Conditions: Primary Myelofibrosis Post-Polycythemia Vera-Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis
Keywords: Ruxolitinib anemia Primary Myelofibrosis PMF Post-Polycythemia Vera-Myelofibrosis PPV-MF Post-Essential Thrombocythemia Myelofibrosis PET-MF adult INC424
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 51
Healthy volunteers: no

Brief summary:
This was a study of treatment with ruxolitinib in patients who presented with transfusion dependent or independent anemia. Starting dose was 10 mg BID. This dose was maintained for the first 12 weeks of the study and up-titrated thereafter unless the subject met criteria for dose hold or dose reduction

Detailed description:
This was a study of treatment with ruxolitinib in patients who present with transfusion dependent or independent anemia at screening defined as an hemoglobin \<10 g/dL with 10 mg BID starting dose with subsequent up titrations (maximum dose 25 mg BID) depending on safety and efficacy. This dosing approach for anemic MF patients will be systematically studied in this prospective multicenter phase II open label single arm trial to determine if the levels of spleen length reduction and symptom improvement are consistent with those reported in previous clinical trials with ruxolitinib in patients with anemia and doses according to platelet counts at the moment of treatment initiation, and whether this lower starting dose and up titration approach may minimize the initial hemoglobin and platelet declines and transfusion requirements.

Arms:
arm 1: 10 mg BID (2 tablets of 5mg) was self-administered as starting dose for all patients. This dose was maintained for the first 12 weeks and titrated up thereafter unless they had met criteria for dose hold or dose reduction. Dose was to have been increased or decreased per standardized dosing paradigm and not to have exceeded 25 mg bid.

Interventions: intervention 1: ruxolitinib
Intervention descriptions: intervention 1: Ruxolitinib was supplied in 5 mg tablets to be taken orally approximately 12 hours apart (morning and night)

Protocol document:
Prot_001.pdf: 
Clinical Development 
INC424/ruxolitinib/Jakavi® 
Oncology Clinical Protocol CINC424A2411 / NCT02966353
A multicenter phase II, open label, single arm study to 
evaluate the efficacy and safety of ruxolitinib in the 
treatment of anemic myelofibrosis patients. 
Authors 
 
 
Document type 
Oncology Clinical Trial Protocol 
EUDRACT number 
2016-003552-75 
Version number 
00 (Original Protocol) 
Development phase 
II 
Document status 
Final 
Release date 
12-Sep-2016
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 19-Nov-2015 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ....................................................................................................................... 6 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 11 
Protocol summary .............................................................................................................. 12 
1 
Background ........................................................................................................................ 14 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 14 
1.1.1 
Inhibition of Janus Kinases (JAK) in MPN .......................................... 15 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 16 
1.2.1 
Overview of ruxolitinib ......................................................................... 16 
2 
Rationale ............................................................................................................................ 28 
2.1 
Study rationale and purpose ................................................................................... 28 
2.2 
Rationale for the study design................................................................................ 29 
 
 30 
2.3 
Rationale for dose and regimen selection .............................................................. 31 
2.4 
Rationale for choice of combination drugs ............................................................ 31 
2.5 
Rationale for choice of comparators drugs ............................................................ 31 
2.6 
Risks and benefits .................................................................................................. 32 
3 
Objectives and endpoints ................................................................................................... 32 
4 
Study design....................................................................................................................... 35 
4.1 
Description of study design ................................................................................... 35 
4.2 
Timing of interim analyses and design adaptations ............................................... 36 
4.3 
Definition of end of study ...................................................................................... 36 
4.4 
Early study termination .......................................................................................... 36 
5 
Population .......................................................................................................................... 36 
5.1 
Patient population .................................................................................................. 36 
5.2 
Inclusion criteria .................................................................................................... 36 
5.3 
Exclusion criteria ................................................................................................... 37 
6 
Treatment ........................................................................................................................... 39 
6.1 
Study treatment ...................................................................................................... 39 
6.1.1 
Dosing regimen ..................................................................................... 39 
6.1.2 
Ancillary treatments .............................................................................. 39 
6.1.3 
Rescue medication ................................................................................ 39 
6.1.4 
Guidelines for continuation of treatment .............................................. 39 


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6.1.5 
Treatment duration ................................................................................ 40 
6.2 
Dose escalation guidelines ..................................................................................... 40 
6.2.1 
Starting dose rationale ........................................................................... 40 
6.2.2 
Provisional dose levels .......................................................................... 41 
6.2.3 
Guidelines for dose escalations ............................................................. 41 
6.3 
Dose modifications ................................................................................................ 43 
6.3.1 
Dose modification and dose delay ........................................................ 43 
6.3.2 
Optional dose tapering strategy in the event of study drug 
discontinuation ...................................................................................... 44 
6.3.3 
Dose interruption and discontinuation of study drug ............................ 44 
6.3.4 
Discontinuation of study drug for hematologic toxicity ....................... 45 
6.3.5 
Restarting or reinstituting previous dose ............................................... 45 
6.3.6 
Treatment of investigational drug overdose .......................................... 46 
6.4 
Concomitant medications ...................................................................................... 47 
6.4.1 
Permitted concomitant therapy .............................................................. 47 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ............ 47 
6.4.3 
Prohibited concomitant therapy............................................................. 48 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) ........................ 48 
6.5 
Patient numbering, treatment assignment or randomization ................................. 48 
6.5.1 
Patient numbering ................................................................................. 48 
6.5.2 
Treatment assignment or randomization ............................................... 49 
6.5.3 
Treatment blinding ................................................................................ 49 
6.6 
Study drug preparation and dispensation ............................................................... 49 
6.6.1 
Study treatment packaging and labeling ............................................... 49 
6.6.2 
Drug supply and storage ........................................................................ 49 
6.6.3 
Study drug compliance and accountability ........................................... 50 
6.6.4 
Disposal and destruction ....................................................................... 50 
7 
Visit schedule and assessments ......................................................................................... 50 
7.1 
Study flow and visit schedule ................................................................................ 50 
7.1.1 
Molecular pre-screening ........................................................................ 54 
7.1.2 
Screening ............................................................................................... 54 
7.1.3 
Treatment period ................................................................................... 55 
7.1.4 
Discontinuation of study treatment ....................................................... 55 
7.1.5 
Withdrawal of consent........................................................................... 56 
7.1.6 
Follow up for safety evaluations ........................................................... 57 
7.1.7 
Lost to follow-up ................................................................................... 57 
7.2 
Assessment types ................................................................................................... 57 


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7.2.1 
Efficacy assessments ............................................................................. 57 
7.2.2 
Safety and tolerability assessments ....................................................... 57 
7.2.3 
Pharmacokinetics .................................................................................. 60 
 
 60 
7.2.5 
Resource utilization ............................................................................... 61 
7.2.6 
Patient reported outcomes ..................................................................... 61 
8 
Safety monitoring and reporting ........................................................................................ 62 
8.1 
Adverse events ....................................................................................................... 62 
8.1.1 
Definitions and reporting ...................................................................... 62 
8.1.2 
Laboratory test abnormalities ................................................................ 64 
8.1.3 
Adverse events of special interest ......................................................... 64 
8.2 
Serious adverse events ........................................................................................... 64 
8.2.1 
Definitions ............................................................................................. 64 
8.2.2 
Reporting ............................................................................................... 65 
8.3 
Pregnancies ............................................................................................................ 66 
8.4 
Warnings and precautions ...................................................................................... 66 
8.5 
Data Monitoring Committee .................................................................................. 66 
8.6 
Steering Committee ............................................................................................... 66 
9 
Data collection and management ....................................................................................... 66 
9.1 
Data confidentiality ............................................................................................... 66 
9.2 
Site monitoring ...................................................................................................... 67 
9.3 
Data collection ....................................................................................................... 68 
9.4 
Database management and quality control ............................................................ 68 
10 Statistical methods and data analysis ................................................................................. 68 
10.1 
Analysis sets .......................................................................................................... 69 
10.1.1 
Full Analysis Set ................................................................................... 69 
10.1.2 
Safety set ............................................................................................... 69 
10.1.3 
Per-Protocol set ..................................................................................... 69 
10.1.4 
Dose-determining analysis set ............................................................... 69 
10.1.5 
Pharmacokinetic analysis set ................................................................. 69 
10.1.6 
Other analysis sets ................................................................................. 69 
10.2 
Patient demographics/other baseline characteristics .............................................. 69 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 70 
10.4 
Primary objective ................................................................................................... 70 
10.4.1 
Variable ................................................................................................. 70 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 70 


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10.4.3 
Handling of missing values/censoring/discontinuations ....................... 71 
10.4.4 
Supportive and Sensitivity analyses ...................................................... 71 
10.5 
Secondary objectives ............................................................................................. 71 
10.5.1 
Secondary efficacy objective(s) ............................................................ 71 
10.5.2 
Other secondary efficacy objectives ..................................................... 71 
10.5.3 
Safety objectives ................................................................................... 72 
10.5.4 
Pharmacokinetics .................................................................................. 74 
 
 74 
10.5.6 
Resource utilization ............................................................................... 74 
10.5.7 
Patient-reported outcomes ..................................................................... 74 
 
 74 
 
 74 
 
 75 
10.7 
Interim analysis ...................................................................................................... 75 
10.8 
Sample size calculation .......................................................................................... 76 
10.9 
Power for analysis of key secondary variables ...................................................... 76 
11 Ethical considerations and administrative procedures ....................................................... 77 
11.1 
Regulatory and ethical compliance ........................................................................ 77 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 77 
11.3 
Informed consent procedures ................................................................................. 77 
11.4 
Discontinuation of the study .................................................................................. 77 
11.5 
Publication of study protocol and results ............................................................... 78 
11.6 
Study documentation, record keeping and retention of documents ....................... 78 
11.7 
Confidentiality of study documents and patient records........................................ 79 
11.8 
Audits and inspections ........................................................................................... 79 
11.9 
Financial disclosures .............................................................................................. 79 
12 Protocol adherence ............................................................................................................ 79 
12.1 
Amendments to the protocol .................................................................................. 80 
13 References (available upon request) .................................................................................. 80 
14 Appendices ........................................................................................................................ 83 
14.1 
Appendix 1 - Diagnostic criteria for PMF, PPV MF, and PET-MF ...................... 83 
14.2 
Appendix 2 - Eastern Cooperative Oncology Group performance status .............. 84 
14.3 
Appendix 3 - Bone marrow biopsy evaluation (Arber et al., 2016) (when 
performed, they are not mandatory) ....................................................................... 85 
14.4 
Appendix 4 - Patient reported outcomes – Questionnaires .................................... 85 
14.5 
Appendix 5 - List of CYP3A4 inhibitors and inducers ......................................... 87 
14.6 
Appendix 6 - Jakavi Summary of Product Characteristics .................................... 88 


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14.6.1 
ANNEX I............................................................................................... 88 
14.6.2 
Annex II............................................................................................... 173 
14.6.3 
ANNEX III .......................................................................................... 176 
 
 
List of figures 
Figure 1-1 
Reduction in palpable spleen length in patients receiving different 
doses of ruxolitinib (Verstovsek 2010b) ............................................... 20 
Figure 1-2 
Reduction in palpable spleen length according to ruxolitinib dose 
when maintained for at least 6 months (Verstovsek 2010b) ................. 21 
Figure 1-3 
Improvements in combined MFSAF score on ruxolitinib..................... 22 
Figure 6-1 
Dosing Up-titration Diagram ................................................................ 42 
Figure 14-1 
Patients achieving the primary endpoint and components of the 
primary endpoint at week 32 ............................................................... 105 
Figure 14-2 
Patients achieving the primary endpoint and components of the 
primary endpoint at week 32 ............................................................... 125 
Figure 14-3 
Patients achieving the primary endpoint and components of the 
primary endpoint at week 32 ............................................................... 147 
Figure 14-4 
Patients achieving the primary endpoint and components of the 
primary endpoint at week 32 ............................................................... 168 


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List of tables 
Table 3-1 
Objectives and related endpoints ........................................................... 33 
Table 6-1 
Dose and treatment schedule ................................................................. 39 
Table 6-2 
Dose modifications for hematologic toxicity ........................................ 43 
Table 6-3 
Restarting or reinstituting previous ruxolitinib dose after safety 
interruptions or dose reductions ............................................................ 46 
Table 7-1 
Visit evaluation schedule ...................................................................... 51 
Table 7-2 
Local Clinical laboratory parameters collection plan ............................ 59 
 
 60 
Table 14-1 
List of CYP3A4 inhibitors and inducers ............................................... 87 
Table 14-2 
Frequency category of adverse drug reactions reported in the 
phase 3 studies (COMFORT-I, COMFORT-II, RESPONSE) .............. 97 
Table 14-3 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume at week 24 in COMFORT-I and at week 48 in 
COMFORT-II (ITT) ............................................................................ 103 
Table 14-4 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume by JAK mutation status (safety set) ........................................ 103 
Table 14-5 
Frequency category of adverse drug reactions reported in the 
phase 3 studies (COMFORT-I, COMFORT-II, RESPONSE) ............ 118 
Table 14-6 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume at week 24 in COMFORT-I and at week 48 in 
COMFORT-II (ITT) ............................................................................ 123 
Table 14-7 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume by JAK mutation status (safety set) ........................................ 124 
Table 14-8 
Frequency category of adverse drug reactions reported in the 
phase 3 studies (COMFORT-I, COMFORT-II, RESPONSE) ............ 139 
Table 14-9 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume at week 24 in COMFORT-I and at week 48 in 
COMFORT-II (ITT) ............................................................................ 144 
Table 14-10 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume by JAK mutation status (safety set) ........................................ 145 
Table 14-11 
Frequency category of adverse drug reactions reported in the 
phase 3 studies (COMFORT-I, COMFORT-II, RESPONSE) ............ 161 
Table 14-12 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume at week 24 in COMFORT-I and at week 48 in 
COMFORT-II (ITT) ............................................................................ 166 
Table 14-13 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume by JAK mutation status (safety set) ........................................ 167 


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List of abbreviations 
 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
b.i.d./BID 
bis in diem/twice a day 
BAT 
Best available therapy 
BUN 
Blood urea nitrogen 
Cmax 
Maximum concentration 
COMFORT 
COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CR 
Complete response 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYPs 
Cytochrome P450 system of metabolizing enzymes, includes isoenzymes 
designated CYP3A4, CYP2C11, CYP2C13 
DAR 
Dosage Administration Record 
DDI 
Drug-Drug Interaction 
DIPSS 
Dynamic International Prognostic Scoring System 
dL 
Deciliter (100 mL) 
DLT 
Dose Limiting Toxicity 
DS&E 
Drug Safety and Epidemiology 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form; the term eCRF can be applied to either EDC or Paper 
EDC 
Electronic Data Capture 
EOT 
End of treatment 
ET 
Essential thrombocythemia 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FPLV 
First patients last visit 
GCP 
Good clinical practice 
HDL 
High Density Lipoprotein 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
 


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INC424 
Ruxolitinib 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System 
and Interactive Web Response System 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IVRS 
Interactive Voice Response System 
IWG MRT 
International Working Group-Myeloproliferative Neoplasms Research and 
Treatment 
JAK 
Janus kinase 
L 
Liter 
LDH 
Lactate dehydrogenase 
LDL 
Low Density Lipoprotein 
LPFV 
Last patient first visit 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical dictionary for regulatory activities 
MF 
Myelofibrosis 
MF-7 
Myelofibrosis 7 Item Symptom Scale 
MFSAF 
Myelofibrosis Symptom Assessment Form 
mg 
Milligram(s) 
mL 
Mililiter(s) 
MM 
Multiple Myeloma 
MPD 
Myeloproliferative disorder 
MPN 
Myeloproliferative neoplasms 
MRI 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
o.d. 
omnia die/once a day 
PD 
Pharmacodynamic (s) 
PE 
Physical examination 
PET-MF 
Post essential thrombocythemia-myelofibrosis 
PGIC 
Patient Global Impression of Change 
PLT 
Platelet 
PK 
Pharmacokinetics 
p.o. 
per os/by mouth/orally 
PHI 
Protected Health Information 
PMF 
Primary myelofibrosis 
PML 
Progressive multifocal leuko-encephalopathy 
PPS 
Per-Protocol Set 
PPV-MF 
Post polycythemia vera-myelofibrosis 
PRO 
Patient Reported Outcomes 


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PS 
Performance status 
PV 
Polycythemia vera 
QD 
Once a Day 
QoL 
Quality of life 
RA 
Rheumatoid Arthritis 
RDC 
Remote data capture 
REB 
Research Ethics Board 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SOP 
Standard Operating Procedure 
T1/2 
Half life 
TD 
Transfusion Dependent 
TI 
Transfusion Independence 
Tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
USA 
United States of America 
VS 
Vital signs 
WBC 
White blood cell count 
WHO 
World Health Organization 
 


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Glossary of terms 
 
 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not 
include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage 
Other study treatment 
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned, unless the patient will be followed for progression and/or survival 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 
Withdrawal of consent 
Withdrawal of consent occurs only when a patient does not want to participate 
in the study any longer, and does not want any further visits or assessments, 
and does not want any further study related contact 


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Protocol summary: 
Title 
A multicenter phase II, open label, single arm study to evaluate the efficacy and 
safety of ruxolitinib in the treatment of anemic myelofibrosis patients. 
Brief title 
Anemia trial in MF patients 
Sponsor and Clinical 
Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
This is a study of treatment with ruxolitinib in patients who present with transfusion 
dependent or independent anemia at screening defined as an hemoglobin <10 g/dL 
with 10 mg BID starting dose with subsequent up titrations depending on safety and 
efficacy. This dosing approach for anemic MF patients will be systematically studied 
in this prospective multicenter phase II open label single arm trial to determine if the 
levels of spleen length reduction and symptom improvement are consistent with 
those reported in previous clinical trials with ruxolitinib in patients with anemia and 
doses according to platelet counts at the moment of treatment initiation, and whether 
this lower starting dose and up titration approach may minimize the initial hemoglobin 
and platelet declines and transfusion requirements. 
Primary Objective 
To determine the spleen length response rate at week 24. 
Secondary Objectives 
• 
To evaluate safety. 
• 
To determine the spleen length response rate at week 48. 
• 
To evaluate the effect of ruxolitinib on spleen length. 
• 
To evaluate the effect of ruxolitinib on symptoms. 
• 
To evaluate the effect of ruxolitinib on Patient Global Impression of Change 
(PGIC). 
• 
To evaluate the effect of ruxolitinib on transfusion requirements. 
Study design 
This is an open-label, single-arm study of treatment with ruxolitinib in patients who 
presents with transfusion dependent or independent anemia at screening defined as 
an hemoglobin <10 g/dL. The starting dose is 10 mg BID for all enrolled patients and 
gradual up titrations will start at week 12 determined by the level of efficacy achieved 
and the tolerability. 
Population 
Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis 
(PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) who have 
splenomegaly that is equal to or greater than 5 cm below the left costal margin and 
with anemia defined by Hb less than 10 g/dL. 
Inclusion criteria 
Key Inclusion criteria: (See Section 5.2 for details) 
• 
Male or female patients aged ≥ 18 years of age. 
• 
Patients must be diagnosed with PMF, according to the 2016 revised 
International Standard Criteria (Arber et al, 2016), PPV MF or PET-MF (Barosi 
2008), irrespective of JAK2 mutation status. 
• 
Patients with palpable splenomegaly that is equal to or greater than 5 cm 
below the left costal margin. 
• 
Patients with a hemoglobin less than 10 g/dL 
• 
Patients with a history of transfusions must have a documented transfusion 
record in the previous 12 weeks to baseline. 
• 
Patients with a peripheral blood blast percentage count of < 10%. 


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Exclusion criteria 
Key Exclusion Criteria (See Section 5.3 for details) 
• 
Patients with prior treatment with any JAK1 or JAK2 inhibitor. 
• 
Patients with inadequate bone marrow reserve at baseline visit as 
demonstrated by at least one of the following: 
• 
ANC that is ≤ 1,000/µL. 
• 
Platelet count that is <50,000/µL without the assistance of growth factors, 
thrombopoietic factors or platelet transfusions. 
• 
Hemoglobin count that is ≤ 6.5 g/dL despite transfusions. 
• 
Patients with severely impaired renal function 
• 
Patients with inadequate liver function 
• 
Patients being treated concurrently with a strong (potent) systemic inhibitor or 
inducer of CYP3A4 at the time of Screening 
• 
Acute viral hepatitis or active chronic hepatitis B or C infection. 
• 
History of progressive multifocal leuko-encephalopathy (PML) 
Investigational therapy 
Ruxolitinib will be self-administered as BID oral treatment. The starting dose is 10 
mg BID for all enrolled patients and gradual up titrations will start at week 12 
determined by the level of efficacy achieved and the tolerability. 
Efficacy assessments 
• 
Spleen length 
• 
Transfusions over time 
Safety assessments 
• 
Adverse events 
• 
Hematology parameters 
• 
Chemistry parameters 
Other assessments 
• 
An assessment of Patient reported outcomes using 
• 
Myelofibrosis 7 Item Symptom Scale (MF-7) 
• 
Separate question on Inactivity to compute Modified MFSAF v2.0. 
• 
Patient Global Impression of Change (PGIC) 
 
 
 
 
 
 
Data analysis 
Data will be summarized with respect to demographic and baseline characteristics 
and safety observations and measurements. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, 
median, minimum, and maximum will be presented. Approximately 50 patients will 
be enrolled in this study. 
Key words 
Ruxolitinib, anemia, Primary Myelofibrosis (PMF), Post-Polycythemia Vera- 
Myelofibrosis (PPV-MF), Post-Essential Thrombocythemia Myelofibrosis (PET-MF) 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Myelofibrosis (MF) is a clonal hematologic neoplastic disease characterized by the presence of 
megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or collagen 
fibrosis (Tefferi A 2008), splenomegaly, anemia, and debilitating constitutional symptoms that 
include fatigue, weight loss, pruritus, night sweats, fever, and bone, muscle, or abdominal pain 
(Mesa et al. 2007), (Abdel-Wahab et al. 2009). MF can either be primary in origin (primary 
myelofibrosis, or PMF) or result from progression of polycythemia vera or essential 
thrombocythemia vera (Tefferi A 2008). The median age at diagnosis of MF is approximately 
65 years. Patients with myelofibrosis have shortened survival that ranges from a median of 
approximately 2 years to 11 years depending on the presence of certain risk factors that define 
their risk category including age, anemia, leukocytosis, etc. 
PMF is a clonal MPN (Myeloproliferative neoplasm) of the pluripotent hemopoietic stem cell, 
in which the proliferation of multiple cell lineages is accompanied by progressive bone marrow 
fibrosis. Marrow fibrosis is thought to be secondary to the release of pro - inflammatory 
cytokines from abnormal clonal cells (primarily megakaryocytes), which act to stimulate 
fibroblast proliferation and fibrosis. Mild to moderate anemia is found in most patients at 
presentation and worsens as myelofi brosis progresses. The anemia is in large p art due to 
reduced erythropoiesis, but may be compounded by hypersplenism, bleeding and iron or folate 
deficiency (Campbell 2006). 
Several prognostic risk scores that are based on survival outcomes have been developed in MF 
to better define treatment choices for physicians and therefore improve patient management. 
The International Prognostic Scoring System (IPSS) was developed by the International 
Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 
(Cervantes et al 2009). The IPSS is used at diagnosis and employs five hematologic and clinical 
variables (age, leukocytosis, anemia, peripheral blood blasts and constitutional symptoms) to 
stratify patients in a low, intermediate-1, intermediate-2 and high- risk category. The dynamic 
IPSS (DIPSS) was subsequently developed to be used for patients evaluated after MF diagnosis 
(Gangat et al 2011). The DIPSS relies upon the same five variables as IPSS but utilizes the 
predictive value of selected cytogenetic abnormalities. These scoring systems are expected to 
facilitate categorizing patients to different risk groups, and thus assist physicians in 
recommending optimal treatment management plans. 
All currently available pharmacologic treatments are either directed towards the management 
of MF-originated anemia or the treatment of MF-symptoms including splenomegaly. As these 
treatments do not cure or modify the disease progression of MF, they are mostly used to treat 
patients in the higher risk categories. MF patients in the lower risk categories (IPSS Low and 
Int-1), by virtue of a relatively asymptomatic disease and an indolent disease course, are 
managed through active surveillance or a ‘watch and wait’ approach until appearance of 
bothersome symptoms or the definitive progression to the higher risk groups. Allogeneic stem 
cell transplantation is the only curative option, but it is ofte n associated with a high rate of 


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mortality and morbidity (Kroger 2008). Other available treatments include splenectomy, 
involved field radiotherapy, erythropoiesis stimulating agents, androgen preparatio ns, 
thalidomide and its analogs, hydroxyurea. More recent advancements in MF treatment include 
the discovery of ruxolitinib, a Janus Kinase (JAK)1 and JAK2 inhibitor. Ruxolitinib is one of 
the first treatments in MF that has demonstrated rapid and durable reductions in MF- related 
splenomegaly, improvement in disease-related symptoms and offers a distinct survival benefit 
(Vannucchi et al. 2015). Final 5 years analysis of both COMFORT I & II have demonstr ated 
that long-term ruxolitinib treatment in patients with MF is associated with durable reductions 
in splenomegaly and significantly longer OS compared with placebo and BAT respectively; 
supporting ruxolitinib as an effective long-term treatment for patients with intermediate-2 and 
high-risk MF. (Harrison 2016; Gupta 2016) 
The recent years have witnessed major advances in the molecular understanding of MF, first 
with the identification of JAK2 and MPL mutations (Kilpivaara 2008) and more recently the 
calreticulin (CALR) gene (Klampfl et al 2008), all of which are associated with an activation 
of the Janus Kinase-Signal Transducer & Activator of Transcription (JAK-STAT) pathway. In 
addition, as also shown in other myeloid malignancies, mutations in a multiplicity of other genes 
involved in the epigenetic and spliceosome regulatory machineries have been reported in MF 
across IPSS risk categories and shown to have a negative prognostic impact. 
These mutations are defined as the ‘high molecular risk’ category (HMR) in PMF based on  
the presence of at least one of the five prognostically detrimental mutated genes (ASXL1, 
EZH2, SRSF2, IDH1 and IDH2). Association between some HMR genes (ASXL1 and SRSF2) 
and anemia has been described (Vannucchi et al 2013). 
 
1.1.1 
Inhibition of Janus Kinases (JAK) in MPN 
A key feature of MPNs is the dysregulation of JAK/STAT signaling. The JAK/STAT pathway 
is involved in normal hematopoiesis, inflammation, and immune function ( Ghoreschi et al. 
2009). The 4 members of the JAK family - JAK1, JAK2, JAK3, and TYK2 - are non-receptor 
tyrosine kinases that play a central role in signal transduction initiated by cytokines (e.g., 
interleukin and interferon signaling), growth factors, and hormones (Ghoreschi et al. 2009). 
Specifically: 
• JAK1 - role in lymphopoiesis and cytokine response; ubiquitously expressed 
• JAK2 - role in erythropoiesis; ubiquitously expressed 
• JAK3 - role in lymphocyte development and proliferation and immune response; 
expressed primarily in hematopoietic cells 
• TYK2 - role in mediation of cytokine signals; ubiquitously expressed 
Upon ligand binding, the receptor undergoes conformational changes that allow JAK 
activation and result in receptor homodimerization (i.e., JAK2/JAK2) or heterodimerization 
(ie, JAK1/JAK2) (Vainchenker 2008). The activated JAKs create docking sites on the  
receptor for STAT (signal transducers and activators of transcription) proteins. STAT proteins, 
once activated, dissociate from the receptor, dimerize, and translocate into the nucleus to 
initiate transcription of target genes (Ghoreschi et al. 2009). Given the importance of this 
interaction, this pathway is also known as the JAK/STAT pathway. 


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Dysregulation of the JAK pathway can occur in a number of ways. Ligand -independent 
activation of the pathway can occur due to mutations in the JAK recept or. In addition, mutations 
in or activation of other modulators of the signaling pathway can result in pathway 
overactivation. Regardless of a particular mutation’s presence or absence, dysregulation of the 
JAK pathway is a hallmark of MPNs. The majority of patients with Myelofibrosis, 
Polycythemia Vera, and Essential thrombocythemia bear a somatic activating mutation in JAK2 
whereby a G>T nucleotide exchange in exon 14 at position 1849 results in a  substitution of 
valine by phenylalanine at amino acid 617 (JAK2 V617F) (Tefferi et al. 2009a). 
Genome-wide association studies suggest that individuals can have a genetic predisposition to 
the development of JAK2 V617F-positive MPNs. Specific haplotypes have been identified that 
preferentially acquire the JAK2 V617F mutation and confer susceptibility to MPNs, which may 
partially explain the phenotypic diversity observed in carriers of the mutation (Tefferi et al. 
2009a), (Olcaydu et al. 2009). 
With frequencies of greater than 95% in PV and approximately 50% in MF and ET (Tefferi et 
al. 2009a), the presence of this mutation is a major criterion in the diagnosis of these diseases. 
Although the JAK2 V617F-activating mutation is the most commonly observed mutation in 
MPNs, it is not the only JAK pathway-activating mutation noted in MPN patients. Mutations 
in exon 12 have also been noted, mostly in PV patients (Scott et al. 2007). Indeed, virtually all 
JAK2 V617F-negative PV patients bear JAK2 exon 12 mutations (Schnittger et al. 2009). Of 
note, these mutations affect the pseudokinase domain or a proximal region (“exon 12” 
mutations) but not the kinase domain. 
Abnormal activation of JAK1 has also been noted in MF patients ( Quintas-Cardama et al 2010). 
In addition to alterations in JAK1 and JAK2, alterations in other members of the JAK pathway 
have been detected in MPN patients. These alterations include a somatic activating mutation in 
the JAK2-associated thrombopoietin receptor gene MPL at codon 515 (MPL W515L/K) and 
various mutations in LNK, a negative regulator of JAK/STAT signaling ( Oh 2010, Patnaik 
2010) and mutations in CALR (Kampfl 2013, Nangalia 2013, Chachoua 2016). Clearly, JAK 
pathway dysregulation, regardless of mutational status, is a key pathophysiological feature of 
MPNs. 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of ruxolitinib 
Dysregulated JAK-STAT signaling, via upregulation of JAK1 and JAK2 or gain of function 
mutations such as JAK2V617F, has been implicated as drivers of BCR-ABL-negative 
myeloproliferative neoplasms (MPN), namely myelofibrosis (MF), polycythemia vera (PV) and 
essential thrombocythemia (ET). Ruxolitinib, which is jointly develo ped in hematology and 
oncology indications by Novartis Pharma AG (Switzerland) and Incyte Corporation (USA), 
specifically binds to and inhibits JAK1, JAK2 and mutated JAK2V617F, leading to inhibition 
of growth factor-mediated cell signaling and tumor cell proliferation. Given this mechanism of 
action of ruxolitinib as a JAK inhibitor and the role played by dysregulation of the JAK pathway 
in the pathogenesis of MPNs, the primary clinical development plan for ruxolitinib focused on 
studies to support regulatory approval in these disorders. 


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Ruxolitinib is currently approved under the trade name of ‘Jakavi’ in over 90 countries for the 
treatment of disease-related splenomegaly or symptoms in adult patients with (primary 
myelofibrosis) PMF, post-polycythemia vera myelofibrosis (PPV-MF) and post-essential 
thrombocythemia myelofibrosis (PET-MF); also EU and other countries have recently 
approved JAKAVI for the treatment of adult patients with polycythemia vera (PV) resistant to 
or intolerant of hydroxyurea. Ruxolitinib is also approved in the USA under the trade name of 
‘Jakafi’ and is indicated for the treatment of patients with intermediate or high risk 
myelofibrosis, including PMF, PPV-MF and PET-MF and for the treatment of PV patients who 
have had an inadequate response to or are intolerant of hydroxyurea (Appendix 6). 
 
1.2.1.1 
Non-clinical experience 
 
1.2.1.1.1 Ruxolitinib preclinical safety 
Ruxolitinib has been evaluated in safety pharmacology, repeat dose toxicity, genotoxicit y, 
reproductive toxicity and carcinogenicity studies. Target organs associated with the 
pharmacological action of ruxolitinib in repeat dose studies include bone marrow, peripheral 
blood and lymphoid tissues. Infections generally associated with immunosupp ression were 
noted in dogs. The potential for ruxolitinib to cause adverse alterations in respiratory, 
neurologic, and cardiovascular parameters in humans is low. 
Ruxolitinib was not teratogenic but was associated with increases in post-implantation loss and 
decreases in fetal weights. No effects were noted on fertility. In a pre - and post-natal 
development study, there were no adverse findings for fertility indices and maternal and 
embryofetal survival, growth, and developmental parameters. Ruxolitinib was not mutagenic or 
clastogenic. Ruxolitinib was not carcinogenic in the Tg.rasH2 transgenic mouse model nor in a 
2-year study in rats. 
Additional toxicology and safety pharmacology information is available in the [Investigator 
Brochure]. 
 
1.2.1.2 
Clinical experience 
 
1.2.1.2.1 Ruxolitinib pharmacokinetics 
Fifteen Phase I , nine Phase II and three Phase III clinical studies (two in MF, one in PV) 
provided clinical pharmacology data on ruxolitinib in healthy volunteers and in patients with 
MF, ET, PV, subjects with renal or hepatic impairment, prostate cancer, pancreatic cancer, 
multiple myeloma (MM) or rheumatoid arthritis (RA). 
Oral absorption of ruxolitinib is rapid and nearly complete, with ≥95% absorption indicating 
high in vivo permeability in the human gastrointestinal tract, consistent with a 
Biopharmaceutical Classification System (BCS) Class I compound. Mean peak plasma 
concentration (Cmax) is achieved 1-2 h post-dose. The effect of food on ruxolitinib exposure is 
minimal and is not expected to be clinically significant; as a result, the drug may be 
administered either with or without food. 
Dose proportional exposure is observed between 5 and 200 mg dose range with linear 
pharmacokinetics (PK). Plasma protein binding is approximately 97% in vitro. There is 


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moderate distribution to organs and tissues with no long-term retention of drug-related material 
in preclinical species and limited drug penetration into the central nervous system (CNS) or 
across the blood-brain barrier. There was >95% [14C] drug recovery in a mass balance study 
with 74% and 22% of the dose excreted in urine and feces of healthy subjects, respectively. 
Less than 1% of the administered dose is recovered in urine and feces as unchanged parent drug. 
The mean terminal elimination half-life (T1/2) is ~3 h with no appreciable accumulation of either 
parent or metabolites with twice daily dosing. 
Metabolism is predominantly via the cytochrome P450 isozyme CYP3A4 to yield oxygenated 
and subsequent conjugated metabolites. Oxidative metabolites of ruxolitinib retain 
pharmacological activity albeit with one half to one fifth of the activity of the parent compound. 
Ex vivo pharmacokinetic/pharmacodynamic (PK/PD) analysis indicates that the total of 8 active 
metabolites contribute to 18% of the overall PD activity of ruxolitinib. 
When administering ruxolitinib with strong CYP3A4 inhibitors, the total daily dose should be 
reduced by approximately 50%. 
No dose adjustment is necessary when co-administering ruxolitinib with strong CYP3A4 
inducers. No dose adjustment is necessary when co-administering ruxolitinib with CYP3A4 
substrates. Ruxolitinib did not decrease the exposure of a fixed dose oral contraceptive 
metabolized via the CYP3A4 pathway, thus demonstrating lack of CYP3A4 induction potential. 
In patients with severe (creatinine clearance (Clcr) <30 mL/min) and moderate renal 
impairment (Clcr = 30-59 mL/min), the recommended starting dose based on platelet count 
should be reduced by approximately 50% to be administered twice a day. Patients on 
hemodialysis should initiate ruxolitinib with a single dose of 15 mg or 20 mg based on platelet 
counts on day of hemodialysis with subsequent doses only on hemodialysis days and following 
each hemodialysis session. Ruxolitinib doses should be titrated based on individual safety and 
efficacy. 
In patients with mild, moderate or severe hepatic impairment, the recommended starting dose 
based on platelet count should be reduced by approximately 50% with subsequent dose titration 
based on individual safety and efficacy. 
Ruxolitinib PK in healthy volunteers was largely comparable between Japanese, Chinese and 
Western subjects and did not lead to a conclusion of meaningful ethnic differences. 
Baseline elevations in inflammatory markers such as tumor necrosis factor alpha (TNFα), 
interleukin (IL)-6, and C-reactive protein (CRP) noted in patients with MF were associated with 
constitutional symptoms such as fatigue, pruritus, and night sweats. Dec reases were observed 
in these markers over the 24 weeks of treatment with ruxolitinib, with no evidence that patients 
became refractory to the effects of ruxolitinib treatment. 
 
1.2.1.2.2 Ruxolitinib clinical safety in healthy volunteers 
The safety profile for ruxolitinib in the Phase I development program was assessed in over 370 
subjects for single or repeat doses. Ruxolitinib has been administered to 40 subjects with 
various degrees of renal impairment and 32 subjects with various degrees of hepatic 
impairment. Additionally, a DDI study with methotrexate was completed in 18 RA patients. 


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AEs were, in general, mild and resolved without interventions. In the first-in-human study one 
subject had hyponatremia after receiving 5 mg ruxolitinib. The hyponatremia was assesse d as 
severe in intensity, unrelated to study medication, reversed within 5 days, and was reported as 
serious adverse event (SAE). 
In the repeat-dose study in healthy subjects, the dose-limiting AE was neutropenia, which 
occurred at a dose of 50 mg b.i.d. Neutropenia as an AE was noted in three subjects, all receiving 
the highest dose of ruxolitinib, 50 mg b.i.d. Neutropenia at the Grade 4 level, assessed as severe, 
led to study drug discontinuation on Day 5 in one subject, and was reported as an SAE. 
Neutrophil count returned to a normal level 12 days after the final dose of study medication. In 
two other subjects, neutropenia was Grade 1 or 2, and resolved with dose interruption or during 
continued dosing. The AE profile was similar for single - and multiple- dose studies, and no 
differences were observed between males and females. The most  frequent (≥2 subjects) 
treatment-emergent AEs (TEAEs) occurring in the Phase I multiple- dose study were: 
neutropenia (4.2%), dizziness (2.8%), headache (2.8%) and nausea (2 .8%). Overall, in healthy 
volunteer studies where frequent sampling of the neutrophil count was performed, a transient, 
reversible decrease in neutrophil count was frequently seen following dosing, which reversed 
after 12-24 h off drug. 
The AE profile of ruxolitinib has also been assessed in 198 healthy volunteers, subjects with 
various degrees of renal (n=32) or hepatic (n=24) impairment, and in patients with RA (n=59) 
receiving ruxolitinib: AEs were, in general, mild and resolved without interventions. 
A thorough QT study was conducted in 50 healthy subjects. There was no indication of a 
QT/QTc prolonging effect of ruxolitinib in single doses up to a supra -therapeutic dose of 200 
mg indicating that ruxolitinib has no effect on cardiac repolarization. 
Please refer to the [Investigator Brochure] for further information. 
 
1.2.1.2.3 Ruxolitinib clinical safety and efficacy in phase I/II/III trials 
 
Phase I/II study of INC424 in patients with primary, post-PV, or post-ET MF 
Study INCB 18424-251 is a completed Phase I/ II open-label study of orally administered 
INC424 (ruxolitinib) in patients with PMF, PPV MF and PET MF. A total of 153 patients were 
enrolled at the following oral dosing levels/regimens: starting dose of 25 mg BID followed by 
escalation up to 50 mg BID; once daily (QD) dosing ranging from 25 mg QD to 200 mg QD. 
The maximum tolerated doses were identified as 25 mg BID or 100 mg QD, based on dose-
limiting thrombocytopenia. In the Phase II component of the trial additional dosing schedules 
were also evaluated including 25 mg BID (with a reduction to 10 mg BID after 2 cycles 
[months] of therapy); 10 mg BID, with dose escalation permitted after 3 cycles (months) of 
therapy; 10 mg BID (in patients with a baseline platelet count of 100 - 200 x 109/L); and 15 mg 
BID (in patients with a baseline platelet count of > 200 x 109/L) with dose increases to 25 mg 
BID (in 5 mg increments). Data from the completed Study INCB 18424 - 251 demonstrate 
marked and durable reductions in spleen size. In this study spleen size was measured as palpable 
length below the left costal margin. Figure 1-1 illustrates the mean reduction in absolute spleen 
size (measured by palpation) for patients receiving 15 mg BID and 25 mg BID, and Figure 1-2 
mean reduction in absolute spleen size (measured by 


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palpation) for patients receiving their originally assigned dose for at least 6 months 
(Verstovsek 2010b). 
 
Figure 1-1 
Reduction in palpable spleen length in patients receiving different 
doses of ruxolitinib (Verstovsek 2010b) 


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Figure 1-2 
Reduction in palpable spleen length according to ruxolitinib dose 
when maintained for at least 6 months (Verstovsek 2010b) 
 
As noted in Figure 1-2, BID regimens are associated with a prompt decrease in spleen size. 
Response rates have been demonstrated to be greatest in the BID dosing cohort, with reduced 
responses in the 50 mg PO QD dosing cohort, and lowest in the 10 mg PO BID dosing cohort 
(Verstovsek 2010b). The majority of patients had a ≥ 25% reduction in spleen size on therapy 
(70% in 10 mg BID cohort; 82% in 15 mg BID dosing cohort; 77% in the 25 mg BID cohort). 
Responses occurred quickly, within 1-2 months of therapy and appear durable (> 1 year in 16 
patients for whom data were available at 1.5 years and all 8 patients for whom data were 
available at 2 years). Best responses were greatest in the 25 mg BID dosing cohort (among 
patients starting at 25 mg BID and maintaining that dosing schedule), although dose 
interruptions were common (60%) primarily due to thrombocytopenia. Based on this profile an 
initial dose of 15 mg ruxolitinib BID is recommended. Spleen reduction occurred regardless of 
presence/absence of the JAK2V617F mutation (data not shown). Progressive MPN are 
associated with weight loss and cachexia. Dysregulation and abnormal elevation of a variety of 
pro-inflammatory cytokines may produce a hypercatabolic state which contributes to the weight 
loss and wasting seen in patients with MF. After an initial weight loss 


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(presumably due to the rapid decrease in splenomegaly and hepatomegaly and loss of ascites 
and/or pleural effusions) there is a gain in total body weight that appears to be dose-dependent. 
Weight gains are present in most patients, including those with body mass index at baseline in 
the lowest quartile (body mass index below ~ 22). 
Improvements in QoL were rapidly demonstrated, typically within 1 month of therapy. The 
Modified Myelofibrosis Symptom Assessment Form (MFSAF) developed by Mesa et al, and 
based on an international internet-based survey of over 1000 patients with MPD, was used to 
probe a range of constitutional symptoms related to splenomegaly (including impaired  ability  
to move around and early satiety) and elevated cytokines (including fatigue, night sweats and 
pruritus) (Mesa 2007). Most patients in the 10 to 25 mg BID dose groups demonstrated a ≥ 50% 
improvement in total or individual symptom scores per the MF -SAF, which assesses 
constitutional symptoms including fatigue, night sweats, and pruritus ( Figure 1-3). These 
responses were durable through 6 months of therapy.  Symptomatic  improvements  were 
similar among the 10, 15, and 25 mg BID dose groups, with improvements in abdominal 
discomfort and pain accompanying the reduction in spleen size. Additionally, patients started   
to gain weight as early as after 2 c ycles of therapy, with patients in the lowest quartile for   
body mass index at baseline gaining more weight than those in the highest quartile. Functional 
improvements in the ability to walk were observed; patients improved their walking ability by 
34, 57, and 71 m after 1, 3, and 6 months, respectively (Verstovsek 2010b). 
 
Figure 1-3 
Improvements in combined MFSAF score on ruxolitinib 
In summary, ruxolitinib is associated with prompt and marked reduction in spleen size, gains in 
total body weight, improvement in ECOG status PS and improvement in constitutional 
symptoms that can be debilitating in this patient population. Re fer to the IB and (Verstovsek 
2010b) for more complete information. Ruxolitinib has been well tolerated by this aged 


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population with advanced disease. Nonhematologic adverse events were uncommon and 
included diarrhea (5.9%), fatigue (4.3%), headache (3.3%), peripheral edema (2.6%), pain in 
extremities (2.6%), urinary tract infections (2.6%), dizziness (2.6%), dyspnea (2.6%), asthenia 
(2%), fever (2%), cardiac murmur (2%), musculoskeletal pain (2%), periph eral neuropathy 
(2%), edema (2%), anxiety (2%), insomnia (2%), epistaxis (2%), flatulence (2%), and nausea 
(2%). The majority of these were Grade 1/ 2 CTCAE toxicity. Grade 3/ 4 nonhematologic 
toxicity included fatigue (1.3%), asthenia (2%), fever (0.7%), anxiety (1.3%) and insomnia 
(1.3%). Hematologic toxicity consisted primarily of anemia and thrombocytopenia. 
Thrombocytopenia appeared to be dose related occurring less frequently in the 15 mg BID 
group (3% Grade 3) than the 25 mg BID group (23% Grade 3; 6 % Grade 4). Thrombocytopenia 
was not related to JAK V617F mutational status. Grade 3 thrombocytopenia occurred in 10% 
of patients receiving 10 mg BID of ruxolitinib, 3% of patients receiving 15 mg BID of 
ruxolitinib, 23% of patients receiving 25 mg BID of ruxolitinib, 60% of patients receiving 50 
mg BID of ruxolitinib, 0% of patients receiving 25 mg QD of ruxolitinib, 27% of patients 
receiving 50 mg QD of ruxolitinib; 33% of patients receiving 100 mg QD; and 0% of patients 
receiving 200 mg QD of ruxolitinib . Thrombocytopenia of Grade 4 severity occurred in 0% of 
patients receiving 10 mg BID of ruxolitinib, 0% of patients receiving 15 mg BID of ruxolitinib, 
6% of patients receiving 25 mg BID of ruxolitinib, 20% of patients receiving 50 mg BID of 
ruxolitinib, 0% of patients receiving 25 mg QD of ruxolitinib, 9% of patients receiving 50 mg 
QD of ruxolitinib, 0% of patients receiving 100 mg QD of ruxolitinib, and 33% of patients 
receiving 200 mg QD of ruxolitinib. Thrombocytopenia occurred more frequently in patients 
with lower baseline platelet counts (< 200 x 109/L), and was reversible within 1 to 3 weeks after 
dose interruption and/or reduction. New onset anemia occurring in patients who were not 
transfusion dependent at baseline occurred in 23% of patients across all dosing intervals, and 
was most common in the 25 mg BID dosing cohort (27%) and least common in the 15 mg BID 
dosing cohort (8%). Anemia, though dose dependent, largely reflects the low Hgb status at 
baseline in this disease population. 
SAEs occurred in 59 (39%) patients, of which 12 were assessed as at least possible related to 
study drug, including bone marrow suppression, febrile neutropenia, syncope, progression to 
CMMoL, B-cell lymphoma, pharyngotonsilitis, pharyngitis, myalgia, sinusitis, and cerebral 
hemorrhage. Of related SAEs reported in the study to date, the most frequent are those reflecting 
inhibition of bone marrow function(s) (i.e., thrombocytopenia) and activation of inflammatory 
cytokines when the inhibitory influence of ruxolitinib i s removed due to drug interruption or 
discontinuation. See (Verstovsek, 2010b) for complete details on INC424/ ruxolitinib clinical 
study findings. 
Fourteen patients discontinued study drug participation due to death, disease progression, 
unacceptable toxicity, or intercurrent illness. Four of 14 discontinuations were thought to be 
“possibly related to study drug, and included the following: (a) a 
 year -old 
 patient 
suffering from intracerebral hemorrhage without thrombocytopenia and associated death on day 
374 of study drug dosed at 25 mg PO BID; (b) 
 year -old 
 with disease progression to 
CMMoL (evidence of CMMoL at screening) on day 147 of 25 mg p.o. BID; (c) 
 year old 
 developed grade 3 thrombocytopenia on day 278 on 50 mg p.o. BID; an d (d) a 
 year-
old 
 developed grade 3 thrombocytopenia on day 57 on 50 mg p.o. BID. 


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During 2 or more years of follow-up, a number of patients discontinued study drug treatment 
including the following: withdrawal of consent, investigators decision to discontinue treatment, 
or other reasons (n = 24); progressive disease (n = 4); toxic effects (n = 2); intercurrent illness 
(n = 3), and death (n = 5). A total of 17 patients died during the follow -up period of which 5 
died on treatment, and 3 died within 30 days of study treatment discontinuation. 
 
Phase 1b study of ruxolitinib in patients with MF and baseline platelet counts 
between 50 x 109/L and less than or equal to 99 x 109/L 
A phase Ib study of ruxolitinib to investigate the safety of ruxolitinib and es tablish the 
maximum safe starting dose in patients with MF who have baseline platelet counts ≥ 50,000/µL 
to 99,000/µL is currently ongoing ( Gisslinger 2012). The (Evaluating Ruxolitinib in Patients 
with Low Baseline Platelet Counts Diagnosed With Myelofibrosis) study is a single-arm, open-
label, dose-finding study in adult patients with PMF, PET-MF, or PPV MF. This study consists 
of two periods: (a) core study period (day 1 to week 24), and (b) an extension period (beyond 
week 24). There are two different dosing strata based on baseline platelet counts (Stratum 1: 
75,000/µL to 99,000/µL starting dose is 5 mg BID; Stratum 2: 50,000/µL to 74,000/µL). A 
preliminary analysis based on an unplanned data cutoff d ate of May 16, 2012 was presented at 
the European Hematology Association meeting in June 2012. An updated analysis was 
presented at the American Society of Hematology meeting in December 2012 (Harrison 2012). 
The data (n=20; PMF n=14, PPV=MF n=5, PET-MF n=1) demonstrates that in this phase 1b 
study of ruxolitinib in thrombocytopenic patients with MF, no DLT has occurred at the first 2 
dose levels in patients with platelet counts of 50,000/µL to 99,000/µL. Ruxolitinib has been 
generally well tolerated, similar to the tolerability reported in the previous studies, and no 
patient has discontinued because of thrombocytopenia. No patient has had platelet counts below 
20,000/ µL. No Grade 3/4 hemorrhagic events were reported. Treatment with ruxolitinib led to 
spleen length reductions from baseline in 17 of 20 patients and three patients have experienced 
complete resolution of palpable splenomegaly as best response on study. 
 
