Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind,
Placebo-controlled Study During Randomized Treatment
BRIEF SUMMARY: For Full Prescribing Information, see package insert.
CONTRAINDICATIONS None.
WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with
Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full
Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi.
Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in
Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose
modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding
Jakafi until recovery [see Adverse Reactions (6.1) in Full Prescribing Information]. Perform a pre-treatment
complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized , and then as clinically
indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information].
Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting
therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and
symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients
receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage
promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher
risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to
countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history
of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with
evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before
starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the
overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with
ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise
patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected
[see Adverse Reactions (6.1) in Full Prescribing Information]. Hepatitis B Hepatitis B viral load (HBV-DNA titer)
increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase,
have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in
patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and
monitored according to clinical guidelines. Symptom Exacerbation Following Interruption or
Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from
myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some
patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing
Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after
discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider
restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without
consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than
thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider
tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer
Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in
patients treated with Jakafi. Perform periodic skin examinations. Lipid Elevations Treatment with Jakafi has
been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL)
cholesterol, and triglycerides. The effect of these lipid parameter elevations on cardiovascular morbidity and
mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12
weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management
of hyperlipidemia.
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) in
Full Prescribing Information] • Risk of Infection [see Warnings and Precautions (5.2) in Full Prescribing Information]
• Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and
Precautions (5.3) in Full Prescribing Information] • Non-Melanoma Skin Cancer [see Warnings and Precautions
(5.4) in Full Prescribing Information]. 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, placebocontrolled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions
were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related
effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see
Table 1]. 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 adverse reactions occurring
in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.
Adverse Reactions
Bruisingb
Jakafi
(N=155)
Placebo
(N=151)
All Gradesa Grade 3
(%)
(%)
Grade 4 All Grades Grade 3
(%)
(%)
(%)
Grade 4
(%)
23
<1
0
15
0
0
c
Dizziness
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
2
0
0
<1
0
0
Herpes Zoster
f
a
b
c
d
e
f
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 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 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 Studya
Jakafi
(N=155)
Laboratory
Parameter
All Gradesb
(%)
Grade 3
(%)
Placebo
(N=151)
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
a
b
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 polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients
received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent
adverse drug reaction was anemia. Table 3 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.