ASH Clinical News November 2016 | Page 67

Table 3: 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

Jakafi
(N=110)
Adverse Events

Best Available Therapy
(N=111)

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Grade 3-4 (%)

16

<1

19

<1

Abdominal Pain

15

<1

15

<1

Diarrhea

15

0

7

<1

Dizziness

15

0

13

0

Fatigue

15

0

15

3

14

<1

23

4

Headache
b

c

Pruritus
Dyspnea

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

d

Edema

8

0

7

0

Arthralgia

7

0

6

<1

Asthenia

7

0

11

2

Epistaxis

6

0

3

0

Herpes Zoster

6

<1

0

0

Nausea

6

0

4

0

e

f

a
b
c
d
e
f

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
includes abdominal pain, abdominal pain lower, and abdominal pain upper
includes dizziness and vertigo
includes dyspnea and dyspnea exertional
includes edema and peripheral edema
includes herpes zoster and post-herpetic neuralgia

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 4.
Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled
Study up to Week 32 of Randomized Treatmenta
Jakafi
(N=110)
Laboratory
Parameter

All Gradesb Grade 3
(%)
(%)

Best Available Therapy
(N=111)
Grade 4
(%)

All Grades
(%)

Grade 3
(%)

Grade 4
(%)

<1

58

0

0

Hematology
Anemia

72

<1

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

a
b

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

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib
is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: 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 (12.3) in Full Prescribing Information].
When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and
Administration (2.3) in Full Prescribing Information]. Fluconazole: 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 (12.3) in Full
Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg
daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: 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 (12.3) in Full
Prescribing Information].
USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are
no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment
with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.
Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis,
at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of
teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and
maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the
clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of
approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of
60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a
pre- and post-natal development study in rats, pregnant animals were dosed with rux olitinib from implantation
through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility
indices or for maternal or embryofetal survival, growth and development parameters at the highest dose
evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing
Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were
excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many
drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants
from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric
patients have not been established. Geriatric Use Of the total number of patients with myelofibrosis in clinical
studies with Jakafi, 52% were 65 years and older, while 15% were 75 years and older. No overall differences in
safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal
Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in
healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate
[CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects
with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was
similar in subjects with various degrees of renal impairment and in those with normal renal function. However,
plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was
most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the
pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite
exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis
cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl
30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and
150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with
polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all
patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and
Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics
of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild
[Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The
mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate
and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination
half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus
2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the
corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort
where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma
concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of
hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is
recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic
impairment [see Dosage and Administration (2.4) in Full Prescribing Information].
OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been
given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased
myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment
should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib.

Jakafi is a registered trademark of Incyte. All rights reserved.
U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013; 9079912
© 2011-2016 Incyte Corporation. All rights reserved.
Revised: March 2016 RUX-1778a