Clinical trial NCT03774472
Conditions: Anatomic Stage I Breast Cancer AJCC v8 Anatomic Stage IA Breast Cancer AJCC v8 Anatomic Stage IB Breast Cancer AJCC v8 Anatomic Stage II Breast Cancer AJCC v8 Anatomic Stage IIA Breast Cancer AJCC v8 Anatomic Stage IIB Breast Cancer AJCC v8 Anatomic Stage III Breast Cancer AJCC v8 Anatomic Stage IIIA Breast Cancer AJCC v8 Anatomic Stage IIIB Breast Cancer AJCC v8 Anatomic Stage IIIC Breast Cancer AJCC v8 Anatomic Stage IV Breast Cancer AJCC v8 Prognostic Stage I Breast Cancer AJCC v8 Prognostic Stage IA Breast Cancer AJCC v8 Prognostic Stage IB Breast Cancer AJCC v8 Prognostic Stage IIA Breast Cancer AJCC v8 Prognostic Stage IIB Breast Cancer AJCC v8 Prognostic Stage III Breast Cancer AJCC v8 Prognostic Stage IIIA Breast Cancer AJCC v8 Prognostic Stage IIIB Breast Cancer AJCC v8 Prognostic Stage IIIC Breast Cancer AJCC v8 Prognostic Stage IV Breast Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center
Start date: 2018-08-20; Completion date: 2024-04-17
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase I/II trial studies the side effects and best dose of hydroxychloroquine when given together with palbociclib and letrozole before surgery in treating patients with estrogen receptor positive, HER2 negative breast cancer. Hydroxychloroquine is a substance that decreases immune responses in the body. Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Estrogen can cause the growth of breast cancer cells. Drugs, such as letrozole, may lessen the amount of estrogen made by the body. Giving hydroxychloroquine, palbociclib, and letrozole before surgery may work better than palbociclib and letrozole in treating patients with breast cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the safety of adding hydroxychloroquine (HCQ) to continuous low dose palbociclib and letrozole and to determine the recommended phase II dose (RP2D) for hydroxychloroquine (HCQ) for the subsequent Phase II study. (Phase I) II. To determine the dose responsiveness of 2 dose levels (400 mg and recommended phase II dose \[RP2D\]) of hydroxychloroquine added to low dose palbociclib and letrozole on pre and post HCQ breast tumor proliferation index (Ki67), autophagy, senescence and cell cycle control. (Phase II, Part I) III. To determine whether hydroxychloroquine added to low dose palbociclib and letrozole can increase the proportion of patients whose tumors achieve complete cell cycle arrest (CCCA, defined as the Ki67 =\< 2.7%) comparing T2 to T1. (Phase II, Part II)

SECONDARY OBJECTIVES:

I. To determine the response rate and clinical benefit rate at 8 weeks of the assigned dose of hydroxychloroquine (HCQ) plus continuous low dose palbociclib and letrozole. (Phase I) II. Determine longer term clinical tumor responsiveness (tumor volume) and tumor biomarker indices (for patients who have extended pre-operative therapy, maximum 24 weeks). (Phase II, Part I) III. Perform exploratory studies on blood-based tumor protein, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) biomarkers with a focus on pathways of cell proliferation, autophagy, senescence and cell cycle control. (Phase II, Part I) IV. To determine the impact of adding hydroxychloroquine to low dose palbociclib and letrozole on breast tumor indices of proliferation, autophagy, senescence, cell cycle control and other intersecting pathways. (Phase II, Part II) V. Determine longer term clinical tumor responsiveness and tumor biomarkers indices (for patients who have extended pre-operative therapy, maximum 24 weeks). (Phase II, Part II) VI. To determine the dose responsiveness of HCQ (400 mg vs. RP2D) on the primary (proportion with CCCA) and secondary clinical/biological endpoints. (Phase II, Part II) VII. To perform exploratory studies on blood-based tumor protein, DNA and RNA biomarkers. (Phase II, Part II) VIII. Obtain additional safety information for the combination of low dose palbociclib, letrozole and hydroxychloroquine. (Phase II, Part II)

OUTLINE: This is a phase I, dose-escalation study of hydroxychloroquine followed by a phase II study.

PHASE I: Patients with advanced, metastatic (stage IV) breast cancer receive hydroxychloroquine orally (PO) once daily (QD), palbociclib PO QD, and letrozole PO QD on days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients with early stage (stage I-III) breast cancer receive hydroxychloroquine PO QD on days 15-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive palbociclib PO QD, and letrozole PO QD on days 1-28, followed by standard of care surgery at week 5. If there is a proliferative benefit with complete cell cycle arrest (CCCA) by biopsy at 4 weeks, cycles may repeat every 28 days for up to 20-24 weeks in the absence of disease progression or unacceptable toxicity, followed by standard of care surgery during weeks 20-24.

After completion of study treatment, patients are followed up within 30 days or every 4 weeks.

Arms: arm 1: PHASE I: Patients with advanced, metastatic (stage IV) breast cancer receive hydroxychloroquine PO QD, palbociclib PO QD, and letrozole PO QD on days 1-28. Cycles repeat every 28 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients with early stage (stage I-III) breast cancer receive hydroxychloroquine PO QD on days 15-28 of cycle 1 and on days 1-28 of subsequent cycles. Patients also receive palbociclib PO QD, and letrozole PO QD on days 1-28, followed by standard of care surgery at week 5. If there is a proliferative benefit with CCCA by biopsy at 4 weeks, cycles may repeat every 28 days for up to 20-24 weeks in the absence of disease progression or unacceptable toxicity, followed by standard of care surgery during weeks 20-24.
Interventions: intervention 1: Hydroxychloroquine intervention 2: Letrozole intervention 3: Palbociclib
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
MD Anderson IND Sponsor Cover Sheet
Protocol ID 
2017-0071 
Protocol Title 
Phase I/II Safety and Efficacy Study of Autophagy Inhibition with 
Hydroxychloroquine to Augment the Antiproliferative and 
Biological Effects of Pre-Operative Palbociclib plus Letrozole for 
Estrogen Receptor-Positive and HER2-negative Breast Cancer 
 
Protocol Version 07 
Version Date 
03/17/2021 
 
Protocol PI 
Debu Tripathy, MD 
Department 
Breast Medical Oncology 
 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
138453 
 
 
 
 
 
 
 
 
 
