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Summary of the safety profile

The safety assessment was based on a total of 982 patients (with MF or PV) receiving Jakavi in phase 2 and 3 studies.

Myelofibrosis

In the randomised period of the two pivotal studies, COMFORT-I and COMFORT-II, the median duration of exposure to Jakavi was 10.8 months (range 0.3 to 23.5 months). The majority of patients (68.4%) were treated for at least 9 months. Of 301 patients, 111 (36.9%) had a baseline platelet count of between 100,000/mm3 and 200,000/mm3 and 190 (63.1%) had a baseline platelet count of >200,000/mm3.

In these clinical studies, discontinuation due to adverse events, regardless of causality, was observed in 11.3% of patients.

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 (82.4%), thrombocytopenia (69.8%) and neutropenia (16.6%).

Anaemia, thrombocytopenia and neutropenia are dose-related effects.

The three most frequent non-haematological adverse drug reactions were bruising (21.3%), dizziness (15.3%) and headache (14.0%).

The three most frequent non-haematological laboratory abnormalities were raised alanine aminotransferase (27.2%), raised aspartate aminotransferase (19.9%) and hypercholesterolaemia (16.9%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4 hypercholesterolaemia, raised aspartate aminotransferase nor CTCAE grade 4 raised alanine aminotransferase were observed.

Long-term safety:

Long term safety data from two pivotal phase 3 studies assessed 457 patients with MF who were treated with ruxolitinib, including patients initially randomised to ruxolitinib (n=301; exposure 0.3–68.1 months, median exposure 33.4 months) and patients who received ruxolitinib after crossing over from control treatments (n=156; exposure: 0.5–59.8 months, median exposure 25.0 months). The cumulative frequency of adverse events in these studies increased proportionally to the increase in the follow-up time. With these updated data, therapy discontinuation due to adverse events was observed in 27.4% of patients treated with ruxolitinib.

Polycythaemia vera

The safety of Jakavi was assessed in 184 patients with PV in two open-label, randomised, controlled studies, the phase 3 RESPONSE study and the phase 3b RESPONSE 2 study. The adverse drug reactions listed below reflect the randomised study period (up to week 32 for RESPONSE and up to week 28 for RESPONSE 2) with equivalent exposure to ruxolitinib and Best Available Therapy (BAT). The median duration of exposure to Jakavi during the randomised study periods was 7.85 months (range 0.03 to 7.85 months).

Discontinuation due to adverse events, regardless of causality, was observed in 2.2% of patients.

Haematological adverse reactions (any CTCAE grade) included anaemia (40.8%) and thrombocytopenia (16.8%). Anaemia or thrombocytopenia CTCAE grade 3 and 4 were reported in respectively 1.1% or 3.3%.

The three most frequent non-haematological adverse reactions were dizziness (9.2%), constipation (8.7%) and hypertension (6.5%).

The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) identified as adverse reactions were raised aspartate aminotransferase (26.1%), raised alanine aminotransferase (22.3%) and hypercholesterolaemia (20.7%). These were all CTCAE grade 1 and 2 with the exception of one CTCAE grade 3 raised alanine aminotransferase event.

Long-term safety was evaluated using data from two phase 3 studies including data from patients initially randomised to ruxolitinib (n=184; exposure 0.03 to 43.5 months, median exposure 18.9 months) and patients who received ruxolitinib after crossing over from control treatments (n=149; exposure: 0.2 to 33.5 months, median exposure 12.0 months): With longer exposure, the cumulative frequency of adverse events increased but no new safety findings emerged. When adjusted for exposure, the adverse events rates were generally comparable with those observed during the comparative periods of the randomised studies.

Tabulated list of adverse drug reactions from clinical studies

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 and grade 4=life-threatening.

Adverse drug reactions from clinical studies (Table 1) 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).

Table 1 Frequency category of adverse drug reactions reported in the phase 3 studies (COMFORT-I, COMFORT-II, RESPONSE, RESPONSE 2)

bcs classification of ciprofloxacin side colspan="" rowspan="" valign="">

Adverse drug reaction

Frequency category for MF patients

Frequency category for PV patients

Infections and infestations

Urinary tract infectionsa,d

Very common

Common

Herpes zostera,d

Common

Common

Sepsis

Common

-

Tuberculosise

Uncommon

-

Blood and lymphatic system disordersb,d

Anaemiab

-

-

CTCAEc grade 4

(<6.5g/dl)

Very common

Uncommon

CTCAEc grade 3

(<8.0 – 6.5g/dl)

Very common

Uncommon

Any CTCAEc grade

Very common

Very common

Thrombocytopeniab

CTCAEc grade 4

(<25,000/mm3)

Common

Uncommon

CTCAEc grade 3

(50,000 – 25,000/mm3)

Common

Common

Any CTCAEc grade

Very common

Very common

Neutropeniab

CTCAEc grade 4

(<500/mm3)

Common

-

CTCAEc grade 3

(<1,000 – 500/mm3)

Common

-

Any CTCAEc grade

Very common

-

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

Very common

Very common

Intracranial bleeding

Common

-

Gastrointestinal bleeding

Common

-

Bruising

Very common

Very common

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

Common

Very common

Metabolism and nutrition disorders

Weight gaina

Very common

Common

Hypercholesterolaemiab

CTCAEc grade 1 and 2

Very common

Very common

Hypertriglyceridaemiab

CTCAEc grade 1

-

Very common

Nervous system disorders

Dizzinessa

Very common

Very common

Headachea

Very common

-

Gastrointestinal disorders

Flatulencea

Common

-

Constipationa

-

Common

Hepatobiliary disorders

Raised alanine aminotransferaseb

CTCAEc grade 3

(> 5x – 20 x ULN)

Common

Uncommon

Any CTCAEc grade

Very common

Very common

Raised aspartate aminotransferaseb

Any CTCAEc grade

Very common

Very common

Vascular disorders

Hypertensiona

-

Very common

a Frequency is based on adverse event data.

- A subject with multiple occurrence of an adverse drug reaction (ADR) is counted only once in that ADR category.

- ADRs reported are on treatment or up to 28 days post treatment end date.

b Frequency is based on laboratory values.

- A subject with multiple occurrences of an ADR is counted only once in that ADR category.

- ADRs reported are on treatment or up to 28 days post treatment end date.

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 ADRs are discussed in the text.

e Frequency is based on all patients exposed to ruxolitinib in clinical studies (N=4755)

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).

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%.

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.

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 pivotal study in PV patients, neutropenia was reported in three patients (1.6%) of which one patient developed CTCAE grade 4 neutropenia.

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 3-4 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.

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.

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 pivotal study 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.

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 0-2 mmHg on ruxolitinib versus a decrease of 2-5 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.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:


Source: http://www.medicines.ie/medicine/15710/SPC


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