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 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 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 Treatment a
Laboratory Parameter
All Grades b (%)
Jakafi ( N = 110 )
Jakafi ( N = 110 )
Grade 3 (%)
Grade 4 (%)
All Grades (%)
Best Available Therapy ( N = 111 )
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 |
a
Presented values are worst Grade values regardless of baseline b
National Cancer Institute Common Terminology Criteria for Adverse Events , version 3.0
Best Available Therapy ( N = 111 )
Adverse Events |
All Grades a (%) |
Grade 3-4 (%) |
All Grades (%) |
Grade 3-4 (%) |
Headache |
16 |
< 1 |
19 |
< 1 |
Abdominal Pain b |
15 |
< 1 |
15 |
< 1 |
Diarrhea |
15 |
0 |
7 |
< 1 |
Dizziness c |
15 |
0 |
13 |
0 |
Fatigue |
15 |
0 |
15 |
3 |
Pruritus |
14 |
< 1 |
23 |
4 |
Dyspnea d |
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 |
Edema e |
8 |
0 |
7 |
0 |
Arthralgia |
7 |
0 |
6 |
< 1 |
Asthenia |
7 |
0 |
11 |
2 |
Epistaxis |
6 |
0 |
3 |
0 |
Herpes Zoster f |
6 |
< 1 |
0 |
0 |
Nausea |
6 |
0 |
4 |
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 C max 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 C max 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 ruxolitinib 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 10 9 / L and 150 X 10 9 / 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 10 9 / L and 150 X 10 9 / 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