 
 
 


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Phase I/II Safety and Efficacy Study of Autophagy Inhibition with 
Hydroxychloroquine to Augment the Antiproliferative and 
Biological Effects of Pre-Operative Palbociclib plus Letrozole for 
Estrogen Receptor-Positive and HER2-negative Breast Cancer 
 
 
Principal Investigator:     Debu Tripathy, MD 
  Professor and Chairman, Breast Medical Oncology 
                                       Dan L. Duncan Building (CPB5.3505) 
 1515 Holcombe Blvd. Unit 1354 
 
 Houston, TX 77030 
 
 
 
Co- Principal Investigator:     Khandan Keyomarsi, MD 
(Translational Sciences)  
 
Co- Principal Investigator: 
Kelly Hunt, MD 
 
 
 
 
 
Protocol Version: 
 
6  
 
IND No.: 
 
138453  
 
 
 
 


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Contents
LIST OF 
...5 
1.0 INTRODUCTION ...................................................................................................... 6 
1.1 Background ............................................................................................................. 6  
1.2   Mechanisms of Resistance to Endocrine Therapy and Rationale for the use of   
Autophagy inhibition with Hydr
..7 
1.3    Rationale for the Use of Pre-
      
Therapy . 
8 
1.4 Risk/Benefit Assessment ....................................................................................... 11 
2.0 STUDY AIMS AND OBJECTIVES ......................................................................... 11 
2.1 Phase I Safety Component (metastatic disease) Objectives and Endpoints 
..11 
2.2 Phase II Window/Neo-adjuvant Component Objectives and Endpoints ................ 12 
3.0 INVESTIGATIONAL PLAN .................................................................................... 13 
3.1 Overall Design ....................................................................................................... 13 
Phase I Safety Component: ........................................................................................... 13 
Phase II Pre-
 .............................................................. 13 
. 12 
3.3 Dose Limiting Toxicity Definition ............................................................................ 14 
3.4 Phase II Part 1 (neo-adjuvant cohorts) .................................................................. 15 
3.5 Phase II Part 2 Window/Neo-adjuvant Component ............................................... 15 
3.6 Phase II Patient Evaluability .................................................................................. 15 
3.7 Replacement of Patients ....................................................................................... 15 
3.8 Target Accrual ....................................................................................................... 15 
4.0 PATIENT SELECTION ........................................................................................... 16 
4.1 Inclusion Criteria .................................................................................................... 16 
4.2 Exclusion Criteria .................................................................................................. 17 
5.0 STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS .......................... 18 
5.1    Patient Identification
 18 
5.2 Schedule of Assessments ..................................................................................... 18 
5.2.1 Baseline Assessments ......................................................................................... 20 
5.2.2 Evaluation During Study Phase II ......................................................................... 21 
5.2.3 Treatment Duration .............................................................................................. 21 
5.2.3.1  Phase I ............................................................................................................. 21 


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5.2.3.2  Phase II ............................................................................................................ 22 
5.2.4  End of treatment visit and Follow up assessments ............................................. 22 
   
1 
   
1 
   
1 
   5.2.8 Imaging assessments Phase I ........................................................................... 22 
   5.2.9  Imaging assessments Phase II ......................................................................... 22 
   5.3 Correlative Biomarker Studies ............................................................................. 23 
   
.......22 
   
.
3 
   
.23 
   
4 
6.0 INVESTIGATIONAL AND NON-INVESTIGATIONAL AGENTS  
   6.1  Palbociclib ........................................................................................................... 25 
   
4 
   
.24 
   
4 
   6.1.4 
.25 
6.2  Hydroxychloroquine ................................................................................................ 25 
   
.
5 
   
6 
   
26  
6.3  Letrozole ................................................................................................................. 26 
6.4 Concomitant Medications
27 
7.0 ADVERSE EVENT MONITORING AND REPORTING .......................................... 27 
7.1 Definition of an Adverse Event .............................................................................. 27 
7.2 Serious Adverse Event (SAE) Reporting ............................................................... 27 
 
7.3 Recording of Adverse Events ................................................................................ 29 
7.4    Assessment of Adverse Events ............................................................................. 30 
7.5 Communications between the Investigator and Supporting Company Pfizer ........ 31 
8.0 STATISTICAL CONSIDERATIONS ....................................................................... 31 
8.1  IND Office Reporting..
 


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9.0 INSTITUTIONAL REVIEW, CONSENT, MEDICAL MONITORING AND RECORD 
KEEPING AND SAFETY MONITORING ...................................................................... 32 
9.1 Informed Consent .................................................................................................... 31 
   9.2  Institutional Review Board Approval .................................................................... 33 
   9.3 Confidentiality ...................................................................................................... 33 
   9.4 Study Medical Monitoring Requirements ............................................................. 33 
   9.5 Data Collection .................................................................................................... 34 
10   REFERENCES 
............................................................................................34 
11  APPENDICES
..37  
Appendix A: Palbociclib (Ibrance) Highli
..37 
Appendix B: Hydroxychloroquine (Plaquenil) Package Insert
69 
Appendix C: Letrozole (Femara Tablets) Package Insert
77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS AND LIST OF DEFINITIONS OF TERMS  
Abbreviation 
Term/Definition  
 
Akt 
 
 
A growth factor pathway component (serine-threonine kinase) 
Alk Phos
 
Alkaline phosphatase 
ALT 
 
 
Alanine aminotransferase 
ANC 
 
 
Absolute neutrophil count 
AST    
 
Aspartate aminotransferase 
ASCO/CAP 
 
American Society of Clinical Oncology/College of American Pathologists 
CBC 
 
 
Complete blood count 
CCCA  
 
Complete cell cycle arrest (Ki67
 
CDK 
 
 
Cyclin-dependent kinase 
DL 
 
 
Dose level 
DLT 
 
 
Dose-limiting toxicity 
DNA 
 
 
Deoxyribonucleic acid 
ECOG  
 
Eastern Cooperative Oncology Group 
ER
 
 
Estrogen receptor 
ESR1  
 
Estrogen receptor-alpha gene 
FDA
 
 
Food and Drug Administration (United States) 
FSH
 
 
Follicle stimulating hormone 
HCQ
 
 
Hydroxychloroquine 
HER2  
 
Human epithelial receptor-2 (HER2/neu) 
JAK/STAT 
 
Janus kinase/signal transducers and activators of transcription 
Ki67
 
 
Kiel antigen, a cellular marker for proliferation 
L 
 
 
Letrozole 
LH 
 
 
Luteinizing hormonal 
MBC
 
 
Metastatic breast cancer 
MCF7  
 
A hormone receptor-positive breast cancer cell line 
mg
 
 
Milligrams 
mTOR  
 
Mammalian target of rapamycin 
P 
 
 
Palbociclib 
p.o. 
 
