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Jakafi (Ruxolitinib) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

  • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)]
  • Risk of Infection [see Warnings and Precautions (5.2)]
  • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)]
  • Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Myelofibrosis

The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies.

In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy.

In a double-blind, randomized, placebo-controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see  Table 11 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 10 ].

Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo.

Table 10 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

Table 10: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0

b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura

c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere's Disease, labyrinthitis

d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present

e includes weight increased, abnormal weight gain

f includes herpes zoster and post-herpetic neuralgia

  Jakafi
(N=155)
Placebo
(N=151)
Adverse Reactions All
Gradesa
(%)
Grade 3
(%)
Grade 4
(%)
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
Bruisingb 23 <1 0 15 0 0
Dizzinessc 18 <1 0 7 0 0
Headache 15 0 0 5 0 0
Urinary Tract Infectionsd 9 0 0 5 <1 <1
Weight Gaine 7 <1 0 1 <1 0
Flatulence 5 0 0 <1 0 0
Herpes Zosterf 2 0 0 <1 0 0

Description of Selected Adverse Drug Reactions

Anemia

In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy.

In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients.

Thrombocytopenia

In the two Phase 3 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 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%).

Neutropenia

In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia.

Table 11 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Table 11: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya

a Presented values are worst Grade values regardless of baseline

b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

  Jakafi
(N=155)
Placebo
(N=151)
Laboratory Parameter All
Gradesb
(%)
Grade 3
(%)
Grade 4
(%)
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
Thrombocytopenia 70 9 4 31 1 0
Anemia 96 34 11 87 16 3
Neutropenia 19 5 2 4 <1 1

Additional Data from the Placebo-controlled Study

25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations.

17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations.

17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations.

Clinical Trial Experience in Polycythemia Vera

In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies]. The most frequent adverse drug reaction was anemia. Table 12 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32.

Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi.

Table 12: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0

b includes abdominal pain, abdominal pain lower, and abdominal pain upper

c includes dizziness and vertigo

d includes dyspnea and dyspnea exertional

e includes edema and peripheral edema

f includes herpes zoster and post-herpetic neuralgia

  Jakafi
(N=110)
Best Available Therapy
(N=111)
Adverse Events All Gradesa
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
Headache 16 <1 19 <1
Abdominal Painb 15 <1 15 <1
Diarrhea 15 0 7 <1
Dizzinessc 15 0 13 0
Fatigue 15 0 15 3
Pruritus 14 <1 23 4
Dyspnead 13 3 4 0
Muscle Spasms 12 <1 5 0
Nasopharyngitis 9 0 8 0
Constipation 8 0 3 0
Cough 8 0 5 0
Edemae 8 0 7 0
Arthralgia 7 0 6 <1
Asthenia 7 0 11 2
Epistaxis 6 0 3 0
Herpes Zosterf 6 <1 0 0
Nausea 6 0 4 0

Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were:

Weight gain, hypertension, and urinary tract infections

Clinically relevant laboratory abnormalities are shown in Table 13.

Table 13: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatmenta

a Presented values are worst Grade values regardless of baseline

b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

  Jakafi
(N=110)
Best Available Therapy
(N=111)
Laboratory Parameter All
Gradesb
(%)
Grade 3
(%)
Grade 4
(%)
All
Grades
(%)
Grade 3
(%)
Grade 4
(%)
Hematology
Anemia 72 <1 <1 58 0 0
Thrombocytopenia 27 5 <1 24 3 <1
Neutropenia 3 0 <1 10 <1 0
Chemistry
Hypercholesterolemia 35 0 0 8 0 0
Elevated ALT 25 <1 0 16 0 0
Elevated AST 23 0 0 23 <1 0
Hypertriglyceridemia 15 0 0 13 0 0

Drug label data at the top of this Page last updated: 2014-12-12

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