Phase II study of ruxolitinib in patients with low baseline platelet counts (50 x 
109/L to 100 x 109/L) 
A 24-week, open-label phase II study of ruxolitinib to investigate the efficacy, hematologic 
effects and dose of ruxolitinib in patients with MF, PPV-MF, and PET-MF and baseline platelet 
counts of 50,000 to 100,000/ µL is ongoing (INCB018424 -258) (Talpaz 2012a). The starting 
dose of ruxolitinib is 5 mg p.o. BID with dose escalation with adequate platelet count by 5 mg 
once daily (i.e. 5 mg p.o. AM and 10 mg p.o.PM) every 4 weeks to a maximum of 10 mg BID. 
Further dose escalation requires evidence of suboptimal efficacy. An initial report with data 
from 41 evaluable patients was presented at the American Society of Hematology meeting in 
December 2012. Among patients who completed 24 weeks  of treatment, most were receiving 
ruxolitinib dose of 10 mg p.o. BID or higher. No patients have discontinued treatment due to 
adverse events. Bleeding related events were reported in 7 patients (17.1%). Grade 1 bruising 
events (contusion n=2 and ecchymosis n=3) were reported in 7 patients. Other bleeding events 
were reported in 4 patients (subdural hematoma secondary to fall, hematochezia, hemorrhoidal 
hemorrhage and epistaxis; all grade 1 except grade 2 


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hematochezia).Phase III ruxolitinib clinical trials (controlled MF study with oral JAK inhibitor 
treatment [COMFORT; (INCB 18424-351 and CINC424A2352)]) 
The results from two Phase III studies in myelofibrosis (COMFORT-I, COMFORT-II) 
demonstrate the effectiveness of ruxolitinib in patients with PMF, PPV-MF and PET-MF. The 
results of these two studies were consistent, demonstrating statistically significant (p < 0.0001) 
differences in rates of ≥35% spleen volume reduction compared with either placebo or an 
investigator’s selection of best available therapy (BAT). Although, the time point for the 
primary endpoint (spleen volume reductions) were different  in COMFORT-I (at Week 24)  
and COMFORT-II (at Week 28) the mean reduction in spleen volume is similar at Week 24 
(31.6% vs. 29.2%, COMFORT-I and COMFORT-II, respectively). 
The COMFORT-I trial is a randomized, double-blind, placebo-controlled Phase III study of the 
oral JAK1/JAK2 inhibitor ruxolitinib in 309 patients with PMF, PPV MF, or PET -MF. Patients 
from 89 sites in the USA, Canada and Australia were randomized 1:1 to receive either 
ruxolitinib (15 mg PO BID or 20 mg PO BID depending on baseline platelet count) or placebo. 
The primary endpoint of the study was the proportion of patients achieving ≥35% reduction in 
spleen volume from baseline to Week 24 as measured by MRI (or CT scan in applicable 
patients) and the secondary endpoints included: duration of maintenance of a ≥35% reduction 
from baseline in spleen volume among patients initially randomized to recei ve ruxolitinib, and 
the proportion of patients with ≥50% reduction in total symptom score from baseline to Week 
24 as measured by the modified MFSAF v2.0 diary. 
A total of 309 patients were enrolled in the study, with 155 randomized to ruxolitinib and 154 
to placebo. The groups were matched for baseline characteristics; the majority of patients had 
high-risk disease (61.2%). Patients were eligible to cross-over in this study, and 36 patients in 
the placebo group (23.4%) crossed over to ruxolitinib. The data cutoff date was 2-Nov-2010, 
the date of last patient last visit. 
Significantly more patients in the ruxolitinib group had a reduction in spleen volume ( ≥35%) 
at week 24 (41.9% vs. 0.7%; P<.0001). A reduction in spleen volume for ≥48 weeks was 
maintained in 67% patients who achieved a response on ruxolitinib. More patients receiving 
ruxolitinib had an improvement of ≥50% in the total symptom score at 24 weeks compared to 
placebo (45.9% vs. 5.3%, P<0.001). Patient’s receiving ruxolitinib also had improvements in 
each symptom assessed on the MF-SAF. Overall survival was a secondary endpoint of 
COMFORT-I. Ten deaths occurred in the ruxolitinib group vs. 14 deaths in the placebo group 
(hazard ratio, 0.67; 95% CI, 0.30 to 1.50; P = 0.33). A survival analysis based on a planned data 
cutoff with 4 additional months of follow-up (median follow-up, 51 weeks) revealed a 
significant survival advantage for patients who received ruxolitinib (13 deaths in the ruxolitinib 
group (8.4%) vs. 24 deaths in the placebo group (15. 6%) (Hazard ratio, 0.50; 95% 
confidence interval, 0.25 to 0.98; P = 0.04). 
Ruxolitinib was well tolerated in COMFORT-I, with most Grade 3/4 nonhematologic toxicities 
occurring in less than 6% patients: fatigue 5.2%, diarrhea 1.9%, dyspnea 1.3%, 
dizziness 0.6%, vomiting 0.6%, arthralgia 1.9%, pyrexia 0.6%, and abdominal pain 2.6% 
(Verstovsek 2012). Hematologic toxicity consisted primarily of anemia and thrombocytopenia. 
Grade 3/4 anemia occurred in 45.2% patients, Grade 3/4 thrombocytopenia occurred in 12.9% 
patients, and Grade 3/4 neutropenia occurred less frequently in 7.1% of patients. 


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Approximately half of the Grade 3/4 anemia and thrombocytopenia events occur during the 
first 8 weeks of therapy. Treatment with ruxolitinib enabled 41.2% to become transfusion 
independent. Anemia and thrombocytopenia was manageable, and thrombocytopenia generally 
responded to dose reduction or temporary dosing interruption. Thirteen deaths occurred in the 
ruxolitinib group vs. 24 deaths in the placebo group (HR, 0.50; 95% confidence interval, 0.25 
to 0.98; P = 0.04). The rate of discontinuation of the study drug because of AEs was 11.0% in 
the ruxolitinib group vs. 10.6% in the placebo group. 
The COMFORT-II study (Study INCB 18424-352) is an open-label, randomized, active- 
comparator trial that compared ruxolitinib therapy to best currently available therapy (BAT) 
[as determined by the investigator for each individual patient randomized to the control group] 
in 219 adult patients with PMF, PPV-MF or PET-MF. The control group therapy could also 
consist of no therapy (i.e., “watchful waiting”), or a combination of agents. COMFORT -II 
assessed the impact of therapy on spleen length; evaluated durability of response; and gave 
additional data on the long-term safety of ruxolitinib use. Patients were randomized in a 2:1 
ratio of ruxolitinib:BAT. At randomization, patients were stratified by IPSS prognostic 
category as having either two prognostic risk factors (intermediate -2 risk), or three or more 
prognostic risk factors (high risk). In COMFORT-II, the randomized treatment phase started 
on Study Day 1 and continued until the patient met defined criteria for disease progression. 
During this phase, all patients in both arms underwent an objective evaluation of spleen length 
using MRI or CT. The percentage of patients achieving a 35% reduction in spleen volume at 
48 weeks was the primary endpoint for efficacy. MRI was the primary modality of spleen 
length (volume) measurement. Patients who were not candidates for MRI (including at sites 
where MRI is unavailable) were evaluated with sequential CT. Spleen volume was assessed  
by a central reader. While investigators were able to follow spleen length by palpation, results 
of MRI (or CT) spleen volume assessments were only to be made known to the investigator if 
a patient had reached a protocol-defined criterion for disease progression based upon increase 
in spleen volume. Patients having reached this endpoint were eligible to continue study 
participation in the extension phase, and if originally randomized to the control group, could 
cross over to receive ruxolitinib if they met safety requirements. 
The rates of leukemic-free survival, progression-free survival, overall survival, and durability 
of response will be determined and compared between the randomized treatment groups, using 
data from both the randomized treatment phase and extension phase. Additional assessments 
will include analysis of JAK mutation status, cytokine levels, and change in symptoms as 
assessed by the EORTC QLQ-C30 and MFSAF v 2.0 questionnaires. 
In the COMFORT-II trial (Harrison 2012), 28% of the patients in the ruxolitinib group had 
≥35% reduction in spleen volume at week 48 vs. 0% in the BAT group (P < 0.0001); the 
corresponding percentages at week 24 were 32% and 0% ( P < 0.001). The mean palpable 
spleen length (48 weeks) had decreased by 56% with ruxolitinib but had increased by 4% with 
BAT. The median duration of response with ruxolitinib was not reached, with 80% of patients 
still having a response at a median follow-up of 12 months. Ruxolitinib treatment was 
associated with an improvement in overall quality-of-life measures and a reduction in 
symptoms associated with MF. The most common hematologic abnormalities (≥ Grade 3) were 
thrombocytopenia and anemia, which were managed with a dose reduction, interruption of 
treatment, or transfusion. One patient in each group discontinued treatment due to 


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thrombocytopenia, and none discontinued due to anemia. Non-hematologic AEs were rare and 
mostly grade 1 or 2. Two cases of AML were reported with the best available therapy. 
ruxolitinib was also well tolerated in the COMFORT-II trial, with most Grade 3/4 non- 
hematologic toxicities occurring in < 3% patients: diarrhea 1%, asthenia 1%, dyspnea 1%, 
pyrexia 2%, nausea 1%, arthralgia 1%, fatigue 1%, pain in extremity 1%, abdominal pain 3%, 
headache 1%, and back pain 2%. Thrombocytopenia and anemia occurred more frequently in 
the patients receiving ruxolitinib vs. BAT, although these events rarely led to treatment 
discontinuation (1 patient in each group discontinued the study due to thrombocytopenia) and 
were generally manageable with dose modifications, transfusions of packed red ce lls, or both. 
AEs leading to dose modification with ruxolitinib occurred in 41% patients. Only 5% of the 
patients receiving ruxolitinib required dose interruptions or reductions due to anemia and 1% 
due to neutropenia. 
When pooling the results of COMFORT-I and COMFORT-II to examine safety of ruxolitinib, 
the incidence of headache was more frequent in ruxolitinib-treated patients (13.6% vs. 6.0% on 
placebo and 5.5% on BAT). Most AEs of headache were Grade 1 or 2. Similarly, dizziness 
(12.0% vs. 6.6% on placebo and 6.8% on BAT) was more frequent in ruxolitinib-treated 
patients, again mostly Grade 1 or 2. When adjusted for patient -year exposure, the differences 
were still present for headache and dizziness. Weight increase was also more frequent in 
ruxolitinib-treated patients than in the control groups (9.6% vs. 1.3% on placebo and 1.4% on 
BAT). Although some of these patients had co-reported AEs of edema, many had a past medical 
history of weight loss and the weight gain usually gradually accumulated over the course of one 
year of treatment. The majority of weight gain AEs were Grade 1 and 2. It is worth noting that 
weight gain may be a beneficial effect in patients with MF, given the catabolic nature of the 
disease and the frequency of weight loss reported as a constitutional symptom. 
Other events with increased frequency in the ruxolitinib arms included bruising (2.6% vs. 1.3% 
on placebo in [COMFORT-I, INCB 18424-351] only), contusion (8.6% vs. 5.3% on placebo 
and 1.4% on BAT), urinary tract infection (7.3% vs. 4.6% on placebo and 2.7% on BAT), 
herpes zoster (4.0% vs. 0.7% on placebo and 0% on BAT) and flatulence (3.3% vs. 1.3% on 
placebo and 0% on BAT). Abdominal pain  was  more  frequent in the control groups than in 
the ruxolitinib group (43% on placebo and 13.7% on BAT vs. 12% on ruxolitinib), as were 
weight decrease (8.6% on placebo and 8.2% on BAT vs. 1% on ruxolitinib , early satiety (8.6% 
on placebo and 0% on BAT vs. 0.3% on ruxolitinib) and splenic infarction (6.0% on placebo 
and 0% on BAT vs. 1.0% on ruxolitinib). 
The most frequently occurring Grade 3 and 4 AEs regardless of study drug relationship were 
hematologic including anemia (14%) and thrombocytopenia (8%) (Source: 120 day safety 
update-Table 2.1-1.4 in [Investigator Brochure]). Non-hematologic Grade 3-4 AEs were 
infrequent and rarely reported more frequently than in the control arms. Two patients (0.7%) 
had febrile neutropenia. In general, the pattern of AEs was similar between the two ruxolitinib 
arms in both studies, although there were some differences in frequency for specific AEs. 
In the ruxolitinib-treated Phase III population, the overall frequency of AEs leading to study 
drug discontinuation was 11%. This frequency was similar across both studies. None of the AEs 
leading to discontinuation was reported in more than two patients in any group. In the 
ruxolitinib-treated Phase III population, the overall frequency of AEs requiring dose reduction 


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or interruption was 59.8%. This frequency was higher than in the control groups (placebo: 
27.2%, BAT: 15.1%). The most frequently reported AEs requiring dose reduction or 
interruption in ruxolitinib treated patients were thrombocytopenia (36.9%), platelet count 
decrease (7.6%) and anemia (5.6%). The high frequency for thrombocytopenia is due to 
protocol-mandated dose reductions and interruptions. Although there were no protocol 
specified guidelines for dose reductions secondary to anemia, some investigators chose to 
reduce a patient’s dose in the setting of anemia to minimize this particular cytopenia. The 
frequency of these AEs was higher than in the control groups. All other AEs requiring dose 
reduction or interruption occurred with a frequency of 1.3% or less in the ruxolitinib treated 
patients. There are no data from the use of ruxolitinib in pregnant women. Animal studies have 
shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was not observed in rats 
or rabbits; however, the exposure margins compared to the highest clinical dose were low and 
the results are therefore of limited relevance for humans.The potential risk for humans is 
unknown. As a precautionary measure, the use of ruxolitinib during pregnancy is 
contraindicated. Women of child-bearing potential should use effective contraception. 
The most frequently reported adverse drug reactions were thrombocytopenia and anemia. 
Hematological adverse reactions (any Common Terminology Criteria for Adverse Events 
[CTCAE] Grade) included anemia (82.4%), thrombocytopenia (69.8%) and  neutropenia  (16.6 
%). Anemia, thrombocytopenia and neutropenia are dose related effects. The three most 
frequent non-hematological adverse reactions were bruising (21.6%), dizziness (15.3%) and 
headache (14.0%). The three most frequent non-hematological laboratory abnormalities were 
raised alanine aminotransferase (27.2%), raised aspartate aminotransferase (18.6%) and 
hypercholesterolemia (16.9%). 
Long-term follow-up of 5 years in patients with MF in the COMFORT studies has shown safety 
and tolerability consistent with previous findings and no new safety signals ha ve emerged 
(Verstovsek 2016, Harrison 2016). 
 
2 
Rationale 
2.1 
Study rationale and purpose 
Ruxolitinib, a potent and selective inhibitor of JAK1 and JAK2 is indicated for treatment of 
disease-related splenomegaly or symptoms in adult patients with myelofibrosis (MF). 
Ruxolitinib effectively treats MF symptoms, spleen enlargement, and provides an overall 
survival benefit compared to placebo or best supportive care. Thrombocytopenia has been 
observed in patients with MF treated with ruxolitinib and is one of the key dose -limiting 
toxicity. Transient hemoglobin drops have also been observed in MF patients treated with 
ruxolitinib and typically reach a nadir between weeks 8 and 12, returning to levels close to 
baseline towards week 24. 
While anemia was adequately managed for patients to continue in the phase III trials by dose 
adjustments and supportive interventions instituted at Investigator’s discretion, the phase III 
study protocols did not define any specific dose modifications for patients with new onset or 
continuing anemia. Many events of Grade 3/4 anemia were treated with transfusions, therefore 
the proportion of patients receiving transfusions on study peaked around Week 12 of 


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treatment and then declined to levels similar to the control groups, mirroring the profile for 
Grade 3/4 anemia incidence (Verstovsek 2012). 
Anemia is one of the diagnostic criteria for myelofibrosis and a known adverse prognostic 
factor. In the International and Dynamic International Prognostic Scoring Systems, Hb levels 
of <100 g/L at the time of diagnosis and during the course of disease, respectively, have been 
shown to have a significant negative impact on overall survival (OS). However, both scoring 
systems were derived and validated prior to the availability of ruxolitinib; additional analyses 
from COMFORT studies characterized the effect of ruxolitinib treatment on the Hb dynamics 
and did assess its impact on OS (Al Ali 2016); consistent with validated prognostic models, 
baseline anemia was associated with decreased OS in the COMFORT studies. Treatment with 
ruxolitinib improved OS as compared with the control arm regardless of baseline anemia status. 
Notably, post baseline anemia that occurred on ruxolitinib therapy did not impact OS and was 
manageable with dose adjustments and RBC transfusions concluding that early onse t 
ruxolitinib-related anemia does not have the same deleterious effect as disease-related anemia. 
(Gupta 2015) 
Considering the typical hemoglobin level for many MF patients is already at the Grade 0/Grade 
1 border (hemoglobin of 10 g/dL), assessment of a dose regimen that might provide clinically 
meaningful symptomatic and spleen size reduction benefits of ruxolitinib while lessening the 
degree of worsening hemoglobin levels is warranted. 
Current label recommendation on starting doses in MF are 5, 15 or 20 mg BID, depending on 
platelet counts 50-100 × 109/L, 100-200 × 109/L or >200 × 109/L respectively, regardless of 
hemoglobin level at baseline. 
There is increasing literature suggesting the use of lower starting doses with up titrations 
depending on safety and efficacy in patients with anemia ( Tabarroki 2013, Cervantes 2014, 
Reilly 2014, Harrison 2013, Ho 2015). 
This multicenter phase II open label single arm study proposes to prospectively evalu ate a 
starting dose of ruxolitinib 10 mg BID for 12 weeks with subsequent up titrations of 15mg BID 
and 20 mg BID in anemic myelofibrosis patients defined as a baseline hemoglobin < 10 g/dL 
(Please see Figure 6-1 for details). The trial will evaluate if this alternative dosing approach 
achieves spleen reduction and symptom improvement to levels consistent with those reported 
in previous clinical trials but with an improved tolerability assessed by inciden ce of adverse 
events and transfusion requirements. 
 
2.2 
Rationale for the study design 
The COMFORT studies compared the effects of ruxolitinib with placebo or best available 
therapy, respectively and showed that ruxolitinib treatment significantly reduced splenomegaly 
and provided marked improvements in MF-related symptoms and quality-of- life (QOL) 
measures compared with controls, regardless of JAK2V617F mutational status. The clinical 
benefit and safety of ruxolitinib treatment in COMFORT -I and COMFORT-II have been 
maintained with subsequent longer-term follow-up. As anticipated, the effect of JAK2 
inhibition on hematopoiesis resulted in dose-dependent anemia and thrombocytopenia. The 
majority of these cytopenias occurred in the first 8 to 12 weeks of treatment, and they were 
generally manageable with dose reductions and/or red blood cell transfusions. 


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There is increasing literature suggesting the use of a 10 mg BID starting dose with subsequent 
up titrations depending on safety and efficacy in patients with anemia at the time of treatment 
initiation with ruxolitinib (Tabarroki 2013, Cervantes 2014, Reilly 2014, Harrison 2013, Ho 
2015). This dosing approach for anemic MF patients will be systematically studied in this 
prospective multicenter phase II open label single arm trial to determine if the levels of spleen 
length reduction and symptom improvement are consistent with those reported in previous 
clinical trials with ruxolitinib in patients with anemia and doses according to platelet counts at 
the moment of treatment initiation, and whether this lower starting dose and up titration 
approach may minimize the initial hemoglobin and platelet declines and transfusion 
requirements. The efficacy and safety of ruxolitinib with starting doses based on platelet counts 
in MF patients including those with anemia at baseline have been well studi ed and characterized 
in several clinical trials (COMFORT I, COMFORT II, JUMP). 
This is an open-label, single-arm study of treatment with ruxolitinib for 48 weeks in patients 
who presents with transfusion dependent or independent anemia at screening defined as an 
hemoglobin <10 g/dL. 
Ruxolitinib will be self-administered as BID oral treatment. The starting dose is 10 mg BID for 
all enrolled patients and gradual up titrations will start at week 12 determined by the level of 
efficacy achieved and the tolerability. 
 


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2.3 
Rationale for dose and regimen selection 
Phase I/II trials evaluated a number of different doses and schedules of ruxolitinib. Based on 
these, two phase III trials evaluated the efficacy and safety of ruxolitinib versus placebo in 
COMFORT I and versus BAT in COMFORT II in a population of patients with primary and 
secondary MF. In both phase III trials a starting dose of 20 mg orally BID wa s administered 
for patients with platelet counts from 200,000/ µL and a lower starting dose of 15 mg orally 
BID in patients with baseline platelet counts from 100,000 to 200,000/ µL. 
Additional studies generated clinical data on the efficacy and tolerability of ruxolitinib in 
patients with MF and platelet counts from 50,000 to 100,000/µL. A starting dose of 5 mg BID 
with subsequent optional up titrations every 4 weeks by dose increments of 5 mg OD was 
evaluated in a phase II open label single arm study INC B18424-258 in a population of patients 
with platelet counts from 50,000 to 100,000/µL. Similarly, an expanded access program and 
phase IIIb study CINC424A2401 (JUMP) that recruited more than 2200 patients allowed the 
inclusion of patients with low platelet counts (50,000 to 100,000/µL) to be treated with a 5 mg 
BID starting dose. 
Furthermore, a Phase Ib study (EXPAND) evaluating the safety and MTD of ruxolitinib in 
patients with lower baseline platelet counts (50,000– 100,000/µL) suggests that higher doses of 
ruxolitinib can be safely administered to patients with lower baseline platelet count. The 
maximum safe starting dose in this ongoing study was reported to be 15 mg BID for patients 
with platelet counts from 75,000 to 100,000/µL and 10 mg BID for patien ts with platelet counts 
from 50,000 to 75,000/µL. 
Anemia may be ameliorated by lowering the dose of ruxolitinib or by concomitant use of 
erythropoietin stimulating agents and/or anabolic steroids (Reilly 2014). This approach may 
make particular sense in patients with anemia at the moment of treatment initiation with 
ruxolitinib in order to avoid further hemoglobin decrease, the need of blood transfusions or have 
them more frequently in patients already receiving regular transfusions for anemia. 
An alternative strategy to start patients at 10 mg BID and titrate the dose up according to 
tolerability and response (Cervantes 2014, Harrison 2013) has anecdotally suggested improved 
tolerance and reduced adverse events yielding fewer treatment discontinuations and has been 
already included in treatment guidelines (Ho 2015, Reilly 2014). 
Based on the above, a starting dose of 10 mg BID will be assigned to patients recruited in this 
phase II open label single arm study followed by gra dual up titrations starting at week 12, based 
on efficacy and safety at the different evaluation visits. This approach assumes that starting at 
a lower dose may impact the rate of the initial hemoglobin decline and the nadir, by decreasing 
the level of JAK-mediated inhibition of hematopoiesis. 
 
2.4 
Rationale for choice of combination drugs 
Not Applicable. 
 
2.5 
Rationale for choice of comparators drugs 
Not applicable. 


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2.6 
Risks and benefits 
The primary clinical risks with ruxolitinib treatment are the potential consequ ences of 
decreased hematopoietic proliferation secondary to the inhibition of growth factor pathways 
associated with JAK2 inhibition. Dose-dependent, reversible thrombocytopenia has been 
observed in patients with MF and represents the DLT. Anemia and, less frequently, neutropenia 
have also been observed in patients with MF treated with ruxolitinib. Increased rates of infection 
and anemia are potential risks of myelosuppression, and there are other consequences of anemia 
including the burden and risks of transfusion. 
Of note, the dosing approach proposed in this study may decrease the risk of patients developing 
cytopenias compared to the standard dose approach utilized in the two phase III pivotal studies. 
A dose escalation starting at week 12 aims to achieve a maintenance dose for each patient that 
maximizes the benefits from ruxolitinib while keeping the treatment well tolerated. The main 
potential benefit of the proposed dosing approach in the study resides in achieving similar levels 
of efficacy seen in previous clinical trial experiences with an improved safety and tolerability 
profile expressed by lower rates of cytopenias and transfusion requirements. 
Appropriate eligibility criteria, as well as specific dose modification and stopping rules, are 
included in this protocol. The risk to patients in this trial may be minimized by compliance with 
the eligibility criteria and study procedures, as well as and close clinical monitoring. There may 
be unforeseen risks with ruxolitinib which could be serious. Please refer to the latest 
[Investigator Brochure]. 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
Refer to Section 10.4 
To determine the spleen length response rate at 
week 24. 
Proportion of patients achieving a 50% reduction in spleen length at week 
24. 
Secondary 
Refer to Section 10.5.1 
To evaluate safety. 
Safety will be assessed by 
• 
Frequency and severity of adverse events and serious adverse events 
and AEs leading to discontinuations. 
• 
Changes in hematology/biochemistry parameters over time. 
To determine the spleen length response rate at 
week 48. 
To evaluate the effect of ruxolitinib on spleen 
length. 
Proportion of patients achieving a 50% reduction in spleen length at week 
48. 
Percent change from baseline in spleen length over time. 
To evaluate the effect of ruxolitinib on symptoms. 
Summary of the Modified MFSAF v2.0 and MF-7 over time. 
To evaluate the effect of ruxolitinib on Patient 
Global Impression of Change (PGIC). 
To evaluate the effect of ruxolitinib on transfusion 
requirements. 
PGIC at each visit where measured. 
 
Summary of transfusions over time. 
For Transfusion Dependent (TD)* patients, the following will be analyzed: 
• 
Transfusion independence (TI) rate (requiring no transfusion for ≥12 
weeks at any time). 
• 
Transfusion response rate (not TD: having 5 or less transfusion for 
≥12 weeks at any time). 


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related parameters 
and serum iron. 


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4 
Study design 
4.1 
Description of study design 
This is a multicenter phase II, open label, single arm study to assess the efficacy and safety of 
ruxolitinib in patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera- 
Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) who 
have splenomegaly that is equal to or greater than 5 cm below the left costal margin and with 
anemia defined by Hb less than 10 g/dL. 
The target number of patients for this trial is 50. 
 
Screening 
Screening evaluations should be performed to determine the eligibility for the study and 
establish a baseline prior to dosing, and should be conducted between Day -28 and Day -1. 
However platelet and hemoglobin counts should be performed within a maximum of 7 days 
from the first dose of ruxolitinib. See Section 7 for complete screening and assessment details. 
 
Treatment Period 
All patients who consent to study participation will start treatment with ruxolitinib upon 
meeting all study eligibility criteria and none of the exclusion criteria. The treatment period 
commences on Day 1 (day of first dose of study drug). Patients will have study visits at Day 1 
and at Weeks 4, 8, 12, 16, 20, 24, and every 12 weeks thereafter. 
Patients will be treated with ruxolitinib 10 mg BID for the first 12 weeks and up titrations 
thereafter. See Section 6.1.1 for details. 
Patients will receive treatment on this trial as long as they benefit from it until 48 weeks after 
Last Patient First Treatment date. 
 
End of Study Treatment (EoT) 
Patients may be discontinued from treatment with the study drug earlier due to unacceptable 
toxicity, disease progression and/or at the discretion of the investigator or the patient. 
Patients who in the opinion of the investigator are still deriving clinical benefit from ruxolitinib 
may continue treatment with commercial ruxolitinib according to local regulations in countries 
with commercially available ruxolitinib. 
Should ruxolitinib not be available to patients commercially after the end of treatment visit, 
every effort will be made to continue provision of ruxolitinib off study. Novartis will have a 
transition plan in place to ensure that patients have access to ruxolitinib without delays to 
treatment. 


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Safety Follow up period 
The safety follow up period is 30 days after the last dose of study treatment. All patients must 
have safety evaluations for 30 days, after the last dose of study treatment. Data collected should 
be added to the Adverse Events CRF and the Concomitant Medications CRF. 
 
4.2 
Timing of interim analyses and design adaptations 
Not applicable. 
 
4.3 
Definition of end of study 
The end of the study (last patient last visit) will occur after completion of the last follow up visit 
of the last patient on treatment with ruxolitinib. 
Patients who in the opinion of the investigator are still deriving clinical benefit from ruxolitinib 
may continue treatment with commercial ruxolitinib according to local regulations in countries 
with commercially available ruxolitinib. 
Should ruxolitinib not be available to patients commercially after the end of treatment visit, 
every effort will be made to continue provision of ruxolitinib off study. Novartis will have a 
transition plan in place to ensure that patients have access to ruxolitinib without delays to 
treatment. 
 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the patient’s interests. The investigator will be responsible for 
informing IRBs and/or ECs of the early termination of the trial. 
 
5 
Population 
5.1 
Patient population 
Adult Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF), or 
Post-Essential Thrombocythemia Myelofibrosis (PET-MF) patients with splenomegaly at 
baseline that is equal to or greater than 5 cm below the left costal margin and with anemia at 
baseline defined by Hb less than 10 g/dL will be eligible to participate in this trial. 
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 


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Written informed consent must be obtained prior to any screening procedures. 
1. Male or female patients aged ≥ 18 years of age. 
2. Patients must be diagnosed with PMF, according to the 2016 revised International 
Standard Criteria (Arber et al. 2016), PPV MF or PET-MF (Barosi 2008), irrespective of 
JAK2 mutation status. 
3. Patients with palpable splenomegaly that is equal to or greater than 5 cm below the left 
costal margin. 
4. Patients with a hemoglobin less than 10 g/dL 
5. Patients with a history of transfusions must have a documented transfusion record in the 
previous 12 weeks to baseline. 
6. Patients with an ECOG performance status of 0, 1, or 2. 
7. Patients with a peripheral blood blast percentage count of < 10%. 
8. Patients must have recovered or stabilized sufficiently from any adverse drug reactions 
associated with prior treatments before beginning treatment with ruxolitinib. 
 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients with prior treatment with any JAK1 or JAK2 inhibitor. 
2. Patients with known hypersensitivity to ruxolitinib or other JAK1/JAK2 inhibitors, or to 
their excipients. 
3. Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a 
suitable donor is available). 
4. Patients with inadequate bone marrow reserve at baseline as demonstrated by at least one 
of the following: 
a. ANC that is ≤ 1,000/µL. 
b. Platelet count that is <50,000/µL without the assistance of growth factors, 
thrombopoietic factors or platelet transfusions. 
c. Hemoglobin count that is ≤ 6.5 g/dL despite transfusions. 
5. Patients with severely impaired renal function defined by: 
Creatinine clearance less than 30 mL/min. 
6. Patients with inadequate liver function defined by any of these: 
a. Total bilirubin ≥ 2.5 x ULN and subsequent determination of direct bilirubin ≥ 2.5 x 
ULN; 
b. Alanine aminotransferase (ALT) > 2.5 x ULN; 
c. Aspartate aminotransferase (AST) > 2.5 x ULN. 
7. Patients being treated concurrently with a strong (potent) systemic inhibitor or inducer of 
CYP3A4 at the time of Screening. 
8. Presence of active bacterial, fungal, parasitic, or viral infection which requires therapy. 
9. Known history of human immunodeficiency virus (HIV) infection or other 
immunodeficiency syndromes such as X-linked agammaglobulinemia and common 
variable immune deficiency. 


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10. Acute viral hepatitis or active chronic hepatitis B or C infection. Patients with inactive 
chronic infection (without viral replication) can be enrolled (See Section 7.2.2.7) 
11. History of progressive multifocal leuko-encephalopathy (PML). 
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of ruxolitinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, small bowel resection). 
13. History or current diagnosis of uncontrolled or significant cardiac disease, including any 
of the following: 
a. Myocardial infarction within last 6 months 
b. Uncontrolled congestive heart failure 
c. Unstable angina within last 6 months 
d. Clinically significant (symptomatic) cardiac arrhythmias (e.g. bradyarrhythmias, 
sustained ventricular tachycardia, and clinically significant second or third degree AV 
block without a pacemaker) 
14. Significant concurrent, uncontrolled medical condition which, in the investigator’s opinion, 
would jeopardize the safety of the patient or compliance with the protocol. 
15. Patients undergoing treatment with another investigational medication or having been 
treated with an investigational medication within 30 days or 5 half-lives (whichever is 
longer) prior to the first dose of study drug. 
16. Patients with a history of malignancy in the past 3 years, except for treated early stage 
squamous or basal cell carcinoma. 
17. Patients who are unable to comprehend or are unwilling to sign an ICF. 
18. Pregnant or nursing (lactating) women 
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
throughout the study duration inclusive of 30 day safety follow up. Highly effective 
contraception methods include: 
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
c. Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that patient. 
d. Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception (in case of oral contraception you 
should have been using the same pill on a stable dose for a minimum of 3 months 
before screening) 


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Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow up hormone level assessment is she 
considered not of child bearing potential. 
 
6 
Treatment 
6.1 
Study treatment 
INC424 (ruxolitinib) tablets will be the only investigational drug in this study. 
 
6.1.1 
Dosing regimen 
 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen 
INC424/ruxolitinib 
5mg Tablet for oral use 
Starting dose 10 mg bid (2 tablets 
of INC424 5mg, approximately 12 
hours apart: morning and night), 
to be increased or decreased per 
standardized dosing paradigm 
and not to exceed 25 mg bid. 
Twice Daily 
(BID),unless 
instructed to 
temporarily withhold 
dosing for safety 
 
INC424 (ruxolitinib) 10 mg BID (2 tablets of INC424 5mg) will be self-administered as starting 
dose for treatment of anemic MF patients. This dose will be maintained for the first  12 weeks 
and titrated up thereafter unless they have met criteria for dose hold or dose reduction. 
Ruxolitinib should be taken orally, approximately 12 hours apart (morning and night) without 
regards to food. Ruxolitinib will be self-administered by the patient in an outpatient setting, and 
each investigator should instruct the patient to take the study drug as per protocol. All dosages 
prescribed and dispensed to the patient and all dose changes during the study must be recorded 
on the appropriate case report form (CRF). 
 
6.1.2 
Ancillary treatments 
Not applicable. 
 
6.1.3 
Rescue medication 
Not applicable. 
 
6.1.4 
Guidelines for continuation of treatment 
See Section 6.3 


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6.1.5 
Treatment duration 
The planned minimum duration of treatment is 48 weeks. Patients may be discontinued from 
treatment with the study drug earlier due to unacceptable toxicity, disease progression and/or 
treatment is discontinued at the discretion of the investigator or the patient. 
 
6.2 
Dose escalation guidelines 
6.2.1 
Starting dose rationale 
Phase I/II trials evaluated a number of different doses and schedules of ruxolitinib. Based on 
these, two phase III trials evaluated the efficacy and safety of ruxolitinib versus placebo in 
COMFORT I and versus BAT in COMFORT II in a population of patients with primary and 
secondary MF. In both phase III trials a starting dose of 20 mg orally BID was administered for 
patients with platelet counts from 200,000/ µL and a lower starting dose of 15 mg orally BID 
in patients with baseline platelet counts from 100,000 to 200,000/ µL. 
Additional studies generated clinical data on the efficacy and tolerability of ruxolitinib in 
patients with MF and platelet counts from 50,000 to 100,000/µL. A starting dose of 5 mg BID 
with subsequent optional up titrations every 4 weeks by dose increments of 5 mg OD was 
evaluated in a phase II open label single arm study INCB18424-258 in a population of patients 
with platelet counts from 50,000 to 100,000/µL. Similarly, an expanded access program and 
phase IIIb study CINC424A2401 that recruited more than 2200 patients allowed the inclusion 
of patients with low platelet counts (50,000 to 100,000/µL) to be treated with a 5 mg BID 
starting dose. 
Furthermore, a Phase Ib study (EXPAND) evaluating the safety and MTD of ruxolitinib in 
patients with lower baseline platelet counts (50,000– 100,000/µL) suggests that higher doses of 
ruxolitinib can be safely administered to patients with lower baseline platelet count. The 
maximum safe starting dose in this ongoing study was reported to be 15 mg BID for patients 
with platelet counts from 75,000 to 100,000/µL and 10 mg BID for patients with platelet counts 
from 50,000 to 75,000/µL. 
Anemia may be ameliorated by lowering the dose of ruxolitinib or by concomitant use of 
erythropoietin stimulating agents and/or anabolic steroids (Reilly 2014). This approach may 
make particular sense in patients with anemia at the moment of treatment initiation with 
ruxolitinib in order to avoid further hemoglobin decrease, the need of blood transfusions or have 
them more frequently in patients already receiving regular transfusions for anemia. 
An alternative strategy to start patients at 10 mg BID and titrate the dose up according to 
tolerability and response (Cervantes 2014, Harrison 2013) has anecdotally suggested improved 
tolerance and reduced adverse events yielding fewer treatment discontinuations and has been 
already included in treatment guidelines (Ho 2015, Reilly 2014). 
Based on the above, a starting dose of 10 mg BID will be assigned to patients recruited in this 
phase II open label single arm study followed by gradual up titrations starting at week 12, based 
on efficacy and safety at the different evaluation visits. This approach assumes that starting at 
a lower dose may impact the rate of the initial hemoglobin decline and the nadir, by decreasing 
the level of JAK-mediated inhibition of hematopoiesis. 


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6.2.2 
Provisional dose levels 
Not Applicable. 
 
6.2.3 
Guidelines for dose escalations 
Dose up titrations will be based on efficacy and platelet counts provided that ANC is >500 µL 
and Hb level is ≥ 6.5 g/dL as follows: 
• A dose of 15 mg BID should be targeted in patients with platelet count ≥ 100 x 109/L and 
≤ 200 x 109/L from week 12. This dose increase is optional for patients that achieved a ≥ 
50% reduction in spleen length at this visit relative to Baseline. 
• A dose of 20 mg BID should be targeted in patients with platelet count ≥ 200 x 109/L from 
week 16. This dose increase is optional for patients that achieved a ≥ 50% reduction in 
spleen length at this visit relative to Baseline. 
• Maximum dose allowed in the study is 25 mg BID and may be used from Week 20 in 
patients that did not achieve a 50% reduction in spleen length relative to Baseline and 
provided that platelet count is ≥ 200 x 109/L at this visit. 
• Patients who did not qualify for a dose increase at Week 12, may qualify for an increase at 
week 16 (from 10 mg BID to 15 mg BID). In that case, the Week 12 dose increase rules 
will apply. Similarly, patients who did not qualify for a dose increase at Week 16, may 
qualify for an increase later (from 15 mg BID to 20 mg BID). In that case, the Week 16 
dose increase rules will apply. 


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Figure 6-1 
Dosing Up-titration Diagram 


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6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment. These dose changes must be recorded on the Dosage Administration Record 
CRF. 
 
6.3.1.1 
Dose modification for hematologic toxicity 
For all patients who receive ruxolitinib, there are mandatory dose decreases or dose 
interruptions for declining platelet counts, hemoglobin or ANC levels that might be observed 
while on ruxolitinib therapy. Deviations to mandatory dose interruptions and/or reductions are 
not allowed. 
Doses may be titrated based on safety. Dosing must be held if platelet counts decline below 
25,000/µL or if ANC that is ≤ 500/µL or Hemoglobin is ≤ 6.5 g/dL despite transfusions, while 
receiving ruxolitinib. 
After dose interruption, when blood counts recover, dosing must be restarted at 5 mg twice daily 
and gradually increased based on careful monitoring of blood cell counts. 
 
Table 6-2 
Dose modifications for hematologic toxicity 
The instructions provided in this table and the criteria for dose reduction / interruption are used 
to determine a protocol deviation. 
Hematology Value at time of 
decline: 
Dose at the time of decline 
25 mg BID 
20 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
Dose reduction to 
Platelet < 125,000 /µL 
20 mg BID 
20 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
Platelet < 100,000 /µL 
15 mg BID 
15 mg BID 
15 mg BID 
10 mg BID 
5 mg BID 
Platelet < 75,000 /µL 
10 mg BID 
10 mg BID 
10 mg BID 
10 mg BID 
5 mg BID 
Platelet < 50,000 /µL 
5 mg BID 
5 mg BID 
5 mg BID 
5 mg BID 
5 mg BID 
Platelet < 25,000 /µL 
Treatment must be interrupted. 
Hemoglobin ≤ 6.5 g/dL despite 
transfusions 
Treatment must be interrupted. 
Absolute neutrophil count < 0.5 
x 109/L 
Treatment must be interrupted. 
 
6.3.1.2 
Dose modification for renal impairment 
No specific dose adjustment is needed in patients with mild or moderate renal impairment. 
Patients diagnosed with severe renal impairment while receiving ruxolitinib should be carefully 
monitored and need to have their doses reduced to avoid adverse drug reactions (ADRs). 


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6.3.1.3 
Dose modification for hepatic impairment 
Patients diagnosed with hepatic impairment while receiving ruxolitinib should be carefully 
monitored and may need to have their dose reduced to avoid adverse drug reactions. 
Patients diagnosed with hepatic impairment while receiving ruxolitinib should have complete 
blood counts, including a white blood cell count differential (neutrophils, lymphocytes, 
eosinophils, basophils, monocytes, and blast cells), monitored at least every one to two weeks 
for the first 6 weeks after initiation of therapy with ruxolitinib and as clinically indicated 
thereafter once their liver function and blood counts have been stabilized. ruxolitinib dose can 
be titrated to reduce the risk of cytopenia. 
 
6.3.1.4 
Dose reduction for non-hematological safety 
Although study guidelines provide for dose reduction/interruption for the management of 
hematologic or non-hematologic toxicities that occur during the course of the study, the 
investigator should determine whether permanent discontinuation of study drug is necessary. 
 
6.3.2 
Optional dose tapering strategy in the event of study drug 
discontinuation 
Following interruption or discontinuation of ruxolitinib, symptoms of myelofibrosis may return 
over a period of approximately one week. There have been cases of patients discontinuing 
ruxolitinib who sustained more severe events, particularly in the presence of acute intercurrent 
illness. It has not been established whether abrupt discontinuation of ruxolitinib contributed to 
these events. Unless abrupt discontinuation is required, gradual tapering of the dose of 
ruxolitinib may be considered, although the utility of the tapering is unproven. 
When a decision is made to permanently discontinue ruxolitinib therapy for reasons other than 
low platelet counts or ANC levels, a dose tapering strategy may be considered, based on 
evaluation of the condition of the patient, current dosing regimen, and the clinical judgment of 
the investigator. If considered to be medically necessary, the investigator may use any treatment 
to manage withdrawal from ruxolitinib including a gradual tapering of the study drug dosage or 
use of other medications to manage adverse drug reactions of discontinuation. Short-term 
courses of corticosteroids have been used to moderate the withdrawal of ruxolitinib and may be 
considered as part of a tapering strategy. Corticosteroids may be started prior to, or concurrent 
with, ruxolitinib tapering. When a decision has been made to discontinue the patient with 
utilization of a tapering strategy, regardless of the use of concomitant medications, safety data 
will continue to be assessed in accordance with the protocol until the end of ruxolitinib 
administration and in the event of an AE through resolution of the AE. 
 
6.3.3 
Dose interruption and discontinuation of study drug 
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of 
adverse drug reaction that may have an unclear relationship to study drug. Except in cases of 
emergency or for protocol mandated holds for ANC, hemoglobin or platelet count, it is 


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recommended that the investigator consult with the Sponsor medical monitor (or other 
representative of the Sponsor) before temporarily interrupting therapy. 
Study drug may be held by the investigator at any time if there is concern about patient safety, 
and for all aspects of the conduct of the protocol the safety of the individual patient is 
paramount. Treating investigators may employ any means necessary to ensure patient safety, 
particularly in medical circumstances not anticipated by this protocol. Dosing must be halted 
immediately if any of the following occur: 
• Platelet counts fall below 25,000/µL 
• ANC levels fall below 500/µL 
• Hemoglobin cannot be maintained ≥6.5 g/dL despite the use of transfusion therapy 
Dosing may be reinstated following dose holding as detailed in Section 6.3.6. In order to provide 
sufficient data to make the dose adjustment decisions, it is recommended that hematology 
parameters be obtained at least weekly for platelet count < 100,000/µL or ANC < 1000/µL and 
at least two times weekly for platelet count < 50,000/µL or ANC < 500/µL. (Note: patients with 
platelet counts of < 10,000/µL should be hospitalized, unless local or national practice does not 
permit it). 
If a patient on a dose-hold requires frequent testing for safety parameters, these tests may be 
performed at a local laboratory. If the study drug is interrupted for any reason for more than 8 
weeks, dosing may not be restarted, except in the case of splenectomy, for which a maximum 
12 week period of study drug interruption is permitted. Although study guidelines provide for 
dose reduction/interruption for the management of hematologic or non-hematologic toxicities 
that occur during the course of the study, the following guidelines should be used to determine 
whether permanent discontinuation of study drug is necessary. 
 
6.3.4 
Discontinuation of study drug for hematologic toxicity: 
Study drug MUST be permanently discontinued if the lowest allowed dose (5 mg BID or 5 
mg QD with concomitant CYP3A4 inhibitor) is not tolerated due to the following: 
• Platelets cannot be maintained ≥ 25,000/µL. 
• Absolute neutrophil count cannot be maintained ≥500/µL. 
• Hemoglobin cannot be maintained ≥6.5 g/dL despite the use of transfusion therapy. 
In the event that any patient permanently discontinues the study drug, regardless of reason, 
reasonable efforts should be made to have the patient return for an early termination visit and 
have the End of Treatment evaluations and Safety Follow up evaluations completed. 
The date the patient discontinued the study drug and the specific reason for discontinuation will 
be recorded in the eCRF. This will include reasons such as discontinued due to disease 
worsening or withdrawn due to adverse event. This information will be used to summarize the 
reasons for study withdrawal. 
 
6.3.5 
Restarting or reinstituting previous dose 
Dosing of ruxolitinib may be restarted or increased following recovery of platelet counts 
and/or ANC to acceptable levels as illustrated in Table 6-3. The objective for restarting or 


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escalating after a reduction for safety is to find the highest safe dose of ruxolitinib for each 
patient, with increases in dose generally not more than in increments of 5 mg BID and not more 
often than every 2 weeks. Similarly, ANC levels that decline to < 500/µL necessitate immediate 
dose interruption (Section 6.3.1.1). ANC level recovery to 500 /µL and above but less than 
750/µL will allow dosing to be restarted at 5 mg BID, and ANC levels between 750/µL, but < 
1000/µL may restart at 10 mg BID. Absolute neutrophil count level increases to above 1000/µL 
will allow a further dose increase. 
After restarting using the guidelines in Table 6-3, if it is found that a patient cannot tolerate the 
lowest allowed dose (5mg BID, or 5mg QD with concomitant CYP3A4 inhibitor, see Section 
6.4.2) without platelets falling below 25,000/µL, neutrophils falling below 500/µL, or Hgb 
falling below 6.5g/dL despite the use of transfusion therapy, drug must be permanently 
discontinued (Section 6.3.1.1). 
 
Table 6-3 
Restarting or reinstituting previous ruxolitinib dose after safety 
interruptions or dose reductions 
 
Current Platelet Count after 
interruption or reduction 
Maximum Dose for Restarting or reinstituting previous dose after 
interruption or reduction 
< 25,000/µL 
Continue hold 
25,000/µL to < 50,000/µL 
5 mg BID 
50,000/µL to < 75,000/µL 
10 mg BID 
75,000/µL to < 125,000/µL 
15 mg BID 
≥125,000/µL 
20 mg BID 
Current ANC Level after 
interruption or reduction 
Dose Restart or Dose Increase Guidelines 
< 500/µL 
Continue hold 
500 to < 750/µL 
5 mg BID for at least 2 weeks; if stable, may increase to 10 mg BID 
750 to < 1000/µL 
10 mg BID for at least 2 weeks; if stable, may increase to 15 mg BID 
1000 to < 1500/µL 
15 mg BID for at least 2 weeks; if stable may increase to 20 mg BID 
≥1500/µL 
20 mg BID 
NOTE: Whether the dose interruption occurred because of neutropenia, thrombocytopenia or both, when 
restarting, both the platelet count and ANC must be considered to determine the restart dose, with the lower 
calculated dose being used. 
 
6.3.6 
Treatment of investigational drug overdose 
There is no known antidote for ruxolitinib overdose. Overdose will be defined as the use of 
ruxolitinib in doses in excess of that specified in the protocol. . Patients overdosed should be 
treated with appropriate supportive care until recovery. Use of ruxolitinib in doses in excess  of 
that specified in the protocol should not be recorded in the eCRFs as an AE of ‘Overdose’. An 
overdose with associated SAEs should be recorded as the SAE diagnosis/symptoms on the 
relevant AE and SAE forms in the eCRFs. An overdose with associated non-serious AEs should 
be recorded as the AE diagnosis/symptoms on the relevant AE forms in the eCRFs. An overdose 
without associated symptoms should not be recorded as an AE in the eCRFs. 


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6.4 
Concomitant medications 
All concomitant medications and treatments must be recorded on the appropriate eCRF. Any 
prior medication received up to 30 days prior to the first dose of study drug will be recorded in 
the CRF. All prior medications used to treat myelofibrosis will be recorded. 
Patients will be instructed not to take any additional medications (including over-the-counter 
products) during the course of the study without consultation with the investigator. 
 