 
By mouth 
PR
 
 
Progesterone receptor 
PI3K 
 
 
Phosphoinositide 3-kinase  
PIK3CA 
 
Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha 
Rb 
 
 
Retinoblastoma protein 
RNA 
 
 
Ribonucleic acid 
RP2D  
 
Recommended phase II dose 
SEER  
 
Survey End Epidemiology Results 
SMC
 
 
Safety and Monitoring Committee 
T. Bili  
 
Total bilirubin 
ULN
 
 
Upper limits of normal (Institutional) 
U/S 
 
 
Ultrasound 
  


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1.0 Introduction 
1.1 Background  
1.1.1 Hormone receptor-positive breast cancer 
Breast cancer is the most common female cancer in the United States. It is estimated that 
252,710 American women will be diagnosed with breast cancer and 40,610 will die from the disease 
in 2017.3 A major cause of death in these patients is disease progression and incurable metastasis. 
The SEER database estimates that ~40,000 breast cancer patients a year either present at diagnosis 
(n=13,900) with metastatic disease or exhibit progression with metastatic disease, sometimes many 
years after completing therapy for early stage disease (n=36,000).4 Of these, an estimated 30,000 
have estrogen receptor (ER)-positive breast cancers.4 Hence, patients with ER+ metastatic breast 
cancer (MBC) represent a majority of breast cancer who die of their disease, the vast majority due to 
metastatic progression. 
1.1.2 Therapies for hormone receptor-positive breast cancer 
In early stage estrogen receptor-positive (ER+) breast cancer, the use of adjuvant endocrine 
therapy (tamoxifen or aromatase inhibitors) lowers the relative risk of recurrence at 10 years by 45 to 
50% and that of mortality by breast cancer death by 30%.5 In the metastatic setting endocrine 
therapy can induce responses and delay progression of disease. However, in the metastatic setting, 
it has been difficult to demonstrate a survival benefit of endocrine therapy.  Few modern-day trials 
have compared endocrine therapy to no endocrine therapy in the absence of chemotherapy since 
treatment induces clear palliation.  More recent trials comparing single-agent to combination 
endocrine therapy agents (e.g. aromatase inhibitors plus the ER down regulator fulvestrant) have 
yielded mixed results.6, 7 In the last few years, the addition of biological therapies that were designed 
to address mechanisms of resistance or with demonstration of preclinical synergy have shown 
improvements in disease-free survival when added to endocrine therapy, but no impact on overall 
survival - although these trials were not designed with the statistical power to survival differences, 
with disease-free survival designated as the primary endpoint.  The addition of the mTOR inhibitor 
everolimus doubled median disease-free survival from 4.1 to 10.6 months when added to the 
aromatase inhibitor exemestane as second-line therapy and was approved by the FDA with final 
survival analysis showing no significant difference in that outcome (median survival of 31.0 vs. 26.6 
months).8, 9 Other biological agents such as PI3 kinase inhibitors, histone deacetylase inhibitors and 
cyclin-dependent kinase CDK) inhibitors are being actively tested in first, second and later lines of 
therapy - so far CDK 4/6 inhibitor palbociclib has been approved by the FDA as outlined in the next 
section.  
In summary, this is a novel investigator initiated study funded by CPRIT grant which aims to 
evaluate the safety and tolerability (phase I) of adding HCQ to continuous low dose palbociclib and 
letrozole in metastatic HR+, HER2- breast cancer and thereafter determine whether the inhibition of 
autophagy with HCQ can decrease proliferation index in a window study (Phase II) in 
postmenopausal women with stage I-III HR+/HER2- breast cancer.  The scientific rationale is based 
on preclinical work that has been done by the trial investigators and published as is well described in 
the protocol. Further the trial has been vetted through our departmental HR positive working group as 
plinary team of collaborators are involved 
and it is well funded. Finally, we have had success with accrual demonstrated to other window trials, 
with several such studies ongoing without any concerns of low accrual. As noted in the trial 
prioritization, this is #3 of 5 trials in the HR+, HER2- patient population but the other ongoing or 
planned trials are expected to have little if any overlap with the activation of protocol 2017-0071.  


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1.1.3 Palbociclib and use in breast cancer 
Palbociclib is a potent and specific cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and anti-
proliferative agent that induces G1 arrest and prevents breast cancer cell growth, most notably in 
ER+ cell lines and other preclinical models, which led to the clinical development of this class of 
inhibitors in hormone receptor-positive breast cancer.11-13 Palbociclib was approved by the FDA in 
February, 2015 based on improved time to disease progression in the first and second-line settings 
for ER+/HER2-negative metastatic breast cancer (MBC).14-17 In the pivotal first-line Phase III trial, 
progression-free survival (primary endpoint) was improved from 14.5 to 24.8 months with the addition 
of palbociclib to the standard first-line aromatase inhibitor letrozole.15 In the second-line setting, the 
addition of palbociclib to the standard second-line estrogen downregulate fulvestrant in a Phase III 
trial also demonstrated a significant improvement in time to progression from 3.8 to 9.2 months.  
However in the first line setting, 66% of patients on the palbociclib experienced grade 3 and 4 
neutropenia, and adverse events necessitate a palbociclib dose reduction in 36% and discontinuation 
in 7.4% of patients.15 Additionally, palbociclib must be dosed with a 7-day break, which was shown to 
be associated with a proliferative burst in a separate neoadjuvant serial biopsy study.18 Also, a 
independent biomarkers to predict response and/or resistance to palbociclib  many patients do not 
respond to therapy, and most importantly, virtually all eventually develop resistance.  Biomarkers that 
may influence response to endocrine therapy and CDK inhibitors including estrogen receptor-alpha 
(ESR1) and PIK3CA mutations, loss of the retinoblastoma protein function, proliferative antigen Ki67 
expression, cyclin D1 gene amplification or loss of the cyclin-dependent kinase inhibitor p16 have not 
shown to be related to palbociclib-associated response or time to progression.13, 17, 19 Importantly, no 
survival benefit yet observed in either of the larger randomized trials or smaller Phase II trial, 
although these trials were not powered for survival differences and diversity of therapies that patients 
may receive in their subsequent management may cloud future survival update analyses.  
 
