ruxolitinib: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

Jakavi

4.1 Therapeutic indications

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets

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)

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

Applies to: Jakavi 5 mg/ml oral solution

Graft versus host disease (GvHD)

4.2 Posology and method of administration

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets

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 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 daily
100 000 to 200 000/mm3
15 mg twice daily
75 000 to less than 100 000/mm3
10 mg twice daily
50 000 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 2 and 3):

Table 2
Starting doses in acute graft versus host disease

Age group
Starting dose
12 years old and above
10 mg twice daily
6 years to less than 12 years old
5 mg twice daily
28 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 dose
12 years old and above
10 mg twice daily
6 years to less than 12 years old
5 mg twice daily
6 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 swallow tablets whole or the oral solution.

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

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

Table 4
Dosing recommendation for MF patients with thrombocytopenia

Dose at time of platelet decline

25 mg twice daily
20 mg twice daily
15 mg twice daily
10 mg twice daily
5 mg twice daily
Platelet count
New dose
100 000 to <125 000/mm3
20 mg twice daily
15 mg twice daily
No change
No change
No change
75 000 to <100 000/mm3
10 mg twice daily
10 mg twice daily
10 mg twice daily
No change
No change
50 000 to <75 000/mm3
5 mg twice daily
5 mg twice daily
5 mg twice daily
5 mg twice 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 5.

Table 5
Dosing recommendations during ruxolitinib therapy 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 not caused by GvHD (no liver GvHD)
>3.0 to 5.0 x upper limit of normal (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 caused by
GvHD (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 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 approximately 50%, to be administered twice daily (see sections 4.4 and 4.5). The concomitant use of ruxolitinib with fluconazole doses greater than 200 mg daily should be avoided.

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 based on platelet count 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 (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 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. 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 is recommended.

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).

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.

Applies to: Jakavi 5 mg/ml oral solution

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
The recommended starting dose of Jakavi in acute and chronic GvHD is based on age (see Tables 1 and 2):

Table 1
Starting doses in acute graft versus host disease

Age group
Starting dose
12 years old and above
10 mg / 2 ml twice daily
6 years to less than 12 years old
5 mg / 1 ml twice daily
28 days to less than 6 years old
8 mg/m2 twice daily (see Table 3)

Table 2
Starting doses in chronic graft versus host disease

Age group
Starting dose
12 years old and above
10 mg / 2 ml twice daily
6 years to less than 12 years old
5 mg / 1 ml twice daily
6 months to less than 6 years old
8 mg/m2 twice daily (see Table 3)

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

The volume of Jakavi to be administered twice daily when using a starting dose of 8 mg/m2 in patients less than 6 years old is presented in Table 3.

Table 3
Volume of Jakavi oral solution (5 mg/ml) to be administered twice daily when using a starting dose of 8 mg/m2 in patients less than 6 years old

Body surface area (BSA) (m2)
Volume (ml)
Min
Max

4.3 Contraindications

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets · Jakavi 5 mg/ml oral solution

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

Pregnancy and lactation.

4.8 Undesirable effects

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets

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
The most frequently reported adverse drug reactions in REACH2 (adult and adolescent patients) were thrombocytopenia, anaemia, neutropenia, increased alanine aminotransferase and increased aspartate aminotransferase. The most frequently reported adverse drug reactions 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 REACH2 and in 45.8% of patients in the paediatric pool. 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 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 in REACH3 (adult and adolescent patients) were anaemia, hypercholesterolemia and increased aspartate aminotransferase. The most frequently reported adverse drug reactions 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 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 non-haematological laboratory abnormalities identified as adverse drug reactions in REACH3 (adult and adolescent patients) and in the pool of paediatric patients (REACH3 and REACH5) were hypercholesterolaemia (52.3% and 54.9%), increased aspartate aminotransferase (52.2% and 45.5%) and increased alanine aminotransferase (43.1% and 50.9%). The majority were grade 1 and 2, however grade 3 laboratory abnormalities reported in the pool of paediatric patients included increased alanine aminotransferase (14.9%) and increased aspartate aminotransferase (11.5%).

