTCAEc grade

Very common

Very common

Weight gain

Very common

Very common

Nervous system disorders

Dizziness

Very common

Very common

Headache

Very common

Very common

Gastrointestinal disorders

Elevated lipase, any CTCAEc grade

Very common

Very common

Constipation

Very common

Very common

Flatulence

Common

Common

Hepatobiliary disorders

Increased alanine aminotransferasea

CTCAEc grade 3

(> 5x – 20 x ULN)

Common

Common

Any CTCAEc grade

Very common

Very common

Increased aspartate aminotransferasea

Any CTCAEc grade

Very common

Very common

Vascular disorders

Hypertension

Very common

Very common

a 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, and neutrophil count <1.5x109/l (or low white blood cell count of grade 2 if neutrophil count is missing), simultaneously in the same lab assessment

c Common Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life‑threatening

d 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, bone pain, 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 after dose discontinuation (see section 4.4).

Table 6 ADRs reported in studies Acute GvHD REACH 1 and Chronic GvHD REACH 3

Acute GvHD (REACH1)

(N=71)

Chronic GvHD (REACH3)

(N=226)

Adverse drug reaction

Frequency category

All grades

(%)

CTCAE3 Grade 3/4

(%)

Frequency category

All grades

(%)

CTCAE3

Grade 3/4

(%)

Infections and infestations

CMV infections

Very common

19.7

8.5 / 0

-

-

- / -

Sepsis

Very common

22.5

4.2 / 16.94

-

-

- / -

Urinary tract infections

Very common

14.1

8.5 / 0

Common

9.3

1.3 / 0

BK virus infections

-

-

- / -

Common

4.9

0.4 / 0

Blood and lymphatic system disorders

Thrombocytopenia1

Very common

84.1

24.0 / 49.2

Very common

34.4

5.9 / 10.7

Anaemia1

Very common

87.1

51.6 / NA

Very common

68.6

14.8 / NA

Neutropenia1

Very common

65.2

29.2 / 15.9

Very common

36.2

9.5 / 6.7

Pancytopenia1,2

Very common

23.9

NA

-

-

- / -

Metabolism and nutrition disorders

Hypercholesterolaemia1,5

Common

1.4

0 / 1.4

Very common

52.3

5.5 / 0.5

Weight gain

-

-

-

Common

3.5

0 / 0

Nervous system disorders

Headache

Very common

21.1

4.2 / 0

Very common

10.2

1.3 / 0

Vascular disorders

Hypertension

Very common

22.5

14.1 / 0

Very common

15.0

5.3 / 0

Gastrointestinal disorders

Increased lipase1

-

-

-

Very common

35.9

9.5 / 0.4

Increased amylase1

-

-

-

Very common

32.4

4.2 / 2.7

Nausea

Very common

32.4

5.6 / 0

-

-

- / -

Constipation

-

-

-

Common

6.6

0 / 0

Hepatobiliary disorders

Increased alanine aminotransferase1

Very common

50.7

9.8 / 0

Very common

43.1

4.7 / 0.9

Increased aspartate aminotransferase1

Very common

50.7

5.8 / 0

Very common

52.2

3.1 / 0.9

Musculoskeletal and connective tissue disorders

Increased blood creatine phosphokinase1

-

-

-

Very common

31.1

1.0 / 1.4

Renal and urinary disorders

Increased blood creatinine1

-

-

-

Very common

38.4

1.3 / 0

NA = not applicable

1 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, and neutrophil count <1.5 x 109/l (or low white blood cell count of grade 2 if neutrophil count is missing), simultaneously in the same laboratory assessment.

3 CTCAE Version 4.03.

4 Grade 4 sepsis includes 16 (8%) grade 4 events and 20 (10%) grade 5 events.

5 Frequency for REACH1 is based on AE data rather than laboratory values, because cholesterol laboratory parameter was not collected in the study. Frequency for REACH3 is based on laboratory values.