1.2 Mechanisms of Resistance to Endocrine Therapy and Rationale for the use of 
Autophagy inhibition with Hydroxychloroquine 
While specific mechanisms of resistance to palbociclib have not been well characterized, 
there are several mechanisms of resistance to conventional endocrine therapies such as tamoxifen 
and aromatase inhibitors, which include activation of receptor tyrosine kinase signaling pathways 
(notably the PI3K/Akt/mTOR pathway), activation mutations in ESR1 and other more general 
alterations such as epigenetic regulation of gene expression other intersecting pathways like NFKB 
and JAK/STAT.20 As described earlier, mTOR and CDK4/6 inhibition with everolimus and palbociclib 
are now approved as biological agents in combination with endocrine therapy, while strategies using 
inhibitors of PI3K, Akt, histone deacetylase are undergoing testing, none so far has been able to 
induce durable enough responses to affect survival, and clinical resistance still emerges with all 
available therapies. 
 


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Our laboratory research group, led by Khandan Keyomarsi, PhD, Professor of Experimental 
Radiation Oncology at MD Anderson, has an extensive investigational track record in area the cell 
cycle pathways in breast cancer. We have shown that at low concentrations of the palbociclib, ER+ 
breast cancer cells arrest in the G1 phase of the cell cycle, but this arrest is reversible due to the 
activation of autophagy. However, at high concentrations of palbociclib, the cells are arrested 
irreversibly in G1, do not undergo autophagy and instead undergo senescence. The low 
concentration of palbociclib are on-target and are specific for inhibition of CDK4 and CDK6, as shown 
with siRNA assays where CDK4 and CDK6 where knocked down.  The high concentrations of 
palbociclib, induce senescence, but these are off target effects of the drug. We also demonstrated 
that if we combine palbociclib with an autophagy inhibitor such as hydroxychloroquine (HCQ), we can 
achieve senescence at a much lower (i.e. on- target) and continuous dosing of palbociclib, in both in 
vitro and in vivo models. Moreover, concomitant treatment with HCQ and palbociclib can mediate a 
synergistic response in ER+ xenograft (MCF7) mouse tumor volume and weight compared to 
palbociclib alone. More strikingly, the tumor volumes with combination treatment did not increase 
even after the treatment was stopped, while the tumor volumes with either palbociclib or HCQ alone 
continuously increased during both the treatment and recovery phases of the experiment. 
Combination treatment showed the desired and expected impairment in autophagic flux. Decrease in 
Rb phosphorylation, a direct readout of CDK 
4/6 inhibition, was more pronounced with the 
addition of HCQ. These results suggest that 
autophagy inhibition significantly improves the 
efficacy of low dose (on target) palbociclib in 
vivo and facilitates the induction of an 
irreversible tumor growth inhibition. We 
propose that palbociclib activates the 
autophagy pathway to protect ER+ breast 
cancer cells from palbociclib-induced 
senescence and inhibition of autophagy 
sensitizes cells to lower doses of palbociclib 
in vitro and in vivo (Figure 1).  
 
We therefore propose using HCQ to 
inhibit autophagy in patients treated with low 
dose (on target) palbociclib and letrozole to 
demonstrate enhanced anti-proliferative effect.  An anti-proliferative effect of endocrine therapy using 
quantification of the proliferative Ki67 antigen has been validated as a long-term predictor of 
outcome.   HCQ is a commonly used and generally safe drug used to treat malaria and as a remittive 
agent for various autoimmune diseases (see more expanded description in Section 6.2). This trial will 
therefore provide evidence of a promising therapeutic effect with lower dose palbociclib plus letrozole 
for a greater therapeutic effect with less side effects. This is needed before proceeding with a more 
definitive trial that could be potentially practice-changing. 
 
1.3 Rationale for the Use of Pre-
Therapy  
We have chosen to perform this trial using the combination of letrozole, palbociclib and HCQ 
in the pre-
Figure 1:  Model for Hydroxychloroquine
to Inhibit Autophagy and Potentiate 
Palbociclib


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from both internal and external advisory board members during the process of a grant proposal 
submission that led to the successful funding of both the laboratory and clinical trial aims of this 
project.  However, the initial lead-in Phase I safety trial that includes HCQ dose escalation with the 
study regimen of continuous low dose palbociclib and letrozole and the determination of the 
recommended Phase 2 dose (RP2D) for HCQ will be conducted in patients with advanced metastatic 
breast cancer, followed by activation of the neoadjuvant/window trial. 
The following rationale support this approach:  
 
Palbociclib is already FDA-approved for metastatic breast cancer with an excellent safety 
record. It is currently in several clinical trials in both the neoadjuvant and adjuvant settings. 
 
Treatment will include letrozole, a standard endocrine therapy as is used clinically for early 
stage breast cancer. 
 
HCQ is an approved drug commonly used for malaria and autoimmune disease and 
particularly safe when used at the doses and timeframes proposed (see more expanded 
description in Section 6.2). 
 
This model allows for safe biopsies as needed for the correlative tissue aims and eliminates 
artifact and variability due to prior therapies as all patients will be previously untreated. 
 
on study drug (2 weeks on low dose palbociclib plus letrozole, then 2 weeks with the addition 
of HCQ) then to proceed with surgery or a research biopsy if additional standard of care 
neoadjuvant therapy is indicated, and then followed by standard of care. 
 
The very first exposure to the combination will be performed in a cohort of patients with 
adva
combination with the study regimen of low dose continuous palbociclib with letrozole.  Once 
safety is established at the specific HCQ dose level, the corresponding arm of the Phase II 
neoadjuvant/window trial will be activated.  This approach will maximize safety by only moving 
to early stage curable population once safety of the study regimen is established in the 
advanced setting.  
 