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

Tabulated list of adverse reactions

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 3 study REACH2 and in the phase 2 study REACH4. REACH2 included 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). The median exposure upon which the adverse drug reaction frequency categories were based was 8.9 weeks (range 0.3 to 66.1 weeks). In the pool of paediatric patients ≥2 years of age (6 patients in REACH2 and 45 patients in REACH4), the median exposure was 16.7 weeks (range 1.1 to 48.9 weeks).

41.4 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 to 155.4 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 or disabling, 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 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 6
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 7
Frequency category of adverse drug reactions reported in clinical studies in GvHD

Acute GvHD
(REACH2)
Acute GvHD
(Paediatric pool)
Chronic
GvHD
(REACH3)
Chronic GvHD
(Paediatric pool)
Adverse drug reaction
Frequency category
Frequency category
Frequency category
Frequency category
Infections and infestations
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
Blood and lymphatic system disorders
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
Metabolism and nutrition disorders
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
Nervous system disorders
Headache
Common
Common
Very common
Very common

CTCAE grade ≥3
Uncommon
N/A5
Common
Common
Vascular disorders
Hypertension
Very common
Very common
Very common
Very common

CTCAE grade ≥3
Common
Very common
Common
Common
Gastrointestinal disorders
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

Hepatobiliary disorders
Increased alanine aminotransferase1
Very common
Very common
Very common
Very common

CTCAE grade 3
Very common
Very common
Common
Very common

CTCAE grade 4
Common
N/A5
Uncommon
Common
Increased aspartate aminotransferase1
Very common
Very common
Very common
Very common

CTCAE grade 3
Common
Common
Common
Very common

CTCAE grade 4
N/A5
N/A5
Uncommon
N/A5
Musculoskeletal and connective tissue disorders
Increased blood creatine phosphokinase1
-6
-6
Very common
Very common

CTCAE grade 3
-6
-6
Common
N/A5

CTCAE grade 4
-6
-6
Common
N/A5
Renal and urinary disorders
Increased blood creatinine1
-6
-6
Very common
Common

CTCAE grade 3
-6
-6
Common
N/A5

CTCAE grade 4
-6
-6
N/A5
N/A5
Frequency is based on new or worsened laboratory abnormalities compared to baseline.
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.
CTCAE Version 4.03.
Grade ≥3 sepsis includes 20 (10%) grade 5 events in REACH2. There were no grade 5 events in the paediatric pool.
Not applicable: no cases reported
“-”: 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 phase 3 acute (REACH2) and chronic (REACH3) GvHD studies, 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 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 phase 3 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 3 acute GvHD study (REACH2), 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 (REACH3), 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 national reporting system listed in Appendix V.

Applies to: Jakavi 5 mg/ml oral solution

Summary of the safety profile

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.

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

Tabulated list of adverse reactions

The safety of Jakavi in chronic GvHD patients was evaluated in the phase 3 study REACH3 and in the phase 2 study REACH5. REACH3 included 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 ≥2 years of age (10 patients in REACH3 and 45 patients in REACH5), the median exposure was 57.1 weeks (range 2.1 to 155.4 weeks).

Adverse drug reactions from clinical studies in acute and chronic GvHD (Table 5) 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 clinical studies in GvHD

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
Blood and lymphatic system disorders
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 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
Nervous system disorders
Headache
Common
Common
Very common
Very common

CTCAE grade ≥3
Uncommon
N/A5
Common
Common
Vascular disorders
Hypertension
Very common
Very common
Very common
Very common

CTCAE grade ≥3
Common
Very common
Common
Common

Gastrointestinal disorders
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
Hepatobiliary disorders
Increased alanine aminotransferase1
Very common
Very common
Very common
Very common