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

Table 7 ADRs reported in the supportive acute GvHD study REACH 2

Acute GvHD (REACH2)

(N=201)

Adverse drug reaction

Frequency category

All grades

(%)

CTCAE3 Grade 3/4

(%)

Infections and infestations

CMV infections

Very common

32.3

10.9 / 0.5

Sepsis

Very common

25.4

4.0 / 17.94

Urinary tract infections

Very common

17.9

6.0 / 0.5

Blood and lymphatic system disorders

Thrombocytopenia1

Very common

85.2

31.3 / 47.7

Anaemia1

Very common

75.0

47.7 / NA

Neutropenia1

Very common

65.1

17.9 / 20.6

Pancytopenia1,2

Very common

32.8

NA

Metabolism and nutrition disorders

Hypercholesterolaemia1

Very common

49.2

3.3 / 5.9

Nervous system disorders

Headache

Common

8.5

0.5 / 0

Vascular disorders

Hypertension

Very common

13.4

5.5 / 0

Gastrointestinal disorders

Nausea

Very common

16.4

0.5 / 0

Hepatobiliary disorders

Increased alanine aminotransferase1

Very common

54.9

17.6 / 1.5

Increased aspartate aminotransferaseAST1

Very common

52.3

7.8 / 0

NA = not applicable

1 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, and neutrophil count <1.5 x 109/l (or low white blood cell count of grade 2 if neutrophil count is missing), simultaneously in the same laboratory assessment.

3 CTCAE Version 4.03.

4 Grade 4 sepsis includes 16 (8%) grade 4 events and 20 (10%) grade 5 events.

Table 8 ADR's reported in clinical studies in acute (REACH2, REACH4) and chronic (REACH3, REACH5) GvHD paediatric pool

Chronic GvHD

Pediatric patients

(REACH3 and REACH5)

(N=55)

Acute GvHD

Pediatric patients

(REACH2 and REACH4)

(N=51)

Adverse drug reaction

Frequency category

All grades (%)

CTCAE2 grade 3 / 4 (%)

Frequency category

All grades (%)

CTCAE3 grade 3 / 4 (%)

Infections and infestations

CMV infections

-6

-6

-6

Very common

31.4

5.9 / 0

Sepsis4

-6

-6

-6

Common

9.8

2.0 / 5.9

Urinary tract infections

Common

5.5

1.8 / 0

Common

9.8

2.0 / 0

BK virus infections

Common

1.8

0 / 0

-6

-6

-6

Blood and lymphatic system disorders

Thrombocytopenia1

Very common

35.2

7.7 / 11.1

Very common

55.1

14.6 / 22.4

Anaemia1

Very common

49.1

17.0 / NA

Very common

70.8

45.8 / NA

Neutropenia1

Very common

59.3

17.3 /11.1

Very common

70.0

32.0 / 22.0

Pancytopenia1,2

-6

-6

-6

Very common

25.5

NA

Metabolism and nutrition disorders

Hypercholesterolaemia1

Very common

54.9

4.1/5.9

Very common

61.2

0 / 0

Weight gain

Common

5.5

3.6 / 0

-6

-6

-6

Nervous system disorders

Headache

Very common

18.2

1.8 / 0

Common

5.9

0 / 0

Vascular disorders

Hypertension

Very common

14.5

3.6 / 0

Very common

17.6

15.7 / 0

Gastrointestinal disorders

Nausea

-6

-6

-6

Common

3.9

0 / 0

Increased lipase1

Very common

20.4

3.8 /1.9

-6

-6

-6

Increased amylase1

Very common

25.9

9.4 / 0

-6

-6

-6

Constipation

Common

5.5

0 / 0

-6

-6

-6

Hepatobiliary disorders

Increased AST1

Very common

45.5

11.5 / 0

Very common

50.0

6.1 / 0

Increased ALT1

Very common

50.9

14.9 / 3.6

Very common

63.3

27.3 / 0

Musculoskeletal and connective tissue disorders

Increased blood CPK1

Very common

22.6

0 / 0

-6

-6

-6

Renal and urinary disorders

Increased blood creatinine1

Common

7.3

0 / 0

-6

-6

-6

1 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, and neutrophil count <1.5 x 109/l (or low white blood cell count of grade 2 if neutrophil count is missing), 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 events in the paediatric pool.

5 Not applicable: no cases reported

6 “-”: not an identified adverse drug reaction in this indication

Description of selected adverse drug reactions

Anaemia

In phase 3 clinical studies in MF, median time to onset of first CTCAE grade 2 or higher anaemia was 1.5 months. One patient (0.3%) discontinued treatment because of anaemia.

