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JAKAFI SIDE EFFECTS

  • Generic Name: ruxolitinib
  • Brand Name: Jakafi
  • Drug Class: , DMARDs, JAK Inhibitors
Last updated on MDtodate: 10/6/2022

SIDE EFFECTS

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

  • Thrombocytopenia, Anemia and Neutropenia
  • Risk of Infection
  • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi
  • Non-Melanoma Skin Cancer

Clinical Trials Experience In Myelofibrosis

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.

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 MF 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 reactions were thrombocytopenia and anemia [see Table 12]. Thrombocytopenia, anemia and neutropenia are dose-related effects. The three most frequent nonhematologic adverse reactions were bruising, dizziness and headache [see Table 11].

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

Table 1 presents the most common nonhematologic adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

Table 1: Myelofibrosis: Nonhematologic Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment

Adverse Reactions Jakafi
(N=155)
Placebo
(N=151)
All Grades* (%) Grade 3 (%) Grade 4 (%) All Grades (%) Grade 3 (%) Grade 4 (%)
Bruising† 23 <1 0 15 0 0
Dizziness‡ 18 <1 0 7 0 0
Headache 15 0 0 5 0 0
Urinary Tract Infections§ 9 0 0 5 <1 <1
Weight Gain¶ 7 <1 0 1 <1 0
Flatulence 5 0 0 <1 0 0
Herpes Zoster# 2 0 0 <1 0 0
*National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
† includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura
‡includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis
§includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present
¶includes weight increased, abnormal weight gain
#includes herpes zoster and post-herpetic neuralgia

 

Description Of Selected Adverse 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 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Study*

Jakafi
(N=155)
Placebo
(N=151)
All Grades1 Grade 3 Grade 4 All Grades Grade 3 Grade 4
Laboratory Parameter (%) (%) (%) (%) (%) (%)
Thrombocytopenia 70 9 4 31 1 0
Anemia 96 34 11 87 16 3
Neutropenia 19 5 2 4 <1 1

 

*Presented values are worst Grade values regardless of baseline
†National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

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 PV resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy . The most frequent adverse reaction was anemia. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi. Table 3 presents the most frequent nonhematologic adverse reactions occurring up to Week 32.

Table 3: Polycythemia Vera: Nonhematologic Adverse Reactions Occurring in ≥ 5% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment

Adverse Reactions Jakafi
(N=110)
Best Available Therapy
(N=111)
All Grades* (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Diarrhea 15 0 7 <1
Dizziness† 15 0 13 0
Dyspnea‡ 13 3 4 0
Muscle Spasms 12 <1 5 0
Constipation 8 0 3 0
Herpes Zoster§ 6 <1 0 0
Nausea 6 0 4 0
Weight Gain¶ 6 0 <1 0
Urinary Tract Infections# 6 0 3 0
Hypertension 5 <1 3 <1
*National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
†includes dizziness and vertigo
‡includes dyspnea and dyspnea exertional
§includes herpes zoster and post-herpetic neuralgia
¶ includes weight increased and abnormal weight gain
#includes urinary tract infection and cystitis

 

Clinically relevant laboratory abnormalities are shown in Table 4.

Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment*

Laboratory Parameter Jakafi
(N=110)
Best Available Therapy (N= 111)
All Grades† (%) 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
*Presented values are worst Grade values regardless of baseline
†National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

 

Clinical Trial Experience In Acute Graft-Versus-Host Disease

In a single-arm, open-label study, 71 adults (ages 18-73 years) were treated with Jakafi for acute GVHD failing treatment with steroids with or without other immunosuppressive drugs [see Clinical Studies]. The median duration of treatment with Jakafi was 46 days (range, 4-382 days).

There were no fatal adverse reactions to Jakafi. An adverse reaction resulting in treatment discontinuation occurred in 31% of patients. The most common adverse reaction leading to treatment discontinuation was infection (10%). Table 5 shows the adverse reactions other than laboratory abnormalities.

Table 5: Acute Graft-Versus-Host Disease: Nonhematologic Adverse Reactions Occurring in ≥ 15% of Patients in the Open-Label, Single-Cohort Study

Adverse Reactions* All Grades† (%) Grade 3-4 (%)
Infections 55 41
Edema 51 13
Hemorrhage 49 20
Fatigue 37 14
Bacterial infections 32 28
Dyspnea 32 7
Viral infections 31 14
Thrombosis 25 11
Diarrhea 24 7
Rash 23 3
Headache 21 4
Hypertension 20 13
Dizziness 16 0
*Selected laboratory abnormalities are listed in Table 16 below
†National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03

 

Selected laboratory abnormalities during treatment with Jakafi are shown in Table 16.

Table 6: Acute Graft-Versus-Host Disease: Selected Laboratory Abnormalities Worsening from Baseline in the Open-Label, Single Cohort Study

Laboratory Parameter Jakafi
(N=71)
Worst grade during treatment
All Grades*(%) Grade 3-4 (%)
Hematology
Anemia 75 45
Thrombocytopenia 75 61
Neutropenia 58 40
Chemistry
Elevated ALT 48 8
Elevated AST 48 6
Hypertriglyceridemia 11 1
*National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03

 

SRC: NLM .

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