CTCAE grade 3
Very common
Very common
Common
Very common

CTCAE grade 4
Common
N/A5
Uncommon
Common
Increased aspartate aminotransferase1
Very common
Very common
Very common
Very common

CTCAE grade 3
Common
Common
Common
Very common

CTCAE grade 4
N/A5
N/A5
Uncommon
N/A5
Musculoskeletal and connective tissue disorders
Increased blood creatine phosphokinase1
-6
-6
Very common
Very common

CTCAE grade 3
-6
-6
Common
N/A5

CTCAE grade 4
-6
-6
Common
N/A5
Renal and urinary disorders
Increased blood creatinine1
-6
-6
Very common
Common

CTCAE grade 3
-6
-6
Common
N/A5

Description of selected adverse drug reactions

Anaemia
In the phase 3 acute (REACH2) and chronic (REACH3) GvHD studies, 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 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 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 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.

Infections
In the phase 3 acute GvHD study (REACH2), 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%).

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

Paediatric patients

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

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets

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 discontinued in MF patients with platelet count less than 50 000/mm3 or absoute 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)”).

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).

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.

Interactions

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 approximately 50%, 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 and symptoms of ruxolitinib-related adverse drug reactions is recommended while on strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes.

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 with known effect

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’.

Applies to: Jakavi 5 mg/ml oral solution

Myelosuppression

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

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

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

Lipid abnormalities/elevations

Major adverse cardiac events (MACE)

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.

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

Second primary malignancies

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

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

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

Special populations

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

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

Interactions

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

Excipients with known effect

Propylene glycol
This medicinal product contains 150 mg propylene glycol in each ml of oral solution.

Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce adverse effects in children less than 5 years old.

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

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets · Jakavi 5 mg/ml oral solution

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.

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 sytemic exposure of substrates of these transporters, such as dabigatran etexilate, ciclosporin, rosuvastatin and potentially digoxin. Therapeutic drug monitoring (TDM) or clinical monitoring of the affected substance is advised.

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

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

4.6 Fertility, pregnancy and lactation

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets · Jakavi 5 mg/ml oral solution

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

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets · Jakavi 5 mg/ml oral solution

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

4.9 Overdose

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets · Jakavi 5 mg/ml oral solution

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

Haemodialysis is not expected to enhance the elimination of ruxolitinib.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets

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

Mechanism of action

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

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 circulating

cytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory mechanisms. MF patients exhibit dysregulated JAK signalling regardless of JAK2V617F mutation status. Activating mutations in JAK2 (V617F or exon 12) are found in >95% of PV patients.

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

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

Pharmacodynamic effects

Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy subjects, MF patients and PV patients. Ruxolitinib resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy subjects and MF patients, 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 patients did 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 these markers were decreased following treatment with ruxolitinib.

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

Clinical efficacy and safety

Myelofibrosis

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Jakavi 5 mg/ml oral solution

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

Mechanism of action

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

Pharmacodynamic effects

Clinical efficacy and safety

Two randomised phase 3, open-label, multi-centre studies investigated Jakavi in patients 12 years of age and older with acute GvHD (REACH2) and chronic GvHD (REACH3) after allogeneic haematopoietic stem cell transplantation (alloSCT) and insufficient response to corticosteroids and/or other 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 randomised 1:1 to Jakavi or BAT. Patients were stratified by severity of acute GvHD at the time of randomisation.
Corticosteroid refractoriness was determined when patients had progression after at least 3 days, failed to achieve a response after 7 days or failed corticosteroid taper.

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

In addition to Jakavi or BAT, patients could have received standard allogeneic stem cell transplantation supportive care including anti-infective medicinal products and transfusion support.
Ruxolitinib was added to continued use of corticosteroids and/or calcineurin inhibitors (CNIs) such as cyclosporine or tacrolimus and/or topical or inhaled corticosteroid therapies per institutional guidelines.

