"The U.S. Food and Drug Administration today approved Imbruvica (ibrutinib) to treat patients with mantle cell lymphoma (MCL), a rare and aggressive type of blood cancer.
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The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
- Myelosuppression [see WARNINGS AND PRECAUTIONS]
- Risk of Infection [see WARNINGS AND PRECAUTIONS]
- Myelofibrosis Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
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 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 88.7% of patients treated for more than 6 months and 24.6% 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 6]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 5].
Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 10.6% of patients treated with placebo.
Table 5 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.
Table 5: Adverse Reactions Occurring in Patients on
Jakafi in the Double-blind, Placebo-controlled Study During Randomized
|All Gradesa (%)||Grade 3 (%)||Grade 4 (%)||All Grades (%)||Grade 3 (%)||Grade 4 (%)|
|Urinary Tract Infectionsd||9.0||0||0||5.3||0.7||0.7|
|aNational Cancer Institute Common Terminology
Criteria for Adverse Events (CTCAE), version 3.0
bincludes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura
cincludes dizziness, postural dizziness, vertigo, balance disorder, Meniere's Disease, labyrinthitis
dincludes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present
eincludes weight increased, abnormal weight gain
fincludes herpes zoster and post-herpetic neuralgia
Description of Selected Adverse Drug Reactions
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 (0.3%) 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.
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 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% 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 (16.5% versus 7.2%).
In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia.
Table 6 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.
Table 6: Worst Hematology Laboratory Abnormalities in
the Placebo-Controlled Studya
|All Gradesb (%)||Grade 3 (%)||Grade 4 (%)||All Grades (%)||Grade 3 (%)||Grade 4 (%)|
|a Presented values are worst Grade values regardless of
b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
Additional Data from the Placebo-controlled Study
25.2% of patients treated with Jakafi and 7.3% 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 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations.
17.4% of patients treated with Jakafi and 6.0% 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 0.6% for Jakafi with no Grade 3 or 4 AST elevations.
16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations.
Read the Jakafi (ruxolitinib) Side Effects Center for a complete guide to possible side effects
Drugs That Inhibit Or Induce Cytochrome P450 Enzymes
Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.
The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics].
When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see DOSAGE AND ADMINISTRATION].
The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics].
Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see DOSAGE AND ADMINISTRATION].
The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics].
Read the Jakafi Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 8/8/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Jakafi Information
Report Problems to the Food and Drug Administration
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