There is ample clinical experience and clinical trial to support the use of neoadjuvant 
endocrine therapy as method to downstage tumors and allow more patients to undergo breast-
conserving surgery.21 Additionally, the neoadjuvant model is a well-established research tool to 
assess newer drugs when added to endocrine therapy to evaluate both clinical as well as biomarker 
based-responses.22  For hormone receptor-positive and HER2-negative breast cancer, the use of 
change in the proliferative antigen Ki67 pre to post treatment has been extensively validated as index 
that correlates with the likelihood of achieving a complete pathological response and with longer term 
outcomes specifically in trials.23-31 The key metrics using this model are obtained after 4 weeks of low 
dose Palbociclib and HCQ (safety) in the Phase I portion and after 2 weeks of low dose palbociclib 
and then 2 additional weeks with the addition of HCQ (efficacy) in the Phase II portion (see Sections 
2.0 and 3.1).   
Therefore, patients can come off study after 4 weeks and proceed with standard therapy 
aromatase inhibitor), neoadjuvant chemotherapy if the patient is known to have the stage, grade and 
other indices that warrant chemotherapy.  Alternatively, they can proceed with definitive 
breast/axillary node surgery. In addition, if the biopsy after both 2 and 4 weeks show suppression of 
proliferative index that is used as the main endpoint of the study (see Section 2.2.1), patient can stay 
on therapy for the typical full neoadjuvant endocrine therapy course which is typically 16-24 weeks. 


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These pragmatic alternatives will maximize accrual and allow patients and their physicians to opt for 
tuation.
1.4 Risk/Benefit Assessment   
Patients on this study will be receiving standard of care therapy (endocrine therapy with 
letrozole) and palbociclib, an FDA-approved and relatively non-toxic therapy that doubles time to 
progression in the metastatic setting, but not approved in the adjuvant or neoadjuvant setting (see 
additional description of palbociclib in Section 6.1). HCQ is an approved drug used for malaria and 
autoimmune disorders that also had a very good safety profile (see additional description of HCQ in 
Section 6.2). One concern of retinal toxicity that is typically seen only after prolonged exposure, will 
be mitigated by baseline ophthalmological exam covered by the study funding, and exclusion of 
those who are felt to be at risk for retinal toxicity as established by the by the American Academy of 
Ophthalmology to exclude preexisting maculopathy.32 In order to exclude unexpected toxicities of the 
proposed combination in patients with early stage breast cancer who may have a reasonably good 
prognosis and chance of cure, a run-in Phase I safety study will be conducted in patients with 
metastatic breast cancer who are also candidates for standard palbociclib and letrozole therapy.  The 
experimental regimen proposed for the window/neoadjuvant protocol, low dose continuous 
palbociclib and standard dose letrozole will be used, in combination with increasing doses of HCQ. 
The benefits of participation of this trial cannot be fully ascertained, but the addition of 
palbociclib has been shown to achieve a high rate of complete cell cycle arrest, a surrogate 
biomarker of long-term benefit.18 While short term exposure (4 weeks) may not affect outcome, 
patients who stay on study for a total of 16-24 weeks prior to surgery may have a greater degree of 
down staging and more conservative surgery (e.g. breast conservation, sentinel node biopsy as 
opposed to axillary dissection). 
 
2.0  STUDY AIMS AND OBJECTIVES 
The overall study aim is to determine whether autophagy inhibition with HCQ can significantly 
decrease proliferation index, a validated surrogate of long term outcome, when added to a 
continuous low dose palbociclib and letrozole. 
2.1 Phase I Safety Component (metastatic disease) Objectives and Endpoints 
 
2.1.1 The primary objective of the Phase I portion in the metastatic setting is to determine the 
safety of adding HCQ to continuous low dose palbociclib and letrozole and to determine the 
recommended phase II dose for HCQ for the subsequent Phase II study. 
 
Primary endpoint is safety, to be assessed continuously using CTCAE V4.03, with physical 
examination and laboratory assessments as indicated on the study schedule. Dose-limiting 
toxicities as defined in Section 3.3. 
 
2.1.2 The secondary objective is to determine the response rate and clinical benefit rate at 8 weeks 
of the assigned HCQ dose plus continuous low dose palbociclib and letrozole. 
 
 
 


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2.2 Phase II Window/Neo-adjuvant Component Objectives and Endpoints 
2.2.1 Phase II - Part 1 Primary Objectives and Endpoints 
To determine the dose responsiveness of 2 dose levels (400 mg and RP2D) of 
hydroxychloroquine added to low dose palbociclib and letrozole on pre and post HCQ breast 
tumor proliferation index (Ki67), autophagy, senescence and cell cycle control.  
 
2.2.2 Phase II - Part 1 Secondary and Additional Objective and Endpoints 
Determine longer term clinical tumor responsiveness (tumor volume) and tumor biomarker 
indices (for patients who have extended pre-operative therapy, maximum 24 weeks).  
 
Perform exploratory studies on blood-based tumor protein, DNA and RNA biomarkers with a 
focus on pathways of cell proliferation, autophagy, senescence and cell cycle control.   
 
2.2.3 Phase II Part 2 Primary Objective and Endpoints 
To determine whether hydroxychloroquine added to low dose palbociclib and letrozole can 
increase the proportion of patients whose tumors achieve complete cell cycle arrest (CCCA, 
defined as the 
) comparing T2 to T1 as shown in Figure 2, see Section 5.3.4).  
 
The primary endpoint is the increase in percentage of all patients who achieve CCCA with low 
dose palbociclib and letrozole (at week 2, time T1) compared to that of low dose palbociclib 
and letrozole with the addition of HCQ (at 5 weeks, day 29, time T2).   
 
A previously conducted trial of neoadjuvant aromatase inhibitor (anastrozole) plus standard 
dose palbociclib estimated the CCCA probability to be 44% with aromatase inhibitor alone 
and powered their study to detect a 50% increase of 44% to 66%18. A 26% CCCA probability 
was seen with anastrozole alone and 86% with the addition of standard dose palbociclib. We 
will aim for a CCCA reference probability of 50% with low-dose palbociclib + letrozole (T1) 
and a CCCA probability of 75% with the addition of HCQ (see Section 8 for statistical plan 
and samples size calculations for the Phase II portion). 
 
2.2.4 Phase II Part 2 Secondary Objectives and Endpoints 
 To determine the impact of adding hydroxychloroquine to low dose palbociclib and 
letrozole on breast tumor indices of proliferation, autophagy, senescence, cell cycle 
control and other intersecting pathways.  
 Determine longer term clinical tumor responsiveness and tumor biomarkers indices (for 
patients who have extended pre-operative therapy, maximum 24 weeks).  
 To determine the dose responsiveness of HCQ (400 mg vs. RP2D) on the primary 
(proportion with CCCA) and secondary clinical/biological endpoints 
 To perform exploratory studies on blood-based tumor protein, DNA and RNA biomarkers. 
 Obtain additional safety information for the combination of low dose palbociclib, letrozole 
and hydroxychloroquine.  
 