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: Jakavi 5 mg tablets / Jakavi 10 mg tablets / Jakavi 15 mg tablets

Absorption

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

Distribution

The mean volume of distribution at steady state is 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 paediatric patients with acute or chronic GvHD and with a body surface area (BSA) below 1 m2. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro is approximately 97%, mostly to albumin. A whole body autoradiography study in rats has shown that ruxolitinib does not penetrate the blood-brain barrier.

Biotransformation

Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from CYP2C9.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Jakavi 5 mg/ml oral solution

Absorption

Distribution

The mean volume of distribution at steady state is approximately 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 paediatric patients with acute or chronic GvHD and with a body surface area (BSA) below 1 m2. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro is approximately 97%, mostly to albumin. A whole body autoradiography study in rats has shown that ruxolitinib does not penetrate the blood-brain barrier.

Biotransformation

Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from CYP2C9.

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu

Opzelura

4.1 Therapeutic indications

Vitiligo

Opzelura is indicated for the treatment of non-segmental vitiligo with facial involvement in adults and adolescents from 12 years of age.

Atopic dermatitis

Opzelura is indicated for the treatment of moderate atopic dermatitis in adult patients for whom topical corticosteroids and topical calcineurin inhibitors are inadequate or inappropriate.

4.2 Posology and method of administration

Opzelura should be initiated and supervised by physicians with experience in the diagnosis and treatment of conditions for which ruxolitinib cream is indicated.

Posology

Vitiligo

The recommended dose is a thin layer of cream applied twice daily to the depigmented skin areas up to a maximum of 10% of body surface area (BSA), with a minimum of 8 hours between two applications of ruxolitinib cream. 10% BSA represents an area as large as 10 times the palm of one hand with the 5 fingers. Ruxolitinib cream should be used at the smallest skin area necessary.

No more than two tubes of 100 grams a month should be used.

Satisfactory repigmentation may require treatment beyond 24 weeks. If there is less than 25% repigmentation in treated areas at week 52, treatment discontinuation should be considered.

Once satisfactory repigmentation is achieved, treatment in those areas can be stopped. If depigmentation recurs after treatment discontinuation, therapy can be reinitiated on the affected areas.

There is no need to consider tapering therapy.

Atopic dermatitis

A thin layer of cream should be applied twice daily to the affected skin area up to a maximum of 20% of BSA, until clearance of the lesions. It is recommended to apply the cream at regular intervals, with a minimum of 8 hours between two applications of ruxolitinib cream. Ruxolitinib cream should be used at the smallest skin area necessary.

No more than 4 tubes of 100 grams a month should be used.

In the event of recurrence of the signs and symptoms, twice daily treatment of the affected areas should be re-initiated as needed.

Treatment should be discontinued if no improvement is seen after 8 weeks of twice daily treatment.

Special populations

Hepatic impairment

No studies with ruxolitinib cream have been performed in patients with hepatic impairment. However, due to limited systemic exposure, dose adjustment is not necessary in patients with hepatic impairment.

Renal impairment

No studies with ruxolitinib cream have been performed in patients with renal impairment. However, due to limited systemic exposure, dose adjustment is not necessary in patients with renal impairment.
As a precautionary measure, ruxolitinib cream should not be used by patients with end stage renal disease, due to lack of data regarding the safety.

Elderly

A limited number of patients aged 65 years and above have been enrolled in the clinical studies with Opzelura in vitiligo and atopic dermatitis to determine whether they respond differently from younger subjects (see section 5.1). No dose adjustment is required in patients aged 65 years and above.

Paediatric population

Vitiligo

For adolescents (12 to 17 years) with vitiligo the posology is the same as for adults.

The safety and efficacy of ruxolitinib cream in children below 12 years of age with vitiligo have not been established. No data are available.

Atopic dermatitis

There is no relevant use of ruxolitinib cream in the paediatric population from birth to less than 3 months of age. The safety and efficacy of ruxolitinib cream in children aged 3 months to 17 years old have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Method of administration

The cream is for cutaneous use only.