6.4.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. At each visit, the patient must be asked about any new 
medications he/she is or has taken. All medications (other than study drug) and significant non-
drug therapies (including physical therapy, herbal/natural medications and blood transfusions) 
administered during the study must be listed on the appropriate CRF. 
All medications taken ≤ 30 days prior to study entry should be recorded on the appropriate Case 
Report Form (eCRF). All prior medications used to treat PMF, PPV MF, or PET-MF  will be 
recorded. All concomitant treatments during the trial will also be recorded in the eCRF. 
The following restrictions apply during the study: 
• No other investigational therapy should be given to patients. 
• No anticancer agents other than the study medication (ruxolitinib) should be given to 
patients until disease progression or withdrawal from the study. If such agents are required 
for a patient then the patient must first be withdrawn from the study. 
 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
The following medications have restrictions on use, dose, or require changes to the way in 
which ruxolitinib is administered during the study: 
• In patients for whom warfarin or heparin use will be initiated, the degree of 
thrombocytopenia should be considered, coagulation parameters monitored, and dose of 
anticoagulant adjusted accordingly. If anticoagulation is required during ruxolitinib 
administration, low molecular weight heparin is preferred, particularly in patients who are: 
elderly, history of CHF, diabetic, hepatic or renal disease, or atrial fibrillation (first 
episode). 
• Low dose aspirin (≤150 mg/day) and non-steroidal anti-inflammatory agents 
(acetaminophen, ibuprofen) may be used. Aspirin doses > 150 mg are prohibited. 
• Inducers or inhibitors of the metabolizing enzyme CYP3A4 (Appendix 5) 
• When concomitant administration of a strong (potent) inhibitor of CYP3A4 metabolizing 
enzymes or dual CYP2C9/CYP3A4 inhibitors (Appendix 5) is required for patient 
management, the dose of ruxolitinib tablets must be reduced by approximately 50% to be 
administered twice daily by decreasing the twice daily dose or by decreasing the 
frequency of dosing to the corresponding once daily dose when twice daily dose is not 
practical.. 
• Note: No dose adjustment of ruxolitinib is needed for use with topical ketoconazole. 


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• Note: More frequent monitoring of hematology parameters and clinical signs and 
symptoms of ruxolitinib related adverse reactions is recommended upon initiation of a 
strong (potent) CYP3A4 inhibitor. 
• No dose adjustment will be made when moderate systemic CYP3A4 inducers (Appendix 5) 
are co-administered with study treatment. 
• Granulocyte growth factors are not allowed while study treatment is being administered 
but may be used for severe neutropenia at the Investigator’s discretion while study 
medication is being withheld. 
• Certain herbal supplements see Appendix 5 are prohibited. Because the composition, 
pharmacokinetics and metabolism of many herbal supplements are unknown, the 
concurrent use of all herbal supplements is strongly discouraged during the study however 
if used during the trial please ensure the treatment is entered on the proper eCRF page (see 
Section 6.4.1). 
 
6.4.3 
Prohibited concomitant therapy 
The following medications are prohibited during the study until treatment discontinuation: 
• Concomitant use of another JAK inhibitor. 
• Any investigational medication (other than ruxolitinib) that is not approved for any 
indication. Use of such medications within 30 days or 5 half-lives, whichever is longer, 
prior to the first dose of study drug and until treatment discontinuation is prohibited. 
• Use of hydroxyurea, interferon, thalidomide, busulfan, lenalidomide, or anagrelide is not 
permitted at any time during participation in the study. These medications should be 
discontinued prior to Day 1 of ruxolitinib therapy. All adverse events attributed to these 
medications should be resolved prior to Day 1 of ruxolitinib treatment. 
• Potent inducers of CYP3A4 (Appendix 5) are not permitted. 
• Aspirin in doses exceeding 150 mg per day is prohibited. 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) 
Not applicable. 
 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Subject No. 
available to the investigator through the Oracle Clinical RDC interface. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT.  Once assigned, the Subject No. must 


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not be reused for any other patient and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to start treatment for any reason, the reason 
will be entered into the Screening Disposition page. 
IRT must be notified within 2 days that the patient fails to start treatment. 
 
6.5.2 
Treatment assignment or randomization 
The investigational treatment ruxolitinib will be provided to all participants and no 
randomization processes will apply. 
 
6.5.3 
Treatment blinding 
All study participants will receive single arm study medication, therefore blinding is not 
applicable. 
 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF. 
 
6.6.1 
Study treatment packaging and labeling 
Study treatment, ruxolitinib, will be provided as global clinical open supply and will be packed 
and labeled under the responsibility of Novartis, Drug Supply Management. 
Study treatment labels will be in the local language and comply with the legal requirements of 
each country, and will include storage conditions, a unique medication number  (corresponding 
to study treatment and strength) but no information about the patient. 
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label. 
Responsible site personnel will identify the study treatment package(s) to dispense by the 
medication number(s) assigned by IRT to the patient. Site personnel will add the patient number 
on the label. The label has 2-parts (base plus tear-off label), immediately before dispensing the 
package to the patient, site personnel will detach the outer part of the label from the package 
and affix it to the patient’s source document (Drug Label Form) for that patient’s unique patient 
number. 
 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment ruxolitinib should be stored 
according to the instructions specified on the drug labels and in the [Investigator’s Brochure]. 


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6.6.3 
Study drug compliance and accountability 
 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. 
Patients will be asked to return all unused study treatment and packaging on a regular basis, at 
the end of the study or at the time of study treatment discontinuation. Compliance will be 
assessed by the investigator and/or study personnel at each patient visit and information 
provided by the patient and/or caregiver will be captured in the Drug Accountability Form. This 
information must be captured in the source document at each patient visit. 
• All doses taken by the patient and all dose changes or interruptions during the study must 
be recorded on the DAR eCRF. 
• The investigator or his/her designee must keep documentation (overall drug accountability 
for the study as well as individual study drug accountability for each patient) of tablets 
administered, tablets used, dose changes, and dates dispensed. 
• Drug accountability will be monitored by the field monitor during site visits and at the 
completion of the study. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
 
6.6.3.3 
Handling of other study treatment 
Not applicable. 
 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate 
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. No CRF will be used as a source document. 


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Table 7-1 
Visit evaluation schedule 
 
Evaluation 
Category 
Protocol 
Section 
Screening 
Day 1 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 36 
Week 48 
Every 12 
weeks 
thereafter (wk 
60, 72, 84, etc) 
End of study 
treatment 
(EoT) 
30 Day Safety 
Follow up 
Day of Visit 
-28 to -1 
1 
28 
56 
84 
112 
140 
168 
252 
336 
420, 504, 
598, etc., 
- 
Visit Windows 
+/- 7 days 
+/- 14 days 
Obtain Informed Consent 
D 
7.1.2 
X 
Eligibility Checklists(s) 
S 
7.1.2.1 
X 
Disposition –Screening 
CRF 
D 
7.1.2.2 
X 
IRT Registration 
D 
7.1.2.1 
X 
Patient history 
Demography 
D 
7.1.2.3 
X 
Inclusion/exclusion 
criteria 
D 
7.1.2.1 
X 
Medical History 
D 
7.1.2.3 
X 
Diagnosis of PMF, PPV 
MF, and PET-MF 
includes bone marrow 
biopsy with grading of 
fibrosis 
D 
7.1.2.3 
X 
MF Treatment history 
D 
7.1.2.3 
X 
Transfusions since last 
visit 
D 
7.2.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medications 
D 
7.1.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Evaluation 
Category 
Protocol 
Section 
Screening 
Day 1 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 36 
Week 48 
Every 12 
weeks 
thereafter (wk 
60, 72, 84, etc) 
End of study 
treatment 
(EoT) 
30 Day Safety 
Follow up 
Day of Visit 
-28 to -1 
1 
28 
56 
84 
112 
140 
168 
252 
336 
420, 504, 
598, etc., 
- 
Visit Windows 
+/- 7 days 
+/- 14 days 
Physical examination 
S 
7.2.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Measurement of spleen 
by palpation 
D 
7.2.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance 
status 
D 
7.2.2.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
D 
7.2.2.5 
X 
Weight 
D 
7.2.2.5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
Hematology 
D 
7.2.2.7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
D 
7.2.2.7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral Hepatitis 
(testing as indicated in 
Section 7.2.2.7 during 
trial for patients with 
inactive chronic infection) 
D 
7.2.2.7 
X 


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Evaluation 
Category 
Protocol 
Section 
Screening 
Day 1 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 36 
Week 48 
Every 12 
weeks 
thereafter (wk 
60, 72, 84, etc) 
End of study 
treatment 
(EoT) 
30 Day Safety 
Follow up 
Day of Visit 
-28 to -1 
1 
28 
56 
84 
112 
140 
168 
252 
336 
420, 504, 
598, etc., 
- 
Visit Windows 
+/- 7 days 
+/- 14 days 
Pregnancy test serum 
D 
7.2.2.7 
X 
X 
Pregnancy test urine 
D 
7.2.2.7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety 
Adverse events 
D 
8.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient reported 
Outcomes 
Myelofibrosis 7 Item 
Symptom Scale (MF-7) 
D 
7.2.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Modified MFSAF v2.0 
D 
7.2.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Global 
Impression of Change 
(PGIC) 
D 
7.2.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug 
administration 
D 
6.1.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
End of Phase Disposition 
D 
7.1.4 
X 


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7.1.1 
Molecular pre-screening 
Not applicable. 
 
7.1.2 
Screening 
Written informed consent must be obtained before any study specific procedure is performed. 
Screening assessments to confirm eligibility should be performed as per the schedule of 
assessments in Table 7-1. 
All assessments should be completed within the 28 day screening period. 
Re-screening of patients will be allowed, if all entry criteria are not met during the screening 
period (-28 days to -1 day). Re-screening should only occur after a patient has failed screening. 
The same patient ID number should be used to rescreen. 
Rescreening of patients is permissible at the discretion of the investigator i.e., a patient is 
screened and is found to be ineligible, they may be rescreened at a later date and entered onto 
the study provided all inclusion and no exclusion criteria are met. Rescreening should not occur 
more often than every 7 days. 
 
7.1.2.1 
Eligibility screening 
Patients must meet all inclusion (Section 5.2) and none of the exclusion (Section 5.3) criteria 
during the Screening phase in order to be eligible to proceed to the Treatment Phase of the 
study. Patient eligibility will be confirmed by using the following processes: 
• Investigative staff will capture patient eligibility within the source documents maintained 
at the site, 
• All screening assessment results must be received and reviewed by the 
investigator/designee to be within protocol required parameters before the patient starts 
study treatment, 
Following registering in the IRT for screening, patient eligibility will be checked by the Sponsor 
once all screening procedures are completed. The eligibility check form will be sent from the 
site to the Sponsor either via fax or email for evaluation. Upon confirmation of eligibility, the 
Sponsor will return the signed eligibility check form via fax or email to the site. 
The investigator site will then contact the IRT to be allowed to assign treatment to the patient. 
Please refer and comply with detailed guidelines in the IRT manual. 
 
7.1.2.2 
Information to be collected on screening failures 
A patient who signs an informed consent but fails to satisfy all eligibility criteria for any reason 
will be considered a screen failure. The reason for not starting dosing will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). 


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Patients who signed ICF but are considered ineligible after signing the study consent will be 
considered as screening failures, and data will be handled in the same manner. 
• Screening Phase Disposition page (including reason for not satisfying eligibility criteria 
and being started on treatment) 
• Informed consent 
• Demography 
• Adverse Events (only if an SAE occurs) 
• Inclusion/Exclusion Criteria 
In order to be officially considered a screen failure, the IRT system should be notified, 
preferably within 2 days of the decision to screen fail the patient. 
 
7.1.2.3 
Patient demographics and other baseline characteristics 
Data to be collected on patient characteristics at screening include: 
• Demography (including: date of birth, patient initials, gender, childbearing potential, race 
and ethnicity, or as allowed by local regulations) 
• Relevant medical history including: Myelofibrosis diagnosis (Appendix 3) and disease 
history, Prior MF Medications (Treatment history), and transfusion history. 
• Prior and Concomitant Medications, surgical and medical procedures 
All medications taken from screening must be recorded on the Prior and Concomitant 
medication eCRF page and updated on a continual basis if there is a new change to the 
medication. 
 
7.1.3 
Treatment period 
Following completion of screening procedures and verifying patient eligibility, the patient will 
be approved for treatment via the IRT. 
The study treatment phase begins on Day 1 with the first administration of ruxolitinib and will 
continue until 48 weeks after Last Patient First Treatment date or the patient is discontinued for 
other reasons as indicated in Section 7.1.4. 
Patients will be assessed as per visit schedule in Table 7-1. 
Visit windows of ± 7 days from scheduled study assessments will apply from Week 4 visit up 
to Week 24 and ± 14 days for visits after Week 24. 
 
7.1.4 
Discontinuation of study treatment 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If   a 
patient decides to discontinue from the study treatment, the investigator should make a 
reas onab l e effort (e.g. telephone, e-mail, letter) to understand  the  primary  reason  for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for 
visits, or become lost to follow-up for any other reason. 


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The investigator may discontinue study treatment for a given patient if, he/she believes that 
continuation would be detrimental to the patient’s well-being. 
In addition to mandatory dose interruptions and/or reductions of Study treatment listed in 
Section 6.3, study treatment may also be discontinued under the following circumstances: 
• Consent is withdrawn 
• Further participation would be injurious to the patient’s health or well-being in the 
investigator’s medical judgment 
• The study is terminated 
• Disease progression 
• Pregnancy 
• Unacceptable toxicity 
• The following deviations from the prescribed dose regimen for study treatment . If the 
study drug is interrupted for any reason for more than 8 weeks, dosing may not be 
restarted, except in the case of splenectomy, for which a maximum 12 week period of 
study drug interruption is permitted. 
• Use of prohibited treatment refer to Appendix 5 
• Any other protocol deviation that results in a significant risk to the patient’s safety 
• Discontinuation from the study for any other reason per the Investigator’s judgement 
Adverse events requiring discontinuation are listed in Section 6.3.4. 
Patients who discontinue study treatment should undergo an end of study treatment visit and 
then enter the follow-up epoch or period. 
The investigator must also contact the IRT to register the patient’s  discontinuation from  
study treatment. 
 
7.1.4.1 
Replacement policy 
Not applicable. 
 
7.1.5 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 
longer, and does not want any further visits or assessments, and does not want any further study 
related contact. 
Novartis will continue to retain and use all research results that have already been collected for 
the study evaluation. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. 


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Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up. 
 
7.1.6 
Follow up for safety evaluations 
All patients must have safety evaluations for 30 days after the last dose of study treatment. 
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF. 
 
Follow-up evaluations 
The following evaluations will be performed within 30 days after the last dose of study 
treatment. The following procedures will be performed and all observations will be recorded in 
the eCRF: 
• Review of concomitant medications. 
• Review of transfusion history 
• A complete physical examination will be performed, including body weight and 
measurement of spleen by palpation. 
• Vital signs to be performed in a sitting position after 5 minutes of rest) 
• Blood sampling for serum chemistry and hematology tests. 
• Record adverse events. 
7.1.7 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF. 
 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Assessments for efficacy will consist of spleen length measurement, transfusion requirements, 
symptom scores using Myelofibrosis 7 Item Symptom Scale, Separate question on Inactivity to 
compute Modified MFSAF v2.0 and PGIC. 
 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing described below as well as collecting of the adverse 
events at every visit. For details on AE collection and reporting, refer to Section 8. 


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7.2.2.1 
Physical examination 
A comprehensive physical examination will be performed. The comprehensive physical 
examination will include the following organ/body system assessments: general appearance, 
skin; HEENT (head, eyes, ears, nose and throat); thyroid; lungs; cardiovascular; abdomen (liver, 
spleen); lymph nodes; neurological examination, assessment of edema and extremities. A 
targeted physical examination will be performed at each visit that will include body systems as 
indicated by patient symptoms, AEs, prior physical examinations, or other findings as 
determined by the investigator. 
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF. 
 
7.2.2.2 
Spleen Measurement 
The physical examination will include a measurement of spleen length. 
The edge of the spleen shall be determined by palpation, measured in centimeters, using a soft 
ruler, from the costal margin to the point of greatest splenic protrusion. The spleen should be 
measured in the same manner at all visits. 
 
7.2.2.3 
Transfusion requirements 
At the screening visit, information on all prior transfusions (Whole blood - PRBC) performed 
during the last 12 weeks prior to screening will be collected and recorded in the appropriate 
eCRF. 
At each subsequent visit, all transfusions (Whole blood - PRBC) performed since the last visit 
will collected and recorded in the appropriate eCRF. 
 
7.2.2.4 
Vital signs 
Vital signs include blood pressure and body temperature measurement. 
 
7.2.2.5 
Height and weight 
Height will be measured at screening. 
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1. 
 
7.2.2.6 
Performance status 
ECOG Performance status scale (Appendix 2) will be used in the timepoints as described in 
the Table 7-1. 
 
7.2.2.7 
Laboratory evaluations 
Clinical laboratory tests (hematology, clinical chemistry, viral hepatitis and pregnancy testing) 
will be performed at the center where the patient is enrolled (local laboratory). 


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All patients will have samples of blood collected on the days noted in the Visit Evaluation 
Schedule Table 7-1. Table 7-2 provides a complete list of laboratory tests that will be performed 
at the local laboratory. 
Hepatitis B testing – At screening, HBV infection status testing will be done for HB-sAG and 
anti HB-c antibody. If HB-sAG is negative and anti HB-c antibody is negative, the patient can 
be enrolled. 
If HB-sAG is positive and/or anti HB-c antibody is positive, the site will determine per local 
procedures if infection is active (with viral replication) or inactive (without viral replication). 
Possible test include, for instance, serology testing for HB-eAG and PCR for HBV DNA. 
Patients with active HBV infection (with viral replication) are not eligible for enrollment. 
Patients with inactive HBV infection (without viral replication) can be enrolled. Monitoring  of 
these patients for reactivation by regular testing, using the same test is required every 12 weeks. 
Treatment in case of reactivation will be as per local procedure. This information will be 
collected in the eCRF. 
Hepatitis C testing – At screening, HCV infection status will be assessed by the means of anti 
HCV antibody screen. The patient can be enrolled if anti HCV antibody is negative. If anti HCV 
antibody is positive then HCV RNA by PCR will be performed. 
Patients with active HCV infection (with viral replication) are not eligible for enrollment. 
Patients with inactive HCV infection (without viral replication) can be enrolled. Monitoring  of 
these patients for reactivation is required by means of HCV RNA by PCR at regular intervals 
as per the local practice. This information will be collected in the eCRF. 
 
Table 7-2 
Local Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White 
blood cells, RBC Morphology,Blasts, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands, Other (absolute value 
preferred , %s are acceptable). 
Chemistry 
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Sodium, 
Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Total Bilirubin, Total 
Cholesterol, LDL Cholesterol, HDL Cholesterol, Total Protein, Triglycerides 
(fasting), Blood Urea Nitrogen (BUN) or Urea, Uric Acid 
Amylase, Lipase, Glucose (fasting) 
Viral Hepatitis 
For hepatitis B: HB-sAG and anti HB-c antibody at screening. 
For Hepatitis C: anti HCV antibody at screening. 
For patients with inactive infection, testing every 12 weeks for reactivation (for 
HBV) and at regular intervals as per the local practice (for HCV). 
Pregnancy Test 
A serum pregnancy test should be performed at screening and EOT visit, while at 
all other timepoints, urinary pregnancy tests are sufficient. 


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7.2.2.8 
Radiological examinations 
Not applicable. 
 
7.2.2.9 
Cardiac assessments 
Not applicable. 
 
7.2.2.10 Tolerability 
Not applicable 
 
7.2.3 
Pharmacokinetics 
Not applicable 
 
 
 


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7.2.5 
Resource utilization 
Not applicable. 
 
7.2.6 
Patient reported outcomes 
Patients with MF often experience significant symptoms that interfere with their quality of life 
(QoL) including, fatigue, early satiety, pruritus, weight loss, weakness and night sweats. The 
effect of ruxolitinib on patient symptoms and QoL will be measured using several assessment 
tools including but not limited to the MF-7, Modified MFSAF v2.0 and the Patient Global 
Impression of Change (PGIC). All questionnaires are patient-reported outcomes (PROs). The 
PRO questionnaires provided electronically (ePRO) are to be completed by the patient. The site 
will review for completeness. 
Instructions for all PROs will be provided as separate documents. Patients must complete the 
questionnaire(s) before other clinical assessments at any given visit. The PRO questionnaires 
should be completed in the same order at each visit to ensure that the patient is answering them 
as consistently as possible. The questionnaires should be given in the following order: 
1. MF-7 
2. Separate question on Inactivity to compute Modified MFSAF v2.0 
3. PGIC 
Patient Reported Outcomes will be collected according to the Visit Schedule outlined in Table 
7-1. The patient should be given sufficient space and time to complete the PRO questionnaires. 


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The site personnel should check the questionnaires for completeness and ask the patient to 
complete any missing responses. The original questionnaire will be kept with the patient’s file 
as the source document. 
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs before any clinical study examinations. This assessment should be documented in study 
source records. If AEs or SAEs are confirmed, study investigators should not encourage the 
patient to change responses reported in the completed questionnaires. Study investigators must 
follow reporting instructions outlined in Section 8 of the study protocol. 
 
MF-7 
The Myelofibrosis 7 Item Symptom Scale (MF-7) (Appendix 4) is a disease specific 
questionnaire comprised of 7 items that measures the severity of seven of the most prevalent 
associated symptoms including: tiredness, early satiety, abdominal discomfort, night sweats, 
itching (pruritus), bone pain (diffuse not joint or arthritis) and pain under ribs on left side. Each 
item is scored on a scale ranging from 0 (absent) to 10 (worst imaginable). The MF-7 score is 
computed as the sum of the observed scores in the individual items to achieve a 0-to- 70 score. 
There would be one recall period of 24 hours used in this questionnaire. 
 
Modified MFSAF v2.0 – Computed through a separate Question on Inactivity 
A separate question on Inactivity (Appendix 4) will measure the severity of this symptom on a 
scale from 0 (absent) to 10 (worst imaginable) and will allow the computation of the MFSAF 
v2.0 questionnaire results, as 6 out of 7 items in the latter PRO are in overlap with MF7 (they 
also share same 0-10 range Likert scale and ascending order, absent to worst imaginable). 
 
PGIC 
The Patient Global Impression of Change (PGIC; Appendix 4) is comprised of a single question 
intended to measure a patient’s perspective of improvement or deterioration over time relative 
to treatment. The PGIC uses a seven-point scale where one (1) equals very much improved and 
seven (7) equals very much worse. 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 


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Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a  separate Adverse 
Event. 
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. Grade 1 to 5 will be used to characterize the severity 
of the Adverse Event. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
life-threatening, and death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
through a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
or its relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2. 
 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if 


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necessary) of any changes in severity, the suspected relationship to the study treatment, the 
interventions required to treat it, and the outcome. 
All patients who have AEs, whether considered associated with the use of the investigational 
product or not, must be monitored to determine the outcome. The clinical course of the AE will 
be followed up according to accepted standards of medical practice, even after the end of the 
period of observation, until a satisfactory explanation is found or the investigator considers it 
medically justifiable to terminate follow-up. Should the AE result in death, a full pathologist’s 
report should be supplied if and when available. 
SAEs must be reported as outlined in Section 8.2.2. In addition, any SAEs which occur as a 
result of protocol specific diagnostic procedures or interventions must also be reported. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
 
8.1.3 
Adverse events of special interest 
 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 


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Note that hospitalizations for the following reasons should not be reported as serious adverse 
events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition 
Note that treatment on an emergency outpatient basis that does not result in hospital admission 
and involves an event not fulfilling any of the definitions of a SAE given above is not a serious 
adverse event. 
 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent 
and until at least 30 days after the patient has stopped study treatment must be reported to 
Novartis within 24 hours of learning of its occurrence. 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
Any SAEs experienced after the 30 day safety evaluation follow-up should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site 
Follow-up information is submitted in the same way as the original SAE Report. Each re- 
occurrence, complication, or progression of the original event should be reported as a follow- 
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse 


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Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
 
8.3 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
 
8.4 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
 
8.5 
Data Monitoring Committee 
Not applicable 
 
8.6 
Steering Committee 
The steering committee will be established comprising investigators participating in the trial, 
i.e. not being members of the DMC and Novartis representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following: 
• What protected health information (PHI) will be collected from patients in this study 


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• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject/patient to revoke their authorization for use of their PHI. 
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned user 
identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements  and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. 


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9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
 
 
 
 
Data for PROs: will be collected by the patient electronically and transferred to the ePRO 
vendor. The data will be sent electronically to Novartis (or a designated CRO). The site will 
enter information regarding sample collection in the eCRF. 
Data about all study treatments dispensed to the patient and all IRT assigned dosage changes 
will be tracked using an Interactive Response Technology. The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis 
personnel. 
 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel will review the data entered by investigational 
staff for completeness and accuracy. Electronic data queries stating the nature of the problem 
and requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
All 
 IVRS and PRO Samples and/or data will be processed centrally and the results 
will be sent electronically to Novartis. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
 
10 
Statistical methods and data analysis 
The primary analysis will be performed when all enrolled patients have completed the week 24 
visit or have discontinued from the study prior to week 24. 
PPI


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The final analysis will occur at the end of the study. All available data from all patients will  be 
analyzed and summarized in a final CSR. 
 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment (ruxolitinib) has 
been assigned and who received one dose of study treatment (ruxolitinib). 
 
10.1.2 
Safety set 
The Safety Set is the same as the FAS. 
 
10.1.3 
Per-Protocol set 
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who had no major 
protocol deviation. 
Any protocol deviations potentially leading to exclusion from the PPS will be specified in the 
study Statistical Analysis Plan (SAP). This population will be used as supportive analyses for 
the primary efficacy endpoint. 
 
10.1.4 
Dose-determining analysis set 
Not applicable. 
 
10.1.5 
Pharmacokinetic analysis set 
Not applicable. 
 
10.1.6 
Other analysis sets 
Not applicable. 
 
10.1.6.1 Efficacy/evaluable set 
Not applicable. 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be listed and 
summarized descriptively for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
Relevant medical histories and current medical at baseline will be summarized separately for 
ongoing and historical medical conditions by system organ class and preferred term, for the 
FAS. 


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10.3 
Treatments (study treatment, concomitant therapies, compliance) 
The Safety set will be used for the analyses below. 
The duration of exposure to study treatment, as well as the actual dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure), cumulative dose 
and average daily dose of ruxolitinib will be summarized by means of descriptive statistics using 
the safety set. 
The number of patients with dose adjustments (dose changes/interruption) and the reasons will 
be summarized for the Safety set and all dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of 
ruxolitinib will be listed and summarized according to the Anatomical Therapeutic Chemical 
(ATC) classification system by means of frequency counts and percentages. These summaries 
will include medications starting on or after the start of study treatment or medications starting 
prior to the start of study treatment and continuing after the start of study treatment. 
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. 
 
10.4 
Primary objective 
The primary objective of this study is to determine the spleen length response rate at week 24. 
 
10.4.1 
Variable 
The primary efficacy variable for this study is the proportion of patients achieving a 50% 
reduction in spleen length at Week 24. 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The assessment of primary efficacy of study treatment will be based on the calculation of 
observed proportion of patients with spleen length response at Week 24 and its posterior 
distribution using a Beta-binomial model. The FAS will be used for the primary analysis. Study 
treatment will be declared efficacious if the following criteria are met: 
a. Observed proportion of patients with ≥50% reduction in spleen length at Week 24 ≥25% 
b. Probability of true response rate ≤15% (considered not clinically meaningful) is less than 
10% 
With 50 patients, criteria ‘a’ and ‘b’ will be met if the observed responder rate is ≥25%, i.e., at 
least 13 patients out of 50 patients have a response at Week 24 which will give a probability of 
“not being clinically meaningful (response ≤15%)” of 0.0243. 
The primary analysis will be performed when all the enrolled patients have been treated with 
ruxolitinib for 24 weeks or discontinued prior to week 24. The point estimate of the proportion 
of patients achieving ≥50% reduction in spleen length at Week 24 along with corresponding 
exact 95% confidence interval using Clopper and Pearson exact method will be presented. 


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10.4.3 
Handling of missing values/censoring/discontinuations 
For the primary analysis, patients with missing baseline spleen length will be excluded from the 
analysis as change from baseline cannot be calculated. 
Patients with missing spleen length at Week 24 or who withdraw earlier from the study will be 
considered as a non-responder. 
 
10.4.4 
Supportive and Sensitivity analyses 
The primary analysis (as described in Section 10.4.2) will also be repeated on the PPS. 
Furthermore, the primary endpoint will be analyzed on patients with non-missing spleen length 
at both baseline and week 24. 
 
10.5 
Secondary objectives 
All secondary efficacy analyses will be performed on the FAS, unless otherwise specified. All 
safety related endpoints will be analyzed on the Safety set unless otherwise specified. 
 
10.5.1 
Secondary efficacy objective(s) 
The spleen length response rate at Week 48 will be evaluated. The point estimate of the 
proportion of patients achieving ≥50% reduction in spleen length at Week 48 along with 
corresponding exact 95% confidence interval using Clopper and Pearson exact method will be 
presented. 
Percent change from baseline in spleen length over time will be evaluated to assess the effect 
of ruxolitinib on spleen length. The analysis will be performed for each visit and at end of 
treatment. This parameter is computed by dividing the difference of spleen length at assessment 
time and at baseline by the length at baseline multiplied by one hundred. 
To evaluate the effect of ruxolitinib on transfusion requirements, the following will be 
summarized: 
• Number and percentage of transfusions over time 
• Proportion of patients who are transfusion dependent (TD). Transfusion dependence is 
defined as per IWG MRT criteria: 6 or more transfusions in 12 weeks prior to baseline. 
• For transfusion dependent (TD) patients, the following will be analyzed: 
• transfusion independence (TI) rate (requiring no transfusion for ≥12 weeks at any 
time) 
• transfusion response rate (not TD: having 5 or less transfusion for ≥12 weeks at any 
time) 
 
10.5.2 
Other secondary efficacy objectives 
Not applicable. 


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10.5.3 
Safety objectives 
 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used, unless specified otherwise. 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 31 after last dose of study medication. 
The safety summary tables will include only assessments collected within 30 days after study 
treatment discontinuation and assessments on or prior to the data cut-off date for ongoing 
patients, unless otherwise specified. 
All data, regardless of the observation period, will be listed and assessments collected in the 
pre-treatment and post-treatment period will be flagged in all the listings. 
 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events leading to treatment 
discontinuations during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized by system organ class and 
preferred term. 
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the post-treatment period will be flagged. 
AEs will be assessed according to the Common Terminology Criteria for AEs (CTCAE version 
4.03). AEs will be coded using the latest MedDRA terminology version during the time of data 
analyses. 
 
10.5.3.3 Laboratory abnormalities 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 


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For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for laboratory tests: 
• Changes from baseline in hematology/biochemistry parameters over time. 
• Listing of all laboratory data (including hematology, biochemistry, and urinary laboratory 
test with values flagged to show the corresponding CTCAE v4.03 grades if applicable and 
the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE v4.03 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
value 
For laboratory tests where grades are not defined by CTCAE v4.03, 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
In addition to the above mentioned tables and listings, figures plotting time course of raw or 
change in laboratory tests over time or box plots will be specified in the SAP and TLF shells. 
 
10.5.3.4 Other safety data 
Vital signs (including weight) and ECOG performance status will be summarized. 
 
Vital signs 
Data on vital signs (including weight) will be tabulated and listed, notable values will be 
flagged. 
The following summaries will also be provided: 
• shift table baseline to worst on-treatment result 
• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
ECOG Performance Status 
The following summaries will also be provided: 
• shift tables comparing the baseline performance score with the worst result during post- 
baseline will be summarized. 
 
10.5.3.5 Supportive analyses for secondary objectives 
Not applicable. 
 
10.5.3.6 Tolerability 
Not applicable. 


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10.5.4 
Pharmacokinetics 
Not applicable. 
 
 
 
 
 
10.5.6 
Resource utilization 
Not applicable. 
 
10.5.7 
Patient-reported outcomes 
The Myelofibrosis 7 Item Symptom Scale (MF-7) along with Modified MFSAF v2.0 (computed 
through the addition of a separate question on Inactivity to the data captured with MF7) and the 
PGIC will be primarily used to collect electronically the patient’s disease- related symptoms 
and patient impression of change. No formal statistical test will be performed. 
Missing items data in a scale will be handled based on each instrument manual. No imputation 
will be applied if the total or subscale scores are missing at a visit. The FAS will be used for 
analyzing PRO data. Descriptive statistics (e.g., mean, median) will be used to summarize the 
scored scales at each scheduled assessment time point for the Myelofibrosis 7 Item Symptom 
Scale (MF-7) and the Modified MFSAF v2.0 score. 
Change from baseline in the domain scores at the time of each assessment will be summarized. 
Patients with an evaluable baseline score and at least one evaluable post baseline score during 
the treatment period will be included in the change from baseline analyses. The number and 
percentage of patients in each PGIC response category at selected time points will be 
summarized. 
 
 


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10.7 
Interim analysis 
No formal interim analysis is planned for this trial. 
The primary analysis will be performed after all patients have completed Week 24 or 
discontinued prior to Week 24. Any other interim updates may be provided to fulfill regulatory 
obligations, to comply with post-approval commitments or for publication purposes. 
The final analysis will occur at the end of the study. All available data from all patients will  be 
analyzed and summarized in a final CSR. 


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10.8 
Sample size calculation 
Approximately 50 patients will be enrolled in this study. Success at Week 24 will be declared 
if the following criteria are met: 
a. Observed proportion of patients with ≥50% reduction in spleen length at Week 24 ≥25% 
b. Probability of true response rate ≤15% (considered not clinically meaningful) is less than 
10% 
With 50 patients, criteria ‘a’ and ‘b’ will be met if the observed responder rate is ≥ 25%, i.e. if 
at least 13 patients out of 50 patients have a response at Week 24. 
 
 
Sample size 
No. of 
responders 
Observed 
responder rate (%) 
Probability of true responder rate 
≤15% 
N=50 
11 
22 
0.1014 
12 
24 
0.0520 
13 
26 
0.0243 
14 
28 
0.0104 
15 
30 
0.0041 
16 
32 
0.0015 
 
 
The operating characteristics of the design are presented in the table below. This table shows 
probability for positive conclusion (i.e. success criteria met at the end of study) under different 
true responder rates. When the true responder rate at Week 24 is ≤ 15%, the probability of 
positive conclusion is ≤ 10% (false success rate). The probability of success is > 90% when the 
true responder rate at Week 24 is 35%. 
 
 
Sample size 
True responder rate (%) 
Probability of positive conclusion 
N=50 
15 
0.0301 
20 
0.1861 
25 
0.4890 
30 
0.7771 
35 
0.9339 
40 
0.9867 
45 
0.9982 
50 
0.9998 
 
10.9 
Power for analysis of key secondary variables 
Not applicable. 


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11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.. 
 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4. 


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11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicines, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 
year of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
patients within 6 months of study completion.. 
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted. 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 
According to Novartis policy, authors of publication will not receive remuneration for their 
writing of a publication, either directly from Novartis or through the professional medical 
writing agency. Author(s) may be requested to present poster or oral presentation at scientific 
congress; however, there will be no honorarium provided for such presentations. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 
 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study  safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 


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evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported  on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 
 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must 


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be considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures within 
3 days) but not later than 10 working days. 
 
13 
References (available upon request) 
Abdel-Wahab OI, Levine RL (2009) Primary myelofibrosis: update on definition, 
pathogenesis, and treatment. Annu Rev Med;60:233-245. 
Al-Ali HK, Stalbovskaya V, Gopalakrishna P et al., 2016. Impact of ruxolitinib treatment on 
the hemoglobin dynamics and the negative prognosis of anemia in patients with myelofibrosis. 
Leukemia & Lymphoma, 1042-8194: 1029-2403 
Arber DA, Orazi A, Hasserjian R, et al. (2016). The 2016 revision to the World Health 
Organization (WHO) classification of myeloid neoplasms and acute leukemia. 
Blood;2016-03-643544 
Barosi G, Mesa RA, Thiele J, et al (2008) Proposed criteria for the diagnosis of post- 
polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement 
from the International Working Group for Myelofibrosis Research and Treatment. 
Leukemia;22:437-438. 
Campbell PJ, Green AR. 2006. The Myeloproliferative Disorders. N Engl J Med;355:2452-66. 
Cervantes F, Dupriez B, Pereira A, et al (2009) New prognostic scoring system for primary 
myelofibrosis based on a study of the International Working Group for Myelofibrosis 
Research and Treatment. Blood;113:2895-2901. 
Cervantes F (2014). How I treat myeloﬁbrosis. Blood; 23 vol.124, No 17, 2635-2642 
Chachoua I, Pecquet C, El-Khoury M et al., (2016) Thrombopoietin receptor activation by 
myeloproliferative neoplasm associated calreticulin mutants. Blood 2016;127(10):1325-35. 
Flockhart DA (2007) Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007).Available from: 
http://medicine.iupui.edu/clinpharm/ddis/table.asp.> (Accessed 25 Jan 2011). 
Gangat et al (2011) DIPSS Plus: A Refined Dynamic International Prognostic Scoring System 
for Primary Myelofibrosis That Incorporates Prognostic Information From Karyotype, Platelet 
Count, and Transfusion Status. JCO February 1, 2011 vol. 29 no. 4 392-397. 


Novartis 
Oncology Clinical Trial Protocol (v00) 
Confidential 
Page 816 
Protocol No. CINC424A2411 
 
 
Ghoreschi K, Laurence A, O'Shea JJ (2009) Janus kinases in immune cell signaling. Immunol 
Rev;228:273-287. 
Gisslinger H, McMullin MF, Jakel N, et al. Phase 1b, open-label, dose-finding study of 
ruxolitinib in patients with myelofibrosis and baseline platelet counts between 50 and ≤ 99 × 
109/L. Haematologica. 2012;97. Abstract 369. 
Gupta V, Harrison CN, Hexner EO et al., 2015. The Impact of Anemia on Overall Survival in 
Patients with Myelofibrosis Treated with Ruxolitinib: An Exploratory Analysis of the 
Comfort Studies. Poster 1604. ASH 2015 meeting. 
Gupta V, Verstovsek S, Mesa RA et al., 2016. Poster 7012 presentation, ASCO 2016. 
Harrison C, Kiladjian KK, Al-Ali HK, et al (2012) JAK inhibition with INC424 versus best 
available therapy for myelofibrosis. N Engl J Med;366:787-798. 
Harrison C, Mesa R, Ross D, et al. (2013) Practical management of patients with 
myelofibrosis receiving ruxolitinib. Expert Review of Hematology6:5, 511-523. 
Harrison CN et al., (2016) Long term findings from COMFORT-II, a phase 3 study of 
ruxolitinib vs best available therapy for myelofibrosis. Leukemia; 30: 1701-1707 
Ho PJ et al., (2015) Practical management of myelofibrosis with ruxolitinib. Intern Med J; 
45(12):1221-30 
Kilpivaara, Levine (2008) JAK2 and MPL mutations in myeloproliferative neoplasms: 
discovery and science. Leukemia (2008) 22, 1813–1817. 
Klampfl et al (2008) Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. N 
Engl J Med 2013;369:2379-90. 
Klampfl T, Heinz G, Ashot SH et al., (2013) Somatic Mutations of Calreticulin in 
Myeloproliferative Neoplasms. N Engl J Med;369:2379-90. 
Kroger (2008) Epigenetic Modulation and Other Options to Improve Outcome of Stem Cell 
Transplantation in MDS. Hematology 2008: 60-67. 
Mesa RA, Niblack J, Wadleigh M, et al (2007) The burden of fatigue and quality of life in 
myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD 
patients. Cancer;109:68-76. 
Nangalia J, Massie CE, Baxter EJ et al., 2013. Somatic CALR Mutations in Myeloproliferative 
Neoplasms with Nonmutated JAK2. N Engl J Med;369:2391-405 
 
 
Oh ST, Simonds EF, Jones C, et al (2010) Novel mutations in the inhibitory adaptor protein 
LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. 
Blood;116:988-992. 
Olcaydu D, Harutyunyan A, Jager R, et al (2009) A common JAK2 haplotype confers 
susceptibility to myeloproliferative neoplasms. Nat Genet;41:450-454. 
Patnaik MM, Lasho TL, Finke CM, et al (2010) WHO-defined 'myelodysplastic syndrome 
with isolated del(5q)' in 88 consecutive patients: survival data, leukemic transformation rates 
and prevalence of JAK2, MPL and IDH mutations. Leukemia;24:1283-1289. 


Novartis 
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Protocol No. CINC424A2411 
 
 
Quintas-Cardama A, Vaddi K, Liu P, et al (2010) Preclinical characterization of the selective 
JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of 
myeloproliferative neoplasms. Blood;115:3109-3117. 
Reilly JT, McMullin MF, Beer PA et al. (2014). Use of JAK inhibitors in the management of 
myelofibrosis: a revision of the British Committee for Standards in Haematology Guidelines 
for Investigation and Management of Myelofibrosis 2012. British Journal of Haematology, 
2014, 167, 418–438. 
Schnittger S, Bacher U, Haferlach C, et al (2009) Detection of JAK2 exon 12 mutations in 15 
patients with JAK2V617F negative polycythemia vera. Haematologica;94(3):414-418. 
Scott LM, Tong W, Levine RL, et al (2007) JAK2 exon 12 mutations in polycythemia vera 
and idiopathic erythrocytosis. N Engl J Med;356:459-468. 
Tabarroki A, Lindner D, Visconte V, et al. (2013) Modified Dose Escalation Of Ruxolitinib: 
A Feasible Therapeutic Approach In The Management Of Myelofibrosis. Blood; 122: 21. 
Talpaz M, Hamburg S, Jamieson K et al (2012a). Preliminary safety and efficacy from a 
Phase II study of ruxolitinib in patients with primary and secondary myelofibrosis with 
platelet counts of 50–100 x109/L. Haematologica. Abstract 0597. 
Tefferi A, Lasho TL, Mesa RA, et al (2007b) Lenalidomide therapy in del(5)(q31)-associated 
myelofibrosis: cytogenetic and JAK2V617F molecular remissions. Leukemia;21:1827-1828. 
Tefferi A (2008) Essential thrombocythemia, polycythemia vera, and myelofibrosis: current 
management and the prospect of targeted therapy. Am J Hematol;83:491-497. 
Tefferi A, Skoda R, Vardiman JW (2009a) Myeloproliferative neoplasms: contemporary 
diagnosis using histology and genetics. Nat Rev Clin Oncol;6:627-637. 
Vainchenker W, Dusa A, Constantinescu SN (2008) JAKs in pathology: role of Janus kinases 
in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol;19:385-393. 
Vannucchi AM et al., (2013) Mutataions and prognosis in primary myelofibrosis. Leukemia. 
27: 1861-1869 
Vannucchi et al (2015) A pooled analysis of overall survival in COMFORT-I and 
COMFORT-II, 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. 
Haematologica June 11, 2015. 
Verstovsek S, Mesa R, Gotlib J, et al (2012) A double-blind, placebo-controlled trial of 
ruxolitinib for myelofibrosis. N Engl J Med;366:799-807. 
 
 
Verstovsek S, Kantarjian H, Mesa R, et al (2010b) Safety and efficacy of INCB018424, an 
oral JAK1 and JAK2 inhibitor, in patients with primary, post-polycythemia vera, or post- 
essential thrombocythemia myelofibrosis. N Engl J Med.363L1117-1127. 
Verstovsek S et al., (2016) EHA2016: COMFORT-I 5 year update. 
Watowitch S (2011) The Erythropoietin Receptor: Molecular Structure and Hematopoietic 
Signaling Pathways. J Investig. Med. 59(7): 1067-1072 


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14 
Appendices 
14.1 
Appendix 1 - Diagnostic criteria for PMF, PPV MF, and PET-MF 
Criteria for post-polycythemia vera myelofibrosis (Barosi 2008) 
Required criteria: 
1. Documentation of a previous diagnosis of polycythemia vera as defined by the WHO criteria (Tefferi 2007b) 
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale)3 or grade 3–4 (on 0–4 scale)4,a 
Additional criteria (two are required): 
1. Anemiab or sustained loss of requirement of either phlebotomy (in the absence of cytoreductive therapy) or 
cytoreductive treatment for erythrocytosis 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm (distance of the tip 
of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly 
4. Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained 
fever (>37.5oC) 
aGrade 2–3 according to the European classification: 
3 diffuse, often coarse fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, 
coarse fiber network with areas of collagenization (positive trichrome stain). 
Grade 3–4 according to the standard classification: 
4 diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of 
collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with 
coarse bundles of collagen, often associated with significant osteosclerosis. 
bBelow the reference range for appropriate age, sex and altitude considerations. 
 
 
Criteria for post-essential thrombocythemia myelofibrosis (Barosi 2008) 
Required criteria: 
1. Documentation of a previous diagnosis of essential thrombocythemia as defined by the WHO criteria (Tefferi 
2007b) 
2. Bone marrow fibrosis grade 2–3 (on 0–3 scale)3 or grade 3–4 (on 0–4 scale)4,a 
Additional criteria (two are required): 
1. Anemiab and a ≥2mg ml-1 decrease from baseline hemoglobin level 
2. A leukoerythroblastic peripheral blood picture 
3. Increasing splenomegaly defined as either an increase in palpable splenomegaly of ≥5 cm (distance of the tip 
of the spleen from the left costal margin) or the appearance of a newly palpable splenomegaly 
4. Increased LDH (above reference level) 
5. Development of ≥1 of three constitutional symptoms: >10% weight loss in 6 months, night sweats, unexplained 
fever (> 37.5oC) 
aGrade 2–3 according to the European classification: 
3 diffuse, often coarse fiber network with no evidence of collagenization (negative trichrome stain) or diffuse, 
coarse fiber network with areas of collagenization (positive trichrome stain). 
Grade 3–4 according to the standard classification: 
4 diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of 
collagen and/or focal osteosclerosis or diffuse and dense increase in reticulin with extensive intersections with 
coarse bundles of collagen, often associated with significant osteosclerosis. 
bBelow the reference range for appropriate age, sex and altitude considerations. 


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Diagnostic criteria for primary myelofibrosis (Arber et al., 2016) 
Criteria for the diagnosis of primary myelofibrosis (PMF) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.2 
Appendix 2 - Eastern Cooperative Oncology Group performance 
status 
Grade 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Diagnosis of overt PMF requires meeting all three major criteria, and at least one minor criterion 
Major Criteria 
1. Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis 
grades 2 or 3* 
2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid 
neoplasms 
3. Presence of JAK2, CALR or MPL mutation or in the absence of these mutations, presence of another clonal 
marker** or absence of reactive myelofibrosis*** 
Minor Criteria 
Presence of at least one of the following, confirmed in two consecutive determinations: 
a. Anemia not attributed to a comorbid condition 
b. Leukocytosis >11 x 109/L 
c. Palpable splenomegaly 
d. LDH increased to above upper normal limit of institutional reference range 
e. Leukoerythroblastos 
* Grading of myelofibrosis: Semiquantitative grading of BM fibrosis (MF) with minor modifications concerning 
collagen and osteosclerosis (Fiber density should be assessed only in hematopoietic areas): 
MF-0 Scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM 
MF-1 Loose network of reticulin with many intersections, especially in perivascular areas 
MF-2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal bundles of thick 
fibers mostly consistent with collagen, and/or focal osteosclerosis (In grades MF-2 or MF-3 an additional trichrome 
stain is recommended) 
MF-3 Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of thick fibers 
consistent with collagen, usually associated with osteosclerosis (In grades MF-2 or MF-3 an additional trichrome 
stain is recommended) 
** in the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying 
mutations (e.g.ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of 
the disease 
*** BM fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell 
leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies 


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14.3 
Appendix 3 - Bone marrow biopsy evaluation (Arber et al., 2016) 
(when performed, they are not mandatory) 
Fibrosis density should be assessed in hematopoietic areas. Grading of 
myelofibrosis: Semi quantitative grading of BM fibrosis (MF) with minor 
modifications concerning collagen and osteosclerosis* 
 
Fibrosis Grade 
Description 
MF-0 
Scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM 
MF-1 
Loose network of reticulin with many intersections, especially in perivascular areas 
MF-2 
Diffuse and dense increase in reticulin with extensive intersections, occasionally with focal 
bundles of thick fibers mostly consistent with collagen, and/or focal 
MF-3 
Diffuse and dense increase in reticulin with extensive intersections and coarse bundles of 
thick fibers consistent with collagen, usually associated with osteosclerosis** 
* Fiber density should be assessed only in hematopoietic areas 
** In grades MF-2 or MF-3 an additional trichrome stain is recommended 
 
14.4 
Appendix 4 - Patient reported outcomes – Questionnaires 
MF-7 Myelofibrosis 7 Item Symptom Scale 
 
Myelofibrosis 7 Item Symptom Scale (MF-7) 
Symptom 
0 to 10 Ranking 
Select the one number that describes the worst severity you have experienced with each of the 
following in the past 24 hours 
Tiredness 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Filling up quickly when you eat 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Abdominal discomfort 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Night Sweats 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Itching (pruritus) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Bone pain (diffuse not joint pain or 
arthritis) 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 
Pain under ribs on left side 
(Absent) 0 1 2 3 4 5 6 7 8 9 10 (Worst Imaginable) 


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Modified MFSAF v2.0 - addition of Question on Inactivity 
During the past 24hrs, what was the worst degree of inactivity (including work and social 
activities) you had due to MF? 
 