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3.0  INVESTIGATIONAL PLAN 
3.1 Overall Design 
This is an open label Phase I/II prospective interventional trial with a safety component in metastatic 
disease followed by 
trial component in the neo-adjuvant (pre-operative) setting. 
 
Phase I Safety Component: 
The Phase I is designed to evaluate the safety and tolerability of adding HCQ to continuous low dose 
palbociclib and letrozole in the metastatic setting and to determine the recommended phase 2 dose 
for HCQ.  A standard 3+3 dose escalation designed will be employed. 
This safety component will be completed before the initiation of the window trial (Phase II) in the pre-
operative setting. 
 
Phase II Pre-
 
-operative palbociclib plus 
letrozole followed by the addition of hydroxychloroquine (HCQ) for postmenopausal patients with 
Stage I-III estrogen receptor-positive and HER2-negative breast cancer (Figure 2).   
Correlative studies using baseline and follow up breast biopsies and blood work are included in the 
research plan. The Phase II portion will assess the change in the percentage of all patients who 
achieve CCCA when adding HCQ to the palbociclib/letrozole combination. 
 
3.2 TRIAL SCHEMATA 
3.2.1
Trial Overview Schema Design and Flow 
 
Figure 1: General schema for both phases of the trial.  The run-in Phase I safety study done in 
the metastatic setting will establish safety and determine the Phase II dose. The Phase II study will 
assess two doses of HCQ (400 mg in 6 patients and RP2D in 30 patients) added to continuous low 
dose palbociclib plus letrozole and assess proliferative index (Ki67) pre and post HCQ administration. 


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3.2.2 Window Component Schema and Design
 
 
  
FIGURE 2. Schema for pre-
Part 1  dose responsiveness 
evaluation at 400 mg/d HCQ followed by Part 2 at RP2D HCQ using same design and biopsy time 
points (T0 [baseline/pretreatment, T1 [after 2 weeks P+L], T2 [after addition of HCQ]), with option to 
proceed with surgery right after T2 biopsy or up to 24 weeks from initiation of therapy.  P=continuous 
low dose palbociclib at 75 mg daily L=letrozole at 2.5 mg daily; HCQ=hydroxychloroquine continuous 
daily at assigned dose; N=number of patients; U/S=ultrasound; RP2D-recommended Phase II dose 
(of HCQ). 
Design for the Safety Component/Phase I 
A cycle will be defined as 28 days, with dose limiting toxicity (DLT) assessed over the first cycle. 
 
The dose of letrozole and palbociclib will be fixed for the safety cohorts at: 
 Palbociclib: 75 mg capsule taken orally once daily on a continuous basis. 
 Letrozole: 2.5mg/d taken orally once daily continuously. 
 


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Hydroxychloroquine Dose Escalation Scheme 
Dose Level (DL)
Hydroxychloroquine
Letrozole 
Palbociclib 
0 (Starting Dose) 400 mg/d 
2.5 mg daily 
75 mg daily (continuous) 
+1 
600 mg/d 
+2 
800 mg/d 
 
The dose escalation portion will use a 3+3 dose escalation design to evaluate escalating dose levels 
of HCQ in combination with palbociclib and letrozole (see dose level table above). Three patients will 
be enrolled at the first dose level (DL 0, 400 mg daily) of the triplet combination. At least 3 patients 
must complete a treatment cycle (28 days) with the triple combination and undergo toxicity 
assessment before any additional patients are enrolled into higher dosing cohorts. Intrapatient dose 
escalation or change of dosing schedule is not allowed. At least 6 evaluable patients are to be 
treated at a dose level for a RP2D to be declared. 
 
 
If 0 out of 3 patients in a dose level experience a DLT in the defined timeframe another 3 
patients will be enrolled at the next higher dose level. 
 
If no more than 1 patient experienced a DLT at a dose level, then more patients will be added 
to that cohort to increase the cohort up to six patients at the same dose level 
 
If no more than one of the first 6 patients treated experiences a DLT, then 3 patients will be 
enrolled at the next higher dose level. 
 
If two or more of the first 6 patients treated within a cohort experience DLT, then this dose 
level will be considered not tolerated and the dose escalation will be halted. If two DLTs are 
seen in any cohort, no further patients will be enrolled at that level and next level lower will be 
declared the RP2D. 
 
The RP2D is defined as the highest dose level at which 6 patients have been treated with at most 1 
instance of DLT. 
 
If two DLTs are seen at the starting dose of 400 mg (DL 0), then this treatment will be declared to not 
be feasible as doses of HCQ < 400 mg may be too low for the intended effects. 
 
The Principal Investigator will monitor safety throughout the study, review patient data and make 
decisions prior to advancing to the next dose level, approve dose escalation, and will also declare the 
establishment for RP2D and declare when the Phase II part of the study can commence. 
 
3.3 Dose Limiting Toxicity (DLT) Definition 
 
A DLT will be defined as: 
 
Any death not clearly due to the underlying disease or extraneous causes 
 
Any grade 3 or higher non-hematologic toxicity 
 
Liver function abnormalities meeting Hy's law  
 
Neutropenic fever  
 
Grade 4 neutropenia or thrombocytopenia > 7 days 
 
Grade 3 or higher thrombocytopenia with bleeding 


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supportive care 
 
Grade 3 or higher fat
 
 
Grade 3 or higher electrolyte abnormality that lasts >72 hours, unless the patient has clinical 
symptoms, in which case all grade 3 or higher electrolyte abnormality regardless of duration 
should count as a DLT. 
 
All AEs of the specified grades should count as DLTs except those that are clearly and 
incontrovertibly due to disease progression or extraneous causes. 
 
The decision to open the Phase II window part of the trial will be made after RP2D has been 
established.  All Safety Data will be reviewed by the Principal investigator and will be used to 
-adjuvant setting.  
 
3.4 Phase II Component (Window/Neo-adjuvant Cohorts) 
uates the combination of pre-operative palbociclib plus 
letrozole followed by the addition of hydroxychloroquine (HCQ) for postmenopausal patients with 
Stage I-III estrogen receptor-positive and HER2-negative breast cancer (Figure 2).   
 