Avoid washing treated skin for at least 2 hours after application of ruxolitinib cream.

The cream should not be applied to the lips to avoid its ingestion.

Patients should be instructed to wash their hands after applying the cream, unless it is their hands that are being treated. If someone else applies the cream to the patient, they should wash their hands after application.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Pregnancy and breastfeeding (see section 4.6).

4.8 Undesirable effects

Summary of the safety profile

The most common adverse reaction is application site acne (5.8% in vitiligo and 4.4% in atopic dermatitis).

Tabulated list of adverse reactions

Adverse reactions are ranked under headings of frequency, with the most frequent first, using 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 1: Adverse reactions
System Organ Class
Frequency
Adverse Reaction
Infections and infestations
Uncommon
Herpes zoster
General disorders and administration site conditions
Common
Application site acne

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

The cream is not for ophthalmic, oral, or intravaginal use (see section 4.2). In cases of accidental exposure in the eyes or mucous membranes, the cream should be thoroughly wiped off and/or rinsed with water.

Non-melanoma skin cancer

Non-melanoma skin cancers (NMSCs), predominantly basal cell carcinomas, have been reported in patients treated with topical ruxolitinib. Most of these patients had risk factors, such as prior phototherapy or prior NMSC. A causal relationship to topical ruxolitinib has not been established.
Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.

Herpes zoster

Cases of herpes zoster reactivation have been reported in patients treated with topical ruxolitinib. If a patient develops herpes zoster, temporary interruption of ruxolitinib cream therapy should be considered until the episode resolves.

Excipients with known effect

Propylene glycol
This medicinal product contains 150 mg propylene glycol (E1520) in each gram of cream which may cause skin irritation.

Cetyl alcohol and stearyl alcohol
This medicinal product contains cetyl alcohol and stearyl alcohol which may cause local skin reactions (e.g. contact dermatitis).

Parahydroxybenzoates
This medicinal product contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Butylated hydroxytoluene
This medicinal product contains butylated hydroxytoluene (E321) which may cause local skin reactions (e.g. contact dermatitis), or irritation to the eyes and mucous membranes.

Polysorbate 20
This medicinal product contains polysorbate 20 (E432) which may cause allergic reactions.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with topically administered ruxolitinib.

The potential for interactions with ruxolitinib is considered to be low because of the limited systemic exposure following topical administration.

Based on in vitro data, ruxolitinib is predominantly cleared by cytochrome P450 3A4 (CYP3A4) metabolism. Interaction potential was evaluated for oral ruxolitinib in dedicated clinical pharmacology studies that included co-administration of strong or moderate CYP3A4 inhibitors or a strong inducer.
The plasma AUC is approximately doubled with co-administration of a potent inhibitor of CYP3A4 while only a modest increase was seen with co-administration of a moderate CYP3A4 inhibitor.

The use of ruxolitinib cream in combination with other topical medicinal products used to treat vitiligo or atopic dermatitis has not been evaluated and co-application on the same skin areas is not recommended. The efficacy and safety of the combination of ruxolitinib cream with narrow-band ultraviolet B (NB-UVB) phototherapy has not been established; no recommendation can be made.

Other topical medicinal products used to treat other conditions on the same skin areas should be applied with a minimum of 2 hours after the application of ruxolitinib cream. This is also applicable to the use of sunscreen or emollients.

4.6 Fertility, pregnancy and lactation

Contraception in women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment and for 4 weeks after discontinuation of treatment.

Pregnancy

There are no or limited amount of data from the use of ruxolitinib in pregnant women. Data on systemic absorption of topical ruxolitinib during pregnancy are lacking. There could also be individual factors (e.g. damaged skin barrier, excessive use) that contribute to an increased systemic exposure.
Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic following oral administration. Teratogenicity was not observed in rats or rabbits (see section 5.3). Opzelura is contraindicated during pregnancy (see section 4.3).