 
0 
(Absent) 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(Worst 
Imaginable) 
 
Patient Global Impression of Change (PGIC) 
Instructions: Circle the answer that is most appropriate. 
Since the start of the treatment you’ve received in this study, your myelofibrosis (MF) 
symptoms are: 
1. Very much improved 
2. Much improved 
3. Minimally improved 
4. No change 
5. Minimally worse 
6. Much worse 
7. Very much worse 


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14.5 
Appendix 5 - List of CYP3A4 inhibitors and inducers 
Table 14-1 
List of CYP3A4 inhibitors and inducers 
 
Category 
Drug Names 
Strong inhibitorsa of 
CYP3A 
boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir/ritonavir, eltegravir/ritonavir, 
grapefruit juice1, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
LCL161, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
sequinavir/ritonavir, telaprevir, telithromycin, voriconazole, indinavir/ritonavir, 
tipranoavir/ritonavir, troleandomycin, 
Moderate inhibitorsb 
of CYP3A 
amprenavir, aprepitant, atazanavir, atazanavir/ritonavir,, casopitant, cimetidine, 
ciprofloxacin, crizotinib, cyclosporin, duranavir, darunavir/ritonavir, diltiazem, 
dronedarone, erythromycin, faldaprevilr, fluconazole2, fosamprenavir, grapefruit juice1, 
imatinib, lomitapide, netupitant,nilotinib, schisandra sphenanthera3, tofisopam, verapamil 
Strong inducersc of 
CYP3A 
avasimibe, carbamazepine, enzalutamide, mitotane,phenytoin, rifampin, St. John’s wort3, 
rifabutin, phenobarbital, 
Moderate inducersd 
of CYP3A 
bosentan, efavirenz, etravirine, genistein3, lersivirine, lopinavir, modafinil, nafcillin, 
ritonavir, semagacestat4, talviraline4, thioridazine, tipranavir, , 
The list of CYP inhibitors and inducers was compiled from the FDA’s “Guidance for Industry, Drug Interaction 
Studies;” from the Indiana University School of Medicine’s “Clinically Relevant” Table (Flockhart 2007) and from 
the University of Washington’s Drug Interaction Database. Note that this may not an exhaustive list. Please refer 
to footnotes. 
1. 
Effect seems to be due to CYP2C19 inhibition by ethinyl estradiol. 
2. 
Fluconazole is a dual CYP3A4 and CYP2C9 inhibitor. Fluconazole is a strong CYP2C9 inhibitor based on 
the AUC ratio of omeprazole, which is also metabolized by CYP3A; fluconazole is a moderate CYP3A 
inhibitor. 
3. 
Herbal product. 
4. 
Drugs not available in the US Market. 
aA strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate for 
that CYP by equal or more than 5-fold. 
bA moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by less than 5-fold but equal to or more than 2-fold 
c A strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate for 
that CYP by equal or more than 80%. 
d A moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that 
CYP by 50-80%. 
 
Dual CYP2C9 and CYP3A4 inhibitors: 
Fluconazole: avoid the concomitant use of ruxolitinib with fluconazole doses ≥ 200 mg daily; 
If clinically necessary to use doses ≥ 200 mg daily consultation with Sponsor is required. Please 
refer to Section 6.4.2; Permitted concomitant therapy requiring caution and/or action. 


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14.6 
Appendix 6 - Jakavi Summary of Product Characteristics 
14.6.1 
ANNEX I 
 
SUMMARY OF PRODUCT CHARACTERISTICS 
 
 This medicinal product is subject to additional monitoring. This will allow quick 
identification of new safety information. Healthcare professionals are asked to report any 
suspected adverse reactions. See section 4.8 for how to report adverse reactions. 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
Jakavi 5 mg tablets 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Each tablet contains 5 mg ruxolitinib (as phosphate). 
Excipient with known effect: 
Each tablet contains 71.45 mg lactose monohydrate. 
For the full list of excipients, see Section 6.1. 
3. 
PHARMACEUTICAL FORM 
Tablet. 
Round curved white to almost white tablets of approximately 7.5 mm in diameter with “NVR” 
debossed on one side and “L5” debossed on the other side. 
 
4. 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
Myelofibrosis (MF) 
Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult 
patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post 
polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. 
Polycythaemia vera (PV) 
Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant 
to or intolerant of hydroxyurea. 
 
4.2 
Posology and method of administration 
Jakavi treatment should only be initiated by a physician experienced in the administration of 
anti-cancer agents. 


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A complete blood cell count, including a white blood cell count differential, must be performed 
before initiating therapy with Jakavi. 
Complete blood count, including a white blood cell count differential, should be monitored 
every 2-4 weeks until Jakavi doses are stabilised, and then as clinically  indicated  (see  section 
4.4). 
Posology 
Starting dose 
The recommended starting dose of Jakavi in myelofibrosis is 15 mg twice daily for patients 
with a platelet count between 100,000/mm3 and 200,000/mm3 and 20 mg twice daily for patients 
with a platelet count of >200,000/mm3. The recommended starting dose of Jakavi in 
polycythaemia vera is 10 mg given orally twice daily. 
There is limited information to recommend a starting dose for patients with platelet counts 
between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these 
patients is 5 mg twice daily and the patients should be titrated cautiously. 
Dose modifications 
Doses may be titrated based on safety and efficacy. Treatment should be discontinued for 
platelet counts less than 50,000/mm3 or absolute neutrophil counts less than 500/mm3. In PV, 
treatment should also be interrupted when haemoglobin is below 8 g/dl. After recovery of blood 
counts above these levels, dosing may be re-started at 5 mg twice daily and gradually increased 
based on careful monitoring of complete blood cell count, including a white blood cell count 
differential. 
Dose reductions should be considered if the platelet count decreases below 100,000/mm3, with 
the goal of avoiding dose interruptions for thrombocytopenia. In PV, dose reductions should 
also be considered if haemoglobin decreases below 12 g/dl and is recommended if it decreases 
below 10 g/dl. 
If efficacy is considered insufficient and blood counts are adequate, doses may be increased by 
a maximum of 5 mg twice daily, up to the maximum dose of 25 mg twice daily. 
The starting dose should not be increased within the first four weeks of treatment and thereafter 
no more frequently than at 2-week intervals. 
The maximum dose of Jakavi is 25 mg twice daily. 
Dose adjustment with concomitant strong CYP3A4 inhibitors or fluconazole 
When Jakavi is administered with strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and 
CYP3A4 enzymes (e.g. fluconazole) the unit dose of Jakavi should be reduced by 
approximately 50%, to be administered twice daily (see section 4.5). Avoid the concomitant use 
of Jakavi with fluconazole doses greater than 200 mg daily. 
More frequent monitoring (e.g. twice a week) of haematology parameters and of clinical signs 
and symptoms of Jakavi-related adverse drug reactions is recommended while on strong 
CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes. 


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Special populations 
Renal impairment 
No specific dose adjustment is needed in patients with mild or moderate renal impairment. 
In patients with severe renal impairment (creatinine clearance less than 30 ml/min) the 
recommended starting dose based on platelet count for MF patients should be reduced by 
approximately 50% to be administered twice daily. The recommended starting dose for PV 
patients with severe renal impairment is 5 mg twice daily. Patients should be carefully 
monitored with regard to safety and efficacy during Jakavi treatment. 
There are limited data to determine the best dosing options for patients with end-stage renal 
disease (ESRD) on haemodialysis. Pharmacokinetic/pharmacodynamic simulations based on 
available data in this population suggest that the starting dose for MF patients with ESRD on 
haemodialysis is a single dose of 15-20 mg or two doses of 10 mg given 12 hours apart, to be 
administered post-dialysis and only on the day of haemodialysis. A single dose of 15 mg is 
recommended for MF patients with platelet count between 100,000/mm3 and 200,000/mm3. A 
single dose of 20 mg or two doses of 10 mg given 12 hours apart is recommended for MF 
patients with platelet count of >200,000/mm3. Subsequent doses (single administration or two 
doses of 10 mg given 12 hours apart) should be administered only on haemodialysis days 
following each dialysis session. 
The recommended starting dose for PV patients with ESRD on haemodialysis is a single dose 
of 10 mg or two doses of 5 mg given 12 hours apart, to be administered post-dialysis and only 
on the day of haemodialysis. These dose recommendations are based on simulations and any 
dose modification in ESRD should be followed by careful monitoring of safety and efficacy in 
individual patients. No data is available for dosing patients who are undergoing peritoneal 
dialysis or continuous venovenous haemofiltration (see section 5.2). 
Hepatic impairment 
In patients with any hepatic impairment the recommended starting dose based on  platelet count 
should be reduced by approximately 50% to be administered twice daily. Subsequent doses 
should be adjusted based on careful monitoring of safety and efficacy. Patients diagnosed with 
hepatic impairment while receiving Jakavi should have complete blood counts, including a white 
blood cell count differential, monitored at least every one to two weeks for the first 6 weeks after 
initiation of therapy with Jakavi and as clinically indicated thereafter once their liver function 
and blood counts have been stabilised. Jakavi dose can be titrated to reduce the risk of cytopenia. 
Older people (≥65 years) 
No additional dose adjustments are recommended for older people. 
Paediatric population 
The safety and efficacy of Jakavi in children aged up to 18 years have not been established. No 
data are available (see section 5.1). 


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Treatment discontinuation 
Treatment may be continued as long as the benefit-risk remains positive. However the treatment 
should be discontinued after 6 months if there has been no reduction in spleen size or 
improvement in symptoms since initiation of therapy. 
It is recommended that, for patients who have demonstrated some degree of clinical 
improvement, ruxolitinib therapy be discontinued if they sustain an increase in their spleen 
length of 40% compared with baseline size (roughly equivalent to a 25% increase in spleen 
volume) and no longer have tangible improvement in disease-related symptoms. 
Method of administration 
Jakavi is to be taken orally, with or without food. 
If a dose is missed, the patient should not take an additional dose, but should take the next usual 
prescribed dose. 
 
4.3 
Contraindications 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Pregnancy and lactation. 
4.4 
Special warnings and precautions for use 
Myelosuppression 
Treatment with Jakavi can cause haematological adverse drug reactions, including 
thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood 
cell count differential, must be performed before initiating therapy with Jakavi. Treatment 
should be discontinued in patients with platelet count less than 50,000/mm3 or absoute 
neutrophil count less than 500/mm3 (see section 4.2). 
It has been observed that patients with low platelet counts (<200,000/mm3) at the start of therapy 
are more likely to develop thrombocytopenia during treatment. 
Thrombocytopenia is generally reversible and is usually managed by reducing the dose or 
temporarily withholding Jakavi (see sections 4.2 and 4.8). However, platelet transfusions may 
be required as clinically indicated. 
Patients developing anaemia may require blood transfusions. Dose modifications or interruption 
for patients developing anaemia may also be considered. 
Patients with a haemoglobin level below 10.0 g/dl at the beginning of the treatment have a 
higher risk of developing a haemoglobin level below 8.0 g/dl during treatment compared to 
patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent 
monitoring of haematology parameters and of clinical signs and symptoms of Jakavi-related 
adverse drug reactions is recommended for patients with baseline haemoglobin below 
10.0 g/dl. 
Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by 
temporarily withholding Jakavi (see sections 4.2 and 4.8). 


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Complete blood counts should be monitored as clinically indicated and dose adjusted as 
required (see sections 4.2 and 4.8). 
Infections 
Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal 
and viral infections. Tuberculosis has been reported in patients receiving Jakavi for MF. Before 
starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, 
as per local recommendations. This can include medical history, possible previous contact with 
tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-
gamma release assay, as applicable. Prescribers are reminded of the risk of false negative 
tuberculin skin test results, especially in patients who are severely ill or immunocompromised. 
Jakavi therapy should not be started until active serious infections have resolved. Physicians 
should carefully observe patients receiving Jakavi for signs and symptoms of infections and 
initiate appropriate treatment promptly (see section 4.8). 
Hepatitis B viral load (HBV-DNA titre) increases, with and without associated elevations in 
alanine aminotransferase and aspartate aminotransferase, have been reported in patients with 
chronic HBV infections taking Jakavi. The effect of Jakavi 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. 
Herpes zoster 
Physicians should educate patients about early signs and symptoms of herpes zoster, advising 
that treatment should be sought as early as possible. 
Progressive multifocal leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) has been reported with Jakavi treatment for 
MF. Physicians should be particularly alert to symptoms suggestive of PML that patients may 
not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be 
monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs 
occur, referral to a neurologist and appropriate diagnostic measures for PML should be 
considered. If PML is suspected, further dosing must be suspended until PML has been 
excluded. 
Non-melanoma skin cancer 
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell 
carcinoma, have been reported in patients treated with ruxolitinib. Most of these patients had 
histories of extended treatment with hydroxyurea and prior NMSC or pre-malignant skin 
lesions. A causal relationship to ruxolitinib has not been established. Periodic skin examination 
is recommended for patients who are at increased risk for skin cancer. 
Special populations 
Renal impairment 
The starting dose of Jakavi should be reduced in patients with severe renal impairment. For 
patients with end-stage renal disease on haemodialysis the starting dose for MF patients should 
be based on platelet counts (see section 4.2). Subsequent doses (single dose of 20 mg 


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or two doses of 10 mg given 12 hours apart in MF patients; single dose of 10 mg or two doses 
of 5 mg given 12 hours apart in PV patients) should be administered only on haemodialysis 
days following each dialysis session. Additional dose modifications should be made with 
careful monitoring of safety and efficacy (see sections 4.2 and 5.2). 
Hepatic impairment 
The starting dose of Jakavi should be reduced by approximately 50% in patients with hepatic 
impairment. Further dose modifications should be based on the safety and efficacy of the 
medicinal product (see sections 4.2 and 5.2). 
Interactions 
If Jakavi is to be co-administered with strong CYP3A4 inhibitors or dual inhibitors of CYP3A4 
and CYP2C9 enzymes (e.g. fluconazole), the unit dose of Jakavi should be reduced by 
approximately 50%, to be administered twice daily (for monitoring  frequency  see  sections 4.2 
and 4.5). 
The concomitant use of cytoreductive therapies or haematopoietic growth factors with Jakavi 
has not been studied. The safety and efficacy of these co-administrations are not known (see 
section 4.5). 
Withdrawal effects 
Following interruption or discontinuation of Jakavi, symptoms of MF may return over a period 
of approximately one week. There have been cases of patients discontinuing Jakavi who 
sustained more severe events, particularly in the presence of acute intercurrent illness. It has not 
been established whether abrupt discontinuation of Jakavi contributed to these events. Unless 
abrupt discontinuation is required, gradual tapering of the dose of Jakavi may be considered, 
although the utility of the tapering is unproven. 
Excipients 
Jakavi contains lactose. Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal 
product. 
 
4.5 
Interaction with other medicinal products and other forms of interaction 
Interaction studies have only been performed in adults. 
Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, 
medicinal products inhibiting these enzymes can give rise to increased ruxolitinib exposure. 
Interactions resulting in dose reduction of ruxolitinib 
CYP3A4 inhibitors 
Strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, saquinavir, telaprevir, telithromycin, voriconazole) 
In healthy subjects co-administration of Jakavi (10 mg single dose) with a strong CYP3A4 
inhibitor, ketoconazole, resulted in ruxolitinib Cmax and AUC that were higher by 33% and 


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91%, respectively, than with ruxolitinib alone. The half-life was prolonged from 3.7 to 
6.0 hours with concurrent ketoconazole administration. 
When administering Jakavi with strong CYP3A4 inhibitors the unit dose of Jakavi should be 
reduced by approximately 50%, to be administered twice daily. Patients should be closely 
monitored (e.g. twice weekly) for cytopenias and dose titrated based on safety and efficacy (see 
section 4.2). 
Dual CYP2C9 and CYP3A4 inhibitors 
50% dose reduction should be considered when using medicinal products which are dual 
inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of 
Jakavi with fluconazole doses greater than 200 mg daily. 
Enzyme inducers 
CYP3A4 inducers (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St.John’s wort (Hypericum perforatum)) 
Patients should be closely monitored and the dose titrated based on safety and efficacy (see 
Section 4.2). 
In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducer 
rifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after 
administration of Jakavi alone. The exposure of ruxolitinib active metabolites was unchanged. 
Overall, the ruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 
induction resulted in minimal effect on the pharmacodynamics. However, this could be related 
to the high ruxolitinib dose resulting in pharmacodynamic effects near Emax. It is possible that 
in the individual patient, an increase of the ruxolitinib dose is needed when initiating treatment 
with a strong enzyme inducer. 
Other interactions to be considered affecting ruxolitinib 
Mild or moderate CYP3A4 inhibitors (such as, but not limited to, ciprofloxacin, erythromycin, 
amprenavir, atazanavir, diltiazem, cimetidine) 
In healthy subjects co-administration of ruxolitinib (10 mg single dose) with erythromycin 500 
mg twice daily for four days resulted in ruxolitinib Cmax and AUC that were higher by 8% and 
27%, respectively, than with ruxolitinib alone. 
No dose adjustment is recommended when ruxolitinib is co-administered with mild or moderate 
CYP3A4 inhibitors (e.g. erythromycin). However, patients should be closely monitored for 
cytopenias when initiating therapy with a moderate CYP3A4 inhibitor. 
Effects of ruxolitinib on other medicinal products 
Substances transported by P-glycoprotein or other transporters 
Ruxolitinib may inhibit P-glycoprotein and breast cancer resistance protein (BCRP) in the 
intestine. This may result in increased sytemic exposure of substrates of these transporters, such 
as dabigatran etexilate, ciclosporin, rosuvastatin and potentially digoxin. Therapeutic drug 
monitoring (TDM) or clinical monitoring of the affected substance is advised. 


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It is possible that the potential inhibition of P-gp and BCRP in the intestine can be minimised 
if the time between administrations is kept apart as long as possible. 
Haematopoietic growth factors 
The concurrent use of haematopoietic growth factors and Jakavi has not been studied. It is not 
known whether the Janus Associated Kinase (JAK) inhibition by Jakavi reduces the efficacy of 
the haematopoietic growth factors or whether the haematopoietic growth factors affect the 
efficacy of Jakavi (see section 4.4). 
Cytoreductive therapies 
The concomitant use of cytoreductive therapies and Jakavi has not been studied. The safety and 
efficacy of this co-administration is not known (see section 4.4). 
A study in healthy subjects indicated that ruxolitinib did not inhibit the metabolism of the oral 
CYP3A4 substrate midazolam. Therefore, no increase in exposure of CYP3A4 substrates is 
anticipated when combining them with Jakavi. Another study in healthy subjects indicated that 
Jakavi does not affect the pharmacokinetics of an oral contraceptive containing ethinylestradiol 
and levonorgestrel. Therefore, it is not anticipated that the contraceptive efficacy of this 
combination will be compromised by co-administration of ruxolitinib. 
 
4.6 
Fertility, pregnancy and lactation 
Pregnancy and contraception in females 
There are no data from the use of Jakavi in pregnant women. 
Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was 
not observed in rats or rabbits. However, the exposure margins compared to the highest clinical 
dose were low and the results are therefore of limited relevance for humans (see section 5.3). 
The potential risk for humans is unknown. As a precautionary measure, the use of Jakavi during 
pregnancy is contraindicated (see section 4.3). Women of child-bearing potential should use 
effective contraception during the treatment with Jakavi. In case pregnancy should occur during 
treatment with Jakavi, a risk/benefit evaluation must  be carried out on an individual basis with 
careful counselling regarding potential risks to the foetus (see Section 5.3). 
Breast-feeding 
Jakavi must not be used during breast-feeding (see section 4.3) and breast-feeding should 
therefore be discontinued when treatment is started. It is unknown whether ruxolitinib and/or 
its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. 
Available pharmacodynamic/toxicological data in animals have shown excretion of  ruxolitinib 
and its metabolites in milk (see section 5.3). 
Fertility 
There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect  
on fertility was observed. 


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4.6 
Effects on ability to drive and use machines 
Jakavi has no or negligible sedating effect. However, patients who experience dizziness after 
the intake of Jakavi should refrain from driving or using machines. 
 
4.8 
Undesirable effects 
Summary of the safety profile 
The safety assessment was based on a total of 855 patients (with MF or PV) receiving Jakavi in    
phase 2 and 3 studies. 
Myelofibrosis 
In the randomised period of the two pivotal studies, COMFORT-I and COMFORT-II, the 
median duration of exposure to Jakavi was 10.8 months (range 0.3 to 23.5 months). The 
majority of patients (68.4%) were treated for at least 9 months. Of 301 patients, 111 (36.9%) 
had a baseline platelet count of between 100,000/mm3 and 200,000/mm3 and 190 (63.1%) had 
a baseline platelet count of >200,000/mm3. 
In these clinical studies, discontinuation due to adverse events, regardless of causality, was 
observed in 11.3% of patients. 
The most frequently reported adverse drug reactions were thrombocytopenia and anaemia. 
Haematological adverse drug reactions (any Common Terminology Criteria for Adverse Events 
[CTCAE] grade) included anaemia (82.4%), thrombocytopenia (69.8%) and neutropenia (16.6%). 
Anaemia, thrombocytopenia and neutropenia are dose-related effects. 
The three most frequent non-haematological adverse drug reactions were bruising (21.3%), dizziness 
(15.3%) and headache (14.0%). 
The three most frequent non-haematological laboratory abnormalities were raised alanine 
aminotransferase (27.2%), raised aspartate aminotransferase (19.9%) and hypercholesterolaemia 
(16.9%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4 hypercholesterolaemia, raised 
aspartate aminotransferase nor CTCAE grade 4 raised alanine aminotransferase were observed. 
Long-term safety: As expected with an extended follow-up period, the cumulative frequency of some 
adverse events increased in the evaluation of the 3-year follow-up safety data (median duration of 
exposure of 33.2 months in COMFORT-I and COMFORT-II for patients initially randomised to 
ruxolitinib) from 457 patients with myelofibrosis treated with ruxolitinib during the randomised and 
extension periods of the two pivotal phase 3 studies. This evaluation included data from patients that 
were initially randomised to ruxolitinib (N=301) and patients that received ruxolitinib after crossing 
over from control treatment arms (N=156). With these updated data, therapy discontinuation due to 
adverse events was observed in 17.1% of patients treated with ruxolitinib. 
Polycythaemia vera 
The safety of Jakavi was assessed in 110 patients with PV in an open-label, randomised, 
controlled phase 3 RESPONSE study. The adverse drug reactions listed below reflect the initial 
study period (up to week 32) with equivalent exposure to ruxolitinib and Best Available 
Therapy (BAT), corresponding to a median duration of exposure to Jakavi of 7.8 months. The 
mean age of patients receiving Jakavi was around 60 years. 


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Discontinuation due to adverse events, regardless of causality, was observed in 3.6% of patients 
treated with Jakavi and 1.8% of patients treated with best available therapy. 
Haematological adverse reactions (any CTCAE grade) included anaemia (43.6%) and 
thrombocytopenia (24.5%). Anaemia or thrombocytopenia CTCAE grade 3 and 4 were reported 
in respectively 1.8% or 5.5%. 
The three most frequent non-haematological adverse reactions were dizziness (15.5%), 
constipation (8.2%) and herpes zoster (6.4%). 
The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) were 
hypercholesterolaemia (30.0%), raised alanine aminotransferase (22.7%) and raised aspartate 
aminotransferase (20.9%). These were all CTCAE grade 1 and 2 with the exception of one 
CTCAE grade 3 raised alanine aminotransferase event. 
Long-term safety: Patients had a median duration of exposure to Jakavi of 18.6 months (range 
0.3 to 35.9 months). With longer exposure, frequency of adverse events increased; however no 
new safety findings emerged. When adjusted for exposure, the adverse event rates were 
generally comparable with those observed during the initial study period. 
Tabulated summary of adverse drug reactions from clinical studies 
In the clinical study programme the severity of adverse drug reactions was assessed based on the 
CTCAE, defining grade 1 = mild, grade 2 = moderate, grade 3 = severe and grade 4=life-threatening. 
Adverse drug reactions from clinical studies (Table 14-2) are listed by MedDRA system organ class. 
Within each system organ class, the adverse drug reactions are ranked by frequency, with the most 
frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction 
is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon 
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). 
 
Table 14-2 
Frequency category of adverse drug reactions reported in the phase 3 
studies (COMFORT-I, COMFORT-II, RESPONSE) 
 
Adverse drug reaction 
Frequency category for MF 
patients 
Frequency category for PV patients 
Infections and infestations 
Urinary tract infectionsa,d 
Very common 
Common 
Herpes zostera,d 
Common 
Common 
Tuberculosise 
Uncommon 
- 
Blood and lymphatic system 
disordersb,d 
Anaemiab 
- 
- 
CTCAEc grade 4 
(<6.5g/dl) 
Very common 
Uncommon 
CTCAEc grade 3 
(<8.0 – 6.5g/dl) 
Very common 
Uncommon 


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Adverse drug reaction 
Frequency category for MF 
patients 
Frequency category for PV patients 
Any CTCAEc grade 
Very common 
Very common 
Thrombocytopeniab 
CTCAEc grade 4 
(<25,000/mm3) 
Common 
Uncommon 
CTCAEc grade 3 
(50,000 – 25,000/mm3) 
Common 
Common 
Any CTCAEc grade 
Very common 
Very common 
Neutropeniab 
CTCAEc grade 4 
(<500/mm3) 
Common 
- 
CTCAEc grade 3 
(<1,000 – 500/mm3) 
Common 
- 
Any CTCAEc grade 
Very common 
- 
Bleeding (any bleeding including 
intracranial, and gastrointestinal 
bleeding, bruising and other 
bleeding) 
Very common 
Very common 
Intracranial bleeding 
Common 
- 
Gastrointestinal bleeding 
Common 
- 
Bruising 
Very common 
Very common 
Other bleeding (including 
epistaxis, post-procedural 
haemorrhage and haematuria) 
Common 
Very common 
Metabolism and nutrition 
disorders 
Weight gaina 
Very common 
Common 
Hypercholesterolaemiab 
CTCAEc grade 1 and 2 
Very common 
Very common 
Hypertriglyceridaemiab 
CTCAEc grade 1 
- 
Very common 
Nervous system disorders 
Dizzinessa 
Very common 
Very common 
Headachea 
Very common 
- 
Gastrointestinal disorders 
Flatulencea 
Common 
- 
Constipationa 
- 
Common 
Hepatobiliary disorders 
Raised alanine aminotransferaseb 


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Adverse drug reaction 
Frequency category for MF 
patients 
Frequency category for PV patients 
CTCAEc grade 3 
(> 5x – 20 x ULN) 
Common 
Uncommon 
Any CTCAEc grade 
Very common 
Very common 
Raised aspartate 
aminotransferaseb 
Any CTCAEc grade 
Very common 
Very common 
Vascular disorders 
Hypertensiona 
- 
Very common 
aFrequency is based on adverse event data. 
• 
A subject with multiple occurrence of an adverse drug reaction (ADR) is counted only once in that ADR 
category. 
• 
ADRs reported are on treatment or up to 28 days post treatment end date. 
bFrequency is based on laboratory values. 
• 
A subject with multiple occurrences of an ADR is counted only once in that ADR category. 
• 
ADRs reported are on treatment or up to 28 days post treatment end date. 
cCommon Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild, grade 2 = moderate, 
grade 3 = severe, grade 4 = life-threatening 
dThese ADRs are discussed in the text. 
eFrequency is based on all patients exposed to ruxolitinib in clinical studies (N=4755) 
Upon discontinuation, MF patients may experience a return of MF symptoms such as fatigue, 
bone pain, fever, pruritus, night sweats, symptomatic splenomegaly and weight loss. In clinical 
studies in MF the total symptom score for MF symptoms gradually returned to baseline value 
within 7 days after dose discontinuation (see Section 4.4). 
Description of selected adverse drug reactions 
Anaemia 
In phase 3 clinical studies in MF, median time to onset of first CTCAE grade 2 or higher anaemia was 
1.5 months. One patient (0.3%) discontinued treatment because of anaemia. 
In patients receiving  Jakavi  mean  decreases  in  haemoglobin  reached  a  nadir  of  approximately  10 
g/litre below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady 
state that was approximately 5 g/litre below baseline. This pattern was observed in patients regardless 
of whether they had received transfusion during therapy. 
In the randomised, placebo-controlled study COMFORT-I 60.6% of Jakavi-treated MF patients and 
37.7% of placebo-treated MF patients received red blood cell transfusions during randomised treatment. 
In the COMFORT-II study the rate of packed red blood cell transfusions was 53.4% in the Jakavi arm 
and 41.1% in the best available therapy arm. 
In the randomised period of the pivotal studies, anaemia was less frequent in PV patients than in MF 
patients (43.6% versus 82.4%). In the PV population, the CTCAE grade 3 and 4 events were reported in 
1.8%, while in the MF patients the frequency was 42.56%. 
Thrombocytopenia 
In the phase 3 clinical studies in MF, 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 50,000/mm3 


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was 14 days. During the randomised period, platelet transfusions were administered to 4.7% of patients 
receiving Jakavi and to 4.0% of patients receiving control regimens. Discontinuation of treatment 
because of thrombocytopenia occurred in 0.7% of patients receiving Jakavi and 0.9% of patients 
receiving control regimens. Patients with a platelet count of 100,000/mm3 to 200,000/mm3 before starting 
Jakavi had a higher frequency of grade 3 or 4 thrombocytopenia compared to patients with platelet count 
>200,000/mm3 (64.2% versus 38.5%). 
In the randomised period of the pivotal studies, the rate of patients experiencing thrombocytopenia  was 
lower in PV (24.5%) patients compared to MF (69.8%) patients. The frequency of severe (i.e. CTCAE 
grade 3 and 4) thrombocytopenia was lower in PV (5.5%) than in MF (11.6%) patients. 
Neutropenia 
In the phase 3 clinical studies in MF, in patients who developed grade 3 or 4 neutropenia, the median 
time to onset was 12 weeks. During the randomised period, dose holding or reductions due to 
neutropenia were reported in 1.0% of patients, and 0.3% of patients discontinued treatment because of 
neutropenia. 
In the randomised period of the pivotal study in PV patients, neutropenia was reported in two patients 
(1.8%) of which one patient developed CTCAE grade 4 neutropenia. 
Bleeding 
In the phase 3 pivotal studies in MF bleeding events (including intracranial and gastrointestinal, bruising 
and other bleeding events) were reported in 32.6% of patients exposed to Jakavi and 23.2% of patients 
exposed to the reference treatments (placebo or best available therapy). The frequency of grade 3-4 
events was similar for patients treated with Jakavi or reference treatments (4.7% versus 3.1%). Most of 
the patients with bleeding events during the treatment reported bruising (65.3%). Bruising events were 
more frequently reported in patients taking Jakavi compared with the reference treatments (21.3% versus 
11.6%). Intracranial bleeding was reported in 1% of patients exposed to Jakavi and 0.9% exposed to 
reference treatments. Gastrointestinal bleeding was reported in 5.0% of patients exposed to Jakavi 
compared to 3.1% exposed to reference treatments. Other bleeding events (including events such as 
epistaxis, post-procedural haemorrhage and haematuria) were reported in 13.3% of patients treated with 
Jakavi and 10.3% treated with reference treatments. 
In the randomised period of the pivotal study in PV patients, bleeding events (including intracranial and 
gastrointestinal, bruising and other bleeding events) were reported in 20% of patients treated with Jakavi 
and 15.3% patients receiving best available therapy. Bruising was reported in similar frequencies in 
Jakavi and BAT arms (10.9% versus 8.1%). No intracranial bleeding or gastrointestinal haemorrhage 
events were reported in patients receiving Jakavi. One patient treated with Jakavi experienced a grade 3 
bleeding event (post-procedural bleeding); no grade 4 bleeding was reported. Other bleeding events 
(including events such as epistaxis, post-procedural haemorrhage, gingival bleeding) were reported in 
11.8% of patients treated with Jakavi and 6.3% treated with best available therapy. 
Infections 
In the phase 3 pivotal studies in MF, grade 3 or 4 urinary tract infection was reported in 1.0% of patients, 
herpes zoster in 4.3% and tuberculosis in 1.0%. In phase 3 clinical studies sepsis was reported in 3.0% 
of patients. An extended follow-up of patients treated with ruxolitinib showed no trends towards an 
increase in the rate of sepsis over time. 
In the randomised period of the pivotal study in PV patients, one (0.9%) CTCAE grade 3 and no grade 
4 urinary tract infection was reported. The rate of herpes zoster was slightly higher in PV (6.4%) 


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patients than in MF (4.0%) patients. There was one report of CTCAE grade 3 post-herpetic neuralgia 
amongst the PV patients. 
Increased systolic blood pressure 
In the phase 3 pivotal clinical studies in MF an increase in systolic blood pressure of 20 mmHg or more 
from baseline was recorded in 31.5% of patients on at least one visit compared with 19.5% of the control-
treated patients. In COMFORT-I (MF patients) the mean increase from baseline in systolic BP was 0-2 
mmHg on Jakavi versus a decrease of 2-5 mmHg in the placebo arm. In COMFORT-II mean values 
showed little difference between the ruxolitinib-treated and the control-treated MF patients. 
In the randomised period of the pivotal study in PV patients, the mean systolic blood pressure 
increased by 0.65 mmHg in the Jakavi arm versus a decrease of 2 mmHg in the BAT arm. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 
Overdose 
There is no known antidote for overdoses with Jakavi. 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, anaemia and thrombocytopenia. 
Appropriate supportive treatment should be given. 
Haemodialysis is not expected to enhance the elimination of ruxolitinib. 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: 
L01XE18 
Mechanism of action 
Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 
(IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These  mediate 
the signalling of a number of cytokines and growth factors that are important for haematopoiesis 
and immune function. 
Myelofibrosis and polycythaemia vera are myeloproliferative neoplasms known to be 
associated with dysregulated JAK1 and JAK2 signalling. The basis for the dysregulation is 
believed to include high levels of circulating cytokines that activate the JAK-STAT pathway, 
gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory 
mechanisms. MF patients exhibit dysregulated JAK signalling regardless of JAK2V617F 
mutation status. Activating mutations in JAK2 (V617F or exon 12) are found in >95% of PV 
patients. 
Ruxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular 
models of haematological malignancies, as well as of Ba/F3 cells rendered 


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cytokine-independent by expressing the JAK2V617F mutated protein, with IC50 ranging from 
80-320 nM. 
Pharmacodynamic effects 
Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy 
subjects, MF patients and PV patients. Ruxolitinib resulted in maximal inhibition of STAT3 
phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy 
subjects and MF patients, indicating no accumulation of either parent or active metabolites. 
Baseline elevations in inflammatory markers associated with constitutional symptoms such as 
TNFα, IL-6 and CRP in subjects with MF were decreased following treatment with ruxolitinib. 
MF patients did not become refractory to the pharmacodynamic effects of  ruxolitinib treatment 
over time. Similarly, patients with PV also presented with baseline elevations in inflammatory 
markers and these markers were decreased following treatment with ruxolitinib. 
In a thorough QT study in healthy subjects, there was no indication of a QT/QTc prolonging 
effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, indicating that 
ruxolitinib has no effect on cardiac repolarisation. 
Clinical efficacy and safety 
Myelofibrosis 
Two randomised phase 3 studies (COMFORT-I and COMFORT-II) were conducted in patients 
with MF (primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential 
thrombocythaemia myelofibrosis). In both studies, patients had palpable splenomegaly at least 
5 cm below the costal margin and risk category of intermediate-2 or high risk based on the 
International Working Group (IWG) Consensus Criteria. The starting dose of Jakavi was based 
on platelet count. 
COMFORT-I was a double-blind, randomised, placebo-controlled study in 309 patients who 
were refractory to or were not candidates for available therapy. The primary efficacy endpoint 
was proportion of subjects achieving ≥35% reduction from baseline in spleen volume  at  week 
24 as measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). 
Secondary endpoints included duration of maintenance of a ≥35% reduction from baseline in 
spleen volume, proportion of patients who had ≥50% reduction in total symptom score, changes 
in total symptom scores from baseline to week 24, as measured by the modified Myelofibrosis 
Symptom Assessment Form (MFSAF) v2.0 diary, and overall survival. 
COMFORT-II was an open-label, randomised study in 219 patients. Patients were randomised 
2:1 to Jakavi versus best available therapy. In the best available therapy arm, 47% of patients 
received hydroxyurea and 16% of patients received glucocorticoids. The primary efficacy 
endpoint was proportion of patients achieving ≥35% reduction from baseline in spleen volume 
at week 48 as measured by MRI or CT. 
Secondary endpoints included proportion of patients achieving a ≥35% reduction of spleen 
volume from baseline at week 24 and duration of maintenance of a ≥35% reduction from 
baseline spleen volume. 


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In COMFORT-I and COMFORT-II, patient baseline demographics and disease characteristics 
were comparable between the treatment arms. 
 
Table 14-3 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume at week 24 in COMFORT-I and at week 48 in COMFORT-II (ITT) 
 
COMFORT-I 
COMFORT-II 
Jakavi 
(N=155) 
Placebo 
(N=153) 
Jakavi 
(N=144) 
Best available 
therapy 
(N=72) 
Time points 
Week 24 
Week 48 
Number (%) of subjects with 
spleen volume reduced by 
≥35% 
65 (41.9) 
1 (0.7) 
41 (28.5) 
0 
95% confidence intervals 
34.1, 50.1 
0, 3.6 
21.3, 36.6 
0.0, 5.0 
p-value 
<0.0001 
<0.0001 
A significantly higher proportion of patients in the Jakavi group achieved ≥35% reduction from 
baseline in spleen volume (Table 14-3) regardless of the presence or absence of the JAK2V617F 
mutation or the disease subtype (primary myelofibrosis, post-polycythaemia vera 
myelofibrosis, post-essential thrombocythaemia myelofibrosis). 
 
Table 14-4 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume by JAK mutation status (safety set) 
 
COMFORT-I 
COMFORT-II 
Jakavi 
Placebo 
Jakavi 
Best available 
therapy 
JAK 
mutation 
status 
Positive 
(N=113) 
n (%) 
Negative 
(N=40) 
n (%) 
Positive 
(N=121) 
n (%) 
Negative 
(N=27) 
n (%) 
Positive 
(N=110) 
n (%) 
Negative 
(N=35) 
n (%) 
Positive 
(N=49) 
n (%) 
Negative 
(N=20) 
n (%) 
Number 
(%) of 
subjects 
with spleen 
volume 
reduced by 
≥35% 
54 (47.8) 
11 (27.5) 
1 (0.8) 
0 
36 (32.7) 
5 (14.3) 
0 
0 
Time point 
After 24 weeks 
After 48 weeks 
The probability of maintaining spleen  response  (≥35%  reduction)  on  Jakavi  for  at  least 24 
weeks was 89% in COMFORT-I and 87% in COMFORT-II; 52% maintained spleen responses 
for at least 48 weeks in COMFORT-II. 
In COMFORT-I, 45.9% subjects in the Jakavi group achieved a ≥50% improvement from 
baseline in the week 24 total symptom score (measured using MFSAF diary v2.0), as compared 
to 5.3% in the placebo group (p<0.0001 using chi-square test). The mean change in the global 
health status at week 24, as measured by EORTC QLQ C30 was +12.3 for Jakavi and -3.4 for 
placebo (p<0.0001). 
In COMFORT-I, after a median follow-up of 34.3 months, the death rate in patients randomised 
to the ruxolitinib arm was 27.1% versus 35.1% in patients randomised to placebo; HR 0.687; 
95% CI 0.459-1.029; p=0.0668. 


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In COMFORT-II, after a median follow-up of 34.7 months, the death rate in patients 
randomised to ruxolitinib was 19.9% versus 30.1% in patients randomised to best available 
treatment (BAT); HR 0.48; 95% CI 0.28-0.85; p=0.009. In both studies, the lower death rates 
noted in the ruxolitinib arm were predominantly driven by the results obtained in the post 
polycythaemia vera and post essential thrombocythaemia subgroups. 
Polycythaemia vera 
A randomised, open-label, active-controlled phase 3 study (RESPONSE) was conducted in 222 
patients with PV who were resistant to or intolerant of hydroxyurea defined based on the 
European LeukemiaNet (ELN) international working group published criteria. 110 patients 
were randomised to the ruxolitinib arm and 112 patients to the BAT arm. The starting dose of 
Jakavi was 10 mg twice daily. Doses were then adjusted in individual patients based on 
tolerability and efficacy with a maximum dose of 25 mg twice daily. BAT was selected by the 
investigator 
on 
a 
patient-by-patient 
basis 
and 
included 
hydroxyurea 
(59.5%), 
interferon/pegylated interferon (11.7%), anagrelide (7.2%), pipobroman (1.8%) and 
observation (15.3%). 
Baseline demographics and disease characteristics were comparable between the two treatments 
arms. The median age was 60 years (range 33 to 90 years). Patients in the ruxolitinib arm had 
PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median 
of approximately 3 years. Most patients (>80%) had received at least two phlebotomies in the 
last 24 weeks prior to screening. Comparative data regarding long-term survival and incidence 
of disease complications is missing. 
The primary composite endpoint was the proportion of patients achieving both an absence of 
phlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volume from baseline at 
week 32. Phlebotomy eligibility was  defined  as  a  confirmed  HCT  of  >45%,  i.e.  at  least 3 
percentage points higher than the HCT obtained at baseline or a confirmed HCT of >48%, 
depending on which was lower. Key secondary endpoints included the proportion of patients 
who achieved the primary endpoint and remained free from progression at week 48, as well as 
the proportion of patients achieving complete haematological remission at week 32. 
The study met its primary objective and a higher proportion of patients in the Jakavi group 
achieved the primary composite endpoint and each of its individual components. Significantly 
more patients treated with Jakavi (20.9%) achieved a primary response (p<0.0001) compared 
to BAT (0.9%). Haematocrit control was achieved in 60% of patients in the Jakavi arm  
compared to 19.6% in the BAT arm and a ≥35% reduction in spleen volume was achieved in 
38.2% of patients in the  Jakavi  arm  compared  to  0.9%  in  the  BAT  arm  (Figure  14-1). 94 
(83.9%) patients randomised to the BAT arm crossed over to ruxolitinib treatment at  Week 32 
or after, limiting the comparison between the two arms after Week 32. 
Both key secondary endpoints were also met. The proportion of patients achieving a complete 
haematological remission was 23.6% on Jakavi compared to 8.9% on BAT (p=0.0028) and the 
proportion of patients achieving a durable primary response at week 48 was 19.1% on Jakavi 
and 0.9% on BAT.(p<0.0001). 


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and 95% CI: 
28.64 (4.50, 12.06) 
 
Figure 14-1 
Patients achieving the primary endpoint and components of the 
primary endpoint at week 32 
 
 
P-value: < .0001 
70 
Odds Ratio (Ruxolitinib/BAT) 
60 
50 
40 
30 
20 
10 
0 
Individual components of Primary 
Response at Week 32 
60 
 
 
 
20 
 
 
 
 
 
.RUX 
.BAT 
Primary Composite 
Endpoint at Week 32 
≥ 35% reduction in 
Spleen Volume 
Hematocrit control 
without phlebotomy 
 
Symptom burden was assessed using the MPN-SAF total symptom score (TSS) electronic 
patient diary, which consisted of 14 questions. At week 32, 49% and 64% of patients treated 
with ruxolitinib achieved a ≥50% reduction in TSS-14 and TSS-5, respectively, compared to 
only 5% and 11% of patients on BAT. 
Treatment benefit perception was measured by the Patient Global Impression of Change (PGIC) 
questionnaire. 66% of patients treated with ruxolitinib compared to 19% treated with BAT 
reported an improvement as early as four weeks after beginning treatment. Improvement in 
perception of treatment benefit was also higher in  patients  treated  with  ruxolitinib at week 
32 (78% versus 33%). 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Jakavi in all subsets of the paediatric population for the treatment of MF (see section 4.2 for 
information on paediatric use). 
 
5.2 
Pharmacokinetic properties 
Absorption 
Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high 
permeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib 
is rapidly absorbed after oral administration with maximal plasma concentration (Cmax) 
achieved approximately 1 hour post-dose. Based on a human mass balance study, oral 
absorption of ruxolitinib, as ruxolitinib or metabolites formed under first-pass, is 95% or 
greater. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single 
dose range of 5-200 mg. There was no clinically relevant change in the pharmacokinetics of 
ruxolitinib upon administration with a high-fat meal. The mean Cmax was moderately decreased 
38 
1 
1 
21 
Percentage e of patientsnts 


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(24%) while the mean AUC was nearly unchanged (4% increase) on dosing with a high-fat 
meal. 


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Distribution 
The mean volume of distribution at steady state is approximately 75 litres in MF and PV 
patients. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro 
is approximately 97%, mostly to albumin. A whole body autoradiography study in rats has 
shown that ruxolitinib does not penetrate the blood-brain barrier. 
Biotransformation 
Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from 
CYP2C9. Parent compound is the predominant entity in human plasma, representing 
approximately 60% of the drug-related material in circulation. Two major and active 
metabolites are present in plasma representing 25% and 11% of parent AUC. These metabolites 
have one half to one fifth of the parent JAK-related pharmacological activity. The sum total of 
all active metabolites contributes to 18% of the overall pharmaco dynamics of ruxolitinib. At 
clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6 
or CYP3A4 based on in vitro studies. In vitro data indicate that ruxolitinib may inhibit P-gp and 
BCRP. 
Elimination 
Ruxolitinib is mainly eliminated through metabolism. The mean elimination half -life of 
ruxolitinib is approximately 3 hours. Following a single oral dose of [14C]-labelled ruxolitinib 
in healthy adult subjects, elimination was predominately through metabolism, with 74% of 
radioactivity excreted in urine and 22% via faeces. Unchanged parent substance accounted for 
less than 1% of the excreted total radioactivity. 
Linearity/non-linearity 
Dose proportionality was demonstrated in the single and multiple dose studies. 
Special populations 
Effects of age, gender or race 
Based on studies in healthy subjects, no relevant differences in ruxolitinib pharmacokinetics 
were observed with regard to gender and race. In a population pharmacokinetic evaluation in 
MF patients, no relationship was apparent between oral clearance and patient age or race. The 
predicted oral clearance was 17.7 l/h in women and 22.1 l/h in men, with 39% inter-subject 
variability in MF patients. Clearance was 12.7 l/h in PV patients, with a 42% inter-subject 
variability and no relationship was apparent between oral clearance and gender, patient age or 
race, based on a population pharmacokinetic evaluation in PV patients. 
Paediatric population 
The safety and effectiveness of Jakavi in paediatric patients have not been established (see 
section 5.1, “Paediatric population”). 
Renal impairment 
Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and 
urinary creatinine. Following a single ruxolitinib dose of 25 mg, the exposure of ruxolitinib was 
similar in subjects with various degrees of renal impairment and in those with 


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normal renal function. However, plasma AUC values of ruxolitinib metabolites tended to 
increase with increasing severity of renal impairment, and were most markedly increased in the 
subjects with severe renal impairment. It is unknown whether the increased metabolite exposure 
is of safety concern. A dose modification is recommended in patients with sev ere renal 
impairment and end-stage renal disease (see section 4.2). Dosing only on dialysis days reduces 
the metabolite exposure, but also the pharmacodynamic effect, especially on the days between 
dialysis. 
Hepatic impairment 
Following a single ruxolitinib dose of 25 mg in patients with varying degrees of hepatic impairment, the 
mean AUC for ruxolitinib was increased in patients with mild, moderate and severe hepatic impairment 
by 87%, 28% and 65%, respectively, compared to patients with normal h epatic function. There was no 
clear relationship between AUC and the degree of hepatic impairment based on Child-Pugh scores. 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). A dose reduction of approximately 50% is recommended for 
patients with hepatic impairment (see section 4.2). 
 
5.3 
Preclinical safety data 
Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity 
and reproductive toxicity studies and in a carcinogenicity study. Target organs associated with 
the pharmacological action of ruxolitinib in repeated dose studies include bone marrow, 
peripheral 
blood 
and 
lymphoid 
tissues. 
Infections 
generally 
associated 
with 
immunosuppression were noted in dogs. Adverse decreases in blood pressure along with 
increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute 
volume was noted in a respiratory study in rats. The margins (based on unbound Cmax) at the 
non-adverse level in the dog and rat studies were 15.7-fold and 10.4-fold greater, respectively, 
than the maximum human recommended dose of 25 mg twice daily. No effects were noted in 
an evaluation of the neuropharmacological effects of ruxolitinib. 
Ruxolitinib decreased foetal weight and increased post-implantation loss in animal studies. 
There was no evidence of a teratogenic effect in rats and rabbits. However, the exposure margins 
compared to the highest clinical dose were low and the results are therefore of limited relevance 
for humans. No effects were noted on fertility. In a pre- and post-natal development study, a 
slightly prolonged gestation period, reduced number of implantation sites, and reduced number 
of pups delivered were observed. In the pups, decreased mean initial body weights and short 
period of decreased mean body weight gain were observed. In lactating rats, ruxolitinib and/or 
its metabolites were excreted into the milk with a concentration that was 13-fold higher than 
the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic. Ruxolitinib 
was not carcinogenic in the Tg.rasH2 transgenic mouse model. 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
• Cellulose, microcrystalline 
• Magnesium stearate 
• Silica, colloidal anhydrous 


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• Sodium starch glycolate (Type A) 
• Povidone 
• Hydroxypropylcellulose 
• Lactose monohydrate 
6.2 
Incompatibilities 
Not applicable. 
 
6.3 
Shelf life 
3 years 
 
6.4 
Special precautions for storage 
Do not store above 30°C. 
 
6.5 
Nature and contents of container 
PVC/PCTFE/Aluminium blister packs containing 14 or 56 tablets or multipacks containing 
168 (3 packs of 56) tablets. 
Not all pack sizes or types may be marketed. 
 
6.6 
Special precautions for disposal 
No special requirements. 
 
7. 
MARKETING AUTHORISATION HOLDER 
Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
8. 
MARKETING AUTHORISATION NUMBER(S) 
EU/1/12/773/004-006 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
23.08.2012 
 
10. 
DATE OF REVISION OF THE TEXT 
Detailed information on this medicinal product is available on the website of the European 
Medicines Agency http://www.ema.europa.eu 
 This medicinal product is subject to additional monitoring. This will allow quick 
identification of new safety information. Healthcare professionals are asked to report any 
suspected adverse reactions. See section 4.8 for how to report adverse reactions. 


