Jakavi Adverse Reactions

Summary of the safety profile: Myelofibrosis: The safety of ruxolitinib (Jakavi) in MF patients was evaluated using long term follow-up data from the two Phase 3 studies COMFORT-I and COMFORT-II including data from patients initially randomized to ruxolitinib (Jakavi) (n=301) and patients who received ruxolitinib (Jakavi) after crossing over from control treatments (n=156). The median exposure upon which the ADR frequency categories for MF patients are based was 30.5 months (range 0.3 to 68.1 months).
The most frequently reported ADRs were anemia (83.8%) and thrombocytopenia (80.5%).
Hematological ADRs (any CTCAE grade; Common Terminology Criteria for Adverse Events) included anemia (83.8%), thrombocytopenia (80.5%) and neutropenia (20.8 %).
Anemia, thrombocytopenia and neutropenia are dose related effects.
The three most frequent non-hematological ADRs were bruising (33.3%), dizziness (21.9%) and urinary tract infections (21.4%).
The three most frequent non-hematological laboratory abnormalities were raised ALT (40.7%), raised AST (31.5%) and hypertriglyceridemia (25.2%). However, no CTCAE grade 3 or 4 hypertriglyceridemia and raised AST or grade 4 raised ALT were observed.
Discontinuation due to AEs, regardless of causality, was observed in 30.0% of patients treated with ruxolitinib.
Polycythemia vera: The safety of ruxolitinib (Jakavi) in PV patients was evaluated using long-term follow-up data from the two phase 3 studies RESPONSE and RESPONSE 2 including data from patients initially randomized to ruxolitinib (Jakavi) (n=184) and patients who received ruxolitinib (Jakavi) after crossing over from control treatments (n=156). The median exposure upon which the ADR frequency categories for PV patients are based was 41.7 months (range 0.03 to 59.7 months).
The most frequently reported ADRs were anemia (61.8%) and increased ALT (45.3%).
Hematological ADRs (any CTCAE grade) included anemia (61.8%) and thrombocytopenia (25.0%). Anemia or thrombocytopenia Grade 3 and 4 were reported in respectively 2.9% and 2.6% of the patients, respectively.
The three most frequent non-hematological ADRs were weight gain (20.3%), dizziness (19.4%) and headache (17.9%).
The three most frequent non-hematological laboratory abnormalities (any CTCAE grade) identified as ADRs were raised ALT (45.3%), raised AST(42.6%)and hypercholesterolemia (34.7%). The majority were Grade 1 to 2 with one CTCAE grade 4 'raised AST'.
Discontinuation due to AEs, regardless of causality, was observed in 19.4% of patients treated with ruxolitinib (Jakavi).
Tabulated summary of adverse drug reactions from clinical trials: ADRs from clinical trials (Table 1) are listed by MedDRA system organ class (SOC). Within each SOC, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each ADR is based on the following convention (CIOMS III): 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).
In the clinical studies program the severity of ADRs was assessed based on the CTCAE defining Grade 1=mild, Grade 2= moderate, Grade 3=severe and Grade 4=life-threatening or disabling. (See Table 4.)

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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 MF clinical studies the total symptom score for MF-symptoms gradually returned to baseline values within 7 days after dose discontinuation.
ADRs from spontaneous reports and literature cases (frequency not known): Tuberculosis as an ADR has been observed post-marketing with ruxolitinib (Jakavi) in PV patients via spontaneous case reports and in the literature. Because cases were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency, which is therefore characterized as 'not known'.
Description of selected adverse drug reactions: Anemia: In phase 3 MF - clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was 1.5 months. One patient (0.3%) discontinued treatment because of anemia.
In patients receiving ruxolitinib (Jakavi) mean decreases in hemoglobin reached a nadir of approximately 15 to 20 g/L below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 10 g/L below baseline. This pattern was observed in patients regardless of whether they had received transfusion during therapy.
In the randomized, placebo controlled study COMFORT-I, 59.4% of ruxolitinib (Jakavi) treated patients and 37.1% of patients receiving placebo received red blood cell transfusions during randomized treatment. In the COMFORT-II study, the rate of packed red blood cell transfusions was 51.4% in the ruxolitinib (Jakavi) arm and 38.4% in the best available therapy arm (BAT).
Thrombocytopenia: In the Phase 3 MF - clinical studies, 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 randomized period platelet transfusions were administered to 4.5% of patients receiving ruxolitinib (Jakavi) and to 5.8% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving ruxolitinib (Jakavi) and 0.9% of patients receiving control regimens. Patients with a platelet count of 100,000/mm3 to 200,000/mm³ before starting ruxolitinib (Jakavi) had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with platelet count >200,000/mm³ (64.2% versus 35.4%).
Neutropenia: In the Phase 3 clinical studies in MF, in patients who developed Grade 3 or 4 neutropenia, the median time of onset was 12 weeks. During the randomized period of the studies dose holding or reductions due to neutropenia were reported in 1% of patients and 0.3% of patients discontinued treatment because of neutropenia.
Urinary tract infections: In the randomized period of the Phase 3 MF clinical studies Grade 3 or 4 urinary tract infection was reported for 1.0% of patients. Urosepsis was reported in 1.0% of patients and kidney infection in 1 patient.
Over the randomized period in the RESPONSE and RESPONSE-2 studies in PV, one (0.5%) Grade 3 to 4 urinary tract infection was observed.
Herpes zoster: The rate of herpes zoster was similar in PV (4.3%) patients and MF patients (4.0%). There was one report of Grade 3 and 4 post herpetic neuralgia amongst the PV patients.