Correlative studies using baseline and follow up breast biopsies and blood work are included in the 
overall research grant. The Phase II portion will assess the change in the percentage of all patients 
who achieve CCCA when adding HCQ to the palbociclib/letrozole combination. 
 
3.5 Phase II Window/Neo-adjuvant Component  Dose Cohorts (Parts 1 and 2) 
 
To estimate the dose responsiveness of HCQ in the main outcome measures as stated on Section 
2.2.3, two groups will be enrolled at the HCQ levels as shown below: 
 
Dose Level 
Groups
Number of 
patients 
Hydroxychloroquine 
dose 
Letrozole 
dose 
Palbociclib dose 
Part 1
6 
400 mg/d p.o. 
2.5 mg/d p.o. 
 
75 mg capsule p.o. daily  
continuously, 28-day cycle 
Part 2
30 
RP2D 
 
An initial group of 6 patients (part 1) will be enrolled at an HCQ dose of 400 mg daily sequentially, 
and then a second group of 30 patients (part 2) will be enrolled at the HCQ dose defined in the 
Phase I portion as RP2D. The main efficacy endpoint statistical plan is based on the 30 patients 
enrolled in part 2 as described in Section 8.0.   
 
The dose of palbociclib for both parts 1 and 2 is fixed at a dose of 75 mg orally daily continuously 
without a break. Letrozole and palbociclib are given for the first 2 weeks, then after the second biopsy 
(T2), HCQ at the assigned dose will be added. After 4 weeks (2 weeks of HCQ) (T2), the primary 
endpoint will have been obtained with analysis of the surgical specimen (or research biopsy at that 
timepoint if additional neoadjuvant endocrine therapy or chemotherapy is indicated as standard of 
care. Details on dosing and dose adjustments are shown in Sections 6.1.4 and 6.2.3. Using the same 
population, treatment and biopsy schema, 30 patients will be enrolled for the phase II Stage 2 portion 
of the trial. 
 


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3.6 Phase II Patient Evaluability 
Patients who meet the eligibility criteria and complete a full 4 weeks of therapy (14 days of low-dose 
palbociclib plus letrozole and 14 days of dose palbociclib plus letrozole with HCQ) will be considered 
evaluable for Phase II.  In addition, the completion of biopsies at T0, T1 and T2 with interpretability of 
Ki67 are required for evaluability. Baseline Ki67 >5% is required to enhance the interpretability of 
CCCA fraction change from T1 to T2. 
 
3.7   Replacement of Patients 
Patients who are not evaluable for dose-limiting toxicity in the Phase I portion and those not 
evaluable for Ki67 at T0, T1 and T2 in the Phase II portion will be replaced. 
 
3.8 Target Accrual 
A total of 54 patients will be enrolled to the study. This includes 2 to 18 patients (up to 6 per dose 
cohort at 400, 600 and 800 mg of HCQ daily and 6 at the RP2D, but as few as 2 patients in the 
unlikely event that the first 2 patients experience DLT at the lowest dose of HCQ (400 mg daily) and 
the study is halted.) in the Phase I metastatic portion, 6 patients for neo-adjuvant Phase II Part 1 and 
30 patients for the Phase II Part 2 portion (25 needed for statistical plan and 5 expected to drop out). 
This does not account for replaced patients (as stated in Sections 3.6 and 3.7). 
 
4.0   PATIENT SELECTION 
4.1 Inclusion Criteria 
Patient eligibility criteria include all of the following: 
1. Signed written informed consent. 
2. Diagnosis of estrogen positive breast cancer, estrogen receptor-positive and HER2-negative by 
ASCO/CAP criteria1, 2. 
 
3. ECOG performance status 0-1. 
4. Female and age 
18 years and postmenopausal defined by: 
a. Age 
55 years and 1 year or more of amenorrhea. 
b. Age < 55 years and 1 year or more of amenorrhea with LH and/or FSH levels in the 
postmenopausal range. 
c. Age < 55 with prior hysterectomy but intact ovaries with LH and/or FSH levels in the 
postmenopausal range 
d. Chemotherapy or medically induced ovarian suppression with 1 year or more of 
amenorrhea and with LH and/or FSH levels in the postmenopausal range. 
e. Status after bilateral oophorectomy (
28 days prior to first study treatment). 
5. Adequate hematological, renal, hepatic function defined as follows: 
a. ANC 
. 
b. Platelet count 
. 


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c. Serum creatinine concentration < 1.5 x ULN. 
d.
Bilirubin level < 1.5 x ULN.
e. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x ULN or alkaline 
. 
6. Metastatic cohorts (Phase I): Diagnosis of Stage IV estrogen positive breast cancer, estrogen 
receptor-positive and HER2-negative by ASCO/CAP criteria1,2 .  
7. Metastatic cohorts (Phase I): Must be a candidate for treatment with CDK4/6 inhibitor and 
endocrine therapy with an aromatase inhibitor as standard of care. 
8. Metastatic cohorts (Phase I): No prior exposure to CDK 4/6 inhibitors. 
9. Neoadjuvant cohorts (Phase II): Diagnosis of Stage I-III estrogen positive breast cancer, 
estrogen receptor-positive and HER2-negative by ASCO/CAP criteria1, 2. If Stage I, clinical 
t
  
10. Neoadjuvant cohorts (Phase II): Baseline tumor Ki67 > 5%. 
11. Neoadjuvant cohorts (Phase II): Surgical candidate and appropriate for pre-operative endocrine 
therapy. 
 
4.2 Exclusion Criteria 
Patient exclusion criteria include any of the following: 
1. Prior exposure to CDK 4/6 inhibitor therapy 
2. History of retinal disease or active visual disturbances (normal baseline study-specified retinal 
exam required). 
3. Acute illness, including infections requiring medical therapy, known bleeding diathesis or need 
for anticoagulation. 
4. Treatment with any of the following medications within 4 weeks before the baseline diagnostic 
biopsy is taken: 
a. Oral estrogens, including hormone replacement therapy (but prior depot estrogen use not 
allowed). 
b. Investigational agents (or 5 half-lives, whichever is longer). 
5. Required concomitant use of any drug that is a strong CYP3A inhibitor or inducer. 
6. Psychological, familial, sociological or geographical conditions that do not permit compliance 
with the study protocol. 
7. Life expectancy of less than 6 months. 
8. Pregnancy, lactation or planning to be pregnant. 
9. Neo-adjuvant cohorts (Phase II): Prior therapy for breast cancer (medical, surgical or radiation 
therapy) 
10. Neo-adjuvant cohorts (Phase II): Clinical T4 disease. 