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1. 
NAME OF THE MEDICINAL PRODUCT 
Jakavi 10 mg tablets 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Each tablet contains 10 mg ruxolitinib (as phosphate). 
Excipient with known effect: 
Each tablet contains 142.90 mg lactose monohydrate. 
For the full list of excipients, see section 6.1. 
3. 
PHARMACEUTICAL FORM 
Tablet. 
Round curved white to almost white tablets of approximately 9.3 mm in diameter with “NVR” 
debossed on one side and “L10” debossed on the other side. 
 
4. 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
Myelofibrosis (MF) 
Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult 
patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post 
polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. 
Polycythaemia vera (PV) 
Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant 
to or intolerant of hydroxyurea. 
 
4.2 
Posology and method of administration 
Jakavi treatment should only be initiated by a physician experienced in the administration of 
anti-cancer agents. 
A complete blood cell count, including a white blood cell count differential, must be performed before 
initiating therapy with Jakavi. 
Complete blood count, including a white blood cell count differential, should be monitored every    2-
4 weeks until Jakavi doses are stabilised, and then as clinically indicated (see section 4.4). 
Posology 
Starting dose 
The recommended starting dose of Jakavi in myelofibrosis is 15 mg twice daily for patients 
with a platelet count between 100,000/mm3 and 200,000/mm3 and 20 mg twice daily for patients 
with a platelet count of >200,000/mm3. The recommended starting dose of Jakavi in 
polycythaemia vera is 10 mg given orally twice daily. 


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There is limited information to recommend a starting dose for patients with platelet counts 
between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these 
patients is 5 mg twice daily and the patients should be titrated cautiously. 
Dose modifications 
Doses may be titrated based on safety and efficacy. Treatment should be discontinued for 
platelet counts less than 50,000/mm3 or absolute neutrophil counts less than 500/mm3. In PV, 
treatment should also be interrupted when haemoglobin is below 8 g/dl. After recovery of blood 
counts above these levels, dosing may be re-started at 5 mg twice daily and gradually increased 
based on careful monitoring of complete blood cell count, including a white blood cell count 
differential. 
Dose reductions should be considered if the platelet count decreases below 100,000/mm3, with 
the goal of avoiding dose interruptions for thrombocytopenia. In PV, dose reductions should 
also be considered if haemoglobin decreases below 12 g/dl and is recommended if it decreases 
below 10 g/dl. 
If efficacy is considered insufficient and blood counts are adequate, doses may be increased by 
a maximum of 5 mg twice daily, up to the maximum dose of 25 mg twice daily. 
The starting dose should not be increased within the first four weeks of treatment and thereafter 
no more frequently than at 2-week intervals. 
The maximum dose of Jakavi is 25 mg twice daily. 
Dose adjustment with concomitant strong CYP3A4 inhibitors or fluconazole 
When Jakavi is administered with strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and 
CYP3A4 enzymes (e.g. fluconazole) the unit dose of Jakavi should be reduced by 
approximately 50%, to be administered twice daily (see section 4.5). Avoid the concomitant 
use of Jakavi with fluconazole doses greater than 200 mg daily. 
More frequent monitoring (e.g. twice a week) of haematology parameters and of clinical signs 
and symptoms of Jakavi-related adverse drug reactions is recommended while on strong 
CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes. 
Special populations 
Renal impairment 
No specific dose adjustment is needed in patients with mild or moderate renal impairment. 
In patients with severe renal impairment (creatinine clearance less than 30 ml/min) the 
recommended starting dose based on platelet count for MF patients should be reduced by 
approximately 50% to be administered twice daily. The recommended starting dose for PV 
patients with severe renal impairment is 5 mg twice daily. Patients should be carefully 
monitored with regard to safety and efficacy during Jakavi treatment. 
There are limited data to determine the best dosing options for patients with end-stage renal 
disease (ESRD) on haemodialysis. Pharmacokinetic/pharmacodynamic simulations based on 
available data in this population suggest that the starting dose for MF patients with ESRD on 
haemodialysis is a single dose of 15-20 mg or two doses of 10 mg given 12 hours apart, to be 


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administered post-dialysis and only on the day of haemodialysis. A single dose of 15 mg is 
recommended for MF patients with platelet count between 100,000/mm3 and 200,000/mm3. A 
single dose of 20 mg or two doses of 10 mg given 12 hours apart is recommended for MF 
patients with platelet count of >200,000/mm3. Subsequent doses (single administration or two 
doses of 10 mg given 12 hours apart) should be administered only on haemodialysis days 
following each dialysis session. 
The recommended starting dose for PV patients with ESRD on haemodialysis is a single dose 
of 10 mg or two doses of 5 mg given 12 hours apart, to be administered post-dialysis and only 
on the day of haemodialysis. These dose recommendations are based on simulations and any 
dose modification in ESRD should be followed by careful monitoring of safety and efficacy in 
individual patients. No data is available for dosing patients who are undergoing peritoneal 
dialysis or continuous venovenous haemofiltration (see section 5.2). 
Hepatic impairment 
In patients with any hepatic impairment the recommended starting dose based on platelet  
count should be reduced by approximately 50% to be administered twice daily. Subsequent 
doses should be adjusted based on careful monitoring of safety and efficacy. Patients 
diagnosed with hepatic impairment while receiving Jakavi should have complete blood counts, 
including a white blood cell count differential, monitored at least every one to two weeks for 
the first 6 weeks after initiation of therapy with Jakavi and as clinically indicated thereafter 
once their liver function and blood counts have been stabilised. Jakavi dose can be titrated to 
reduce the risk of cytopenia. 
Older people (≥65 years) 
No additional dose adjustments are recommended for older people. 
Paediatric population 
The safety and efficacy of Jakavi in children aged up to 18 years have not been established. 
No data are available (see section 5.1). 
Treatment discontinuation 
Treatment may be continued as long as the benefit-risk remains positive. However the treatment 
should be discontinued after 6 months if there has been no reduction in spleen size or 
improvement in symptoms since initiation of therapy. 
It is recommended that, for patients who have demonstrated some degree of clinical 
improvement, ruxolitinib therapy be discontinued if they sustain an increase in their spleen 
length of 40% compared with baseline size (roughly equivalent to a 25% increase in spleen 
volume) and no longer have tangible improvement in disease-related symptoms. 
Method of administration 
Jakavi is to be taken orally, with or without food. 
If a dose is missed, the patient should not take an additional dose, but should take the next usual 
prescribed dose. 


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4.3 
Contraindications 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Pregnancy and lactation. 
4.4 
Special warnings and precautions for use 
Myelosuppression 
Treatment with Jakavi can cause haematological adverse drug reactions, including 
thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood 
cell count differential, must be performed before initiating therapy with Jakavi. Treatment 
should be discontinued in patients with platelet count less than 50,000/mm3 or absoute 
neutrophil count less than 500/mm3 (see section 4.2). 
It has been observed that patients with low platelet counts (<200,000 /mm3) at the start of 
therapy are more likely to develop thrombocytopenia during treatment. 
Thrombocytopenia is generally reversible and is usually managed by reducing the dose or 
temporarily withholding Jakavi (see sections 4.2 and 4.8). However, platelet transfusions may 
be required as clinically indicated. 
Patients developing anaemia may require blood transfusions. Dose modifications or interruption 
for patients developing anaemia may also be considered. 
Patients with a haemoglobin level below 10.0 g/dl at the beginning of the treatment have a 
higher risk of developing a haemoglobin level below 8.0 g/dl during treatment compared to 
patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent 
monitoring of haematology parameters and of clinical signs and symptoms of Jakavi -related 
adverse drug reactions is recommended for patients with baseline haemoglobin below 
10.0 g/dl. 
Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by 
temporarily withholding Jakavi (see sections 4.2 and 4.8). 
Complete blood counts should be monitored as clinically indicated and dose adjusted as 
required (see sections 4.2 and 4.8). 
Infections 
Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal 
and viral infections. Tuberculosis has been reported in patients receiving Jakavi for MF. Before 
starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, 
as per local recommendations. This can include medical history, possible previous contact with 
tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-
gamma release assay, as applicable. Prescribers are reminded of the risk of false negative 
tuberculin skin test results, especially in patients who are severely ill or immunocompromised. 
Jakavi therapy should not be started until active serious infections have resolved. Physicians 
should carefully observe patients receiving Jakavi for signs and symptoms of infections and 
initiate appropriate treatment promptly (see section 4.8). 
Hepatitis B viral load (HBV-DNA titre) increases, with and without associated elevations in 


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alanine aminotransferase and aspartate aminotransferase, have been reported in patients with 
chronic HBV infections taking Jakavi. The effect of Jakavi on viral replication in patie nts with 
chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and 
monitored according to clinical guidelines. 
Herpes zoster 
Physicians should educate patients about early signs and symptoms of herpes zoster, advising 
that treatment should be sought as early as possible. 
Progressive multifocal leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) has been reported with Jakavi treatment for 
MF. Physicians should be particularly alert to symptoms suggestive of PML that patients may 
not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be 
monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs 
occur, referral to a neurologist and appropriate diagnostic measures for PML should be 
considered. If PML is suspected, further dosing must be suspended until PML has been 
excluded. 
Non-melanoma skin cancer 
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell 
carcinoma, have been reported in patients treated with ruxolitinib. Most of these patients had 
histories of extended treatment with hydroxyurea and prior NMSC or pre -malignant skin 
lesions. A causal relationship to ruxolitinib has not been established. Periodic skin examination 
is recommended for patients who are at increased risk for skin cancer. 
Special populations 
Renal impairment 
The starting dose of Jakavi should be reduced in patients with severe renal impairment. For 
patients with end-stage renal disease on haemodialysis the starting dose for MF patients should 
be based on platelet counts (see section 4.2). Subsequent doses (single dose of 20 mg or two 
doses of 10 mg given 12 hours apart in MF patients; single dose of 10 mg or two doses of 5 mg 
given 12 hours apart in PV patients) should be administered only on haemodialysis days 
following each dialysis session. Additional dose modifications should be made with careful 
monitoring of safety and efficacy (see sections 4.2 and 5.2). 
Hepatic impairment 
The starting dose of Jakavi should be reduced by approximately 50% in patients with hepatic 
impairment. Further dose modifications should be based on the safety and efficacy of the 
medicinal product (see sections 4.2 and 5.2). 
Interactions 
If Jakavi is to be co-administered with strong CYP3A4 inhibitors or dual inhibitors of CYP3A4 
and CYP2C9 enzymes (e.g. fluconazole), the unit dose of Jakavi should be reduced by 
approximately 50%, to be administered twice daily (for monitoring frequency  see  sections 4.2 
and 4.5). 


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The concomitant use of cytoreductive therapies or haematopoietic growth factors with Jakavi 
has not been studied. The safety and efficacy of these co -administrations are not known (see 
section 4.5). 
Withdrawal effects 
Following interruption or discontinuation of Jakavi, symptoms of MF may return over a period 
of approximately one week. There have been cases of patients discontinuing Jakavi who 
sustained more severe events, particularly in the presence of acute intercurrent illness. It has not 
been established whether abrupt discontinuation of Jakavi contributed to these events. Unless 
abrupt discontinuation is required, gradual tapering of the dose of Jakavi may be considered, 
although the utility of the tapering is unproven. 
Excipients 
Jakavi contains lactose. Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal 
product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
Interaction studies have only been performed in adults. 
Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, 
medicinal products inhibiting these enzymes can give rise to increased ruxolitinib exposure. 
Interactions resulting in dose reduction of ruxolitinib 
CYP3A4 inhibitors 
Strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, saquinavir, telaprevir, telithromycin, voriconazole) 
In healthy subjects co-administration of Jakavi (10 mg single dose) with a strong CYP3A4 
inhibitor, ketoconazole, resulted in ruxolitinib Cmax and AUC that were higher by 33% and 91%, 
respectively, than with ruxolitinib alone. The half-life was prolonged from 3.7 to 
6.0 hours with concurrent ketoconazole administration. 
When administering Jakavi with strong CYP3A4 inhibitors the unit dose of Jakavi should be 
reduced by approximately 50%, to be administered twice daily. Patients should be closely 
monitored (e.g. twice weekly) for cytopenias and dose titrated based on safety and efficacy (see 
section 4.2). 
Dual CYP2C9 and CYP3A4 inhibitors 
50% dose reduction should be considered when using medicinal products which are dual 
inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of 
Jakavi with fluconazole doses greater than 200 mg daily. 
Enzyme inducers 


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CYP3A4 inducers (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St.John’s wort (Hypericum perforatum)) 
Patients should be closely monitored and the dose titrated based on safety and efficacy (see 
section 4.2). 
In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducer 
rifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after 
administration of Jakavi alone. The exposure of ruxolitinib active metabolites was unchanged. 
Overall, the ruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 
induction resulted in minimal effect on the pharmacodynamics. However, this could be related 
to the high ruxolitinib dose resulting in pharmacodynamic effects near E max. It is possible that 
in the individual patient, an increase of the ruxolitinib dose is needed when initiating treatment 
with a strong enzyme inducer. 
Other interactions to be considered affecting ruxolitinib 
Mild or moderate CYP3A4 inhibitors (such as, but not limited to, ciprofloxacin, erythromycin, 
amprenavir, atazanavir, diltiazem, cimetidine) 
In healthy subjects co-administration of ruxolitinib (10 mg single dose) with erythromycin 500 
mg twice daily for four days resulted in ruxolitinib Cmax and AUC that were higher by 8% and 
27%, respectively, than with ruxolitinib alone. 
No dose adjustment is recommended when ruxolitinib is co-administered with mild or moderate 
CYP3A4 inhibitors (e.g. erythromycin). However, patients should be closely monitored for 
cytopenias when initiating therapy with a moderate CYP3A4 inhibitor. 
Effects of ruxolitinib on other medicinal products 
Substances transported by P-glycoprotein or other transporters 
Ruxolitinib may inhibit P-glycoprotein and breast cancer resistance protein (BCRP) in the 
intestine. This may result in increased sytemic exposure of substrates of these transporters, such 
as dabigatran etexilate, ciclosporin, rosuvastatin and potentially digoxin. Therapeutic drug 
monitoring (TDM) or clinical monitoring of the affected substance is advised. 
It is possible that the potential inhibition of P-gp and BCRP in the intestine can be minimised 
if the time between administrations is kept apart as long as possible. 
Haematopoietic growth factors 
The concurrent use of haematopoietic growth factors and Jakavi has not been studied. It is not 
known whether the Janus Associated Kinase (JAK) inhibition by Jakavi reduces the efficacy of 
the haematopoietic growth factors or whether the haematopoietic growth factors affect the 
efficacy of Jakavi (see section 4.4). 
Cytoreductive therapies 
The concomitant use of cytoreductive therapies and Jakavi has not been studied. The safety and 
efficacy of this co-administration is not known (see section 4.4). 
A study in healthy subjects indicated that ruxolitinib did not inhibit the metabolism of the oral 
CYP3A4 substrate midazolam. Therefore, no increase in exposure of CYP3A4 substrates is 


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anticipated when combining them with Jakavi. Another study in healthy subjects indicated that 
Jakavi does not affect the pharmacokinetics of an oral contracepti ve containing ethinylestradiol 
and levonorgestrel. Therefore, it is not anticipated that the contraceptive efficacy of this 
combination will be compromised by co-administration of ruxolitinib. 
 
4.6 
Fertility, pregnancy and lactation 
Pregnancy and contraception in females 
There are no data from the use of Jakavi in pregnant women. 
Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was 
not observed in rats or rabbits. However, the exposure margins compared to the highest clinical 
dose were low and the results are therefore of limited relevance for humans (see section 5.3). 
The potential risk for humans is unknown. As a precautionary measure, the use of Jakavi during 
pregnancy is contraindicated (see section 4.3). Women of child-bearing potential should use 
effective contraception during the treatment with Jakavi. In case pregnancy should occur during 
treatment with Jakavi, a risk/benefit evaluation must  be carried out on an individual basis with 
careful counselling regarding potential risks to the foetus (see section 5.3). 
Breast-feeding 
Jakavi must not be used during breast-feeding (see section 4.3) and breast-feeding should 
therefore be discontinued when treatment is started. It is unknown whether ruxolitinib and/or 
its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. 
Available pharmacodynamic/toxicological data in animals have shown excretion of  ruxolitinib 
and its metabolites in milk (see section 5.3). 
Fertility 
There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect 
on fertility was observed. 
 
4.7 
Effects on ability to drive and use machines 
Jakavi has no or negligible sedating effect. However, patients who experience dizziness after 
the intake of Jakavi should refrain from driving or using machines. 
 
4.8 
Undesirable effects 
Summary of the safety profile 
The safety assessment was based on a total of 855 patients (with MF or PV) receiving Jakavi 
in phase 2 and 3 studies. 
Myelofibrosis 
In the randomised period of the two pivotal studies, COMFORT-I and COMFORT-II, the 
median duration of exposure to Jakavi was 10.8 months (range 0.3 to 23.5 months). The 
majority of patients (68.4%) were treated for at least 9 months. Of 301 patients, 111 (36.9%) 
had a baseline platelet count of between 100,000/mm3 and 200,000/mm3 and 190 (63.1%) had 
a baseline platelet count of >200,000/mm3. 


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In these clinical studies, discontinuation due to adverse events, regardless of causality, was 
observed in 11.3% of patients. 
The most frequently reported adverse drug reactions were thrombocytopenia and anaemia. 
Haematological adverse drug reactions (any Common Terminology Criteria for Adverse Events 
[CTCAE] grade) included anaemia (82.4%), thrombocytopenia (69.8%) and neutropenia 
(16.6%). 
Anaemia, thrombocytopenia and neutropenia are dose-related effects. 
The three most frequent non-haematological adverse drug reactions were bruising (21.3%), 
dizziness (15.3%) and headache (14.0%). 
The three most frequent non-haematological laboratory abnormalities were raised alanine 
aminotransferase 
(27.2%), 
raised 
aspartate 
aminotransferase 
(19.9%) 
and 
hypercholesterolaemia (16.9%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4 
hypercholesterolaemia, raised aspartate aminotransferase nor CTCAE grade 4 raised alanine 
aminotransferase were observed. 
Long-term safety: As expected with an extended follow-up period, the cumulative frequency 
of some adverse events increased in the evaluation of the 3 -year follow-up safety data (median 
duration of exposure of 33.2 months in COMFORT-I and COMFORT-II for patients initially 
randomised to ruxolitinib) from 457 patients with myelofibrosis treated with ruxolitinib during 
the randomised and extension periods of the two pivotal phase 3 studies. This evaluation 
included data from patients that were initially randomised to ruxolitinib (N=301) and patients 
that received ruxolitinib after crossing over from control treatment arms (N=156). With these 
updated data, therapy discontinuation due to adverse events was observed in 17.1% of patients 
treated with ruxolitinib. 
Polycythaemia vera 
The safety of Jakavi was assessed in 110 patients with PV in an open-label, randomised, 
controlled phase 3 RESPONSE study. The adverse drug reactions listed below reflect the initial 
study period (up to week 32) with equivalent exposure to ruxolitinib and Best Available 
Therapy (BAT), corresponding to a median duration of exposure to Jakavi of 7.8 months. The 
mean age of patients receiving Jakavi was around 60 years. 
Discontinuation due to adverse events, regardless of causality, was observed in 3.6% of patients 
treated with Jakavi and 1.8% of patients treated with best available therapy. 
Haematological adverse reactions (any CTCAE grade) included anaemia (43.6 %) and 
thrombocytopenia (24.5%). Anaemia or thrombocytopenia CTCAE grade 3 and 4 were reported 
in respectively 1.8% or 5.5%. 
The three most frequent non-haematological adverse reactions were dizziness (15.5%), 
constipation (8.2%) and herpes zoster (6.4%). 
The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) were 
hypercholesterolaemia (30.0%), raised alanine aminotransferase (22.7%) and raised aspartate 
aminotransferase (20.9%). These were all CTCAE grade 1 and 2 with the exception of one 
CTCAE grade 3 raised alanine aminotransferase event. 


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Long-term safety: Patients had a median duration of exposure to Jakavi of 18.6 months (range 
0.3 to 35.9 months). With longer exposure, frequency of adverse events increased; however no 
new safety findings emerged. When adjusted for exposure, the adverse event rates were 
generally comparable with those observed during the initial study period. 
Tabulated summary of adverse drug reactions from clinical studies 
In the clinical study programme the severity of adverse drug reactions was assessed based on 
the  CTCAE,  defining  grade 1  =  mild,  grade 2  =  moderate,  grade 3   =   severe   and grade 
4=life-threatening. 
Adverse drug reactions from clinical studies (Table14-5) are listed by MedDRA system organ 
class. Within each system organ class, the adverse drug reactions are ranked by frequency, with 
the most frequent reactions first. In addition, the corresponding frequency category for each 
adverse drug reaction is based on the following convention: very co mmon (≥1/10); common 
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare 
(<1/10,000). 
 
Table 14-5 
Frequency category of adverse drug reactions reported in the phase 3 
studies (COMFORT-I, COMFORT-II, RESPONSE) 
 
 
Adverse drug reaction 
Frequency category for MF 
patients 
Frequency category for PV patients 
Infections and infestations 
Urinary tract infectionsa,d 
Very common 
Common 
Herpes zostera,d 
Common 
Common 
Tuberculosise 
Uncommon 
- 
Blood and lymphatic system 
disordersb,d 
Anaemiab 
- 
- 
CTCAEc grade 4 
(<6.5g/dl) 
Very common 
Uncommon 
CTCAEc grade 3 
(<8.0 – 6.5g/dl) 
Very common 
Uncommon 
Any CTCAEc grade 
Very common 
Very common 
Thrombocytopeniab 
CTCAEc grade 4 
(<25,000/mm3) 
Common 
Uncommon 
CTCAEc grade 3 
(50,000 – 25,000/mm3) 
Common 
Common 
Any CTCAEc grade 
Very common 
Very common 
Neutropeniab 
CTCAEc grade 4 
(<500/mm3) 
Common 
- 
CTCAEc grade 3 
(<1,000 – 500/mm3) 
Common 
- 


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Any CTCAEc grade 
Very common 
- 
Bleeding (any bleeding including 
intracranial, and gastrointestinal 
bleeding, bruising and other 
bleeding) 
Very common 
Very common 
Intracranial bleeding 
Common 
- 
Gastrointestinal bleeding 
Common 
- 
Bruising 
Very common 
Very common 
Other bleeding (including 
epistaxis, post-procedural 
haemorrhage and haematuria) 
Common 
Very common 
Metabolism and nutrition 
disorders 
Weight gaina 
Very common 
Common 
Hypercholesterolaemiab 
CTCAEc grade 1 and 2 
Very common 
Very common 
Hypertriglyceridaemiab 
CTCAEc grade 1 
- 
Very common 
Nervous system disorders 
Dizzinessa 
Very common 
Very common 
Headachea 
Very common 
- 
Gastrointestinal disorders 
Flatulencea 
Common 
- 
Constipationa 
- 
Common 
Hepatobiliary disorders 
Raised alanine aminotransferaseb 
CTCAEc grade 3 
(> 5x – 20 x ULN) 
Common 
Uncommon 
Any CTCAEc grade 
Very common 
Very common 
Raised aspartate 
aminotransferaseb 
Any CTCAEc grade 
Very common 
Very common 
Vascular disorders 
Hypertensiona 
- 
Very common 
aFrequency is based on adverse event data. 
• A subject with multiple occurrence of an adverse drug reaction (ADR) is counted only once in that ADR 
category. 
• ADRs reported are on treatment or up to 28 days post treatment end date. 
bFrequency is based on laboratory values. 
• A subject with multiple occurrences of an ADR is counted only once in that ADR category. 
• ADRs reported are on treatment or up to 28 days post treatment end date. 
cCommon Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild, grade 2 = moderate, 
grade 3 = severe, grade 4 = life-threatening 
dThese ADRs are discussed in the text. 
eFrequency is based on all patients exposed to ruxolitinib in clinical studies (N=4755) 
Upon discontinuation, MF patients may experience a return of MF symptoms such as fatigue, 
bone pain, fever, pruritus, night sweats, symptomatic splenomegaly and weight loss. In clinical 
studies in MF the total symptom score for MF symptoms gradually returned to baseline value 
within 7 days after dose discontinuation (see section 4.4). 


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Description of selected adverse drug reactions 
Anaemia 
In phase 3 clinical studies in MF, median time to onset of first CTCAE grade 2 or higher anaemia was 
1.5 months. One patient (0.3%) discontinued treatment because of anaemia. 
In patients receiving  Jakavi  mean  decreases  in  haemoglobin  reached  a  nadir  of  approximately  10 
g/litre below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady 
state that was approximately 5 g/litre below baseline. This pattern was observed in patients regardless 
of whether they had received transfusion during therapy. 
In the randomised, placebo-controlled study COMFORT-I 60.6% of Jakavi-treated MF patients and 
37.7% of placebo-treated MF patients received red blood cell transfusions during randomised treatment. 
In the COMFORT-II study the rate of packed red blood cell transfusions was 53.4% in the Jakavi arm 
and 41.1% in the best available therapy arm. 
In the randomised period of the pivotal studies, anaemia was less frequent in PV patients than in MF 
patients (43.6% versus 82.4%). In the PV population, the CTCAE grade 3 and 4 events were reported 
in 1.8%, while in the MF patients the frequency was 42.56%. 
Thrombocytopenia 
In the phase 3 clinical studies in MF, 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 50,000/mm3 was 14 days. During the randomised period, platelet transfusions 
were administered to 4.7% of patients receiving Jakavi and to 4.0% of patients receiving control 
regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of 
patients receiving Jakavi and 0.9% of patients receiving control regimens. Patients with a 
platelet count of 100,000/mm 3 to 200,000/mm3 before starting Jakavi had a higher frequency 
of grade 3 or 4 thrombocytopenia compared to patients with platelet count >200,000/mm3 
(64.2% versus 38.5%). 
In the randomised period of the pivotal studies, the rate of patients experiencing 
thrombocytopenia was lower in PV (24.5%) patients compared to MF (69.8%) patients. The 
frequency of severe (i.e. CTCAE grade 3 and 4) thrombocytopenia was lower in PV (5.5%) 
than in MF (11.6%) patients. 
Neutropenia 
In the phase 3 clinical studies in MF, in patients who developed grade 3 or 4 neutropenia, the 
median time to onset was 12 weeks. During the randomised period, dose holding or reductions 
due to neutropenia were reported in 1.0% of patients, and 0.3% of patients discontinued 
treatment because of neutropenia. 
In the randomised period of the pivotal study in PV patients, neutropenia was reported in two 
patients (1.8%) of which one patient developed CTCAE grade 4 neutropenia. 
Bleeding 
In the phase 3 pivotal studies in MF bleeding events (including intracranial and gastrointestinal, 
bruising and other bleeding events) were reported in 32.6% of patients exposed to Jakavi and 
23.2% of patients exposed to the reference treatments (placebo or best 


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available therapy). The frequency of grade 3-4 events was similar for patients treated with 
Jakavi or reference treatments (4.7% versus 3.1%). Most of the patients with bleeding events 
during the treatment reported bruising (65.3%). Bruising events were more frequently reported 
in patients taking Jakavi compared with the reference treatments (21.3% versus 11.6%). 
Intracranial bleeding was reported in 1% of patients exposed to Jakavi and 0.9% exposed to 
reference treatments. Gastrointestinal bleeding was reported in 5.0% of patients exposed to 
Jakavi compared to 3.1% exposed to reference treatments. Other bleeding events (including 
events such as epistaxis, post-procedural haemorrhage and haematuria) were reported in 13.3% 
of patients treated with Jakavi and 10.3% treated with reference treatments. 
In the randomised period of the pivotal study in PV patients, bleeding events (including intracranial and 
gastrointestinal, bruising and other bleeding events) were reported in 20% of patients treated with Jakavi 
and 15.3% patients receiving best available therapy. Bruising was reported in similar frequencies in 
Jakavi and BAT arms (10.9% versus 8.1%). No intracranial bleeding or gastrointestinal haemorrhage 
events were reported in patients receiving Jakavi. One patient treated with Jakavi experienced a grade 3 
bleeding event (post-procedural bleeding); no grade 4 bleeding was reported. Other bleeding events 
(including events such as epistaxis, post -procedural haemorrhage, gingival bleeding) were reported in 
11.8% of patients treated with Jakavi and 6.3% treated with best available therapy. 
Infections 
In the phase 3 pivotal studies in MF, grade 3 or 4 urinary tract infection was reported in 1.0% of patients, 
herpes zoster in 4.3% and tuberculosis in 1.0%. In phase 3 clinical studies sepsis was reported in 3.0% 
of patients. An extended follow-up of patients treated with ruxolitinib showed no trends towards an 
increase in the rate of sepsis over time. 
In the randomised period of the pivotal study in PV patients, one (0.9%) CTCAE grade 3 and no grade 
4 urinary tract infection was reported. The rate of herpes zoster was slightly higher in PV (6.4%) patients 
than in MF (4.0%) patients. There was one report of CTCAE grade 3 post-herpetic neuralgia amongst 
the PV patients. 
Increased systolic blood pressure 
In the phase 3 pivotal clinical studies in MF an increase in systolic blood pressure of 20 mmHg or more 
from baseline was recorded in 31.5% of patients on at least one visit compared with 19.5% of the control-
treated patients. In COMFORT-I (MF patients) the mean increase from baseline in systolic BP was 0-2 
mmHg on Jakavi versus a decrease of 2-5 mmHg in the placebo arm. In COMFORT-II mean values 
showed little difference between the ruxolitinib-treated and the control-treated MF patients. 
In the randomised period of the pivotal study in PV patients, the mean systolic blood pressure increased 
by 0.65 mmHg in the Jakavi arm versus a decrease of 2 mmHg in the BAT arm. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 
Overdose 
There is no known antidote for overdoses with Jakavi. Single doses up to 200 mg have been 
given with acceptable acute tolerability. Higher than recommended repeat doses are 


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associated 
with 
increased 
myelosuppression 
including 
leukopenia, 
anaemia 
and 
thrombocytopenia. Appropriate supportive treatment should be given. 
Haemodialysis is not expected to enhance the elimination of ruxolitinib. 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: 
L01XE18 
Mechanism of action 
Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 
(IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively).  These mediate 
the signalling of a number of cytokines and growth factors that are important for haematopoiesis 
and immune function. 
Myelofibrosis and polycythaemia vera are myeloproliferative neoplasms known to be 
associated with dysregulated JAK1 and JAK2 signalling. The basis for the dysregulation is 
believed to include high levels of circulating cytokines that activate the JAK -STAT pathway, 
gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory 
mechanisms. MF patients exhibit dysregulated JAK signalling regardless of JAK2V617F 
mutation status. Activating mutations in JAK2 (V617F or exon 12) are found in >95% of PV 
patients. 
Ruxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular 
models of haematological malignancies, as well as of Ba/F3 cells rendered cytokine-
independent by expressing the JAK2V617F mutated protein, with IC 50 ranging from 80-320 
nM. 
Pharmacodynamic effects 
Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy 
subjects, MF patients and PV patients. Ruxolitinib resulted in maximal inhibition of STAT3 
phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy 
subjects and MF patients, indicating no accumulation of either parent or active metabolites. 
Baseline elevations in inflammatory markers associated with constitutional symptoms such as 
TNFα, IL-6 and CRP in subjects with MF were decreased following treatment with ruxolitinib. 
MF patients did not become refractory to the pharmacodynamic effects of ruxolitinib  
treatment over time. Similarly, patients with PV also presented with baseline elevations in 
inflammatory markers and these markers were decreased following treatment with ruxolitinib. 
In a thorough QT study in healthy subjects, there was no indication of a QT/QTc prolonging 
effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, indicating that 
ruxolitinib has no effect on cardiac repolarisation. 
Clinical efficacy and safety 
Myelofibrosis 


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Two randomised phase 3 studies (COMFORT-I and COMFORT-II) were conducted in patients 
with MF (primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential 
thrombocythaemia myelofibrosis). In both studies, patients had palpable splenomegaly at least 
5 cm below the costal margin and risk category of intermediate -2 or high risk based on the 
International Working Group (IWG) Consensus Criteria. The starting dose of Jakavi was based 
on platelet count. 
COMFORT-I was a double-blind, randomised, placebo-controlled study in 309 patients who 
were refractory to or were not candidates for available therapy. The primary efficacy endpoint 
was proportion of subjects achieving ≥35%  reduction from baseline in spleen volume at  week 
24 as measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). 
Secondary endpoints included duration of maintenance of a ≥35% reduction from baseline in 
spleen volume, proportion of patients who had ≥50% reduction in total symptom score, changes 
in total symptom scores from baseline to week 24, as measured by the modified Myelofibrosis 
Symptom Assessment Form (MFSAF) v2.0 diary, and overall survival. 
COMFORT-II was an open-label, randomised study in 219 patients. Patients were randomised 
2:1 to Jakavi versus best available therapy. In the best available therapy arm, 47% of patients 
received hydroxyurea and 16% of patients received glucocorticoids. The primary efficacy 
endpoint was proportion of patients achieving ≥35% reduction from baseline in spleen volume 
at week 48 as measured by MRI or CT. 
Secondary endpoints included proportion of patients achieving a ≥35% reduction of spleen 
volume from baseline at week 24 and duration of maintenance of a ≥35% reduction from 
baseline spleen volume. 
In COMFORT-I and COMFORT-II, patient baseline demographics and disease characteristics 
were comparable between the treatment arms. 
 
Table 14-6 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume at week 24 in COMFORT-I and at week 48 in COMFORT-II (ITT) 
 
COMFORT-I 
COMFORT-II 
Jakavi 
(N=155) 
Placebo 
(N=153) 
Jakavi 
(N=144) 
Best available 
therapy 
(N=72) 
Time points 
Week 24 
Week 48 
Number (%) of subjects with 
spleen volume reduced by 
≥35% 
65 (41.9) 
1 (0.7) 
41 (28.5) 
0 
95% confidence intervals 
34.1, 50.1 
0, 3.6 
21.3, 36.6 
0.0, 5.0 
p-value 
<0.0001 
<0.0001 
A significantly higher proportion of patients in the Jakavi group achieved ≥35% reduction from 
baseline in spleen volume (Table 14-6) regardless of the presence or absence of the JAK2V617F 
mutation or the disease subtype (primary myelofibrosis, post-polycythaemia vera 
myelofibrosis, post-essential thrombocythaemia myelofibrosis). 


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Table 14-7 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume by JAK mutation status (safety set) 
 
COMFORT-I 
COMFORT-II 
Jakavi 
Placebo 
Jakavi 
Best available 
therapy 
JAK mutation 
status 
Positive 
(N=113) 
n (%) 
Negative 
(N=40) 
n (%) 
Positive 
(N=121) 
n (%) 
Negative 
(N=27) 
n (%) 
Positive 
(N=110) 
n (%) 
Negative 
(N=35) 
n (%) 
Positive 
(N=49) 
n (%) 
Negative 
(N=20) 
n (%) 
Number (%) of 
subjects with 
spleen volume 
reduced by 
≥35% 
54 (47.8) 
11 (27.5) 
1 
(0.8) 
0 
36 (32.7) 
5 
(14.3) 
0 
0 
Time point 
After 24 weeks 
After 48 weeks 
The probability of maintaining spleen  response  (≥35%  reduction)  on  Jakavi  for  at  least 24 
weeks was 89% in COMFORT-I and 87% in COMFORT-II; 52% maintained spleen responses 
for at least 48 weeks in COMFORT-II. 
In COMFORT-I, 45.9% subjects in the Jakavi group achieved a ≥50% improvement from 
baseline in the week 24 total symptom score (measured using MFSAF diary v2.0), as compared 
to 5.3% in the placebo group (p<0.0001 using chi-square test). The mean change in the global 
health status at week 24, as measured by EORTC QLQ C30 was +12.3 for Jakavi and -3.4 for 
placebo (p<0.0001). 
In COMFORT-I, after a median follow-up of 34.3 months, the death rate in patients randomised 
to the ruxolitinib arm was 27.1% versus 35.1% in patients randomised to placebo; HR 0.687; 
95% CI 0.459-1.029; p=0.0668. 
In COMFORT-II, after a median follow-up of 34.7 months, the death rate in patients 
randomised to ruxolitinib was 19.9% versus 30.1% in patients randomised to best available 
treatment (BAT); HR 0.48; 95% CI 0.28-0.85; p=0.009. In both studies, the lower death rates 
noted in the ruxolitinib arm were predominantly driven by the results obtained in the post 
polycythaemia vera and post essential thrombocythaemia subgroups. 
Polycythaemia vera 
A randomised, open-label, active-controlled phase 3 study (RESPONSE) was conducted in 222 
patients with PV who were resistant to or intolerant of hydroxyurea defined based on the 
European LeukemiaNet (ELN) international working group published criteria. 110 patients 
were randomised to the ruxolitinib arm and 112 patients to the BAT arm. The starting dose of 
Jakavi was 10 mg twice daily. Doses were then adjusted in individual patients based on 
tolerability and efficacy with a maximum dose of 25 mg twice daily. BAT was selected by the 
investigator 
on 
a 
patient-by-patient 
basis 
and 
included 
hydroxyurea 
(59.5%), 
interferon/pegylated interferon (11.7%), anagrelide (7.2%), pipobroman (1.8%) and 
observation (15.3%). 
Baseline demographics and disease characteristics were comparable between the two treatments 
arms. The median age was 60 years (range 33 to 90 years). Patients in the ruxolitinib arm had 
PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median 
of approximately 3 years. Most patients (>80%) had received at 


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least two phlebotomies in the last 24 weeks prior to screening. Comparative data regarding 
long-term survival and incidence of disease complications is missing. 
The primary composite endpoint was the proportion of patients achieving both an absence of 
phlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volume from baseline at 
week 32.  Phlebotomy eligibility was defined  as  a confirmed HCT  of >45%,  i.e.  at  least    3 
percentage points higher than the HCT obtained at baseline or a confirmed HCT of >48%, 
depending on which was lower. Key secondary endpoints included the proportion of patients 
who achieved the primary endpoint and remained free from progression at week 48, as well as 
the proportion of patients achieving complete haematological remission at week 32. 
The study met its primary objective and a higher proportion of patients in the Jakav i group 
achieved the primary composite endpoint and each of its individual components. Significantly 
more patients treated with Jakavi (20.9%) achieved a primary response (p<0.0001) compared 
to BAT (0.9%). Haematocrit control was achieved in 60% of patient s in the Jakavi arm 
compared to 19.6% in the BAT arm and a ≥35% reduction in spleen volume was achieved in 
38.2% of patients  in the Jakavi  arm compared  to 0.9% in the BAT  arm ( Figure  14-2).      94 
(83.9%) patients randomised to the BAT arm crossed over to ruxolitinib treatment at  Week 32 
or after, limiting the comparison between the two arms after Week 32. 
Both key secondary endpoints were also met. The proportion of patients achieving a complete 
haematological remission was 23.6% on Jakavi compared to 8.9% on BAT (p=0.0028) and the 
proportion of patients achieving a durable primary response at week 48 was 19.1% on Jakavi 
and 0.9% on BAT.(p<0.0001). 
 
Figure 14-2 
Patients achieving the primary endpoint and components of the 
primary endpoint at week 32 
 
 
P-value: < .0001 
Odds Ratio (Ruxolitinib/BAT) 
70 
60 
Individual components of Primary 
Response at Week 32 
60 
 
 
 
.RUX 
.BAT 
 
50 
40 
 
30 
20 
20 
 
10 
 
0 
Primary Composite 
Endpoint at Week 32 
 
≥ 35% reduction in 
Spleen Volume 
 
Hematocrit control 
without phlebotomy 
 
Symptom burden was assessed using the MPN-SAF total symptom score (TSS) electronic 
1 
1 
21 
38 
and 95% CI: 
28.64 (4.50, 12.06) 
Percentage e of patientsnts 


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patient diary, which consisted of 14 questions. At week 32, 49% and 64% of patients treated 
with ruxolitinib achieved a ≥50% reduction in TSS-14 and TSS-5, respectively, compared to 


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only 5% and 11% of patients on BAT. 
Treatment benefit perception was measured by the Patient Global Impression of Change (PGIC) 
questionnaire. 66% of patients treated with ruxolitinib compared to 19% treated with BAT 
reported an improvement as early as four weeks after beginning treatment. Improvement in 
perception of treatment benefit was  also higher in  patients treated with ruxolitinib at  week 32 
(78% versus 33%). 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Jakavi in all subsets of the paediatric population for the treatment of MF (see section 4.2 for 
information on paediatric use). 
 
5.2 
Pharmacokinetic properties 
Absorption 
Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high 
permeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib 
is rapidly absorbed after oral administration with maximal plasma concentration (Cmax) 
achieved approximately 1 hour post-dose. Based on a human mass balance study, oral 
absorption of ruxolitinib, as ruxolitinib or metabolites formed under first-pass, is 95% or 
greater. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single 
dose range of 5-200 mg. There was no clinically relevant change in the pharmacokinetics of 
ruxolitinib upon administration with a high-fat meal. The mean Cmax was moderately decreased 
(24%) while the mean AUC was nearly unchanged (4% increase) on dosing with a high-fat 
meal. 
Distribution 
The mean volume of distribution at steady state is approximately 75 litres in MF and PV 
patients. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro 
is approximately 97%, mostly to albumin. A whole body autoradiography study in rats has 
shown that ruxolitinib does not penetrate the blood-brain barrier. 
Biotransformation 
Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from 
CYP2C9. Parent compound is the predominant entity in human plasma, representing 
approximately 60% of the drug-related material in circulation. Two major and active 
metabolites are present in plasma representing 25% and 11% of parent AUC. These metabolites 
have one half to one fifth of the parent JAK-related pharmacological activity. The sum total of 
all active metabolites contributes to 18% of the overall pharmacodynamics of ruxolitinib. At 
clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6 
or CYP3A4 based on in vitro studies. In vitro data indicate that ruxolitinib may inhibit P-gp and 
BCRP. 


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Elimination 
Ruxolitinib is mainly eliminated through metabolism. The mean elimination half -life of 
ruxolitinib is approximately 3 hours. Following a single oral dose of [14C]-labelled ruxolitinib 
in healthy adult subjects, elimination was predominately through metabolism, with 74% of 
radioactivity excreted in urine and 22% via faeces. Unchanged parent substance accounted for 
less than 1% of the excreted total radioactivity. 
Linearity/non-linearity 
Dose proportionality was demonstrated in the single and multiple dose studies. 
Special populations 
Effects of age, gender or race 
Based on studies in healthy subjects, no relevant differences in ruxolitinib pharmacokinetics 
were observed with regard to gender and race. In a population pharmacokinetic evaluation in 
MF patients, no relationship was apparent between oral clearance and patient age or race. The 
predicted oral clearance was 17.7 l/h in women and 22.1 l/h in men, with 39% inter-subject 
variability in MF patients. Clearance was 12.7 l/h in PV patients, with a 42% inter-subject 
variability and no relationship was apparent between oral clearance and gender, patient age or 
race based on a population pharmacokinetic evaluation in PV patients. 
Paediatric population 
The safety and effectiveness of Jakavi in paediatric patients have not been established (see 
section 5.1, “Paediatric population”). 
Renal impairment 
Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and 
urinary creatinine. Following a single ruxolitinib dose of 25 mg, the exposure 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 tended to increase with 
increasing severity of renal impairment, and were most markedly increased in the subjects with 
severe renal impairment. It is unknown whether the increased metabolite exposure is of safety 
concern. A dose modification is recommended in patient s with severe renal impairment and 
end-stage renal disease (see section 4.2). Dosing only on dialysis days reduces the metabolite 
exposure, but also the pharmacodynamic effect, especially on the days between dialysis. 
Hepatic impairment 
Following a single ruxolitinib dose of 25 mg in patients with varying degrees of hepatic 
impairment, the mean AUC for ruxolitinib was increased in patients with mild, moderate and 
severe hepatic impairment by 87%, 28% and 65%, respectively, compared to patients with 
normal hepatic function. There was no clear relationship between AUC and the degree of 
hepatic impairment based on Child-Pugh scores. 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). A dose reduction of approximately 50% is recommended for patients with 
hepatic impairment (see section 4.2). 


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5.3 
Preclinical safety data 
Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity 
and reproductive toxicity studies and in a carcinogenicity study. Target organs associated with 
the pharmacological action of ruxolitinib in repeated dose studies include bone marrow, 
peripheral 
blood 
and 
lymphoid 
tissues. 
Infections 
generally 
associated 
with 
immunosuppression were noted in dogs. Adverse decreases in blood pressure along with 
increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute 
volume was noted in a respiratory study in rats. The margins (based on unbound Cmax) at the 
non-adverse level in the dog and rat studies were 15.7-fold and 10.4-fold greater, respectively, 
than the maximum human recommended dose of 25 mg twice daily. No effects were noted in 
an evaluation of the neuropharmacological effects of ruxolitinib. 
Ruxolitinib decreased foetal weight and increased post-implantation loss in animal studies. 
There was no evidence of a teratogenic effect in rats and rabbits. However, the exposure margins 
compared to the highest clinical dose were low and the results are therefore of limited relevance 
for humans. No effects were noted on fertility. In a pre- and post-natal development study, a 
slightly prolonged gestation period, reduced number of implantation sites, and reduced number 
of pups delivered were observed. In the pups, decreased mean initial body weights and short 
period of decreased mean body weight gain were observed. In lactating rats, ruxolitinib and/or 
its metabolites were excreted into the milk with a concentration that was 13-fold higher than 
the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic. Ruxolitinib 
was not carcinogenic in the Tg.rasH2 transgenic mouse model. 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
• 
Cellulose, microcrystalline 
• 
Magnesium stearate 
• 
Silica, colloidal anhydrous 
• 
Sodium starch glycolate (Type A) 
• 
Povidone 
• 
Hydroxypropylcellulose 
• 
Lactose monohydrate 
6.2 
Incompatibilities 
Not applicable. 
 
6.3 
Shelf life 
3 years 
 
6.4 
Special precautions for storage 
Do not store above 30°C. 


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6.5 
Nature and contents of container 
PVC/PCTFE/Aluminium blister packs containing 14 or 56 tablets or multipacks containing 
168 (3 packs of 56) tablets. 
Not all pack sizes or types may be marketed. 
 
6.6 
Special precautions for disposal 
No special requirements. 
 
7. 
MARKETING AUTHORISATION HOLDER 
Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
8. 
MARKETING AUTHORISATION NUMBER(S) 
EU/1/12/773/014-016 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
23.08.2012 
 
10. 
DATE OF REVISION OF THE TEXT 
Detailed information on this medicinal product is available on the website of the European 
Medicines Agency http://www.ema.europa.eu 


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 This medicinal product is subject to additional monitoring. This will allow quick 
identification of new safety information. Healthcare professionals are asked to report any 
suspected adverse reactions. See section 4.8 for how to report adverse reactions. 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
Jakavi 15 mg tablets 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Each tablet contains 15 mg ruxolitinib (as phosphate). 
Excipient with known effect: 
Each tablet contains 214.35 mg lactose monohydrate. 
For the full list of excipients, see section 6.1. 
3. 
PHARMACEUTICAL FORM 
Tablet. 
Ovaloid curved white to almost white tablets of approximately 15.0 x 7.0 mm with “NVR” 
debossed on one side and “L15” debossed on the other side. 
 
4. 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
Myelofibrosis (MF) 
Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult 
patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post 
polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. 
Polycythaemia vera (PV) 
Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant 
to or intolerant of hydroxyurea. 
 