Breast-feeding

No data are available regarding the presence of ruxolitinib in human milk, the effects on the breastfed child, or the effects on milk production after topical application of Opzelura. Following oral administration of ruxolitinib to lactating rats, ruxolitinib and/or its metabolites were present in the milk with a concentration 13-fold higher than the maternal plasma concentration. In juvenile rat studies, oral administration of ruxolitinib resulted in effects on growth and bone measures (see section 5.3). Opzelura is contraindicated during breast-feeding (see section 4.3) and treatment must be discontinued approximately 4 weeks before the beginning of breastfeeding.

Fertility

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

4.7 Effects on ability to drive and use machines

Ruxolitinib cream has no or negligible influence on the ability to drive and use machines.

4.9 Response rate difference (95% CI)

21.2c
(14.271, 28.143)
- 15.5d
(8.515, 22.561)
- a Primary and key secondary outcomes were corrected using multiple imputation method.
b p-value < 0.0001 c p-value < 0.001 d p-value < 0.005 e p-value < 0.01

Figure 1:
Proportion of patients achieving F-VASI75 during the 52 week treatment period
(intent-to-treat) – pooled data from study TRuE-V1 and TRuE-V2

At week 52, the observed response rate for F-VASI90, T-VASI50 and VNS was 30.3%, 51.1%, and 36.3% respectively for the ITT pooled population.

Durability of response

A Phase 3, double-blind, vehicle-controlled, randomised, withdrawal and treatment-extension study of ruxolitinib cream twice daily enrolled 458 eligible patients with vitiligo who had completed either of the parent studies using ruxolitinib (TRuE-V1 and TRuE-V2; week 52); patients were assigned to either cohort A or B with a follow-up up to 104 weeks.

Cohort A comprised 116 patients who reached ≥ F-VASI90 at week 52 of the parent study. These patients were re-randomised to either ruxolitinib or vehicle (i.e. withdrawal) to study relapse (< F-VASI75). A relapse occurred in 15% of patients in the ruxolitinib group, and in 29% of patients in the vehicle group. In the latter group, the majority of relapses (9/16) occurred during the first 4 months after stopping ruxolitinib cream. Among the 16 patients in the vehicle group who relapsed and were retreated, re-treatment resulted in a regained F-VASI75 in 12 (75%) patients in a median of 12 weeks and F-VASI90 was regained by 11 (69%) patients in a median of 15 weeks.
Cohort B comprised 342 patients who reached < F-VASI90 at week 52 of the parent study. These patients continued with open-label ruxolitinib treatment; at week 104, among patients originally randomised to ruxolitinib cream twice daily, 66% reached F-VASI75, and 34% reached F-VASI90.

Safety

Safety in the long-term extension study up to 104 weeks cumulatively was consistent with the profile reported in the parent studies up to 52 weeks.

Clinical efficacy in atopic dermatitis

The efficacy and safety of ruxolitinib cream was evaluated in a pivotal double-blind, randomised, vehicle-controlled study (TRuE-AD4) in adult patients with moderate atopic dermatitis who had inadequate response to, were intolerant to, or were contraindicated to topical corticosteroids and topical calcineurin inhibitors.

The pivotal, double-blind, randomised, vehicle-controlled study (TRuE-AD4), enrolled a total of 241 patients, 18 years of age and older with moderate atopic dermatitis, defined by an Eczema Area and Severity Index (EASI) score > 7, an Investigator’s Global Assessment (IGA) score of 3, 10-20% Body Surface Area (BSA) involvement (excluding scalp), an Itch Numeric Rating Scale (Itch NRS) score of ≥ 4, and a Dermatology Life Quality Index (DLQI) score > 10. Enrolled patients had a documented inadequate response to, were intolerant to, or were contraindicated to topical corticosteroids and topical calcineurin inhibitors. Patients were randomised 2:1 to treatment with ruxolitinib 1.5% cream twice daily (BID) or vehicle cream BID for 8 weeks, followed by a 16-week, vehicle-controlled extension, double-blind period for patients with an adequate response (at least EASI50 from baseline) and an open-label escape arm. During the double-blind, vehicle-controlled extension period, patients applied study drug to active lesions only.