In patients receiving ruxolitinib mean decreases in haemoglobin reached a nadir of approximately 10 g/litre below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 5 g/litre below baseline. This pattern was observed in patients regardless of whether they had received transfusion during therapy.

In the randomised, placebo‑controlled study COMFORT‑I 60.6% of Jakavi‑treated MF patients and 37.7% of placebo‑treated MF patients received red blood cell transfusions during randomised treatment. 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 MF patients (40.8% versus 82.4%). In the PV population, the CTCAE grade 3 and 4 events were reported in 2.7%, while in the MF patients the frequency was 42.56%.

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

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

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

Thrombocytopenia

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

In the randomised period of the pivotal studies, the rate of patients experiencing thrombocytopenia was 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 2 acute GvHD study (REACH1) Grade 3 and 4 thrombocytopenia was observed in 24.0% and 49.2% of patients, respectively. In the phase 3 acute GvHD study (REACH2) Grade 3 and 4 thrombocytopenia was observed in 31.3% and 47.7% of patients, respectively.

In the phase 3 chronic GvHD study (REACH3), grade 3 and 4 thrombocytopenia was lower (5.9% and 10.7%) than in acute GvHD.

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

Neutropenia

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

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

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

In the phase 3 chronic GvHD study (REACH3) grade 3 and 4 neutropenia was lower (9.5% and 6.7%) than in acute GvHD.

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

Bleeding

In the 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 and 23.2% of patients exposed to the reference treatments (placebo or best available therapy). The frequency of grade 3 to 4 events was similar for patients treated with ruxolitinib or reference treatments (4.7% versus 3.1%). Most of the patients with bleeding events during the treatment reported bruising (65.3%). Bruising events were more frequently reported in patients taking ruxolitinib compared with the reference treatments (21.3% versus 11.6%). Intracranial bleeding was reported in 1% of patients exposed to ruxolitinib and 0.9% exposed to reference treatments. Gastrointestinal bleeding was reported in 5.0% of patients exposed to ruxolitinib compared to 3.1% exposed to reference treatments. Other bleeding events (including events such as epistaxis, post‑procedural haemorrhage 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 of bleeding events increased proportionally to the increase in the follow-up time. Bruising events were the most frequently reported bleeding events (33.3%). Intracranial and gastrointestinal bleeding events were 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 and gastrointestinal, bruising and other bleeding events) were reported in 16.8% of patients treated with ruxolitinib, 15.3% of patients receiving best available therapy in RESPONSE study and 12.0% of patients receiving best available therapy in RESPONSE 2 study. Bruising was reported in 10.3% of patients treated with ruxolitinib, 8.1% of patients receiving best available therapy in RESPONSE study and 2.7% of patients receiving best available therapy in RESPONSE 2 study. No intracranial bleeding or gastrointestinal haemorrhage events were reported in patients receiving ruxolitinib. One patient treated with ruxolitinib experienced a grade 3 bleeding event (post‑procedural bleeding); no grade 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 treated with best available therapy in RESPONSE 2 study.

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

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

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

Infections

In the phase 3 pivotal studies in MF, grade 3 or 4 urinary tract infection was reported in 1.0% of patients, herpes zoster in 4.3% and tuberculosis in 1.0%. In phase 3 clinical studies sepsis was reported in 3.0% of patients. An extended follow-up of patients treated with ruxolitinib showed no trends towards 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 no grade 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 neuralgia amongst the PV patients. Pneumonia was reported in 0.5% of patients treated with ruxolitinib compared to 1.6% of patients in reference treatments. No patients in the ruxolitinib arm reported sepsis or tuberculosis.

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

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

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

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

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

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

Elevated lipase

In the randomised period of the RESPONSE study, the worsening of lipase values was higher in the ruxolitinib 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, the frequencies 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 4 elevation of lipase values. No concurrent signs and symptoms of pancreatitis with elevated lipase values 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 the ruxolitinib 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 of pancreatitis were reported.

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

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

Increased systolic blood pressure

In the phase 3 pivotal clinical studies in MF an increase in systolic blood pressure of 20 mmHg or more from baseline was recorded in 31.5% of patients on at least one visit compared with 19.5% of the control‑treated patients. In COMFORT‑I (MF patients) the mean increase from baseline in systolic BP was 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 MF patients.

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

Special populations

Paediatric patients

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

Elderly

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

Haemodialysis is not expected to enhance the elimination of ruxolitinib.