4.2 
Posology and method of administration 
Jakavi treatment should only be initiated by a physician experienced in the administration of 
anti-cancer agents. 
A complete blood cell count, including a white blood cell count differential, must be performed before 
initiating therapy with Jakavi. 
Complete blood count, including a white blood cell count differential, should be monitored every    2-
4 weeks until Jakavi doses are stabilised, and then as clinically indicated (see section 4.4). 
Posology 
Starting dose 


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The recommended starting dose of Jakavi in myelofibrosis is 15 mg twice daily for patients with a 
platelet count between 100,000/mm3 and 200,000/mm3 and 20 mg twice daily for patients with a platelet 
count of >200,000/mm3. The recommended starting dose of Jakavi in polycythaemia vera is  10 mg 
given orally twice daily. 
There is limited information to recommend a starting dose for patients with platelet counts 
between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these 
patients is 5 mg twice daily and the patients should be titrated cautiously. 
Dose modifications 
Doses may be titrated based on safety and efficacy. Treatment should be discontinued for platelet counts 
less than 50,000/mm3 or absolute neutrophil counts less than 500/mm3. In PV, treatment should also be 
interrupted when haemoglobin is below 8 g/dl. After recovery of blood counts above these levels, dosing 
may be re-started at 5 mg twice daily and gradually increased based on careful monitoring of complete 
blood cell count, including a white blood cell count differential. 
Dose reductions should be considered if the platelet count decreases below 100,000/ mm3, with the goal 
of avoiding dose interruptions for thrombocytopenia. In PV, dose reductions should also be considered 
if haemoglobin decreases below 12 g/dl and is recommended if it decreases below 10 g/dl. 
If efficacy is considered insufficient and blood counts are adequate, doses may be increased by a 
maximum of 5 mg twice daily, up to the maximum dose of 25 mg twice daily. 
The starting dose should not be increased within the first four weeks of treatment and thereafter no more 
frequently than at 2-week intervals. 
The maximum dose of Jakavi is 25 mg twice daily. 
Dose adjustment with concomitant strong CYP3A4 inhibitors or fluconazole 
When Jakavi is administered with strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 
enzymes (e.g. fluconazole) the unit dose of Jakavi should be reduced by approximately 50%, to be 
administered twice daily (see section 4.5). Avoid the concomitant use of Jakavi with fluconazole doses 
greater than 200 mg daily. 
More frequent monitoring (e.g. twice a week) of haematology parameters and of clinical signs and 
symptoms of Jakavi-related adverse drug reactions is recommended while on strong CYP3A4 inhibitors 
or dual inhibitors of CYP2C9 and CYP3A4 enzymes. 
Special populations 
Renal impairment 
No specific dose adjustment is needed in patients with mild or moderate renal impairment. 
In patients with severe renal impairment (creatinine clearance less than 30 ml/min) the 
recommended starting dose based on platelet count for MF patients should be reduced by 
approximately 50% to be administered twice daily. The recommended starting dose for PV 
patients with severe renal impairment is 5 mg twice daily. Patients should be carefully 
monitored with regard to safety and efficacy during Jakavi treatment. 
There are limited data to determine the best dosing options for patients with end -stage renal 
disease (ESRD) on haemodialysis. Pharmacokinetic/pharmacodynamic simulations based on 
available data in this population suggest that the starting dose for MF patients with ESRD on 
haemodialysis is a single dose of 15 -20 mg or two doses of 10 mg given 12 hours apart, to be 


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administered post-dialysis and only on the day of haemodialysis. A single dose of 15 mg is 
recommended for MF patients with platelet count between 100,000/mm3 and 200,000/mm3. A 
single dose of 20 mg or two doses of 10 mg given 12 hours apart is recommended for MF 
patients with platelet count of >200,000/mm3. Subsequent doses (single administration or two 
doses of 10 mg given 12 hours apart) should be administered only on haemodialysis days 
following each dialysis session. 
The recommended starting dose for PV patients with ESRD on haemodialysis is a single dose 
of 10 mg or two doses of 5 mg given 12 hours apart, to be administered post-dialysis and only 
on the day of haemodialysis. These dose recommendations are based on simulations and any 
dose modification in ESRD should be followed by careful monitoring of safety and efficacy in 
individual patients. No data is available for dosing patients who are undergoing peritoneal 
dialysis or continuous venovenous haemofiltration (see section 5.2). 
Hepatic impairment 
In patients with any hepatic impairment the recommended starting dose based on platelet  
count should be reduced by approximately 50% to be administered twice daily. Subsequent 
doses should be adjusted based on careful monitoring of safety and efficacy. Patients 
diagnosed with hepatic impairment while receiving Jakavi should have complete blood counts, 
including a white blood cell count differential, monitored at least every one to two weeks for 
the first 6 weeks after initiation of therapy with Jakavi and as clinically indicated thereafter 
once their liver function and blood counts have been stabilised. Jakavi dose can be titrated to 
reduce the risk of cytopenia. 
Older people (≥65 years) 
No additional dose adjustments are recommended for older people. 
Paediatric population 
The safety and efficacy of Jakavi in children aged up to 18 years have not been established. 
No data are available (see section 5.1). 
Treatment discontinuation 
Treatment may be continued as long as the benefit-risk remains positive. However the treatment 
should be discontinued after 6 months if there has been no reduction in spleen size or 
improvement in symptoms since initiation of therapy. 
It is recommended that, for patients who have demonstrated some degree of clinical 
improvement, ruxolitinib therapy be discontinued if they sustain an increase in their spleen 
length of 40% compared with baseline size (roughly equivalent to a 25% increase in spleen 
volume) and no longer have tangible improvement in disease-related symptoms. 
Method of administration 
Jakavi is to be taken orally, with or without food. 
If a dose is missed, the patient should not take an additional dose, but should take the next usual 
prescribed dose. 


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4.3 
Contraindications 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Pregnancy and lactation. 
4.4 
Special warnings and precautions for use 
Myelosuppression 
Treatment with Jakavi can cause haematological adverse drug reactions, including 
thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood 
cell count differential, must be performed before initiating therapy with Jakavi. Treatment 
should be discontinued in patients with platelet count less than 50,000/mm 3 or absoute 
neutrophil count less than 500/mm3 (see section 4.2). 
It has been observed that patients with low platelet counts (<200,000/mm3) at the start of 
therapy are more likely to develop thrombocytopenia during treatment. 
Thrombocytopenia is generally reversible and is usually managed by reducing the dose or 
temporarily withholding Jakavi (see sections 4.2 and 4.8). However, platelet transfusions may 
be required as clinically indicated. 
Patients developing anaemia may require blood transfusions. Dose modifications or interruption 
for patients developing anaemia may also be considered. 
Patients with a haemoglobin level below 10.0 g/dl at the beginning of the treatment have a 
higher risk of developing a haemoglobin level below 8.0 g/dl during treatment compared to 
patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent 
monitoring of haematology parameters and of clinical signs and symptoms of Jakavi-related 
adverse drug reactions is recommended for patients with baseline haemoglobin below 
10.0 g/dl. 
Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by 
temporarily withholding Jakavi (see sections 4.2 and 4.8). 
Complete blood counts should be monitored as clinically indicated and dose adjusted as 
required (see sections 4.2 and 4.8). 
Infections 
Patients should be assessed for the risk of developing serious bacte rial, mycobacterial, fungal 
and viral infections. Tuberculosis has been reported in patients receiving Jakavi for MF. Before 
starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, 
as per local recommendations. This can include medical history, possible previous contact with 
tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-
gamma release assay, as applicable. Prescribers are reminded of the risk of false negative 
tuberculin skin test results, especially in patients who are severely ill or immunocompromised. 
Jakavi therapy should not be started until active serious infections have resolved. Physicians 
should carefully observe patients receiving Jakavi for signs and symptoms of infections and 
initiate appropriate treatment promptly (see section 4.8). 
Hepatitis B viral load (HBV-DNA titre) increases, with and without associated elevations in 


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alanine aminotransferase and aspartate aminotransferase, have been reported in patients with 
chronic HBV infections taking Jakavi. The effect of Jakavi 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. 
Herpes zoster 
Physicians should educate patients about early signs and symptoms of herpes zoster, advising 
that treatment should be sought as early as possible. 
Progressive multifocal leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) has been reported with Jakavi treatment for 
MF. Physicians should be particularly alert to symptoms suggestive of PML that patients may 
not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should be 
monitored for any of these new or worseni ng symptoms or signs, and if such symptoms/signs 
occur, referral to a neurologist and appropriate diagnostic measures for PML should be 
considered. If PML is suspected, further dosing must be suspended until PML has been 
excluded. 
Non-melanoma skin cancer 
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell 
carcinoma, have been reported in patients treated with ruxolitinib. Most of these patients had 
histories of extended treatment with hydroxyurea and prior NMSC or pre -malignant skin 
lesions. A causal relationship to ruxolitinib has not been established. Periodic skin examination 
is recommended for patients who are at increased risk for skin cancer. 
Special populations 
Renal impairment 
The starting dose of Jakavi should be reduced in patients with severe renal impairment. For 
patients with end-stage renal disease on haemodialysis the starting dose for MF patients should 
be based on platelet counts (see section 4.2). Subsequent doses (single dose of 20 mg or two 
doses of 10 mg given 12 hours apart in MF patients; single dose of 10 mg or two doses of 5 mg 
given 12 hours apart in PV patients) should be administered only on haemodialysis days 
following each dialysis session. Additional dose modifications should be made with careful 
monitoring of safety and efficacy (see sections 4.2 and 5.2). 
Hepatic impairment 
The starting dose of Jakavi should be reduced by approximately 50% in patients with hepatic 
impairment. Further dose modifications should be based on the safety and efficacy of the 
medicinal product (see sections 4.2 and 5.2). 
Interactions 
If Jakavi is to be co-administered with strong CYP3A4 inhibitors or dual inhibitors of CYP3A4 
and CYP2C9 enzymes (e.g. fluconazole), the unit dose of Jakavi should be reduced by 
approximately 50%, to be administered twice daily (for monitoring frequency  see  sections 4.2 
and 4.5). 


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The concomitant use of cytoreductive therapies or haematopoietic growth factors with Jakavi 
has not been studied. The safety and efficacy of these co -administrations are not known (see 
section 4.5). 
Withdrawal effects 
Following interruption or discontinuation of Jakavi, symptoms of MF may return over a period 
of approximately one week. There have been cases of patients discontinuing Jakavi who 
sustained more severe events, particularly in the presence of acute intercurrent illness. It has not 
been established whether abrupt discontinuation of Jakavi contributed to these events. Unless 
abrupt discontinuation is required, gradual tapering of the dose of Jakavi may be considered, 
although the utility of the tapering is unproven. 
Excipients 
Jakavi contains lactose. Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal 
product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
Interaction studies have only been performed in adults. 
Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, 
medicinal products inhibiting these enzymes can give rise to increased ruxolitinib exposure. 
Interactions resulting in dose reduction of ruxolitinib 
CYP3A4 inhibitors 
Strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, saquinavir, telaprevir, telithromycin, voriconazole) 
In healthy subjects co-administration of Jakavi (10 mg single dose) with a strong CYP3A4 
inhibitor, ketoconazole, resulted in ruxolitinib Cmax and AUC that were higher by 33% and 91%, 
respectively, than with ruxolitinib alone. The half-life was prolonged from 3.7 to 
6.0 hours with concurrent ketoconazole administration. 
When administering Jakavi with strong CYP3A4 inhibitors the unit dose of Jakavi should be 
reduced by approximately 50%, to be administered twice daily. Patients should be closely 
monitored (e.g. twice weekly) for cytopenias and dose titrated based on safety and efficacy (see 
section 4.2). 
Dual CYP2C9 and CYP3A4 inhibitors 
50% dose reduction should be considered when using medicinal products which are dual 
inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of 
Jakavi with fluconazole doses greater than 200 mg daily. 
Enzyme inducers 


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CYP3A4 inducers (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St.John’s wort (Hypericum perforatum)) 
Patients should be closely monitored and the dose titrated based on safety and efficacy (see 
section 4.2). 
In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducer 
rifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after 
administration of Jakavi alone. The exposure of ruxolitinib active metabolites was unchanged. 
Overall, the ruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 
induction resulted in minimal effect on the pharmacodynamics. However, this could be related 
to the high ruxolitinib dose resulting in pharmacodynamic effects near E max. It is possible that 
in the individual patient, an increase of the ruxolitinib dose is needed when initiating treatment 
with a strong enzyme inducer. 
Other interactions to be considered affecting ruxolitinib 
Mild or moderate CYP3A4 inhibitors (such as, but not limited to, ciprofloxacin, erythromycin, 
amprenavir, atazanavir, diltiazem, cimetidine) 
In healthy subjects co-administration of ruxolitinib (10 mg single dose) with erythromycin 500 
mg twice daily for four days resulted in ruxolitinib Cmax and AUC that were higher by 8% and 
27%, respectively, than with ruxolitinib alone. 
No dose adjustment is recommended when ruxolitinib is co-administered with mild or moderate 
CYP3A4 inhibitors (e.g. erythromycin). However, patients should be closely monitored for 
cytopenias when initiating therapy with a moderate CYP3A4 inhibitor. 
Effects of ruxolitinib on other medicinal products 
Substances transported by P-glycoprotein or other transporters 
Ruxolitinib may inhibit P-glycoprotein and breast cancer resistance protein (BCRP) in the 
intestine. This may result in increased sytemic exposure of substrates of these transporters, such 
as dabigatran etexilate, ciclosporin, rosuvastatin and potentially digoxin. Therapeutic drug 
monitoring (TDM) or clinical monitoring of the affected substance is advised. 
It is possible that the potential inhibition of P-gp and BCRP in the intestine can be minimised 
if the time between administrations is kept apart as long as possible. 
Haematopoietic growth factors 
The concurrent use of haematopoietic growth factors and Jakavi has not been studied. It is not 
known whether the Janus Associated Kinase (JAK) inhibition by Jakavi reduces the efficacy of 
the haematopoietic growth factors or whether the haematopoietic growth factors affect the 
efficacy of Jakavi (see section 4.4). 
Cytoreductive therapies 
The concomitant use of cytoreductive therapies and Jakavi has not been studied. The safety and 
efficacy of this co-administration is not known (see section 4.4). 
A study in healthy subjects indicated that ruxolitinib did not inhibit the metabolism of the oral 
CYP3A4 substrate midazolam. Therefore, no increase in exposure of CYP3A4 substrates is 


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anticipated when combining them with Jakavi. Another study in healthy subjects indicated that 
Jakavi does not affect the pharmacokinetics of an oral contrac eptive containing ethinylestradiol 
and levonorgestrel. Therefore, it is not anticipated that the contraceptive efficacy of this 
combination will be compromised by co-administration of ruxolitinib. 
 
4.6 
Fertility, pregnancy and lactation 
Pregnancy and contraception in females 
There are no data from the use of Jakavi in pregnant women. 
Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was 
not observed in rats or rabbits. However, the exposure margins compared to the highe st clinical 
dose were low and the results are therefore of limited relevance for humans (see section 5.3). 
The potential risk for humans is unknown. As a precautionary measure, the use of Jakavi during 
pregnancy is contraindicated (see section 4.3). Women of child-bearing potential should use 
effective contraception during the treatment with Jakavi. In case pregnancy should occur during 
treatment with Jakavi, a risk/benefit evaluation must  be carried out on an individual basis with 
careful counselling regarding potential risks to the foetus (see section 5.3). 
Breast-feeding 
Jakavi must not be used during breast-feeding (see section 4.3) and breast-feeding should 
therefore be discontinued when treatment is started. It is unknown whether ruxolitinib and/or 
its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. 
Available pharmacodynamic/toxicological data in animals have shown excretion of  ruxolitinib 
and its metabolites in milk (see section 5.3). 
Fertility 
There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect 
on fertility was observed. 
 
4.7 
Effects on ability to drive and use machines 
Jakavi has no or negligible sedating effect. However, patients who experience dizziness after 
the intake of Jakavi should refrain from driving or using machines. 
 
4.8 
Undesirable effects 
Summary of the safety profile 
The safety assessment was based on a total of 855 patients (with MF or PV) receiving Jakavi in    
phase 2 and 3 studies. 
Myelofibrosis 
In the randomised period of the two pivotal studies, COMFORT-I and COMFORT-II, the 
median duration of exposure to Jakavi was 10.8 months (range 0.3 to 23.5 months). The 
majority of patients (68.4%) were treated for at least 9 months. Of 301 patients, 111 (36.9%) 
had a baseline platelet count of between 100,000/mm3 and 200,000/mm3 and 190 (63.1%) had 
a baseline platelet count of >200,000/mm3. 


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In these clinical studies, discontinuation due to adverse events, regardless of causality, was 
observed in 11.3% of patients. 
The most frequently reported adverse drug reactions were thrombocytopenia and anaemia. 
Haematological adverse drug reactions (any Common Terminology Criteria for Adverse Events 
[CTCAE] grade) included anaemia (82.4%), thrombocytopenia (69.8%) and neutropenia (16.6%). 
Anaemia, thrombocytopenia and neutropenia are dose-related effects. 
The three most frequent non-haematological adverse drug reactions were bruising (21.3%), dizziness 
(15.3%) and headache (14.0%). 
The three most frequent non-haematological laboratory abnormalities were raised alanine 
aminotransferase 
(27.2%), 
raised 
aspartate 
aminotransferase 
(19.9%) 
and 
hypercholesterolaemia (16.9%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4 
hypercholesterolaemia, raised aspartate aminotransferase nor CTCAE grade 4 raised alanine 
aminotransferase were observed. 
Long-term safety: As expected with an extended follow-up period, the cumulative frequency 
of some adverse events increased in the evaluation of the 3 -year follow-up safety data (median 
duration of exposure of 33.2 months in COMFORT-I and COMFORT-II for patients initially 
randomised to ruxolitinib) from 457 patients with myelofibrosis treated with ruxolitinib during 
the randomised and extension periods of the two pivot al phase 3 studies. This evaluation 
included data from patients that were initially randomised to ruxolitinib (N=301) and patients 
that received ruxolitinib after crossing over from control treatment arms (N=156). With these 
updated data, therapy discontinuation due to adverse events was observed in 17.1% of patients 
treated with ruxolitinib. 
Polycythaemia vera 
The safety of Jakavi was assessed in 110 patients with PV in an open-label, randomised, 
controlled phase 3 RESPONSE study. The adverse drug reactions listed below reflect the initial 
study period (up to week 32) with equivalent exposure to ruxolitinib and Best Available 
Therapy (BAT), corresponding to a median duration of exposure to Jakavi of 7.8 months. The 
mean age of patients receiving Jakavi was around 60 years. 
Discontinuation due to adverse events, regardless of causality, was observed in 3.6% of patients 
treated with Jakavi and 1.8% of patients treated with best available therapy. 
Haematological adverse reactions (any CTCAE grade) included anaemia (43.6%) and 
thrombocytopenia (24.5%). Anaemia or thrombocytopenia CTCAE grade 3 and 4 were reported 
in respectively 1.8% or 5.5%. 
The three most frequent non-haematological adverse reactions were dizziness (15.5%), 
constipation (8.2%) and herpes zoster (6.4%). 
The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) were 
hypercholesterolaemia (30.0%), raised alanine aminotransferase (22.7%) and raised aspartate 
aminotransferase (20.9%). These were all CTCAE grade 1 and 2 with the exception of one 
CTCAE grade 3 raised alanine aminotransferase event. 


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Long-term safety: Patients had a median duration of exposure to Jakavi of 18.6 months (range 
0.3 to 35.9 months). With longer exposure, frequency of adverse events increased; howev er no 
new safety findings emerged. When adjusted for exposure, the adverse event rates were 
generally comparable with those observed during the initial study period. 
Tabulated summary of adverse drug reactions from clinical studies 
In the clinical study programme the severity of adverse drug reactions was assessed based on the 
CTCAE, defining grade 1 = mild, grade 2 = moderate, grade 3 = severe and grade 4=life-threatening. 
Adverse drug reactions from clinical studies (Table 14-8) are listed by MedDRA system organ class. 
Within each system organ class, the adverse drug reactions are ranked by frequency, with the most 
frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction 
is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon 
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). 
 
Table 14-8 
Frequency category of adverse drug reactions reported in the phase 3 
studies (COMFORT-I, COMFORT-II, RESPONSE) 
 
Adverse drug reaction 
Frequency category for MF 
patients 
Frequency category for PV patients 
Infections and infestations 
Urinary tract infectionsa,d 
Very common 
Common 
Herpes zostera,d 
Common 
Common 
Tuberculosise 
Uncommon 
- 
Blood and lymphatic system 
disordersb,d 
Anaemiab 
- 
- 
CTCAEc grade 4 
(<6.5g/dl) 
Very common 
Uncommon 
CTCAEc grade 3 
(<8.0 – 6.5g/dl) 
Very common 
Uncommon 
Any CTCAEc grade 
Very common 
Very common 
Thrombocytopeniab 
CTCAEc grade 4 
(<25,000/mm3) 
Common 
Uncommon 
CTCAEc grade 3 
(50,000 – 25,000/mm3) 
Common 
Common 
Any CTCAEc grade 
Very common 
Very common 
Neutropeniab 
CTCAEc grade 4 
(<500/mm3) 
Common 
- 
CTCAEc grade 3 
(<1,000 – 500/mm3) 
Common 
- 
Any CTCAEc grade 
Very common 
- 


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Adverse drug reaction 
Frequency category for MF 
patients 
Frequency category for PV patients 
Bleeding (any bleeding including 
intracranial, and gastrointestinal 
bleeding, bruising and other 
bleeding) 
Very common 
Very common 
Intracranial bleeding 
Common 
- 
Gastrointestinal bleeding 
Common 
- 
Bruising 
Very common 
Very common 
Other bleeding (including 
epistaxis, post-procedural 
haemorrhage and haematuria) 
Common 
Very common 
Metabolism and nutrition 
disorders 
Weight gaina 
Very common 
Common 
Hypercholesterolaemiab 
CTCAEc grade 1 and 2 
Very common 
Very common 
Hypertriglyceridaemiab 
CTCAEc grade 1 
- 
Very common 
Nervous system disorders 
Dizzinessa 
Very common 
Very common 
Headachea 
Very common 
- 
Gastrointestinal disorders 
Flatulencea 
Common 
- 
Constipationa 
- 
Common 
Hepatobiliary disorders 
Raised alanine aminotransferaseb 
CTCAEc grade 3 
(> 5x – 20 x ULN) 
Common 
Uncommon 
Any CTCAEc grade 
Very common 
Very common 
Raised aspartate aminotransferaseb 
Any CTCAEc grade 
Very common 
Very common 
Vascular disorders 
Hypertensiona 
- 
Very common 
aFrequency is based on adverse event data. 
- 
A subject with multiple occurrence of an adverse drug reaction (ADR) is counted only once in that ADR 
category. 
- 
ADRs reported are on treatment or up to 28 days post treatment end date. 
bFrequency is based on laboratory values. 
- A subject with multiple occurrences of an ADR is counted only once in that ADR category. 
- ADRs reported are on treatment or up to 28 days post treatment end date. 
cCommon Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild, grade 2 = moderate, 
grade 3 = severe, grade 4 = life-threatening 
dThese ADRs are discussed in the text. 
eFrequency is based on all patients exposed to ruxolitinib in clinical studies (N=4755) 


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Upon discontinuation, MF patients may experience a return of MF symptoms such as fatigue, 
bone pain, fever, pruritus, night sweats, symptomatic splenomegaly and weight loss. In clinical 
studies in MF the total symptom score for MF symptoms gradually returned to baseline value 
within 7 days after dose discontinuation (see section 4.4). 
Description of selected adverse drug reactions 
Anaemia 
In phase 3 clinical studies in MF, median time to onset of first CTCAE grade 2 or higher 
anaemia was 1.5 months. One patient (0.3%) discontinued treatment because of anaemia. 
In patients receiving Jakavi mean decreases in haemoglobin reached a nadir of approximately 
10 g/litre below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach 
a new steady state that was approximately 5 g/litre below baseline. This pattern was observed 
in patients regardless of whether they had received transfusion during therapy. 
In the randomised, placebo-controlled study COMFORT-I 60.6% of Jakavi-treated MF patients 
and 37.7% of placebo-treated MF patients received red blood cell transfusions during 
randomised treatment. In the COMFORT-II study the rate of packed red blood cell transfusions 
was 53.4% in the Jakavi arm and 41.1% in the best available therapy arm. 
In the randomised period of the pivotal studies, anaemia was less frequent in PV patients than 
in MF patients (43.6% versus 82.4%). In the PV population, the CTCAE grade 3 and 4 events 
were reported in 1.8%, while in the MF patients the frequency was 42.56%. 
Thrombocytopenia 
In the phase 3 clinical studies in MF, 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 50,000/mm3 was 14 days. During the randomised period, platelet transfusions 
were administered to 4.7% of patients receiving Jakavi and to 4.0% of patients receiving control 
regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of 
patients receiving Jakavi and 0.9% of patients receiving control regimens. Patients with a 
platelet count of 100,000/mm 3 to 200,000/mm3 before starting Jakavi had a higher frequency 
of grade 3 or 4 thrombocytopenia compared to patients with platelet count >200,000/mm3 
(64.2% versus 38.5%). 
In the randomised period of the pivotal studies, the rate of patients experiencing 
thrombocytopenia was lower in PV (24.5%) patients compared to MF (69.8%) patients. The 
frequency of severe (i.e. CTCAE grade 3 and 4) thrombocytopenia was lower in PV (5.5%) 
than in MF (11.6%) patients. 
Neutropenia 
In the phase 3 clinical studies in MF, in patients who developed grade 3 or 4 neutropenia, the 
median time to onset was 12 weeks. During the randomised period, dose holding or reductions 
due to neutropenia were reported in 1.0% of patients, and 0.3% of patients discontinued 
treatment because of neutropenia. 


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In the randomised period of the pivotal study in PV patients, neutropenia was reported in two 
patients (1.8%) of which one patient developed CTCAE grade 4 neutropenia. 
Bleeding 
In the phase 3 pivotal studies in MF bleeding events (including intracranial and gastrointestinal, 
bruising and other bleeding events) were reported in 32.6% of patients exposed to Jakavi and 
23.2% of patients exposed to the reference treatments (placebo or best available therapy). The 
frequency of grade 3-4 events was similar for patients treated with Jakavi or reference 
treatments (4.7% versus 3.1%). Most of the patients with bleeding events during the treatment 
reported bruising (65.3%). Bruising events were more frequently reported in patients taking 
Jakavi compared with the reference treatments (21.3% versus 11.6%). Intracranial bleeding was 
reported in 1% of patients exposed to Jakavi and 0.9% exposed to reference treatments. 
Gastrointestinal bleeding was reported in 5.0% of patients exposed to Jakavi compared to 3.1% 
exposed to reference treatments. Other bleeding events (including events such as epistaxis, post-
procedural haemorrhage and haematuria) were reported in 13.3% of patients treated with Jakavi 
and 10.3% treated with reference treatments. 
In the randomised period of the pivotal study in PV patients, bleeding events (including 
intracranial and gastrointestinal, bruising and other bleeding events) were reported in 20% of 
patients treated with Jakavi and 15.3% patients receiving best available therapy. Bruising was 
reported in similar frequencies in Jakavi and BAT arms (10.9% versus 8.1%). No intracranial 
bleeding or gastrointestinal haemorrhage events were reported in patients receiving Jakavi. One 
patient treated with Jakavi experienced a grade 3 bleeding event (post-procedural bleeding); no 
grade 4 bleeding was reported. Other bleeding events (including events such as epistaxis, post-
procedural haemorrhage, gingival bleeding) were reported in 11.8% of patients treated with 
Jakavi and 6.3% treated with best available therapy. 
Infections 
In the phase 3 pivotal studies in MF, grade 3 or 4 urinary tract infection was reported in 1.0% 
of patients, herpes zoster in 4.3% and tuberculosis in 1.0%. In phase 3 clinical studies sepsis 
was reported in 3.0% of patients. An extended follow-up of patients treated with ruxolitinib 
showed no trends towards an increase in the rate of sepsis over time. 
In the randomised period of the pivotal study in PV patients, one (0.9%) CTCAE grade 3 and 
no grade 4 urinary tract infection was reported. The rate of herpes zoster was slightly higher  in 
PV (6.4%) patients than in MF (4.0%) patients. There was one report of CTCAE grade 3 post-
herpetic neuralgia amongst the PV patients. 
Increased systolic blood pressure 
In the phase 3 pivotal  clinical  studies  in  MF  an  increase  in  systolic  blood  pressure  of  20 
mmHg or more from baseline was recorded in 31.5% of patients on at least one visit compared 
with 19.5% of the control-treated patients. In COMFORT-I (MF patients) the mean increase 
from baseline in systolic  BP  was  0 -2 mmHg  on  Jakavi  versus  a  decrease  of  2-5 mmHg 
in the placebo arm. In COMFORT-II mean values showed little difference between the 
ruxolitinib-treated and the control-treated MF patients. 
In the randomised period of the pivotal study in PV patients, the mean systolic blood pressure 
increased by 0.65 mmHg in the Jakavi arm versus a decrease of 2 mmHg in the BAT arm. 


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Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. 
It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting 
system listed in Appendix V. 
 
4.9 
Overdose 
There is no known antidote for overdoses with Jakavi. 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, anaemia and thrombocytopenia. Appropriate supportive 
treatment should be given. 
Haemodialysis is not expected to enhance the elimination of ruxolitinib. 
 
5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: 
L01XE18 
Mechanism of action 
Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 
(IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively).  These mediate 
the signalling of a number of cytokines and growth factors that are important for haematopoiesis 
and immune function. 
Myelofibrosis and polycythaemia vera are myeloproliferative neoplasms known to be 
associated with dysregulated JAK1 and JAK2 signalling. The basis for the dysregulation is 
believed to include high levels of circulating cytokines that activate the JAK -STAT pathway, 
gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory 
mechanisms. MF patients exhibit dysregulated JAK signalling regardless of JAK2V617F 
mutation status. Activating mutations in JAK2 (V617F or exon 12) are found in >95% of PV 
patients. 
Ruxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular 
models of haematological malignancies, as well as of Ba/F3 cells rendered cytokine-
independent by expressing the JAK2V617F mutated protein, with IC 50 ranging from 80-320 
nM. 
Pharmacodynamic effects 
Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy 
subjects, MF patients and PV patients. Ruxolitinib resulted in maximal inhibition of STAT3 
phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy 
subjects and MF patients, indicating no accumulation of either parent or active metabolites. 
Baseline elevations in inflammatory markers associated with constitutional symptoms such as 
TNFα, IL-6 and CRP in subjects with MF were decreased following treatment with ruxolitinib. 


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MF patients did not become refractory to the pharmacodynamic effects of ruxolitinib treatment 
over time. Similarly, patients with PV also presented with baseline elevations in inflammatory 
markers and these markers were decreased following treatment with ruxolitinib. 
In a thorough QT study in healthy subjects, there was no indication of a QT/QTc prolonging 
effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, indicating that 
ruxolitinib has no effect on cardiac repolarisation. 
Clinical efficacy and safety 
Myelofibrosis 
Two randomised phase 3 studies (COMFORT-I and COMFORT-II) were conducted in patients 
with MF (primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential 
thrombocythaemia myelofibrosis). In both studies, patients had palpable splenomegaly at least 
5 cm below the costal margin and risk category of intermediate -2 or high risk based on the 
International Working Group (IWG) Consensus Criteria. The starting dose of Jakavi was based 
on platelet count. 
COMFORT-I was a double-blind, randomised, placebo-controlled study in 309 patients who 
were refractory to or were not candidates for available therapy. The primary efficacy endpoint 
was proportion of subjects achieving  ≥35% reduction from baseline in spleen volume at  week 
24 as measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). 
Secondary endpoints included duration of maintenance of a ≥35% reduction from baseline in 
spleen volume, proportion of patients who had ≥50% reduction in total symptom score, changes 
in total symptom scores from baseline to week 24, as measured by the modified Myelofibrosis 
Symptom Assessment Form (MFSAF) v2.0 diary, and overall survival. 
COMFORT-II was an open-label, randomised study in 219 patients. Patients were randomised 
2:1 to Jakavi versus best available therapy. In the best available therapy arm, 47% of patients 
received hydroxyurea and 16% of patients received glucocorticoids. The primary efficacy 
endpoint was proportion of patients achieving ≥35% reduction from baseline in spleen volume 
at week 48 as measured by MRI or CT. 
Secondary endpoints included proportion of patients achieving a ≥35% reduction of spleen 
volume from baseline at week 24 and duration of maintenance of a ≥35% reduction from 
baseline spleen volume. 
In COMFORT-I and COMFORT-II, patient baseline demographics and disease characteristics 
were comparable between the treatment arms. 
 
Table 14-9 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume at week 24 in COMFORT-I and at week 48 in COMFORT-II (ITT) 
 
COMFORT-I 
COMFORT-II 
Jakavi 
(N=155) 
Placebo 
(N=153) 
Jakavi 
(N=144) 
Best available 
therapy 
(N=72) 
Time points 
Week 24 
Week 48 


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Number (%) of subjects with 
spleen volume reduced by 
≥35% 
65 (41.9) 
1 (0.7) 
41 (28.5) 
0 
95% confidence intervals 
34.1, 50.1 
0, 3.6 
21.3, 36.6 
0.0, 5.0 
p-value 
<0.0001 
<0.0001 
A significantly higher proportion of patients in the Jakavi group achieved ≥35% reduction from 
baseline in spleen volume (Table 14-9) regardless of the presence or absence of the JAK2V617F 
mutation or the disease subtype (primary myelofibrosis, post-polycythaemia vera 
myelofibrosis, post-essential thrombocythaemia myelofibrosis). 
 
Table 14-10 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume by JAK mutation status (safety set) 
 
COMFORT-I 
COMFORT-II 
Jakavi 
Placebo 
Jakavi 
Best available 
therapy 
JAK 
mutation 
status 
Positive 
(N=113) 
n (%) 
Negative 
(N=40) 
n (%) 
Positive 
(N=121) 
n (%) 
Negative 
(N=27) 
n (%) 
Positive 
(N=110) 
n (%) 
Negative 
(N=35) 
n (%) 
Positive 
(N=49) 
n (%) 
Negative 
(N=20) 
n (%) 
Number 
(%) of 
subjects 
with 
spleen 
volume 
reduced 
by ≥35% 
54 (47.8) 
11 (27.5) 
1 
(0.8) 
0 
36 (32.7) 
5 
(14.3) 
0 
0 
Time 
point 
After 24 weeks 
After 48 weeks 
The probability of maintaining spleen  response  (≥35%  reduction)  on  Jakavi  for  at  least 24 
weeks was 89% in COMFORT-I and 87% in COMFORT-II; 52% maintained spleen responses 
for at least 48 weeks in COMFORT-II. 
In COMFORT-I, 45.9% subjects in the Jakavi group achieved a ≥50% improvement from 
baseline in the week 24 total symptom score (measured using MFSAF diary v2.0), as compared 
to 5.3% in the placebo group (p<0.0001 using chi-square test). The mean change in the global 
health status at week 24, as measured by EORTC QLQ C30 was +12.3 for Jakavi and -3.4 for 
placebo (p<0.0001). 
In COMFORT-I, after a median follow-up of 34.3 months, the death rate in patients randomised 
to the ruxolitinib arm was 27.1% versus 35.1% in patients randomised to placebo; HR 0.687; 
95% CI 0.459-1.029; p=0.0668. 
In COMFORT-II, after a median follow-up of 34.7 months, the death rate in patients 
randomised to ruxolitinib was 19.9% versus 30.1% in patients randomised to best available 
treatment (BAT); HR 0.48; 95% CI 0.28-0.85; p=0.009. In both studies, the lower death rates 
noted in the ruxolitinib arm were predominantly driven by the results obtained in the post 
polycythaemia vera and post essential thrombocythaemia subgroups. 


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Polycythaemia vera 
A randomised, open-label, active-controlled phase 3 study (RESPONSE) was conducted in 222 
patients with PV who were resistant to or intolerant of hydroxyurea defined based on the 
European LeukemiaNet (ELN) international working group published criteria. 110 patients 
were randomised to the ruxolitinib arm and 112 patients to the BAT arm. The starting dose of 
Jakavi was 10 mg twice daily. Doses were then adjusted in individual patients based on 
tolerability and efficacy with a maximum dose of 25 mg twice daily. BAT was selected by the 
investigator 
on 
a 
patient-by-patient 
basis 
and 
included 
hydroxyurea 
(59.5%), 
interferon/pegylated interferon (11.7%), anagrelide (7.2%), pipobroman (1.8%) and 
observation (15.3%). 
Baseline demographics and disease characteristics were comparable between the two treatments 
arms. The median age was 60 years (range 33 to 90 years). Patients in the ruxolitinib arm had 
PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median 
of approximately 3 years. Most patients (>80%) had received at least two phlebotomies in the 
last 24 weeks prior to screening. Comparative data regarding long-term survival and incidence 
of disease complications is missing. 
The primary composite endpoint was the proportion of patients achieving both an absence of 
phlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volume from baseline at 
week 32. Phlebotomy eligibility was  defined  as  a  confirmed  HCT  of  >45%,  i.e.  at  least 3 
percentage points higher than the HCT obtained at baseline or a confirmed HCT of >48%, 
depending on which was lower. Key secondary endpoints included the proportion of pa tients 
who achieved the primary endpoint and remained free from progression at week 48, as well as 
the proportion of patients achieving complete haematological remission at week 32. 
The study met its primary objective and a higher proportion of patients in the Jakavi group 
achieved the primary composite endpoint and each of its individual components. Significantly 
more patients treated with Jakavi (20.9%) achieved a primary response (p<0.0001) compared 
to BAT (0.9%). Haematocrit control was achieved in 60% of patients in the Jakavi arm 
compared to 19.6% in the BAT arm and a ≥35% reduction in spleen volume was achieved in 
38.2% of patients  in the Jakavi  arm compared  to 0.9% in the BAT  arm ( Figure 14-3).       94 
(83.9%) patients randomised to the BAT arm crossed over to ruxolitinib treatment at  Week 32 
or after, limiting the comparison between the two arms after Week 32. 
Both key secondary endpoints were also met. The proportion of patients achieving a complete 
haematological remission was 23.6% on Jakavi compared to 8.9% on BAT (p=0.0028) and the 
proportion of patients achieving a durable primary response at week 48 was 19.1% on Jakavi 
and 0.9% on BAT.(p<0.0001). 


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Figure 14-3 
Patients achieving the primary endpoint and components of the 
primary endpoint at week 32 
 
 
P-value: < .0001 
Odds Ratio (Ruxolitinib/BAT) 
70 
 
60 
Individual components of Primary 
Response at Week 32 
 
60 
 
 
 
.RUX 
.BAT 
 
50 
 
40 
 
30 
20 
20 
 
10 
 
 
0 
Primary Composite 
Endpoint at Week 32 
 
≥ 35% reduction in Spleen 
Volume 
 
Hematocrit control without 
phlebotomy 
 
Symptom burden was assessed using the MPN-SAF total symptom score (TSS) electronic 
patient diary, which consisted of 14 questions. At week 32, 49% and 64% of patients treated 
with ruxolitinib achieved a ≥50% reduction in TSS-14 and TSS-5, respectively, compared to 
only 5% and 11% of patients on BAT. 
Treatment benefit perception was measured by the Patient Global Impress ion of Change 
(PGIC) questionnaire. 66% of patients treated with ruxolitinib compared to 19% treated with 
BAT reported an improvement as early as four weeks after beginning treatment. Improvement 
in perception of treatment benefit was also higher in  patients treated  with  ruxolitinib  at week 
32 (78% versus 33%). 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Jakavi in all subsets of the paediatric population for the treatment of MF (see section 4.2 for 
information on paediatric use). 
 
5.2 
Pharmacokinetic properties 
Absorption 
Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high 
permeability, high solubility and rapid dissolution characteristics. In clinic al studies, ruxolitinib 
is rapidly absorbed after oral administration with maximal plasma concentration (Cmax) 
achieved approximately 1 hour post-dose. Based on a human mass balance study, oral 
absorption of ruxolitinib, as ruxolitinib or metabolites formed under first-pass, is 95% or 
1 
1 
21 
38 
and 95% CI: 
28.64 (4.50, 12.06) 
Percentage e of patientsnts 


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greater. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single 
dose range of 5-200 mg. There was no clinically relevant change in the 


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pharmacokinetics of ruxolitinib upon administration with a high-fat meal. The mean Cmax was 
moderately decreased (24%) while the mean AUC was nearly unchanged (4% increase) on 
dosing with a high-fat meal. 
Distribution 
The mean volume of distribution at steady state is approximately 75 litres in MF and PV 
patients. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro 
is approximately 97%, mostly to albumin. A whole body autoradiography study in rats has 
shown that ruxolitinib does not penetrate the blood-brain barrier. 
Biotransformation 
Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from 
CYP2C9. Parent compound is the predominant entity in human plasma, representing 
approximately 60% of the drug-related material in circulation. Two major and active 
metabolites are present in plasma representing 25% and 11% of parent AUC. These metabolites 
have one half to one fifth of the parent JAK-related pharmacological activity. The sum total of 
all active metabolites contributes to 18% of the overall pharm acodynamics of ruxolitinib. At 
clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6 
or CYP3A4 based on in vitro studies. In vitro data indicate that ruxolitinib may inhibit P-gp and 
BCRP. 
Elimination 
Ruxolitinib is mainly eliminated through metabolism. The mean elimination half -life of 
ruxolitinib is approximately 3 hours. Following a single oral dose of [14C]-labelled ruxolitinib 
in healthy adult subjects, elimination was predominately through metabolism, with 74% of 
radioactivity excreted in urine and 22% via faeces. Unchanged parent substance accounted for 
less than 1% of the excreted total radioactivity. 
Linearity/non-linearity 
Dose proportionality was demonstrated in the single and multiple dose studies. 
Special populations 
Effects of age, gender or race 
Based on studies in healthy subjects, no relevant differences in ruxolitinib pharmacokinetics 
were observed with regard to gender and race. In a population pharmacokinetic evaluation in 
MF patients, no relationship was apparent between oral clearance and patient age or race. The 
predicted oral clearance was 17.7 l/h in women and 22.1 l/h in men, with 39% inter-subject 
variability in MF patients. Clearance was 12.7 l/h in PV patients, with a 42% inter-subject 
variability and no relationship was apparent between oral clearance and gender, patient age or 
race, based on a population pharmacokinetic evaluation in PV patients. 
Paediatric population 
The safety and effectiveness of Jakavi in paediatric patients have not been established (see 
section 5.1, “Paediatric population”). 


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Renal impairment 
Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and 
urinary creatinine. Following a single ruxolitinib dose of 25 mg, the exposure 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 tended to increase with 
increasing severity of renal impairment, and were most markedly increased in the subjects with 
severe renal impairment. It is unknown whether the increased metabolite exposure is of safety 
concern. A dose modification is recommended in patients with severe renal impairment and 
end-stage renal disease (see section 4.2). Dosing only on dialysis days reduces the metabolite 
exposure, but also the pharmacodynamic effect, especially on the days between dialysis. 
Hepatic impairment 
Following a single ruxolitinib dose of 25 mg in patients with varying degrees of hepatic 
impairment, the mean AUC for ruxolitinib was increased in patients with mild, moderate and 
severe hepatic impairment by 87%, 28% and 65%, respectively, compared to patients with 
normal hepatic function. There was no clear relationship between AUC and the degree of 
hepatic impairment based on Child-Pugh scores. 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). A dose reduction of approximately 50% is recommended for patients with 
hepatic impairment (see section 4.2). 
 
5.3 
Preclinical safety data 
Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity 
and reproductive toxicity studies and in a carcinogenicity study. Target organs associated with 
the pharmacological action of ruxolitinib in repeated dose studies include bone marrow, 
peripheral 
blood 
and 
lymphoid 
tissues. 
Infections 
generally 
associated 
with 
immunosuppression were noted in dogs. Adverse decreases in blood pressure along with 
increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute 
volume was noted in a respiratory study in rats. The margins (based on unbound Cmax) at the 
non-adverse level in the dog and rat studies were 15.7-fold and 10.4-fold greater, respectively, 
than the maximum human recommended dose of 25 mg twice daily. No effects were noted in 
an evaluation of the neuropharmacological effects of ruxolitinib. 
Ruxolitinib decreased foetal weight and increased post-implantation loss in animal studies. 
There was no evidence of a teratogenic effect in rats and rabbits. However, the exposure margins 
compared to the highest clinical dose were low and the results are therefore of limited relevance 
for humans. No effects were noted on fertility. In a pre- and post-natal development study, a 
slightly prolonged gestation period, reduced number of implantation sites, and reduced number 
of pups delivered were observed. In the pups, decreased mean initial body weights and short 
period of decreased mean body weight gain were observed. In lactating rats, ruxolitinib and/or 
its metabolites were excreted into the milk with a concentration that was 13-fold higher than 
the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic. Ruxolitinib 
was not carcinogenic in the Tg.rasH2 transgenic mouse model. 


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6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
• 
Cellulose, microcrystalline 
• 
Magnesium stearate 
• 
Silica, colloidal anhydrous 
• 
Sodium starch glycolate (Type A) 
• 
Povidone 
• 
Hydroxypropylcellulose 
• 
Lactose monohydrate 
6.2 
Incompatibilities 
Not applicable. 
 
6.3 
Shelf life 
3 years 
 
6.4 
Special precautions for storage 
Do not store above 30°C. 
 
6.5 
Nature and contents of container 
PVC/PCTFE/Aluminium blister packs containing 14 or 56 tablets or multipacks containing 
168 (3 packs of 56) tablets. 
Not all pack sizes or types may be marketed. 
 
6.6 
Special precautions for disposal 
No special requirements. 
 
7. 
MARKETING AUTHORISATION HOLDER 
Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
8. 
MARKETING AUTHORISATION NUMBER(S) 
EU/1/12/773/007-009 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
23.08.2012 


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10. 
DATE OF REVISION OF THE TEXT 
Detailed information on this medicinal product is available on the website of the European 
Medicines Agency http://www.ema.europa.eu 


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 This medicinal product is subject to additional monitoring. This will allow quick 
identification of new safety information. Healthcare professionals are asked to report any 
suspected adverse reactions. See section 4.8 for how to report adverse reactions. 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
Jakavi 20 mg tablets 
 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
Each tablet contains 20 mg ruxolitinib (as phosphate). 
Excipient with known effect: 
Each tablet contains 285.80 mg lactose monohydrate. 
For the full list of excipients, see section 6.1. 
 
3. 
PHARMACEUTICAL FORM 
Tablet. 
Elongated curved white to almost white tablets of approximately 16.5 x 7.4 mm with “NVR” 
debossed one one side and “L20” debossed on the other side. 
 
4. 
CLINICAL PARTICULARS 
 
4.1 
Therapeutic indications 
Myelofibrosis (MF) 
Jakavi is indicated for the treatment of disease-related splenomegaly or symptoms in adult 
patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post 
polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. 
Polycythaemia vera (PV) 
Jakavi is indicated for the treatment of adult patients with polycythaemia vera who are resistant 
to or intolerant of hydroxyurea. 
 
4.2 
Posology and method of administration 
Jakavi treatment should only be initiated by a physician experienced in the administration of 
anti-cancer agents. 
A complete blood cell count, including a white blood cell count differential, must be performed 
before initiating therapy with Jakavi. 
Complete blood count, including a white blood cel l count differential, should be monitored 
every 2-4 weeks until Jakavi doses are stabilised, and then as clinically  indicated  (see  section 
4.4). 


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Posology 
Starting dose 
The recommended starting dose of Jakavi in myelofibrosis is 15 mg twice daily for patients 
with a platelet count between 100,000/mm3 and 200,000/mm3 and 20 mg twice daily for patients 
with a platelet count of >200,000/mm3. The recommended starting dose of Jakavi in 
polycythaemia vera is 10 mg given orally twice daily. 
There is limited information to recommend a starting dose for patients with platelet counts 
between 50,000/mm3 and <100,000/mm3. The maximum recommended starting dose in these 
patients is 5 mg twice daily and the patients should be titrated cautiously. 
Dose modifications 
Doses may be titrated based on safety and efficacy. Treatment should be discontinued for 
platelet counts less than 50,000/mm3 or absolute neutrophil counts less than 500/mm3. In PV, 
treatment should also be interrupted when haemoglobin is below 8 g/dl. After recovery of blood 
counts above these levels, dosing may be re-started at 5 mg twice daily and gradually increased 
based on careful monitoring of complete blood cell count, including a white blood cell count 
differential. 
Dose reductions should be considered if the platelet count decreases below 100,000/mm3, with 
the goal of avoiding dose interruptions for thrombocytopenia. In PV, dose reductions should 
also be considered if haemoglobin decreases below 12 g/dl and is recommended if it decreases 
below 10 g/dl. 
If efficacy is considered insufficient and blood counts are adequate, doses may be increased by 
a maximum of 5 mg twice daily, up to the maximum dose of 25 mg twice daily. 
The starting dose should not be increased within the first four weeks of tre atment and thereafter 
no more frequently than at 2-week intervals. 
The maximum dose of Jakavi is 25 mg twice daily. 
Dose adjustment with concomitant strong CYP3A4 inhibitors or fluconazole 
When Jakavi is administered with strong CYP3A4 inhibitors or dual inhibitors of CYP2C9 and 
CYP3A4 enzymes (e.g. fluconazole) the unit dose of Jakavi should be reduced by 
approximately 50%, to be administered twice daily (see section 4.5). Avoid the concomitant 
use of Jakavi with fluconazole doses greater than 200 mg daily. 
More frequent monitoring (e.g. twice a week) of haematology parameters and of clinical signs 
and symptoms of Jakavi-related adverse drug reactions is recommended while on strong 
CYP3A4 inhibitors or dual inhibitors of CYP2C9 and CYP3A4 enzymes. 
Special populations 
Renal impairment 
No specific dose adjustment is needed in patients with mild or moderate renal impairment. 
In patients with severe renal impairment (creatinine clearance less than 30 ml/min) the 
recommended starting dose based on platelet count for MF patients should be reduced by 
approximately 50% to be administered twice daily. The recommended starting dose for PV 


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patients with severe renal impairment is 5 mg twice daily. Patients should be carefully 
monitored with regard to safety and efficacy during Jakavi treatment. 
There are limited data to determine the best dosing options for patients with end -stage renal 
disease (ESRD) on haemodialysis. Pharmacokinetic/pharmacodynamic simulations based on 
available data in this population suggest that the starting dose for MF patients with ESRD on 
haemodialysis is a single dose of 15 -20 mg or two doses of 10 mg given 12 hours apart, to be 
administered post-dialysis and only on the day of haemodialysis. A single dose of 15 mg is 
recommended for MF patients with platelet count between 100,000/mm3 and 200,000/mm3. A 
single dose of 20 mg or two doses of 10 mg given 12 hours apart is recommended for MF 
patients with platelet count of >200,000/mm3. Subsequent doses (single administration or two 
doses of 10 mg given 12 hours apart) should be administered only on haemodialysis days 
following each dialysis session. 
The recommended starting dose for PV patients with ESRD on haemodialysis is a single dose 
of 10 mg or two doses of 5 mg given 12 hours apart, to be administered post-dialysis and only 
on the day of haemodialysis. These dose recommendations are based on simulations and any 
dose modification in ESRD should be followed by careful monitoring of safety and efficacy in 
individual patients. No data is available for dosing patients who are undergoing peritoneal 
dialysis or continuous venovenous haemofiltration (see section 5.2). 
Hepatic impairment 
In patients with any hepatic impairment the recommended starting dose based on platelet  
count should be reduced by approximately 50% to be administered twice daily. Subsequent 
doses should be adjusted based on careful monitoring of safety and efficacy. Patients 
diagnosed with hepatic impairment while receiving Jakavi should have complete blood counts, 
including a white blood cell count differential, monitored at least every one to two weeks for 
the first 6 weeks after initiation of therapy with Jakavi and as clinically indicated thereafter 
once their liver function and blood counts have been stabilised. Jakavi dose can be ti trated to 
reduce the risk of cytopenia. 
Older people (≥65 years) 
No additional dose adjustments are recommended for older people. 
Paediatric population 
The safety and efficacy of Jakavi in children aged up to 18 years have not been established. 
No data are available (see section 5.1). 
Treatment discontinuation 
Treatment may be continued as long as the benefit-risk remains positive. However the treatment 
should be discontinued after 6 months if there has been no reduction in spleen size or 
improvement in symptoms since initiation of therapy. 
It is recommended that, for patients who have demonstrated some degree of clinical 
improvement, ruxolitinib therapy be discontinued if they sustain an increase in their spleen 
length of 40% compared with baseline size (roughly equivalent to a 25% increase in spleen 
volume) and no longer have tangible improvement in disease-related symptoms. 