Endpoints

In study TRuE-AD4, the co-primary efficacy endpoints were the proportion of patients reaching EASI75 (defined as ≥ 75% improvement in EASI score from baseline) and the proportion of patients achieving IGA Treatment Success (IGA-TS; defined as an IGA score of 0 [clear] or 1 [almost clear] and a ≥ 2-grade improvement from baseline) at week 8. Key secondary endpoints included the proportion of patients reaching ITCH4 (defined as ≥ 4-point improvement in Itch NRS score from baseline) at week 8, day 7, day 3, and day 2. Additional clinically relevant secondary endpoints included the proportion of patients achieving IGA-TS, EASI75, ITCH4, as well as change from baseline in DLQI, Patient-Oriented Eczema Measure (POEM), Patient-Reported Outcomes Measurement Information System (PROMIS) Short Form Sleep-Related Impairment (8a) and PROMIS Short Form Sleep Disturbance (8b), at each postbaseline visit.

Baseline characteristics

In study TRuE-AD4, the mean age was 39 years and 7.9% of patients were 65 years of age or older.
Females constituted 54% of patients, 81% of patients were White, 5.8% were Black, and 10% were Asian. Patients had long-standing atopic dermatitis of 20 years (mean) before study entry. Recent (within the last 12 months) prior treatments for atopic dermatitis included topical corticosteroids (96%) and topical calcineurin inhibitors (81%), as well as systemic therapies (30%) and phototherapy (8.7%). The mean EASI score was 13, the mean Itch NRS score was 7.4, and the mean total % BSA affected was 15%. The mean DLQI score was 19, the mean POEM score was 20 (with no patients having a POEM score of 0-2), and the mean PROMIS 8a and PROMIS 8b scores were 22 and 24, respectively. Baseline characteristics were generally similar across the treatment groups.

Clinical response

In study TRuE-AD4, ruxolitinib cream was statistically significantly superior to vehicle cream at week 8 with respect to the co-primary endpoints, EASI75 (Table 3 and Figure 2) and IGA-TS (Table 3), and all of the key secondary endpoints, ITCH4 at week 8 (Table 3 and Figure 3), and ITCH4 at day 7, 3 and 2, with separation between the ruxolitinib cream and vehicle cream treatment groups at Day 1 (Figure 3).

The proportion of patients reaching IGA-TS increased from baseline during the double-blind, vehicle- controlled period (Table 3), with separation between the ruxolitinib cream and vehicle cream treatment groups at week 2 (29% and 2.5%, respectively) and week 4 (49% and 9.9%, respectively).

Table 3:
Efficacy results of ruxolitinib cream, co-primary and selected key secondary endpoints at week 8

TRuE-AD4
(intent-to-treat)

Ruxolitinib cream
Vehicle

(N = 160)
(N = 81)
EASI75 (%)

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excluding corticosteroids, ATC code: D11AH09

Mechanism of action

Ruxolitinib is a Janus Kinase (JAK) inhibitor with selectivity for the JAK1 and JAK2 isoforms.
Intracellular JAK signalling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, and subsequent modulation of gene expression.

Autoimmune IFNγ producing cytotoxic T lymphocytes are thought to be directly responsible for melanocyte destruction in human vitiligo. Recruitment of cytotoxic lymphocytes to lesional skin is mediated via IFNγ dependent chemokines, such as CXCL10. Downstream signalling of IFNγ is JAK1/2 dependent and treatment with ruxolitinib reduces CXCL10 levels in vitiligo patients.

Multiple inflammatory and pruritic cytokines involved in the pathogenesis of atopic dermatitis, such as IL-4, IL-5, IL-13, IL-22, IL-31, and thymic stromal lymphopoietin (TSLP), require JAK/STAT pathway activation for downstream biological activity.