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Method of administration 
Jakavi is to be taken orally, with or without food. 
If a dose is missed, the patient should not take an addit ional dose, but should take the next 
usual prescribed dose. 
 
4.3 
Contraindications 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
Pregnancy and lactation. 
4.4 
Special warnings and precautions for use 
Myelosuppression 
Treatment with Jakavi can cause haematological adverse drug reactions, including 
thrombocytopenia, anaemia and neutropenia. A complete blood count, including a white blood 
cell count differential, must be performed before initiating therapy with Jakavi. Treatment 
should be discontinued in patients with platelet count less than 50,000/mm 3 or absoute 
neutrophil count less than 500/mm3 (see section 4.2). 
It has been observed that patients with low platelet counts (<200,000 /mm3) at the start of 
therapy are more likely to develop thrombocytopenia during treatment. 
Thrombocytopenia is generally reversible and is usually managed by reducing the dose or 
temporarily withholding Jakavi (see sections 4.2 and 4.8). However, platelet transfusions may 
be required as clinically indicated. 
Patients developing anaemia may require blood transfusions. Dose modifications or interruption 
for patients developing anaemia may also be considered. 
Patients with a haemoglobin level below 10.0 g/dl at the beginning of the treatment have a 
higher risk of developing a haemoglobin level below 8.0 g/dl during treatment compared to 
patients with a higher baseline haemoglobin level (79.3% versus 30.1%). More frequent 
monitoring of haematology parameters and of clinical signs and symptoms of Jakavi-related 
adverse drug reactions is recommended for patients with baseline haemoglobin below 
10.0 g/dl. 
Neutropenia (absolute neutrophil count <500) was generally reversible and was managed by 
temporarily withholding Jakavi (see sections 4.2 and 4.8). 
Complete blood counts should be monitored as clinically indicated and dose adjusted as 
required (see sections 4.2 and 4.8). 
Infections 
Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal 
and viral infections. Tuberculosis has been reported in patients receiving Jakavi for MF. Before 
starting treatment, patients should be evaluated for active and inactive (“latent”) tuberculosis, 
as per local recommendations. This can include medical history, possible previous contact with 
tuberculosis, and/or appropriate screening such as lung x-ray, tuberculin test and/or interferon-
gamma release assay, as applicable. Prescribers are reminded of the risk 


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of false negative tuberculin skin test results, especially in patients wh o are severely ill or 
immunocompromised. Jakavi therapy should not be started until active serious infections have 
resolved. Physicians should carefully observe patients receiving Jakavi for signs and symptoms 
of infections and initiate appropriate treatment promptly (see section 4.8). 
Hepatitis B viral load (HBV-DNA titre) increases, with and without associated elevations in 
alanine aminotransferase and aspartate aminotransferase, have been reported in patients with 
chronic HBV infections taking Jakavi. The effect of Jakavi 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. 
Herpes zoster 
Physicians should educate patients about early signs and symptoms of herpes zoster, advising 
that treatment should be sought as early as possible. 
Progressive multifocal leukoencephalopathy 
Progressive multifocal leukoencephalopathy (PML) has been reported with Jakavi treatment 
for MF. Physicians should be particularly alert to symptoms suggestive of PML that patients 
may not notice (e.g., cognitive, neurological or psychiatric symptoms or signs). Patients should 
be monitored for any of these new or worsening symptoms or signs, and if such symptoms/signs 
occur, referral to a neurologist and appropriate diagnostic measures for PML should be 
considered. If PML is suspected, further dosing must be suspended until PML has been 
excluded. 
Non-melanoma skin cancer 
Non-melanoma skin cancers (NMSCs), including basal cell, squamous cell, and Merkel cell 
carcinoma, have been reported in patients treated with ruxolitinib. Most of these patients had 
histories of extended treatment with hydroxyurea and prior NMSC or pre -malignant skin 
lesions. A causal relationship to ruxolitinib has not been established. Periodic skin examination 
is recommended for patients who are at increased risk for skin cancer. 
Special populations 
Renal impairment 
The starting dose of Jakavi should be reduced in patients with severe renal impairment . For 
patients with end-stage renal disease on haemodialysis the starting dose for MF patients should 
be based on platelet counts (see section 4.2). Subsequent doses (single dose of 20 mg or two 
doses of 10 mg given 12 hours apart in MF patients; single dose of 10 mg or two doses of 5 mg 
given 12 hours apart in PV patients) should be administered only on haemodialysis days 
following each dialysis session. Additional dose modifications should be made with careful 
monitoring of safety and efficacy (see sections 4.2 and 5.2). 
Hepatic impairment 
The starting dose of Jakavi should be reduced by approximately 50% in patients with hepatic 
impairment. Further dose modifications should be based on the safety and efficacy of the 
medicinal product (see sections 4.2 and 5.2). 
Interactions 


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If Jakavi is to be co-administered with strong CYP3A4 inhibitors or dual inhibitors of CYP3A4 
and CYP2C9 enzymes (e.g. fluconazole), the unit dose of Jakavi should be reduced by 
approximately 50%, to be administered twice daily (for monitoring frequency  see  sections 4.2 
and 4.5). 
The concomitant use of cytoreductive therapies or haematopoietic growth factors with Jakavi 
has not been studied. The safety and efficacy of these co -administrations are not known (see 
section 4.5). 
Withdrawal effects 
Following interruption or discontinuation of Jakavi, symptoms of MF may return over a period 
of approximately one week. There have been cases of patients discontinuing Jakavi who 
sustained more severe events, particularly in the presence of acute i ntercurrent illness. It has 
not been established whether abrupt discontinuation of Jakavi contributed to these events. 
Unless abrupt discontinuation is required, gradual tapering of the dose of Jakavi may be 
considered, although the utility of the tapering is unproven. 
Excipients 
Jakavi contains lactose. Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal 
product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
Interaction studies have only been performed in adults. 
Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9. Thus, 
medicinal products inhibiting these enzymes can give rise to increased ruxolitinib exposure. 
Interactions resulting in dose reduction of ruxolitinib 
CYP3A4 inhibitors 
Strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, saquinavir, telaprevir, telithromycin, voriconazole) 
In healthy subjects co-administration of Jakavi (10 mg single dose) with a strong CYP3A4 
inhibitor, ketoconazole, resulted in ruxolitinib Cmax and AUC that were higher by 33% and 91%, 
respectively, than with ruxolitinib alone. The half-life was prolonged from 3.7 to 
6.0 hours with concurrent ketoconazole administration. 
When administering Jakavi with strong CYP3A4 inhibitors the unit dose of Jakavi should be 
reduced by approximately 50%, to be administered twice daily. Patients should be closely 
monitored (e.g. twice weekly) for cytopenias and dose titrated based on safety and efficacy (see 
section 4.2). 
Dual CYP2C9 and CYP3A4 inhibitors 
50% dose reduction should be considered when using medicinal products which are dual 
inhibitors of CYP2C9 and CYP3A4 enzymes (e.g. fluconazole). Avoid the concomitant use of 
Jakavi with fluconazole doses greater than 200 mg daily. 


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Enzyme inducers 
CYP3A4 inducers (such as, but not limited to, avasimibe, carbamazepine, phenobarbital, 
phenytoin, rifabutin, rifampin (rifampicin), St.John’s wort (Hypericum perforatum)) 
Patients should be closely monitored and the dose titrated based on safety and efficacy (see 
section 4.2). 
In healthy subjects given ruxolitinib (50 mg single dose) following the potent CYP3A4 inducer 
rifampicin (600 mg daily dose for 10 days), ruxolitinib AUC was 70% lower than after 
administration of Jakavi alone. The exposure of ruxolitinib active metabolites was unchanged. 
Overall, the ruxolitinib pharmacodynamic activity was similar, suggesting the CYP3A4 
induction resulted in minimal effect on the pharmacodynamics. However, this could be related 
to the high ruxolitinib dose resulting in pharmacodynamic effects near E max. It is possible that 
in the individual patient, an increase of the ruxolitinib dose is needed when initiating treatment 
with a strong enzyme inducer. 
Other interactions to be considered affecting ruxolitinib 
Mild or moderate CYP3A4 inhibitors (such as, but not limited to, ciprofloxacin, erythromycin, 
amprenavir, atazanavir, diltiazem, cimetidine) 
In healthy subjects co-administration of ruxolitinib (10 mg single dose) with erythromycin 500 
mg twice daily for four days resulted in ruxolitinib Cmax and AUC that were higher by 8% and 
27%, respectively, than with ruxolitinib alone. 
No dose adjustment is recommended when ruxolitinib is co-administered with mild or moderate 
CYP3A4 inhibitors (e.g. erythromycin). However, patients should be closely monitored for 
cytopenias when initiating therapy with a moderate CYP3A4 inhibitor. 
Effects of ruxolitinib on other medicinal products 
Substances transported by P-glycoprotein or other transporters 
Ruxolitinib may inhibit P-glycoprotein and breast cancer resistance protein (BCRP) in the 
intestine. This may result in increased sytemic exposure of substrates of these transporters, such 
as dabigatran etexilate, ciclosporin, rosuvastatin and potentially digoxin. Therapeutic drug 
monitoring (TDM) or clinical monitoring of the affected substance is advised. 
It is possible that the potential inhibition of P-gp and BCRP in the intestine can be minimised 
if the time between administrations is kept apart as long as possible. 
Haematopoietic growth factors 
The concurrent use of haematopoietic growth factors and Jakavi has not been studied. It is not 
known whether the Janus Associated Kinase (JAK) inhibition by Jakavi reduces the efficacy of 
the haematopoietic growth factors or whether the haematopoietic growth factors affect the 
efficacy of Jakavi (see section 4.4). 
Cytoreductive therapies 
The concomitant use of cytoreductive therapies and Jakavi has not been studied. The safety and 
efficacy of this co-administration is not known (see section 4.4). 
A study in healthy subjects indicated that ruxolitinib did not inhibit the metabolism of the oral 


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CYP3A4 substrate midazolam. Therefore, no increase in exposure of CYP3A4 substrates is 
anticipated when combining them with Jakavi. Another study in healthy subjects indicated that 
Jakavi does not affect the pharmacokinetics of an oral contraceptive containing ethinylestradiol 
and levonorgestrel. Therefore, it is not anticipated that the contraceptive efficacy of this 
combination will be compromised by co-administration of ruxolitinib. 
 
4.6 
Fertility, pregnancy and lactation 
Pregnancy and contraception in females 
There are no data from the use of Jakavi in pregnant women. 
Animal studies have shown that ruxolitinib is embryotoxic and foetotoxic. Teratogenicity was 
not observed in rats or rabbits. However, the exposure margins compared to the highest clinical 
dose were low and the results are therefore of limited relevance for humans (see section 5.3). 
The potential risk for humans is unknown. As a precautionary mea sure, the use of Jakavi during 
pregnancy is contraindicated (see section 4.3). Women of child-bearing potential should use 
effective contraception during the treatment with Jakavi. In case pregnancy should occur during 
treatment with Jakavi, a risk/benefit evaluation must  be carried out on an individual basis with 
careful counselling regarding potential risks to the foetus (see section 5.3). 
Breast-feeding 
Jakavi must not be used during breast-feeding (see section 4.3) and breast-feeding should 
therefore be discontinued when treatment is started. It is unknown whether ruxolitinib and/or 
its metabolites are excreted in human milk. A risk to the breast-fed child cannot be excluded. 
Available pharmacodynamic/toxicological data in animals have shown excretion of  ruxolitinib 
and its metabolites in milk (see section 5.3). 
Fertility 
There are no human data on the effect of ruxolitinib on fertility. In animal studies, no effect 
on fertility was observed. 
 
4.7 
Effects on ability to drive and use machines 
Jakavi has no or negligible sedating effect. However, patients who experience dizziness after 
the intake of Jakavi should refrain from driving or using machines. 
 
4.8 
Undesirable effects 
Summary of the safety profile 
The safety assessment was based on a total of 855 patients (with MF or PV) receiving Jakavi in    
phase 2 and 3 studies. 
Myelofibrosis 
In the randomised period of the two pivotal studies, COMFORT -I and COMFORT-II, the 
median duration of exposure to Jakavi was 10.8 months (range 0.3 to 23.5 months). The 
majority of patients (68.4%) were treated for at least 9 months. Of 301 patients, 111 (36.9%) 


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had a baseline platelet count of between 100,000/mm3 and 200,000/mm3 and 190 (63.1%) had 
a baseline platelet count of >200,000/mm3. 
In these clinical studies, discontinuation due to adverse events, regardless of causality, was 
observed in 11.3% of patients. 
The most frequently reported adverse drug reactions were thrombocytopenia and anaemia. 
Haematological adverse drug reactions (any Common Terminology Criteria for Adverse Events 
[CTCAE] grade) included anaemia (82.4%), thrombocytopenia (69.8%) and neutropenia (16.6%). 
Anaemia, thrombocytopenia and neutropenia are dose-related effects. 
The three most frequent non-haematological adverse drug reactions were bruising (21.3%), dizziness 
(15.3%) and headache (14.0%). 
The three most frequent non-haematological laboratory abnormalities were raised alanine 
aminotransferase (27.2%), raised aspartate aminotransferase (19.9%) and hypercholesterolaemia 
(16.9%). In phase 3 clinical studies in MF, neither CTCAE grade 3 or 4 hypercholesterolaemia, raised 
aspartate aminotransferase nor CTCAE grade 4 raised alanine aminotransferase were observed. 
Long-term safety: As expected with an extended follow-up period, the cumulative frequency of some 
adverse events increased in the evaluation of the 3-year follow-up safety data (median duration of 
exposure of 33.2 months in COMFORT-I and COMFORT-II for patients initially randomised to 
ruxolitinib) from 457 patients with myelofibrosis treated with ruxolitinib during the randomised and 
extension periods of the two pivotal phase 3 studies. This evaluation included data from patients that 
were initially randomised to ruxolitinib (N=301) and patients that received ruxolitinib after crossing 
over from control treatment arms (N=156). With these updated data, therapy discontinuation due to 
adverse events was observed in 17.1% of patients treated with ruxolitinib. 
Polycythaemia vera 
The safety of Jakavi was assessed in 110 patients with PV in an open-label, randomised, 
controlled phase 3 RESPONSE study. The adverse drug reactions listed below reflect the initial 
study period (up to week 32) with equivalent exposure to ruxolitinib and Best Available 
Therapy (BAT), corresponding to a median duration of exposure to Jakavi of 7.8 months. The 
mean age of patients receiving Jakavi was around 60 years. 
Discontinuation due to adverse events, regardless of causality, was observed in 3.6% of patients 
treated with Jakavi and 1.8% of patients treated with best available therapy. 
Haematological adverse reactions (any CTCAE grade) included anaemia (43.6%) and 
thrombocytopenia (24.5%). Anaemia or thrombocytopenia CTCAE grade 3 and 4 were reported 
in respectively 1.8% or 5.5%. 
The three most frequent non-haematological adverse reactions were dizziness (15.5%), 
constipation (8.2%) and herpes zoster (6.4%). 
The three most frequent non-haematological laboratory abnormalities (any CTCAE grade) were 
hypercholesterolaemia (30.0%), raised alanine aminotransferase (22.7%) and raised aspartate 
aminotransferase (20.9%). These were all CTCAE grade 1 and 2 with the exception of one 
CTCAE grade 3 raised alanine aminotransferase event. 
Long-term safety: Patients had a median duration of exposure to Jakavi of 18.6 months (range 
0.3 to 35.9 months). With longer exposure, frequency of adverse events increased; however 


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no new safety findings emerged. When adjusted for exposure, the adverse event rates were 
generally comparable with those observed during the initial study period. 
Tabulated summary of adverse drug reactions from clinical studies 
In the clinical study programme the severity of adverse drug reactions was assessed based on the 
CTCAE, defining grade 1 = mild, grade 2 = moderate, grade 3 = severe and grade 4=life-threatening. 
Adverse drug reactions from clinical studies (Table 14-11) are listed by MedDRA system organ 
class. Within each system organ class, the adverse drug reactions are ranked by frequency, with 
the most frequent reactions first. In addition, the corresponding frequency category for each 
adverse drug reaction is based on the following convention: very common (≥1/10); common 
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to 
<1/1,000); very rare (<1/10,000). 
 
Table 14-11 
Frequency category of adverse drug reactions reported in the phase 3 
studies (COMFORT-I, COMFORT-II, RESPONSE) 
 
Adverse drug reaction 
Frequency category for MF 
patients 
Frequency category for PV 
patients 
Infections and infestations 
Urinary tract infectionsa,d 
Very common 
Common 
Herpes zostera,d 
Common 
Common 
Tuberculosise 
Uncommon 
- 
Blood and lymphatic system 
disordersb,d 
Anaemiab 
- 
- 
CTCAEc grade 4 
(<6.5g/dl) 
Very common 
Uncommon 
CTCAEc grade 3 
(<8.0 – 6.5g/dl) 
Very common 
Uncommon 
Any CTCAEc grade 
Very common 
Very common 
Thrombocytopeniab 
CTCAEc grade 4 
(<25,000/mm3) 
Common 
Uncommon 
CTCAEc grade 3 
(50,000 – 25,000/mm3) 
Common 
Common 
Any CTCAEc grade 
Very common 
Very common 
Neutropeniab 
CTCAEc grade 4 
(<500/mm3) 
Common 
- 
CTCAEc grade 3 
(<1,000 – 500/mm3) 
Common 
- 


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Adverse drug reaction 
Frequency category for MF 
patients 
Frequency category for PV 
patients 
Any CTCAEc grade 
Very common 
- 
Bleeding (any bleeding 
including intracranial, and 
gastrointestinal bleeding, 
bruising and other bleeding) 
Very common 
Very common 
Intracranial bleeding 
Common 
- 
Gastrointestinal bleeding 
Common 
- 
Bruising 
Very common 
Very common 
Other bleeding (including 
epistaxis, post-procedural 
haemorrhage and 
haematuria) 
Common 
Very common 
Metabolism and nutrition 
disorders 
Weight gaina 
Very common 
Common 
Hypercholesterolaemiab 
CTCAEc grade 1 and 2 
Very common 
Very common 
Hypertriglyceridaemiab 
CTCAEc grade 1 
- 
Very common 
Nervous system disorders 
Dizzinessa 
Very common 
Very common 
Headachea 
Very common 
- 
Gastrointestinal disorders 
Flatulencea 
Common 
- 
Constipationa 
- 
Common 
Hepatobiliary disorders 
Raised alanine 
aminotransferaseb 
CTCAEc grade 3 
(> 5x – 20 x ULN) 
Common 
Uncommon 
Any CTCAEc grade 
Very common 
Very common 
Raised aspartate 
aminotransferaseb 
Any CTCAEc grade 
Very common 
Very common 
Vascular disorders 
Hypertensiona 
- 
Very common 
aFrequency is based on adverse event data. 
- 
A subject with multiple occurrence of an adverse drug reaction (ADR) is counted only once in 
that ADR category. 
- 
ADRs reported are on treatment or up to 28 days post treatment end date. 
bFrequency is based on laboratory values. 
- 
A subject with multiple occurrences of an ADR is counted only once in that ADR category. 
- 
ADRs reported are on treatment or up to 28 days post treatment end date. 
cCommon Terminology Criteria for Adverse Events (CTCAE) version 3.0; grade 1 = mild, grade 2 = 
moderate, grade 3 = severe, grade 4 = life-threatening 
dThese ADRs are discussed in the text. 
eFrequency is based on all patients exposed to ruxolitinib in clinical studies (N=4755) 
Upon discontinuation, MF patients may experience a return of MF symptoms such as fatigue, 
bone pain, fever, pruritus, night sweats, symptomatic splenomegaly and weight loss. In 


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clinical studies in MF the total symptom score for MF symptoms gradually returned to 
baseline value within 7 days after dose discontinuation (see section 4.4). 
Description of selected adverse drug reactions 
Anaemia 
In phase 3 clinical studies in MF, median time to onset of first CTCAE grade 2 or higher anaemia was 
1.5 months. One patient (0.3%) discontinued treatment because of anaemia. 
In patients receiving  Jakavi  mean  decreases  in  haemoglobin  reached  a  nadir  of  approximately  10 
g/litre below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady 
state that was approximately 5 g/litre below baseline. This pattern was observed in patients regardless 
of whether they had received transfusion during therapy. 
In the randomised, placebo-controlled study COMFORT-I 60.6% of Jakavi-treated MF patients and 
37.7% of placebo-treated MF patients received red blood cell transfusions during randomised treatment. 
In the COMFORT-II study the rate of packed red blood cell transfusions was 53.4% in the Jakavi arm 
and 41.1% in the best available therapy arm. 
In the randomised period of the pivotal studies, anaemia was less frequent in PV patients than in MF 
patients (43.6% versus 82.4%). In the PV population, the CTCAE grade 3 and 4 events were reported 
in 1.8%, while in the MF patients the frequency was 42.56%. 
Thrombocytopenia 
In the phase 3 clinical studies in MF, 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 50,000/mm3 was 
14 days. During the randomised period, platelet transfusions were administered to 4.7% of patients 
receiving Jakavi and to 4.0% of patients receiving cont rol regimens. Discontinuation of treatment 
because of thrombocytopenia occurred in 0.7% of patients receiving Jakavi and 0.9% of patients 
receiving control regimens. Patients with a platelet count of 100,000/mm 3 to 200,000/mm3 before 
starting Jakavi had a higher frequency of grade 3 or 4 thrombocytopenia compared to patients with 
platelet count >200,000/mm3 (64.2% versus 38.5%). 
In the randomised period of the pivotal studies, the rate of patients experiencing thrombocytopenia was 
lower in PV (24.5%) patients compared to MF (69.8%) patients. The frequency of severe (i.e. CTCAE 
grade 3 and 4) thrombocytopenia was lower in PV (5.5%) than in MF (11.6%) patients. 
Neutropenia 
In the phase 3 clinical studies in MF, in patients who developed grade 3 or 4 neutropenia, the median 
time to onset was 12 weeks. During the randomised period, dose holding or reductions due to 
neutropenia were reported in 1.0% of patients, and 0.3% of patients discontinued treatment because of 
neutropenia. 
In the randomised period of the pivotal study in PV patients, neutropenia was reported in two patients 
(1.8%) of which one patient developed CTCAE grade 4 neutropenia. 
Bleeding 
In the phase 3 pivotal studies in MF bleeding events (including intracranial and gastrointestinal, bruising 
and other bleeding events) were reported in 32.6% of patients exposed to Jakavi and 23.2% of patients 
exposed to the reference treatments (placebo or best available therapy). The frequency of grade 3-4 
events was similar for patients treated with Jakavi or refer ence treatments (4.7% versus 3.1%). Most of 
the patients with bleeding events during the treatment reported bruising (65.3%). 


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Bruising events were more frequently reported in patients taking Jakavi compared with the reference 
treatments (21.3% versus 11.6%). Intracranial bleeding was reported in 1% of patients exposed to Jakavi 
and 0.9% exposed to reference treatments. Gastrointestinal bleeding was reported in 5.0% of patients 
exposed to Jakavi compared to 3.1% exposed to reference treatments. Other bleedin g events (including 
events such as epistaxis, post-procedural haemorrhage and haematuria) were reported in 13.3% of 
patients treated with Jakavi and 10.3% treated with reference treatments. 
In the randomised period of the pivotal study in PV patients, blee ding events (including intracranial and 
gastrointestinal, bruising and other bleeding events) were reported in 20% of patients treated with Jakavi 
and 15.3% patients receiving best available therapy. Bruising was reported in similar frequencies in 
Jakavi and BAT arms (10.9% versus 8.1%). No intracranial bleeding or gastrointestinal haemorrhage 
events were reported in patients receiving Jakavi. One patient treated with Jakavi experienced a grade 3 
bleeding event (post-procedural bleeding); no grade 4 bleeding was reported. Other bleeding events 
(including events such as epistaxis, post -procedural haemorrhage, gingival bleeding) were reported in 
11.8% of patients treated with Jakavi and 6.3% treated with best available therapy. 
Infections 
In the phase 3 pivotal studies in MF, grade 3 or 4 urinary tract infection was reported in 1.0% of patients, 
herpes zoster in 4.3% and tuberculosis in 1.0%. In phase 3 clinical studies sepsis was reported in 3.0% 
of patients. An extended follow-up of patients treated with ruxolitinib showed no trends towards an 
increase in the rate of sepsis over time. 
In the randomised period of the pivotal study in PV patients, one (0.9%) CTCAE grade 3 and no grade 
4 urinary tract infection was reported. The rate of herpes zoster was slightly higher in PV (6.4%) patients 
than in MF (4.0%) patients. There was one report of CTCAE grade 3 post-herpetic neuralgia amongst 
the PV patients. 
Increased systolic blood pressure 
In the phase 3 pivotal clinical studies in MF an increase in systolic blood p ressure of 20 mmHg or more 
from baseline was recorded in 31.5% of patients on at least one visit compared with 19.5% of the control-
treated patients. In COMFORT-I (MF patients) the mean increase from baseline in systolic BP was 0-2 
mmHg on Jakavi versus a decrease of 2-5 mmHg in the placebo arm. In COMFORT-II mean values 
showed little difference between the ruxolitinib-treated and the control-treated MF patients. 
In the randomised period of the pivotal study in PV patients, the mean systolic blood pressure 
increased by 0.65 mmHg in the Jakavi arm versus a decrease of 2 mmHg in the BAT arm. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactio ns via the national reporting system listed in Appendix V. 
 
4.9 
Overdose 
There is no known antidote for overdoses with Jakavi. 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, anaemia and thrombocytopenia. Appropriate supportive 
treatment should be given. 
Haemodialysis is not expected to enhance the elimination of ruxolitinib. 


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5. 
PHARMACOLOGICAL PROPERTIES 
 
5.1 
Pharmacodynamic properties 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: 
L01XE18 
Mechanism of action 
Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 
(IC50 values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate 
the signalling of a number of cytokines and growth factors that are important for haematopoiesis 
and immune function. 
Myelofibrosis and polycythaemia vera are myeloproliferative neoplasms known to be 
associated with dysregulated JAK1 and JAK2 signalling. The basis for the dysregulation is 
believed to include high levels of circulating cytokines that activate the JAK -STAT pathway, 
gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory 
mechanisms. MF patients exhibit dysregulated JAK signalling regardless of JAK2V617F 
mutation status. Activating mutations in JAK2 (V617F or exon 12) are found in >95% of PV 
patients. 
Ruxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular 
models of haematological malignancies, as well as of Ba/F3 cells rendered cytokine-
independent by expressing the JAK2V617F mutated protein, with IC 50 ranging from 80-320 
nM. 
Pharmacodynamic effects 
Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy 
subjects, MF patients and PV patients. Ruxolitinib resulted in maximal inhibition of STAT3 
phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy 
subjects and MF patients, indicating no accumulation of either parent or active metabolites. 
Baseline elevations in inflammatory markers associated with constitutional symptoms such as 
TNFα, IL-6 and CRP in subjects with MF were decreased following treatment with ruxolitinib. 
MF patients did not become refractory to the pharmacodynamic effects of ruxolitinib  
treatment over time. Similarly, patients with PV also presented with baseline elevations in 
inflammatory markers and these markers were decreased following treatment with ruxolitinib. 
In a thorough QT study in healthy subjects, there was no indication of a QT/QTc prolonging 
effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, indicating that 
ruxolitinib has no effect on cardiac repolarisation. 
Clinical efficacy and safety 
Myelofibrosis 
Two randomised phase 3 studies (COMFORT-I and COMFORT-II) were conducted in patients 
with MF (primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential 
thrombocythaemia myelofibrosis). In both studies, patients had palpable splenomegaly at least 
5 cm below the costal margin and risk category of intermediate -2 or 


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high risk based on the International Working Group (IWG) Consensus Criteria. The starting 
dose of Jakavi was based on platelet count. 
COMFORT-I was a double-blind, randomised, placebo-controlled study in 309 patients who 
were refractory to or were not candidates for available therapy. The primary efficacy endpoint 
was proportion of subjects achieving  ≥35% reduction from baseline in spleen volume at  week 
24 as measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT). 
Secondary endpoints included duration of maintenance of a ≥35% reduction from baseline in 
spleen volume, proportion of patients who had ≥50% reduction in total symptom score, changes 
in total symptom scores from baseline to week 24, as measured by the modified Myelofibrosis 
Symptom Assessment Form (MFSAF) v2.0 diary, and overall survival. 
COMFORT-II was an open-label, randomised study in 219 patients. Patients were randomised 
2:1 to Jakavi versus best available therapy. In the best available therapy arm, 47% of patients 
received hydroxyurea and 16% of patients received glucocorticoids. The primary efficacy 
endpoint was proportion of patients achieving ≥35% reduction from baseline in spleen volume 
at week 48 as measured by MRI or CT. 
Secondary endpoints included proportion of patients achieving a ≥35% reduction of spleen 
volume from baseline at week 24 and duration of maintenance of a ≥35% reduction from 
baseline spleen volume. 
In COMFORT-I and COMFORT-II, patient baseline demographics and disease characteristics 
were comparable between the treatment arms. 
 
Table 14-12 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume at week 24 in COMFORT-I and at week 48 in COMFORT-II (ITT) 
 
COMFORT-I 
COMFORT-II 
Jakavi 
(N=155) 
Placebo 
(N=153) 
Jakavi 
(N=144) 
Best available 
therapy 
(N=72) 
Time points 
Week 24 
Week 48 
Number (%) of subjects with 
spleen volume reduced by 
≥35% 
65 (41.9) 
1 (0.7) 
41 (28.5) 
0 
95% confidence intervals 
34.1, 50.1 
0, 3.6 
21.3, 36.6 
0.0, 5.0 
p-value 
<0.0001 
<0.0001 
A significantly higher proportion of patients in the Jakavi group achieved ≥35% reduction from 
baseline in spleen volume (Table 14-12) regardless of the presence or absence of the 
JAK2V617F mutation or the disease subtype (primary myelofibrosis, post-polycythaemia vera 
myelofibrosis, post-essential thrombocythaemia myelofibrosis). 


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Table 14-13 
Percentage of patients with ≥35% reduction from baseline in spleen 
volume by JAK mutation status (safety set) 
 
COMFORT-I 
COMFORT-II 
Jakavi 
Placebo 
Jakavi 
Best available 
therapy 
JAK mutation 
status 
Positive 
(N=113) 
n (%) 
Negative 
(N=40) 
n (%) 
Positive 
(N=121) 
n (%) 
Negative 
(N=27) 
n (%) 
Positive 
(N=110) 
n (%) 
Negative 
(N=35) 
n (%) 
Positive 
(N=49) 
n (%) 
Negative 
(N=20) 
n (%) 
Number (%) of 
subjects with 
spleen volume 
reduced by 
≥35% 
54 (47.8) 
11 (27.5) 
1 
(0.8) 
0 
36 (32.7) 
5 
(14.3) 
0 
0 
Time point 
After 24 weeks 
After 48 weeks 
The probability of maintaining spleen  response  (≥35%  reduction)  on  Jakavi  for  at  least 24 
weeks was 89% in COMFORT-I and 87% in COMFORT-II; 52% maintained spleen responses 
for at least 48 weeks in COMFORT-II. 
In COMFORT-I, 45.9% subjects in the Jakavi group achieved a ≥50% improvement from 
baseline in the week 24 total symptom score (measured using MFSAF diary v2.0), as compared 
to 5.3% in the placebo group (p<0.0001 using chi-square test). The mean change in the global 
health status at week 24, as measured by EORTC QLQ C30 was +12.3 for Jakavi and -3.4 for 
placebo (p<0.0001). 
In COMFORT-I, after a median follow-up of 34.3 months, the death rate in patients randomised 
to the ruxolitinib arm was 27.1% versus 35.1% in patients randomised to placebo; HR 0.687; 
95% CI 0.459-1.029; p=0.0668. 
In COMFORT-II, after a median follow-up of 34.7 months, the death rate in patients 
randomised to ruxolitinib was 19.9% versus 30.1% in patients randomised to best available 
treatment (BAT); HR 0.48; 95% CI 0.28-0.85; p=0.009. In both studies, the lower death rates 
noted in the ruxolitinib arm were predominantly driven by the result s obtained in the post 
polycythaemia vera and post essential thrombocythaemia subgroups. 
Polycythaemia vera 
A randomised, open-label, active-controlled phase 3 study (RESPONSE) was conducted in 222 
patients with PV who were resistant to or intolerant of hydroxyurea defined based on the 
European LeukemiaNet (ELN) international working group published criteria. 110 patients 
were randomised to the ruxolitinib arm and 112 patients to the BAT arm. The starting dose of 
Jakavi was 10 mg twice daily. Doses were then adjusted in individual patients based on 
tolerability and efficacy with a maximum dose of 25 mg twice daily. BAT was selected by the 
investigator 
on 
a 
patient-by-patient 
basis 
and 
included 
hydroxyurea 
(59.5%), 
interferon/pegylated interferon (11.7%), anagrelide (7.2%), pipobroman (1.8%) and 
observation (15.3%). 
Baseline demographics and disease characteristics were comparable between the two treatments 
arms. The median age was 60 years (range 33 to 90 years). Patients in the ruxolitinib arm had 
PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median 
of approximately 3 years. Most patients (>80%) had received at 


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least two phlebotomies in the last 24 weeks prior to screening. Comparative data regarding 
long-term survival and incidence of disease complications is missing. 
The primary composite endpoint was the proportion of patients achieving both an absence of 
phlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volume from baseline at 
week 32. Phlebotomy eligibility was  defined  as  a  confirmed  HCT  of  >45%,  i.e.  at  least 3 
percentage points higher than the HCT obtained at baseline or a confirmed HCT of >48%, 
depending on which was lower. Key secondary endpoints included the proportion of patients 
who achieved the primary endpoint and remained free from progression at week 48, as well as 
the proportion of patients achieving complete haematological remission at week 32. 
The study met its primary objective and a higher proportion of patients in the Jakavi group 
achieved the primary composite endpoint and each of its individual components. Significantly 
more patients treated with Jakavi (20.9%) achieved a primary response (p<0.0001) compared 
to BAT (0.9%). Haematocrit control was achieved in 60% of patients in the Ja kavi arm 
compared to 19.6% in the BAT arm and a ≥35% reduction in spleen volume was achieved in 
38.2% of patients in the  Jakavi  arm  compared  to  0.9%  in  the  BAT  arm  (Figure  14-4). 94 
(83.9%) patients randomised to the BAT arm crossed over to ruxolitinib tre atment at Week 32 
or after, limiting the comparison between the two arms after Week 32. 
Both key secondary endpoints were also met. The proportion of patients achieving a complete 
haematological remission was 23.6% on Jakavi compared to 8.9% on BAT (p=0.00 28) and the 
proportion of patients achieving a durable primary response at week 48 was 19.1% on Jakavi 
and 0.9% on BAT.(p<0.0001). 
 
Figure 14-4 
Patients achieving the primary endpoint and components of the 
primary endpoint at week 32 
 
 
P-value: < .0001 
Odds Ratio (Ruxolitinib/BAT) 
70 
60 
Individual components of Primary 
Response at Week 32 
60 
 
 
 
.RUX 
.BAT 
 
50 
40 
 
30 
20 
20 
 
10 
 
0 
Primary Composite 
Endpoint at Week 32 
 
≥ 35% reduction in 
Spleen Volume 
 
Hematocrit control 
without phlebotomy 
 
Symptom burden was assessed using the MPN-SAF total symptom score (TSS) electronic 
1 
1 
21 
38 
and 95% CI: 
28.64 (4.50, 12.06) 
Percentage e of patientsnts 


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patient diary, which consisted of 14 questions. At week 32, 49% and 64% of patients treated 
with ruxolitinib achieved a ≥50% reduction in TSS-14 and TSS-5, respectively, compared to 


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only 5% and 11% of patients on BAT. 
Treatment benefit perception was measured by the Patient Global Impression of Change (PGIC) 
questionnaire. 66% of patients treated with ruxolitinib compared to 19% treated with BAT 
reported an improvement as early as four weeks after beginning treatment. Improvement in 
perception of treatment benefit was  also higher in patients  treated with ruxolitinib  at week 32 
(78% versus 33%). 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Jakavi in all subsets of the paediatric population for the treatment of MF (see section 4.2 for 
information on paediatric use). 
 
5.2 
Pharmacokinetic properties 
Absorption 
Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high 
permeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib 
is rapidly absorbed after oral administration with maximal plasma concentration (Cmax) 
achieved approximately 1 hour post-dose. Based on a human mass balance study, oral 
absorption of ruxolitinib, as ruxolitinib or metabolites formed under first-pass, is 95% or 
greater. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single 
dose range of 5-200 mg. There was no clinically relevant change in the pharmacokinetics of 
ruxolitinib upon administration with a high-fat meal. The mean Cmax was moderately decreased 
(24%) while the mean AUC was nearly unchanged (4% increase) on dosing with a high-fat 
meal. 
Distribution 
The mean volume of distribution at steady state is approximately 75 litres in MF and PV 
patients. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro 
is approximately 97%, mostly to albumin. A whol e body autoradiography study in rats has 
shown that ruxolitinib does not penetrate the blood-brain barrier. 
 
Biotransformation 
Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from 
CYP2C9. Parent compound is the predominant entity in human plasma, representing 
approximately 60% of the drug-related material in circulation. Two major and active 
metabolites are present in plasma representing 25% and 11% of parent AUC. These metabolites 
have one half to one fifth of the parent JAK-related pharmacological activity. The sum total of 
all active metabolites contributes to 18% of the overall pharmacodynamics of ruxolitinib. At 
clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6 
or CYP3A4 based on in vitro studies. In vitro data indicate that ruxolitinib may inhibit P-gp and 
BCRP. 
Elimination 


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Ruxolitinib is mainly eliminated through metabolism. The mean elimination half -life of 
ruxolitinib is approximately 3 hours. Following a single oral dose of [14C]-labelled ruxolitinib 
in healthy adult subjects, elimination was predominately through metabolism, with 74% of 
radioactivity excreted in urine and 22% via faeces. Unchanged parent substance accounted for 
less than 1% of the excreted total radioactivity. 
Linearity/non-linearity 
Dose proportionality was demonstrated in the single and multiple dose studies. 
Special populations 
Effects of age, gender or race 
Based on studies in healthy subjects, no relevant differences in ruxolitinib pharmacokinetics 
were observed with regard to gender and race. In a population pharmacokinetic evaluation in 
MF patients, no relationship was apparent between oral clearance and patient age or race. The 
predicted oral clearance was 17.7 l/h in women and 22.1 l/h in men, with 39% inter-subject 
variability in MF patients. Clearance was 12.7 l/h in PV patients, with a 42% inter-subject 
variability and no relationship was apparent between oral clearance and gender, patient age or 
race, based on a population pharmacokinetic evaluation in PV patients. 
Paediatric population 
The safety and effectiveness of Jakavi in paediatric patients have not been established (see 
section 5.1, “Paediatric population”). 
Renal impairment 
Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and 
urinary creatinine. Following a single ruxolitinib dose of 25 mg, the exposure 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 tended to increase with 
increasing severity of renal impairment, and were most markedly increased in the subjects with 
severe renal impairment. It is unknown whether the increased metabolite exposure is of safety 
concern. A dose modification is recommended in patients with severe renal impairment and 
end-stage renal disease (see section 4.2). Dosing only on dialysis days reduces the metabolite 
exposure, but also the pharmacodynamic effect, especially on the days between dialysis. 
Hepatic impairment 
Following a single ruxolitinib dose of 25 mg in patients with varying degrees of hepatic 
impairment, the mean AUC for ruxolitinib was increased in patients with mild, moderate and 
severe hepatic impairment by 87%, 28% and 65%, respectively, compared to patients with 
normal hepatic function. There was no clear relationship between AUC and the degree of 
hepatic impairment based on Child-Pugh scores. 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). A dose reduction of approximately 50% is recommended for patients with 
hepatic impairment (see section 4.2). 


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5.3 
Preclinical safety data 
Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity 
and reproductive toxicity studies and in a carcinogenicity study. Target organs associated with 
the pharmacological action of ruxolitinib in repeated dose studies include bone marrow, 
peripheral 
blood 
and 
lymphoid 
tissues. 
Infections 
generally 
associated 
with 
immunosuppression were noted in dogs. Adverse decreases in blood pressure along with 
increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute 
volume was noted in a respiratory study in rats. The margins (based on unbound Cmax) at the 
non-adverse level in the dog and rat studies were 15.7-fold and 10.4-fold greater, respectively, 
than the maximum human recommended dose of 25 mg twice daily. No effects were noted in 
an evaluation of the neuropharmacological effects of ruxolitinib. 
Ruxolitinib decreased foetal weight and increased post-implantation loss in animal studies. 
There was no evidence of a teratogenic effect in rats and rabbits. However, the exposure margins 
compared to the highest clinical dose were low and the results are therefore of limited relevance 
for humans. No effects were noted on fertility. In a pre- and post-natal development study, a 
slightly prolonged gestation period, reduced number of implantation sites, and reduced number 
of pups delivered were observed. In the pups, decreased mean initial body weights and short 
period of decreased mean body weight gain were observed. In lactating rats, ruxolitinib and/or 
its metabolites were excreted into the milk with a concentration that was 13-fold higher than 
the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic. Ruxolitinib 
was not carcinogenic in the Tg.rasH2 transgenic mouse model. 
 
6. 
PHARMACEUTICAL PARTICULARS 
 
6.1 
List of excipients 
• 
Cellulose, microcrystalline 
• 
Magnesium stearate 
• 
Silica, colloidal anhydrous 
• 
Sodium starch glycolate (Type A) 
• 
Povidone 
• 
Hydroxypropylcellulose 
• 
Lactose monohydrate 
6.2 
Incompatibilities 
Not applicable. 
 
6.3 
Shelf life 
3 years 
 
6.4 
Special precautions for storage 
Do not store above 30°C. 


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6.5 
Nature and contents of container 
PVC/PCTFE/Aluminium blister packs containing 14 or 56 tablets or multipacks containing 
168 (3 packs of 56) tablets. 
Not all pack sizes or types may be marketed. 
 
6.6 
Special precautions for disposal 
No special requirements. 
 
7. 
MARKETING AUTHORISATION HOLDER 
Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
8. 
MARKETING AUTHORISATION NUMBER(S) 
EU/1/12/773/010-012 
 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
23.08.2012 
 
10. 
DATE OF REVISION OF THE TEXT 
Detailed information on this medicinal product is available on the website of the European 
Medicines Agency http://www.ema.europa.eu 


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14.6.2 
Annex II 
 
A. 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
 
B. 
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
 
C. 
OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 
 
 
D. 
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 


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A. 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
Name and address of the manufacturer responsible for batch release 
Novartis Pharma GmbH 
Roonstrasse 25 
D-90429 Nürnberg 
Germany 
 
 
B. 
Conditions or restrictions regarding supply and use 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of 
Product Characteristics, section 4.2). 
 
 
C. 
Other conditions and requirements of the Marketing Authorisation 
• 
Periodic Safety Update Reports 
The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 9 months following authorisation. Subsequently, the marketing authorisation 
holder shall submit periodic safety update reports for this product in accordance with the 
requirements set out in the list of Union reference dates (EURD list) provided for under  Article 
107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. 
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 
• 
Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
An updated RMP should be submitted: 
• 
At the request of the European Medicines Agency; 
• 
Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be 
submitted at the same time. 
An updated RMP shall be submitted annually until renewal. 
• 
Obligation to conduct post-authorisation measures 


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The MAH shall complete, within the stated timeframe, the below measures: 
 
 
Description 
Due date 
Follow-up efficacy and safety data from the extension phase of studies INCB 
18424-351 and INC424A2352 including data on the time related endpoints 
(overall survival, progression free survival and leukaemia free survival) should be 
provided annually. 
Annually in 
October 
Post-Authorisation efficacy study to provide long-term efficacy and safety data of 
Week 80 CSR: 
ruxolitinib including (late) achievement of response, duration of (various) 
responses, as well as incidence of AEs including haematological transformation 
June 2015 
and second malignancies from the study B2301. 
Final CSR: 
December 2019 


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14.6.3 
ANNEX III 
 
 
LABELLING AND PACKAGE LEAFLET 
 
 
A. LABELLING 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
CARTON OF UNIT PACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
 
Jakavi 5 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 5 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
14 tablets 
56 tablets 


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5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 
 
 
Oral use. 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/004 
14 tablets 
EU/1/12/773/005 
56 tablets 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 5 mg 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
OUTER CARTON OF MULTIPACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 5 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 5 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
Multipack: 168 (3 packs of 56) tablets. 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/006 
168 tablets (3x56) 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 5 mg 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
INTERMEDIATE CARTON OF MULTIPACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 5 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 5 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
56 tablets. Component of a multipack. Not to be sold separately. 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use. 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/006 
168 tablets (3x56) 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 5 mg 


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MINIMUM PARTICULARS TO APPEAR ON BLISTER OR STRIPS 
BLISTERS 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 5 mg tablets 
Ruxolitinib 
 
 
 
2. 
NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
Novartis Europharm Limited 
 
 
 
 
3. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
4. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
5. 
OTHER 
 
 
Monday 
Tuesday 


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Wednesday 
Thursday 
Friday 
Saturday 
Sunday 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
CARTON OF UNIT PACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 10 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 10 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
14 tablets 
56 tablets 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use. 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
 
10. SPECIAL PRECAUTIONS FOR  DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/014 
14 tablets 
EU/1/12/773/015 
56 tablets 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 10 mg 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
OUTER CARTON OF MULTIPACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 10 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 10 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
Multipack: 168 (3 packs of 56) tablets. 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/016 
168 tablets (3x56) 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 10 mg 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
INTERMEDIATE CARTON OF MULTIPACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 10 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 10 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
56 tablets. Component of a multipack. Not to be sold separately. 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use. 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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6 Protocol No. 
 
 
Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/016 
168 tablets (3x56) 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 10 mg 


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MINIMUM PARTICULARS TO APPEAR ON BLISTER OR STRIPS 
BLISTERS 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 10 mg tablets 
Ruxolitinib 
 
 
 
2. 
NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
Novartis Europharm Limited 
 
 
 
 
3. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
4. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
5. 
OTHER 
 
 
Monday 


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Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Sunday 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
CARTON OF UNIT PACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 15 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 15 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
14 tablets 
56 tablets 


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5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 
 
 
Oral use. 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/007 
14 tablets 
EU/1/12/773/008 
56 tablets 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 15 mg 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
OUTER CARTON OF MULTIPACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 15 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 15 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
Multipack: 168 (3 packs of 56) tablets. 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/009 
168 tablets (3x56) 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 15 mg 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
INTERMEDIATE CARTON OF MULTIPACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 15 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 15 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
56 tablets. Component of a multipack. Not to be sold separately. 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use. 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/009 
168 tablets (3x56) 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 15 mg 


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MINIMUM PARTICULARS TO APPEAR ON BLISTER OR STRIPS 
BLISTERS 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 15 mg tablets 
Ruxolitinib 
 
 
 
2. 
NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
Novartis Europharm Limited 
 
 
 
 
3. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
4. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
5. 
OTHER 
 
 
Monday 
Tuesday 


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Wednesday 
Thursday 
Friday 
Saturday 
Sunday 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
CARTON OF UNIT PACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 20 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 20 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
14 tablets 
56 tablets 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use. 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/010 
14 tablets 
EU/1/12/773/011 
56 tablets 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 20 mg 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
OUTER CARTON OF MULTIPACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 20 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 20 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
Multipack: 168 (3 packs of 56) tablets. 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/012 
168 tablets (3x56) 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 20 mg 


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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
INTERMEDIATE CARTON OF MULTIPACK 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 20 mg tablets 
Ruxolitinib 
 
 
 
2. 
STATEMENT OF ACTIVE SUBSTANCE(S) 
 
 
Each tablet contains 20 mg ruxolitinib (as phosphate). 
 
 
 
 
3. 
LIST OF EXCIPIENTS 
 
 
Contains lactose. 
 
 
 
 
4. 
PHARMACEUTICAL FORM AND CONTENTS 
 
 
Tablets 
 
56 tablets. Component of a multipack. Not to be sold separately. 
 
 
 
 
5. 
METHOD AND ROUTE(S) OF ADMINISTRATION 


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Oral use. 
Read the package leaflet before use. 
 
 
 
 
6. 
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
 
Keep out of the sight and reach of children. 
 
 
 
 
7. 
OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
 
8. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
9. 
SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
 
 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL  OF  UNUSED  MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
 
11. 
NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 


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Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
 
 
12. 
MARKETING AUTHORISATION NUMBER(S) 
 
 
EU/1/12/773/012 
168 tablets (3x56) 
 
 
 
 
13. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
14. 
GENERAL CLASSIFICATION FOR SUPPLY 
 
 
Medicinal product subject to medical prescription. 
 
 
 
 
15. 
INSTRUCTIONS ON USE 
 
 
 
 
16. 
INFORMATION IN BRAILLE 
 
 
Jakavi 20 mg 


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MINIMUM PARTICULARS TO APPEAR ON BLISTER OR STRIPS 
BLISTERS 
 
 
 
 
1. 
NAME OF THE MEDICINAL PRODUCT 
 
 
Jakavi 20 mg tablets 
Ruxolitinib 
 
 
 
2. 
NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
Novartis Europharm Limited 
 
 
 
 
3. 
EXPIRY DATE 
 
 
EXP 
 
 
 
 
4. 
BATCH NUMBER 
 
 
Lot 
 
 
 
 
5. 
OTHER 
 
 
Monday 
Tuesday 


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Wednesday 
Thursday 
Friday 
Saturday 
Sunday 


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B. PACKAGE LEAFLET 
Package leaflet: Information for the patient 
Jakavi 5 mg tablets 
Jakavi 10 mg tablets 
Jakavi 15 mg tablets 
Jakavi 20 mg tablets 
ruxolitinib 
 
This medicine is subject to additional monitoring. This will allow quick identification of 
new safety information. You can help by reporting any side effects you may get. See the end 
of section 4 for how to report side effects 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- 
Keep this leaflet. You may need to read it again. 
- 
If you have any further questions, ask your doctor or pharmacist. 
- 
This medicine has been prescribed for you only. Do not pass it on to others. It may harm 
them, even if their signs of illness are the same as yours. 
- 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible 
side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Jakavi is and what it is used for 
2. What you need to know before you take Jakavi 
3. How to take Jakavi 
4. Possible side effects 
5. How to store Jakavi 
6. Contents of the pack and other information 
 
1. What Jakavi is and what it is used for 
Jakavi contains the active substance ruxolitinib. 
Jakavi is used to treat adult patients with an enlarged spleen or with symptoms related to 
myelofibrosis, a rare form of blood cancer. 


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Jakavi is also used to treat patients with polycythaemia vera who are resistant to or intolerant 
of hydroxyurea. 
How Jakavi works 
Enlargement of the spleen is one of the characteristics of myelofibrosis. Myelofibrosis is a 
disorder of the bone marrow, in which the marrow is replaced by scar tissue. The abnormal 
marrow can no longer produce enough normal blood cells and as a result the spleen becomes 
significantly enlarged. By blocking the action of certain enzymes (called Janus Associated 
Kinases), Jakavi can reduce the size of the spleen in patients with myelofibros is and relieve 
symptoms such as fever, night sweats, bone pain and weight loss in patients with myelofibrosis. 
Jakavi can help reduce the risk of serious blood or vascular complications. 
Polycythaemia vera is a disorder of the bone marrow, in which the mar row produce too many 
red blood cells. The blood becomes thicker as a result of the increased red blood cells. Jakavi 
can relieve the symptoms, reduce spleen size and the volume of red blood cells produced in 
patients with polycythaemia vera by selectively blocking enzymes called Janus Associated 
Kinases (JAK1 and JAK2), thus potentially reducing the risk of serious blood or vascular 
complications. 
If you have any questions about how Jakavi works or why this medicine has been prescribed 
for you, ask your doctor. 
 
2. What you need to know before you take Jakavi 
Follow all the doctor’s instructions carefully. They may differ from the general information 
contained in this leaflet. 
Do not take Jakavi 
• 
if you are allergic to ruxolitinib or any of the other ingredients of this medicine (listed in 
section 6). 
• 
if you are pregnant or breast-feeding. 
If either of the above applies to you, tell your doctor who will then decide whether you should 
start treatment with Jakavi. 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Jakavi 
• 
if you have any infections. It may be necessary to treat your infection before starting 
Jakavi. It is important that you tell your doctor if you have ever had tuberculosis or if you 
have been in close contact with someone who has or has had tuberculosis. Your doctor 
may perform tests to see if you have tuberculosis. It is important that you tell your doctor 
if you have ever had hepatitis B. 
• 
if you have any kidney problems. Your doctor may need to prescribe a different dose of 
Jakavi. 
• 
if you have or have ever had any liver problems. Your doctor may need to prescribe a 
different dose of Jakavi. 
• 
if you are taking other medicines (see section “Other medicines and Jakavi”). 


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• 
if you have ever had tuberculosis. 
• 
if you have ever had skin cancer. 
Talk to your doctor or pharmacist during your treatment with Jakavi 
• 
if you experience unexpected bruising and/or bleeding, unusual tiredness, shortness of 
breath during exercise or at rest, unusually pale skin, or frequent infections (these are 
signs of blood disorders). 
• 
if you experience fever, chills or other symptoms of infections. 
• 
if you experience chronic coughing with blood-tinged sputum, fever, night sweats and 
weight loss (these can be signs of tuberculosis). 
• 
if you have any of the following symptoms or if anyone close to you notices that you 
have any of these symptoms: confusion or difficulty thinking, loss of balance or difficulty 
walking, clumsiness, difficulty speaking, decreased strength or weakness on one side of 
your body, blurred and/or loss of vision. These may be signs of a serious brain infection 
and your doctor may suggest further testing and follow-up. 
• 
if you develop painful skin rash with blisters (these are signs of shingles). 
• 
if you notice skin changes. This may require further observation, as certain types of skin 
cancer (non-melanoma) have been reported. 
Blood tests 
Before you start treatment with Jakavi, your doctor will perform blood tests to determine the 
best starting dose for you. You will need to have further blood tests during treatment so that 
your doctor can monitor the amount of blood cells (white cells, red cells and platelets) in your 
body and assess how you are responding to the treatment and whether Jakavi is having an 
unwanted effect on these cells. Your doctor may need to adjust the dose or stop treatment. 
Stopping Jakavi 
When you stop taking Jakavi, the myelofibrosis symptoms may come back. Your doctor may 
want to gradually reduce the amount of Jakavi taken each day, before stopping it completely. 
Children and adolescents 
Do not give this medicine to children or adolescents aged below 18 years because the use of 
Jakavi in children has not been studied. 
Other medicines and Jakavi 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
It is particularly important that you mention any of the following medicines containing any of 
the following active substances, as your doctor may need to adjust the Jakavi dose for you. 
The following may increase the risk of side effects with Jakavi: 
• 
Some medicines used to treat infections. These include medicines used to treat fungal 
diseases (such as ketoconazole, itraconazole, posaconazole, fluconazole and 
voriconazole), medicines used to treat certain types of bacterial infections (antibiotics 
such as clarithromycin, telithromycin, ciprofloxacin, or erythromycin), medicines to treat 
viral infections, including HIV infection/AIDS (such as apranevir, atazanavir, indinavir, 


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lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir), medicines to treat hepatitis C 
(boceprevir, telaprevir). 
• 
Nefazodone, a medicine to treat depression. 
• 
Mibefradil or diltiazem, medicines to treat hypertension and chronic angina pectoris. 
• 
Cimetidine, a medicine to treat heartburn. 
The following may reduce the effectiveness of Jakavi: 
• 
Avasimibe, a medicine to treat heart disease. 
• 
Phenytoin, carbamazepine or phenobarbital and other anti-epileptics used to stop seizures 
or fits. 
• 
Rifabutin or rifampicin, medicines used to treat tuberculosis (TB). 
• 
St. John’s wort (Hypericum perforatum), a herbal product used to treat depression. 
While you are taking Jakavi you should never start a new medicine without checking first 
with the doctor who prescribed Jakavi. This includes prescription medicines, non-prescription 
medicines and herbal or alternative medicines. 
Pregnancy and breast-feeding 
Do not take Jakavi during pregnancy. Talk to your doctor about how to take appropriate 
measures to avoid becoming pregnant during your treatment with Jakavi. 
Do not breast-feed while taking Jakavi. Tell your doctor if you are breast-feeding. 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, 
ask your doctor or pharmacist for advice before taking this medicine. 
Driving and using machines 
If you experience dizziness after taking Jakavi, do not drive or use machines. 
Jakavi contains lactose 
Jakavi contains lactose (milk sugar). If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicine. 
 
3. How to take Jakavi 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your 
doctor or pharmacist if you are not sure. 
The dose of Jakavi depends on the patient’s blood cell count. Your doctor will measure the amount of 
blood cells in your body and find the best dose for you, particularly if you have liver or kidney problems. 
• 
The recommended starting dose in myelofibrosis is 15 mg twice daily or 20 mg twice 
daily, depending on your blood cell count. 
• 
The recommended starting dose in polycythaemia vera is 10 mg twice daily, depending 
on your blood cell count. 
• 
The maximum dose is 25 mg twice daily. 


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Your doctor will always tell you exactly how many Jakavi tablets to take. 
During the treatment your doctor may recommend a lower or higher dose to you if the results 
of blood tests show that this is necessary, if you have problems with your liver or kidneys, or if 
you also need treatment with certain other medicines. 
If you receive dialysis, take either one single dose or two separate doses of Jakavi only on dialysis days, 
after the dialysis has been completed. Your doctor will tell you if you should take one or two doses and 
how many tablets to take for each dose. 
You should take Jakavi every day at the same time, either with or without food. 
You should continue taking Jakavi for as long as your doctor tells you to. This is a long-term treatment. 
Your doctor will regularly monitor your condition to make sure that the treatment is having the desired 
effect. 
If you have questions about how long to take Jakavi, talk to your doctor or pharmacist. 
If you experience certain side effects (e.g. blood disorders), your doctor might need to change the 
amount of Jakavi you have to take or tell you to stop taking Jakavi for a while. 
If you take more Jakavi than you should 
If you accidentally take more Jakavi than your doctor prescribed, contact your doctor or pharmacist 
immediately. 
If you forget to take Jakavi 
If you forgot to take Jakavi simply take your next dose at the scheduled time. Do not tak e a double dose 
to make up for a forgotten dose. 
If you stop taking Jakavi 
If you interrupt your treatment with Jakavi your myelofibrosis-related symptoms may come 
back. Therefore, you should not stop taking Jakavi without discussing it with your doctor. 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
4. Possible side effects 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
Most of the side effects of Jakavi are mild to moderate and will generally disappear after a few days to 
a few weeks of treatment. 
Tell your doctor immediately if you experience any of the following side effects. Some are very 
common (may affect more than 1 in 10 people), some are common (may affect up to 1 in 10 people): 
• 
any sign of bleeding in the brain, such as sudden altered level of consciousness, persistent 
headache, numbness, tingling, weakness or paralysis (common) 
• 
any sign of bleeding in the stomach or intestine, such as passing black or bloodstained 
stools, or vomiting blood (common) 
• 
unexpected bruising and/or bleeding, unusual tiredness, shortness of breath during 
exercise or at rest, unusually pale skin, or frequent infections (possible symptoms of 
blood disorders) (very common) 


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• 
painful skin rash with blisters (possible symptoms of shingles (herpes zoster)) (common) 
• 
fever, chills or other symptoms of infections (very common) 
• 
low level of red blood cells (anaemia), low level of white blood cells (neutropenia) or 
low level of platelets (thrombocytopenia) (very common) 
Other side effects with Jakavi 
Very common: 
• 
high level of cholesterol or fat in the blood (hypertriglyceridaemia) 
• 
abnormal liver function test results 
• 
dizziness 
• 
headache 
• 
urinary tract infections 
• 
weight gain 
Common: 
• 
frequently passing wind (flatulence) 
• 
constipation 
• 
high blood pressure (hypertension), which may also be the cause of dizziness and 
headaches 
Uncommon: 
• 
tuberculosis 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information 
on the safety of this medicine. 
 
5. How to store Jakavi 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the carton or blister after 
“EXP”. 
Do not store above 30°C. 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist 
how to throw away medicines you no longer use. These measures will help protect the 
environment. 


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6. Contents of the pack and other information 
What Jakavi contains 
• 
The active substance of Jakavi is ruxolitinib. 
• 
Each 5 mg Jakavi tablet contains 5 mg of ruxolitinib. 
• 
Each 10 mg Jakavi tablet contains 10 mg of ruxolitinib. 
• 
Each 15 mg Jakavi tablet contains 15 mg of ruxolitinib. 
• 
Each 20 mg Jakavi tablet contains 20 mg of ruxolitinib. 
• 
The other ingredients are: microcrystalline cellulose, magnesium stearate, colloidal anhydrous 
silica, sodium starch glycolate, povidone, hydroxypropylcellulose, lactose monohydrate. 
What Jakavi looks like and contents of the pack 
Jakavi 5 mg tablets are white to almost white round tablets with “NVR” debossed on one side 
and “L5” debossed on the other side. 
Jakavi 10 mg tablets are white to almost white round tablets with “NVR” debossed on one 
side and “L10” debossed on the other side. 
Jakavi 15 mg tablets are white to almost white oval tablets with “NVR” debossed on one side 
and “L15” debossed on the other side. 
Jakavi 20 mg tablets are white to almost white elongated tablets with “NVR” debossed on one 
side and “L20” debossed on the other side. 
 
Jakavi tablets are supplied in blister packs containing 14 or 56 tablets or multipacks 
containing 168 (3 packs of 56) tablets 
 
Not all packs may be marketed in your country. 
 
Marketing Authorisation Holder 
Novartis Europharm Limited 
Frimley Business Park 
Camberley GU16 7SR 
United Kingdom 
 
 
Manufacturer 
Novartis Pharma GmbH 
Roonstrasse 25 
90429 Nuremberg 
Germany 


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Oncology Clinical Trial Protocol (v00) 
Confidential 
Page 232
6 Protocol No. 
 
 
For any information about this medicine, please contact the local representative of the 
Marketing Authorisation Holder: 
 
 
België/Belgique/Belgien 
Novartis Pharma N.V. 
Tél/Tel: +32 2 246 16 11 
Lietuva 
Novartis Pharma Services Inc. 
Tel: +370 5 269 16 50 
 
България 
Novartis Pharma Services Inc. 
Тел.: +359 2 489 98 28 
Luxembourg/Luxemburg 
Novartis Pharma N.V. 
Tél/Tel: +32 2 246 16 11 
 
Česká republika 
Novartis s.r.o. 
Tel: +420 225 775 111 
Magyarország 
Novartis Hungária Kft. Pharma 
Tel.: +36 1 457 65 00 
 
Danmark 
Novartis Healthcare A/S 
Tlf: +45 39 16 84 00 
Malta 
Novartis Pharma Services Inc. 
Tel: +356 2122 2872 
 
Deutschland 
Novartis Pharma GmbH 
Tel: +49 911 273 0 
Nederland 
Novartis Pharma B.V. 
Tel: +31 26 37 82 111 
 
Eesti 
Novartis Pharma Services Inc. 
Tel: +372 66 30 810 
Norge 
Novartis Norge AS 
Tlf: +47 23 05 20 00 
 
Ελλάδα 
Novartis (Hellas) A.E.B.E. Τηλ: +30 210 281 17 12 


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Oncology Clinical Trial Protocol (v00) 
Confidential 
Page 233
6 Protocol No. 
 
Österreich 
N
o
v
a
r
t
i
s 
P
h
a
r
m
a 
G
m
b
H 
T
e
l
: 
+
4
3 
1 
8
6 
6
5
7
0 


Novartis 
Oncology Clinical Trial Protocol (v00) 
Confidential 
Page 234
6 Protocol No. 
 
 
España 
Novartis Farmacéutica, S.A. 
Tel: +34 93 306 42 00 
Polska 
Novartis Poland Sp. z o.o. 
Tel.: +48 22 375 4888 
 
France 
Novartis Pharma S.A.S. 
Tél: +33 1 55 47 66 00 
Portugal 
Novartis Farma - Produtos Farmacêuticos, S.A. 
Tel: +351 21 000 8600 
 
Hrvatska 
Novartis Hrvatska d.o.o. 
Tel. +385 1 6274 220 
România 
Novartis Pharma Services Romania SRL 
Tel: +40 21 31299 01 
 
Ireland 
Novartis Ireland Limited 
Tel: +353 1 260 12 55 
Slovenija 
Novartis Pharma Services Inc. 
Tel: +386 1 300 75 50 
 
Ísland 
Vistor hf. 
Sími: +354 535 7000 
Slovenská republika 
Novartis Slovakia s.r.o. 
Tel: +421 2 5542 5439 
 
Italia 
Novartis Farma S.p.A. 
Tel: +39 02 96 54 1 
Suomi/Finland 
Novartis Finland Oy 
Puh/Tel: +358 (0)10 6133 200 
 
Κύπρος 
Novartis Pharma Services Inc. 
Τηλ: +357 22 690 690 
Sverige 
Novartis Sverige AB 
Tel: +46 8 732 32 00 


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Oncology Clinical Trial Protocol (v00) 
Confidential 
Page 235
6 Protocol No. 
 
 
Latvija 
Novartis Pharma Services Inc. 
Tel: +371 67 887 070 
United Kingdom 
Novartis Pharmaceuticals UK Ltd. 
Tel: +44 1276 698370 


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Oncology Clinical Trial Protocol (v00) 
Confidential 
Page 236
6 Protocol No. 
 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency 
website: http://www.ema.europa.eu 

SAP_000.pdf: 
Clinical Development
INC424/ruxolitinib/Jakavi®
REALISE (CINC424A2411) / NCT02966353
A multicenter phase II, open label, single arm study to 
evaluate the efficacy and safety of Ruxolitinib in the 
treatment of anemic myelofibrosis patients.
Statistical Analysis Plan (SAP) Amendment 1
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
12-Mar-2019
Number of pages:
29
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis  


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and 
title impacted 
(Current)
12 
Mar
2019
Before 
DBL
To 
modify 
visit 
windowing rules
Analysis Visit window 
table modified to exclude 
EOT in visit window
Section 2.1.1
To remove text
Removed 
text 
for 
“Significant 
non-drug 
therapies” as it is not 
captured in the study
Section 2.4.2
To add Spleen response 
definition and analysis
by IWG-MRT criteria
and also
to add an 
analysis 
for 
primary 
endpoint at any time 
during the study.
Add 
definition 
and 
analysis of spleen response 
as per IWG MRT Criteria 
as per the recommendation 
from steering committee 
Section 2.5.4
To add an analysis on 
transfusion requirements 
amd modify some text
Added clarification that 
unit of blood transfusion 
will be used for analysis 
and not the episode of 
transfusion; An analysis 
for transfusion dependent
rate added for patient who 
were not TD at baseline 
Section 2.7.2
To add some decription 
on Adverse Event of 
Specail Interest (AESI)
Add a breif discription on 
AESI and a listing is 
proposed for AESI
Section 2.8.1.1
To remove analysis
Shift tables based on 
low/normal/high 
ranges 
removed
Section 2.8.3
To remove analysis
Shift table for baseline 
ECOG score vs worst 
post-baseline ECOG score 
removed. ECOG 
score 
over time will only be 
listed
Section 2.8.4.2
To add description of 
PRO related derivations 
and few analysis
Added analysis on PRO
similar to spleen response 
at Week 24
Section 2.11


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SAP Amendment 1
CINC424A2411
Date
Time 
point
Reason for update
Outcome for update
Section and 
title impacted 
(Current)
To add description of 
DIPSS score calculation 
Added 
definition 
and 
criteria to calculate DIPSS 
risk scores and risk groups
Section 5


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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................12
2.2.1
Full Analysis Set ...................................................................................12
2.2.2
Safety set ...............................................................................................12
2.2.3
Per-Protocol set .....................................................................................12
2.2.4
Subgroup of interest ..............................................................................13
2.3
Patient disposition, demographics and other baseline characteristics ...................13
2.3.1
Patient disposition.................................................................................13
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................14
2.4.1
Study treatment / compliance................................................................14
2.4.2
Prior, concomitant and post therapies...................................................15
2.5
Analysis of the primary objective..........................................................................16
2.5.1
Primary endpoint...................................................................................16
2.5.2
Statistical hypothesis, model, and method of analysis..........................16
2.5.3
Handling of missing values/censoring/discontinuations.......................16
2.5.4
Supportive and Sensitivity analyses......................................................16
2.6
Analysis of the key secondary objective ...............................................................17
2.7
Analysis of secondary efficacy objective(s)..........................................................17
2.7.1
Secondary endpoints .............................................................................17
2.7.2
Statistical hypothesis, model, and method of analysis..........................17
2.8
Safety analyses.......................................................................................................18
2.8.1
Adverse events (AEs)............................................................................18
2.8.2
Deaths....................................................................................................19
2.8.3
Laboratory data .....................................................................................19
2.8.4
Other safety data ...................................................................................20
2.9
Pharmacokinetic endpoints....................................................................................21
2.10
PD and PK/PD analyses.........................................................................................21
2.11
Patient-reported outcomes .....................................................................................21


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22
22
22
2.13
Other Exploratory analyses....................................................................................23
2.14
Interim analysis......................................................................................................23
3
Sample size calculation .....................................................................................................23
4
Change to protocol specified analyses ..............................................................................24
5
Appendix ...........................................................................................................................24
5.1
Imputation rules.....................................................................................................24
5.1.1
Study drug.............................................................................................24
5.1.2
AE, ConMeds and safety assessment date imputation..........................25
5.2
AEs coding/grading ...............................................................................................26
5.3
Laboratory parameters derivations ........................................................................26
5.4
Time windows for box plots..................................................................................27
5.5
Dynamic International Prognostic Scoring System (DIPSS) ................................28
5.6
Statistical models...................................................................................................28
5.6.1
Primary analysis....................................................................................28
5.6.2
Key secondary analysis.........................................................................29
6
Reference...........................................................................................................................29


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List of abbreviations
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
CRO
Clinical Research Organization
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DI
Dose Intensity
DIPSS
Dynamic International Prognostic Scoring System
ECOG PS
Eastern Cooperative Oncology Group Performance Status
EOT
End of Treatment
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
ICF
Informed Consent Form
IWG-MRT
International Working Group for Myelofibrosis Research and Treatment
LCM 
Lower Costal Margin
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MF-7
Myelofibrosis 7 Item Symptom Scale
MFSAF
Myelofibrosis Symptom Assessment Form
NR
Not reached
PD
Pharmacodynamic
NCI
National Cancer Institute
PDI
Planned Dose Intensity 
PET-MF
Post-Essential Thrombocythemia Myelofibrosis
PGIC
Patient Global Impression of Change
PK
Pharmacokinetics
PMF
Primary Myelofibrosis
PPV-MF
Post-Polycythemia Vera-Myelofibrosis
PT
Preferred Term
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
RDI
Relative Dose Intensity
SAE
Serious Adverse Event
TBIL
Total Bilirubin
TD
Transfusion Dependent
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
TD
Transfusion Dependent


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CINC424A2411
TI
Transfusion Independent
ULN
Upper Limit of Normal
WBC
White Blood Cell


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1
Introduction
This SAP describes the detailed statistical methodology of the study CINC424A2411: A Phase 
II study designed to assess the efficacy and safety of ruxolitinib in patients with Primary 
Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF), or Post-Essential 
Thrombocythemia Myelofibrosis (PET-MF).
Data will be analyzed by Novartis according to the Data analysis Section 10 of the study 
protocol which is available in Appendix 16.1.1 of the clinical study report. Important 
information is given in the following sections and details are provided, as applicable, in 
Appendix 16.1.9 of the clinical study report.
1.1
Study design
This is a multicenter phase II, open label, single arm study to assess the efficacy and safety of
ruxolitinib in patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera-  
Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF) who
have splenomegaly that is equal to or greater than 5 cm below the left costal margin and with
anemia defined by Hb less than 10 g/dL.
The target number of patients for this trial is 50. The primary anlysis will be performed when 
all enrolled patients have completed the Week 24 visit or have discontinued from the study prior 
to Week 24.
No interim analysis is planned for this study.
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below:
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
To determine the spleen length response rate 
at Week 24.
Proportion of patients achieving a 50% 
reduction in spleen length at Week 24
Secondary
To evaluate safety.
Safety will be assessed by
Frequency and severity of adverse events and 
serious adverse events and AEs leading to 
discontinuations.
Changes 
in 
hematology/biochemistry 
parameters over time.
To determine the spleen length response rate 
at Week 48.
Proportion of patients achieving a 50% 
reduction in spleen length at Week 48.


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To evaluate the effect of ruxolitinib on spleen 
length.
Percent change from baseline in spleen length 
over time.
To evaluate the effect of ruxolitinib on
symptoms.
Summary of the Modified MFSAF v2.0 and 
MF-7 over time.
To evaluate the effect of ruxolitinib on 
Patient
Global Impression of Change 
(PGIC).
PGIC at each visit where measured.
To evaluate the effect of ruxolitinib on 
transfusion requirements.
Summary of transfusions over time.
For Transfusion Dependent (TD)* patients, 
the following will be analyzed:
Transfusion 
independence 
(TI) 
rate 
(requiring no transfusion for ≥12 weeks at 
any time).
Transfusion response rate (not TD: having 5 
or less transfusion for ≥12 weeks at any time).
2
Statistical methods
2.1
Data analysis general information
With SAS® ver. 9.4 or higher, the analysis for this study will be conducted by statisticians and
statistical programmers from Novartis or designated CRO after all patients have either
completed or have been prematurely discontinued from the study.
Unless otherwise specified, qualitative data (e.g., gender) will be described using frequency and 
percentages, a missing category will be included as applicable; while quantitative data will be 
described using descriptive statistics: n, mean, standard deviation, median, minimum, and 
maximum.


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Unless otherwise stated, summary tables/figures/listings will be on all patients included in the
population under consideration.
All statistical analyses will be performed using all data collected in the database up to data cut-
off date. Only data with an assessment date or event start date (e.g. vital sign assessment date 
or start date of an adverse event) prior to or on the cut-off date will be included in the analysis.
All the events with start dates before or on the cut-off date and end date after the cut-off date 
will be reported as ‘continuing at the cut-off date’. The same rule will be applied to events 
starting before or on the cut-off date and not having documented end date. This approach applies, 
in particular, to adverse event and concomitant medication reports. For these events, the end 
date will not be imputed and therefore will appear as missing in listings.
The final analysis will occur at the end of the study. All available data from all patients will be 
analyzed and summarized in a final CSR.
2.1.1
General definitions 
Study treatment
Study treatment for this study is “ruxolitinib”.
Date of enrollment
In this study, the date of enrollment is the date first ICF is signed.
Date of the first/last administration of study treatment
Date of the first administration of study treatment is derived as the first date when a non-zero 
dose of study treatment is administered. 
Date of the last administration of study treatment is derived as the last date when a non-zero 
dose of study treatment is administered.
Reference start date
Reference start date for this study will be defined as the date of the first administration of study 
treatment.
Study day
The study day for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) will be calculated as the difference 
between the date of the event (onset date of an event, assessment date etc.) and the start of study 
treatment plus 1. The first day of study treatment is therefore study Day 1. Example: if start of 
study treatment is on 05-Jan-2014 and start date of an adverse event is on 09-Jan-2014 then the 
study day of the adverse event onset is 5. For safety assessments before start of study treatment, 
the study day is negative and derived by (date of event – start date of study treatment). For 
example: if start of study treatment is on 05-Jan-2014 and date of lab measurement is on 02-
Jan-2014 then the study day of the laboratory abnormality is -3. Note, the day of start of study 
treatment is day 1, and the day before the date of first study treatment is day – 1, not day 0. 
Units conversion
If duration is reported in weeks, duration in days will be divided by 7.


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Baseline
Baseline is the result of an investigation describing the “true” state of the subject before start of 
study treatment administration.
The last available assessment on or before the date of start of study treatment (as defined in 
Section 2.1.3) is taken as “baseline” assessment. In case time of assessment and time of 
treatment start is captured, the last available assessment before the treatment start date/time is 
used for baseline.
On-treatment assessment/event and observation periods
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of subject’s first informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date)
3. post-treatment period: starting at day 30+1 after last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on-treatment and 
post-treatment deaths will be provided. In particular, summary tables for adverse events (AEs) 
will summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
However, all safety data (including those from the pre- and post-treatment period) will be listed 
and those collected during the post-treatment period will be flagged.
Analysis Visit Windows
In order to summarize data collected over time (including unscheduled visits), the assessments 
will be time slotted. The following general rule will be applied in creating the assessment 
windows: If more than one assessment is done within the same time window, the assessment 
performed closest to the target date will be used. If 2 assessments within a time window are 
equidistant from the target date, then the earlier of the 2  assessments will be used. If there are 
multiple assessments on the same date, then the worst case will be used.  Data from all 
assessments (scheduled and unscheduled), including multiple assessments, will be listed.
Analysis Visit windows
Assessment
Target day of assessment
Time Interval
Baseline
1       
≤ Day 1 
Week 4
28
Day 2 to day 42
Week 8
56
Day 43 to day 70
Week 12
84
Day 71 to day 98
Week 16
112
Day 99 to day 126
Week 20
140
Day 127 to day 154


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Week 24
168
Day 155 to day 210
Week 36
252
Day 211 to day 294
Week 36+(12*k)
d=k*84+252, k=1,2,3,etc.
Day d-41 to day d+42
2.2
Analysis sets
2.2.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment (ruxolitinib) has 
been assigned and who received one dose of study treatment (ruxolitinib).
2.2.2
Safety set
The Safety set is the same as the FAS.
2.2.3
Per-Protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who had no major 
protocol deviation.
The following major protocol deviations will lead to exclusion from the PPS:

Patient with less than 12 years of age at screening

Patients with unconfirmed diagnosis of PMF, PPV-MF or PET-MF, as reviewed by 
clinical team

Patient without palpable splenomegaly or with a spleen length below 5 cm at baseline

Patient with hemoglobin >= than 10 g/dL at baseline

Patient had prior treatment with any JAK1 or JAK2 inhibitor

Patient has known hypersensitivity to ruxolitinib or other JAK1/JAK2 inhibitors, or to 
their excipients

Treatment with another investigational medication or treated with an investigational 
medication within 30 days or 5 half-lives (whichever is longer) prior to the first dose of 
study drug

Patient unable to comprehend or are unwilling to sign an ICF or Patient did not sign ICF 
or amended ICF

Concomitant use of another JAK inhibitor

Use of investigational medication not approved for any indication within 30 days or 5 
half-lives, whichever is longer, prior to the first dose of study drug and until treatment 
discontinuation

Use of hydroxyurea, interferon, thalidomide, busulfan, lenalidomide, or anagrelide on 
Day 1 of ruxolitinib therapy and at any time during participation in the study

Use of potent CYP3A4 inducers in combination with ruxolitinib


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2.2.4
Subgroup of interest
Not Applicable.
2.3
Patient disposition, demographics and other baseline 
characteristics
Demographic and other baseline data (including disease characteristics) will be listed and 
summarized descriptively for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.
Relevant medical histories and current medical at baseline will be summarized separately for
ongoing and historical medical conditions by system organ class and preferred term, for the 
FAS.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm using the FAS. The number (%) of treated patients included in the FAS will be 
presented. 
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients enrolled,

Number (%) of patients who completed the study treatment,

Number (%) of patients who are still on-treatment

Number (%) of patients who discontinued the study treatment and reasons for 
discontinuation,

Number (%) of patients who discontinued the study and reasons for discontinuation.
Disposition data will also be listed.
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Handling Plan) by overall for the FAS. All 
protocol deviations will be listed.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized  by 
overall.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized for Safety Set. 
Duration of exposure will be categorized into time intervals; frequency counts and percentages 
will be presented for the number (%) of patients in each interval. The number (%) of patients 
who have dose changes or interruption, and the reasons, will be summarized for the Safety Set.
Subject level listings of all doses administered while on treatment along with the reasons for a 
dose change will be produced.
Duration of exposure to study treatment:
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug:
Duration of exposure (days) to study treatment = [(date of last non-zero dose 
administration of study treatment) – (date of first non-zero dose administration of study 
treatment) + 1 day].
(see Section 2.1.1.3 for definition for the dates first/last administration).
The duration includes the periods of temporary ruxolitinib interruption (s).
The duration of exposure will be summarized by descriptive statistics, as well as by duration 
category (<= 4 Weeks, >4 – <= 8 Weeks, >8 – <= 12 Weeks, >12 – <= 16 Weeks, >16 – <= 
20 Weeks, >20 – <= 24 Weeks, >24 – <= 36 Weeks, and in interval of 12 Weeks thereafter).
Duration of on study:
The duration of on study is defined as the time interval from the enrollment date to the last 
contact date.
Duration of on study (days) = [(end of study date – (enrollment date) +1 day]
The duration of study will be summarized by descriptive statistics, as well as by duration 
category (<= 4 Weeks, >4 – <= 8 Weeks,  >8 – <= 12 Weeks, >12 – <= 16 Weeks, >16 – <= 
20 Weeks, >20 – <= 24 Weeks, >24 – <= 36 Weeks, and in interval of 12 Weeks thereafter).
Cumulative dose:
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for Safety Set. 
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration. 
The actual cumulative dose  refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF. 
For patients who did not take any drug, the cumulative dose is by definition equal to zero.


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The actual cumulative dose is the sum of the non-zero doses recorded over the dosing period 
and the planned cumulative dose is the planned starting dose summed over the same dosing 
period.
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
DI (mg / day) = Actual Cumulative dose (mg) / Duration of exposure to study treatment 
(day).
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (mg / day) = Planned Cumulative dose (mg) / Duration of exposure (day).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg / day)  / PDI (mg / day).  
DI and RDI will be summarized for Safety Set.
Dose reductions, interruptions or permanent discontinuations:
The number of subjects who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized for Safety Set. 
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption.
Reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level or where the actual dose administered/total daily dose is lower than the calculated 
dose amount based on the prescribed dose. Therefore any dose change to correct a dosing error 
will not be considered a dose reduction.  Only dose change is collected in the CRF, number of 
reductions will be derived programmatically  based on the change and the  direction of the 
change.
2.4.2
Prior, concomitant and post therapies
Prior medications or therapies are defined as drugs or therapies taken and stopped prior to first 
dose of study treatment. Post-treatment therapies will include all therapies that start after the 
last non-zero dose of study treatment.


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Concomitant medications prior to and after the start of ruxolitinib will be listed and summarized 
according to the Anatomical Therapeutic Chemical (ATC) classification system by means of 
frequency counts and percentages. These summaries will include medications starting on or 
after the start of study treatment or medications starting prior to the start of study treatment and 
continuing after the start of study treatment.
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed.
2.5
Analysis of the primary objective
The primary objective of this study is to determine the spleen length response rate at week 24.
2.5.1
Primary endpoint
The primary efficacy variable for this study is the proportion of patients achieving a 50% 
reduction in spleen length at Week 24. The FAS will be used for the primary analysis.
2.5.2
Statistical hypothesis, model, and method of analysis
The assessment of primary efficacy of study treatment will be based on the calculation of the 
observed proportion of patients with spleen length response at Week 24 and its posterior 
distribution using a Beta-binomial model. A patient will be a responder if he/she achieves a 50% 
reduction in spleen length at Week 24.
Study treatment will be declared efficacious if the following criteria are met:
a. Observed proportion of patients with ≥50% reduction in spleen length at Week 24 ≥25%
b. Probability of true response rate ≤15% (considered not clinically meaningful) is less than 10%
With 50 patients, criteria ‘a’ and ‘b’ will be met if the observed responder rate is ≥25%, i.e., at 
least 13 patients out of 50 patients have a response at Week 24 which will give a probability of 
“not being clinically meaningful (response ≤15%)” of 0.0243.
The primary analysis will be performed when all the enrolled patients have been treated with 
ruxolitinib for 24 weeks or discontinued prior to Week 24. The point estimate of the proportion 
of patients achieving ≥50% reduction in spleen length at Week 24 along with corresponding 
exact 95% confidence interval using Clopper and Pearson exact method will be presented.
2.5.3
Handling of missing values/censoring/discontinuations
For the primary analysis, patients with missing baseline spleen length will be excluded from the 
analysis as change from baseline cannot be calculated.
Patients with missing spleen length at Week 24 or who withdraw earlier from the study will be 
considered as a non-responder.
2.5.4
Supportive and Sensitivity analyses
The primary analysis (as described in Section 2.5.2) will also be repeated on the PPS. 
Furthermore, the primary endpoint will be analyzed on patients with non-missing spleen length 
at both baseline and Week 24. Proportion of patients achieving a 50% reduction in spleen length 


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at any time during the study will also be reported along with corresponding exact 95% 
confidence interval using Clopper and Pearson exact method.
IWG-MRT response criteria will also be used to analyze spleen length response rate at Week 
24. Response as per IWG-MRT criteria is defined as follows:

A baseline splenomegaly that is palpable at 5-10 cm, below the LCM at baseline, 
becomes not palpable, post-baseline or

A baseline splenomegaly that is palpable at >10 cm at baseline, below the LCM, 
decreases by ≥50%, post-baseline

A baseline splenomegaly that is palpable at <5 cm at baseline,  below the LCM, is not 
eligible for spleen response
Patients meeting response criteria as per above definition will be considered as responders or 
else will be non-responders. The point estimate of the proportion of responders along with 
corresponding exact 95% confidence interval using Clopper and Pearson exact method will be 
presented at Week 24. The same analysis will be repeated for proportion of responders as per 
IWG-MRT response criteria for spleen at any time during the study.
2.6
Analysis of the key secondary objective
There is no key secondary objective for this study.
2.7
Analysis of secondary efficacy objective(s)
All secondary efficacy analyses will be performed on the FAS unless otherwise specified.
2.7.1
Secondary endpoints
The secondary efficacy variables for this study are:

the proportion of patients achieving a 50% reduction in spleen length at Week 48

percent change from baseline in spleen length over time

summary of transfusions over time
2.7.2
Statistical hypothesis, model, and method of analysis
The spleen length response rate at Week 48 will be evaluated. The point estimate of the 
proportion of patients achieving ≥50% reduction in spleen length at Week 48 along with 
corresponding exact 95% confidence interval using Clopper and Pearson exact method will be 
presented.
Percent change from baseline in spleen length over time will be evaluated to assess the effect 
of ruxolitinib on spleen length. The analysis will be performed for each visit and at end of 
treatment. This parameter is computed by dividing the difference of spleen length at assessment 
time and at baseline by the length at baseline multiplied by one hundred.
To evaluate the effect of ruxolitinib on transfusion requirements, the following will be 
summarized:


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
Number and percentage of transfusions over time

Proportion of patients who are transfusion dependent (TD). Transfusion dependence is 
defined as per IWG-MRT criteria: 6 or more units of transfusion in 12 weeks prior to 
baseline.

For transfusion dependent (TD) patients at baseline, the following will be analyzed:

transfusion independence (TI) rate (requiring no unit of transfusion for ≥12 weeks at 
any time during the study)

transfusion response rate (not TD: having 5 or less units of transfusion for ≥12 weeks 
at any time during the study)

For patients who were not transfusion dependent (TD) at baseline, the following will be 
analyzed:

transfusion dependence (TD) rate (requiring 6 or more units of transfusion for ≥12 
weeks at any time during the study)
2.8
Safety analyses
For all safety analyses, the Safety set will be used, unless specified otherwise.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE eCRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs starting during the post-treatment period will 
be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency.
The following adverse event summaries will be produced by treatment; overview of adverse 
events and deaths (number and % of subjects who died), with any AE, any SAE, AEs by SOC 
and PT, summarized by relationship (all AEs and AEs related to study treatment), seriousness 
(SAEs and non-SAEs), leading to treatment discontinuation (drug withdrawn), leading to dose 
interruption/adjustment (dose increased or dose reduced), requiring additional therapy (concomitant 
medication or non-drug therapy) and leading to fatal outcome. In addition, a summary of serious 
and non-serious adverse events with number of occurrences will be produced (an occurrence is 
defined as >1 day between start and prior end date of record of same preferred term) as per EudraCT 
requirements.


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2.8.1.1
Adverse events of special interest / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound INC424. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 
level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) 
may also be used. A NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad. For each specified AESI, number and percentage of patients with at least one event of 
the AESI occurring during on treatment period will be summarized.
A Case Retrieval Sheet (CRS; an Excel file) with the exact composition of the adverse events 
groupings is to be used to map reported adverse events to the AESIs groupings (termed Specific 
Event Categories (SECs) in the CRS). This file may be updated (i.e. it is a living document) 
based on review of accumulating trial data. The latest version of the CRS document available 
at the time of the analyses will be used.
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class, and preferred term. 
All deaths will be listed for the Safety set, post-treatment deaths will be flagged. A separate 
listing of deaths prior to starting treatment will be provided for all screened subjects. 
2.8.3
Laboratory data
The summaries will include all assessments available for the lab parameter collected no later 
then 30 days after the last study treatment administration date (see Section 2.1.1.3).
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter):

Changes from baseline in hematology/biochemistry parameters over time.

Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline.

Shift tables using CTC grades to compare baseline to the worst on-treatment value

.

Trends of lab parameter values over time (baseline and selected on-treatment timepoints) 
should be displayed via boxplots based on time windows and corresponding tables 
displaying the statistics used for the box plots by the selected time points. 
The following listings will be produced for the laboratory data:


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
Listings of all laboratory data, with CTC grade and classification relative to the laboratory 
normal range. Lab data collected during the post-treatment period will be flagged.

Listing of all CTC grade 3 or 4 laboratory toxicities
Liver function parameters
Liver function parameters of interest are total bilirubin (TBIL), ALT, AST and alkaline 
phosphatase (ALP).
The number (%) of subjects with worst post-baseline values will be summarized:

ALT or AST > 3xULN 

ALT or AST > 5xULN 

ALT or AST > 8xULN 

ALT or AST > 10xULN 

ALT or AST > 20xULN 

TBL > 2xULN 

TBL > 3xULN 

ALT or AST > 3xULN & TBIL > 2xULN 

ALT or AST > 3xULN & TBIL > 2xULN & ALP < 2xULN (potential Hy’s law) 
Potential Hy’s Law events are defined as those patients with a concurrent occurrence of AST 
or ALT > 3xULN and TBIL > 2xULN and ALP < 2xULN in the same assessment sample during 
the on-treatment period. Further medical review has to be conducted to assess potential 
confounding factors such as, liver metastates, liver function at baseline etc. 
2.8.4
Other safety data
2.8.4.1
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: body temperature (°C), systolic and diastolic blood 
pressure (mmHg).
For analysis of vital signs, notable criteria are provided in Table 1-2 below.
Table 2-1
Clinically notable changes in vital signs
Vital sign (unit)
Clinically notable criteria
above normal value 
below normal value
Systolic blood 
pressure (mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure (mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Body temperature
>= 39.1
-


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The number and percentage of subjects with notable vital sign values (high/low) will be 
presented for the Safety Set.
A listing of all vital sign assessments will be produced and notable values will be flagged. In 
the listing, the assessments collected during the post-treatment period will be flagged.
2.8.4.2
ECOG performance status
The ECOG PS scale will be used to assess the physical health of patients, ranging from 0 (most 
active) to 5 (least active):
Table 2-2
ECOG Performance Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
ECOG scores over time will only be listed.
2.9
Pharmacokinetic endpoints  
Not Applicable
2.10
PD and PK/PD analyses
Not Applicable
2.11
Patient-reported outcomes
The Myelofibrosis 7 Item Symptom Scale (MF-7) along with Modified MFSAF v2.0 (computed 
through the addition of a separate question on Inactivity to the data captured with MF7) and the 
PGIC will be primarily used to collect electronically the patient’s disease-related symptoms and 
patient impression of change. No formal statistical test will be performed.
Missing items data in a scale will be handled based on each instrument manual. No imputation 
will be applied if the total or subscale scores are missing at a visit. The FAS will be used for 
analyzing PRO data. Descriptive statistics (e.g., mean, median) will be used to summarize the 
scored scales at each scheduled assessment time point for the Myelofibrosis 7 Item Symptom 
Scale (MF-7) and the Modified MFSAF v2.0 score.
Change from baseline in the domain scores at the time of each assessment will be summarized. 
Patients with an evaluable baseline score and at least one evaluable post-baseline score during 
the treatment period will be included in the change from baseline analyses. The number and 


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percentage of patients in each PGIC response category at selected time points will be 
summarized.
Proportion of patients with at least 50% reduction in MF-7 and modified MFSAF v2.0 from 
baseline will also be reported at Week 24 along with its 95% CI using exact Clopper-pearson 
method.


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2.13
Other Exploratory analyses
Not Applicable.
2.14
Interim analysis
No formal interim analysis is planned for this trial.
The primary analysis will be performed after all patients have completed Week 24 or 
discontinued prior to Week 24. Any other interim updates may be provided to fulfill regulatory 
obligations to comply with post-approval commitments, or for publication purposes.
The final analysis will occur at the end of the study. All available data from all patients will be 
analyzed and summarized in a final CSR.
3
Sample size calculation
Approximately 50 patients will be enrolled in this study. Success at Week 24 will be declared 
if the following criteria are met:
a. Observed proportion of patients with ≥50% reduction in spleen length at Week 24 ≥25%
b. Probability of true response rate ≤15% (considered not clinically meaningful) is less than 10%
With 50 patients, criteria ‘a’ and ‘b’ will be met if the observed responder rate is ≥ 25%, i.e. if 
at least 13 patients out of 50 patients have a response at Week 24.
Sample 
Size
No. of 
responders
Observed 
responder rate (%)
Probability of true responder rate 
≤15%
N=50
11
22
0.1014
12
24
0.0520
13
26
0.0243


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14
28
0.0104
15
30
0.0041
16
32
0.0015
The operating characteristics of the design are presented in the table below. This table shows 
the probability for positive conclusion (i.e. success criteria met at the end of the study) under 
different true responder rates. When the true responder rate at Week 24 is ≤15%, the probability 
of positive conclusion is ≤10% (false success rate). The probability of success is > 90% when 
the true responder rate at Week 24 is 35%.
Sample Size
True responder rate (%)
Probability of positive conclusion
N=50
15
0.0301
20
0.1861
25
0.4890
30
0.7771
35
0.9339
40
0.9867
45
0.9982
50
0.9998
4
Change to protocol specified analyses
Not Applicable.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date. 
Scenario 1 should not applicable for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available: 


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Please note that date of assessment on EOT CRT might be very different from last date of dose. 
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
            Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
            Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year 
of EOT date and mm < the month of  EOT date: 
            Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment: 
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
5.1.2
AE, ConMeds and safety assessment date imputation.
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  


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Missing 
Element
Rule

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule
(*=last treatment date plus 30 days not > (death date, cut-off date, withdrawl 
of consent date))
day, month, 
and year
Completely missing end dates (incl. ongoing events) will be imputed by the 
end date of the on-treatment period* 
day, month
If partial end date contains year only, set end date = earliest of 31DecYYYY 
or end date of the on-treatment period * 
day
If partial end date contains month and year, set end date = earliest of last 
day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
5.1.2.1
Other imputations
Not applicable
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of laboratory 
CTC grades will be based on the observed laboratory values only, clinical assessments will not 
be taken into account. The criteria to assign CTC grades are given in <Novartis internal criteria 


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for CTC grading of laboratory parameters>. The latest available version of the document based 
on the underlying CTCAE version 4.03 at the time of analysis will be used. 
For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by 
the low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 is not applicable. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labeled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
Imputation Rules
CTC grading for blood differential is based on an absolute value. However, these data may not 
be reported as absolute counts but rather as percentage of WBC.
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential.
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1, calcium values in mmol/L will be converted to mg/dL by dividing by 0.2495. 
For calculation of laboratory CTC grades 0 and 1, the normal range for derived corrected 
calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assiged as described above for grading.
5.4
Time windows for box plots
All scheduled/unscheduled assessments should be assigned to time windows. In case of multiple 
values per window, the one closest to the planned visit date should be used. If 2 values are 
equidistant to the planned visit date, the selection should be made by selecting the one assessed 
by central (if any) and otherwise - for multiple central assessments or ECGs / vital signs 
equidistant to the planned visit - the last value. 
Boxplots should display boxes (25th – 75th percentiles) and median (line) as well as joint mean 
(dot) values. Whiskers extend to the 5th – 95th percentiles with any values outside the whiskers 
not being displayed. A footnote to the box plot should explain that these values are not displayed. 
However, all values are used to calculate mean and percentiles displayed on the graph, and 


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corresponding summary tables should be generated. The number of observations used for this 
analysis is to be stated at the bottom.
5.5
Dynamic International Prognostic Scoring System (DIPSS)

The Dynamic International Prognostic Scoring System (DIPSS) can be used to assess a 
patient’s prognosis as conditions change over time.

DIPSS risk score will be derived for both Primary and secondary MF patients at baseline 
Risk Factor
Points
0
1
2
Hemoglobin
≥10 g/dL
…
<10 g/dL
WBC count
≤ 25×109 L
> 25 ×109 L
…
Constitutional symptoms
No
Yes
…
Age
≤ 65 years
> 65 years
…
Peripheral blood blasts
< 1 %
≥ 1 %
…
The risk level is assigned by the total score:
Risk Group
Points
Median Survival, Years
High
5-6
1.5
Intermediate 2
3-4
4
Intermediate 1
1-2
14.2
Low
0
NR
5.6
Statistical models
5.6.1
Primary analysis
Calculation of posterior probability 
The efficacy criteria for this study are:
1. Observed proportion of patients with ≥50% reduction in spleen length at Week 24 ≥25%
2. Probability of true response rate ≤15% (considered not clinically meaningful) is less than 
10%
Let p denote the proportion of patients with ≥50% reduction in spleen length at Week 24 and 
follow a beta prior distribution Beta [a,b], where a>0, b>0. Let y out of n patients acheive 
≥50% reduction in spleen length at Week 24. Therefore, the posterior distribution of p
is Beta( a+ y, b+ n-y) [Spiegelhalter et al. 2004].
A minimally informative unimodal Beta prior [Neuenschwander et al. 2008] Beta [1/3,1] will 
be used.   The parameters were chosen so that the posterior probability of the true response rate
≤15% (considered not clinically meaningful) is equal to 0.0243.
The efficacy criteria will be assessed based on the actual number of patients enrolled in the 
study. For example, if the total number of patients is 50, the efficacy criteria requires that at 
least 13 patients who have ≥50% reduction in spleen length at Week 24. In that case, the 
posterior distribution is Beta (0.333+13, 1+50-13) and the probability of success is > 90% when 
the true reponder rate is 35%.


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Confidence interval for response rate
Responses will be summarized in terms of percentage rates with 100(1 −α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ
with EXACT statement for one-way table [Clopper and Pearson 1934].
5.6.2
Key secondary analysis
Not Applicable.
6
Reference
1. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
2. Neuenschwander B, Branson M and Gsponer T (2008). Critical aspects of the Bayesian 
approach to Phase I cancer trials. Statistics in Medicine, 27, 2420-2439.
3. Spiegelhalter DJ, Abrams KR and Myles JP (2004). Bayesian Approaches to Clinical 
Trials and Health-care Evaluation. Chichester, Wiley.