Clinical efficacy and safety in vitiligo

Efficacy
Two double-blind, randomised, vehicle-controlled studies of identical design (TRuE-V1 and TRuE-V2) enrolled a total of 674 patients who have vitiligo on the face and total body vitiligo area (facial and nonfacial) not exceeding 10% BSA, with disease extent at initiation ranging from 3.2% to 10.1% of BSA, aged 12 years and older (10.7% of patients were 12 to 17 years of age and 6.7% were 65 years or older). Females constituted 53.1% of patients, 81.9% of patients were White, 4.7% were Black, and 4.2% were Asian. The majority of patients had Fitzpatrick skin types III, IV, V, or VI (67.5%).

In both studies, patients were randomised 2:1 to treatment with ruxolitinib cream or vehicle twice daily for 24 weeks with affected BSA not exceeding 10%, followed by an additional 28 weeks of treatment with ruxolitinib cream BID for all patients. The primary efficacy endpoint was the proportion of patients achieving a 75% repigmentation in the facial Vitiligo Area Scoring Index (F-VASI75) at week 24. Key secondary endpoints included the proportions of patients achieving a 90% repigmentation in F-VASI (F-VASI90), 50% improvement in total body Vitiligo Area Scoring Index (T-VASI50), and a Vitiligo Noticeability Scale (VNS) score of 4 or 5 (vitiligo "a lot less noticeable" or "no longer noticeable").

Repigmentation of treated vitiligo lesions and superiority of ruxolitinib cream over vehicle cream were observed for both studies, as demonstrated by statistically significant differences in response rates for F-VASI75/90, T-VASI50, and VNS score of 4 or 5 at week 24 (Table 2).

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Absorption

Vitiligo

The pharmacokinetics of ruxolitinib cream were investigated in 429 patients with vitiligo aged 12 years and older (12.6% were 12-17 years of age) with a mean ± STD BSA involvement of 7.31 ± 2.02% (range 3.2% to 10.0%). Patients applied approximately 1.58 mg/cm2 of ruxolitinib cream (dose range was approximately 0.18 grams to 8.4 grams of ruxolitinib cream per application) to the same skin areas twice daily for 24 weeks.

The mean ± STD (median; geometric mean) steady state trough plasma concentration was 56.9 ± 62.6 nM (35.8 nM; 27.4 nM) with a projected AUC0-12h at 683 ± 751 h*nM, which is approximately 25% of the observed mean AUC0-12h at steady state (2716 h*nM) following 15 mg twice daily oral administration in healthy participants. The mean (geometric mean) topical

bioavailability for ruxolitinib cream in vitiligo patients in the pooled data of the two Phase 3 studies was 9.72% (5.78%).

Atopic dermatitis

The pharmacokinetics of ruxolitinib cream were investigated in 114 patients with moderate atopic dermatitis aged 18 years and older with a mean ± STD BSA involvement of 15.2 ± 2.99% (range 10.0% to 20%). Patients applied approximately 3.97 grams of ruxolitinib cream (dose range was approximately 0.12 grams to 8.5 grams of ruxolitinib cream per application) to the same skin areas twice daily for 8 weeks.

The mean ± STD (median; geometric mean) steady state trough plasma concentration was 82.3 ± 98.4 nM (49.6 nM; 42.7 nM) with a projected AUC0-12h at 987.6 ± 1181 h*nM, which is approximately 36% of the observed mean AUC0-12h at steady state (2716 h*nM) following 15 mg twice daily oral administration in healthy participants. The mean (geometric mean) topical bioavailability for ruxolitinib cream in atopic dermatitis patients in the Phase 3 study was 8.87% (4.97%).

Distribution

Based on an in vitro study, ruxolitinib is 97% bound to human plasma proteins, mostly to albumin.

Biotransformation

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.