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11. Neo-adjuvant cohorts (Phase II): Inoperable or metastatic (Stage IV) breast cancer based on 
standard evaluation. 
 
5.0
STUDY PROCEDURES AND SCHEDULE OF ASSESSMENTS 
 
5.1 Patient Identification 
 
Eligible patients will be referred by members of the MD Anderson Department of Breast 
Medical Oncology or screened through electronic medical records and our Departmental database. 
Process for consent is detailed in Section 9. 
 
5.2 Schedule of Assessments 
Table 1  Study Procedures and Assessments Phase I 
 
Baseline
C1
W1 
C1
W2 
C1
W3 
C1
W4 
C2
W5 
C2
W6 
C2
W7 
C2
W8 
C3 
W1 
C4+ 
W1 
Off 
Study 
Day 
 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D1 
Scheduling 
timeframe
-14d 
+/- 2
+/- 2
+/- 2
+/- 2
+/- 2
+/- 2
+/- 2
+/- 2
+/- 2 
+/- 2 
Within 
30 D
Laboratory
XA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
assessment)  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam/ 
Weight/Vital signs 
XA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
performance 
status evaluation 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmologic 
Exam 
XB 
 
 
 
 
 
 
 
 
 
 
X 
Imaging 
Assessments 
XA 
 
 
 
 
 
 
 
XC 
 
 
Tumor Biopsy 
XC 
 
 
 
 
XC 
 
 
 
 
 
Palbociclib
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCQ  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Letrozole 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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Table 2  Study Procedures and Assessments Phase II 
 
Abbreviations: W=week (week 1 is the same as day 1 prior to starting palbociclib); HCQ = hydroxychloroquine; D = day; W = week
Laboratory assessments: Baseline, then weekly x 8 for Phase I and x 4 for Phase II, then as indicated until off study labs include 
CBC/differential, electrolytes, BUN, creatinine, glucose, albumin, AST, ALT, total bilirubin, alkaline  phosphatase. Baseline only: 
PT, PTT, urinalysis with microscopic exam. Baseline urine or serum pregnancy test for both Phase I and II. 
Superscripts:  
A=  Phase I: Laboratory assessment must be done within 14 days of C1 D1. Any imaging assessments already completed during 
the regular work-up of the patient within 28 days prior to starting study treatment, including before signing the main study ICF can 
be considered as the baseline images for this study; Phase II: done within 2 weeks prior to starting therapy (low dose 
palbociclib/letrozole). 
B= done within 8 weeks prior to starting study medication 
C= Phase I  baseline biopsy can of metastatic tumor pre-treatment or primary lesion (optional) or can be from archival tissue if 
available (either primary or metastasis). Week 5 biopsy (optional) can be +/- 1 week. Phase II  biopsies are mandatory- third 
biopsy done either at W5 for patients going on to surgery at that time, for those waiting until between weeks 20-24, biopsy done 
pre-operatively. Patients who know in advance that they will proceed with surgery at T2 will not need a biopsy and biomarkers will 
be measured on the surgical specimen. Imaging will be done at end of Cycle 2 (Week 8) +/- 1 week (prior to cycle 3 drug), and 
every 8-12 weeks (+/- 2 weeks) thereafter 
D= Phase II 
Sample of surgical specimen (or core needle biopsy if patients is going on to standard of care neoadjuvant 
endocrine or chemotherapy) will be taken for analysis as outlined in Section 5.3. 
 
 
 
Baseline 
W1 
W2 
W3 
W4 
W5 
Off Study 
Day 
 
D1 
D8 
D15 
D22 
D29 
 
Scheduling Window 
-14 D 
+/- 2 
+/- 2 
+/- 2 
+/- 2 
+/- 2 
Within 30 D 
Laboratory 
XA 
X 
X 
X 
X 
X 
X 
Adverse event 
assessment)  
 
X 
X 
X 
X 
X 
X 
Physical Exam/ 
Weight/Vital Signs 
XA 
X 
X 
X 
X 
X 
X 
ECOG performance 
status evaluation 
X 
X 
X 
X 
X 
X 
X 
Ophthalmologic 
Exam 
XB 
 
 
 
 
 
X 
Breast ultrasound 
XA 
 
 
 
 
X 
 
Research blood 
XA 
 
 
X 
 
X 
X 
Biopsy (or surgery) 
XA 
 
 
X 
 
XD 
 
Low dose 
palbociclib + 
letrozole 
 
X 
X 
X 
X 
 
 
HCQ 
 
 
 
X 
X 
 
 


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5.2.1
Baseline Assessments  
All patients will undergo a baseline standard evaluation for newly diagnosed breast cancer 
including (note that some baseline tests can be done prior to day 1 (week 1) as shown on Tables 
1 and 2):  
 
Review of systems all organ systems will be examined. 
 
Physical examination, vital signs, weight, height, and evaluation of ECOG performance 
status.   
 
Standard of care pathological diagnosis of breast cancer, imaging (Phase II: breast 
ultrasound; Phase II: CT, MRI) and clinical staging.   
 
Laboratory studies: CBC/differential, electrolytes, BUN, creatinine, glucose, albumin, AST, 
ALT, Total Bilirubin, Alkaline phosphatase, PT, PTT. 
 
Urinalysis 
 
Ophthalmological exam per latest guidelines of the American Academy of Ophthalmology 
(AAO) for baseline screening with HCQ treatment. 
 
Fresh Tumor Biopsy (Phase II only). 
 
Research blood draw (Phase II only). 
 
Baseline urine or serum pregnancy test for both Phase I and II. 
 
ECOG performance status 
Grade ECOG 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 housework, 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 
 
5.2.2 Evaluation During Study Phase II 
 
Patients will be evaluated with an organ-specific review of systems and physical exam at 
weeks 2, 3, 4, and those 
(as 
described in Sections 1.3, 3.2.2 and 5.2-Table 2) and stay on study until definitive surgery at 
week 16 to 24 will undergo additional evaluation at weeks 6, 8 and every 4 weeks thereafter 
until the last pre-operative visit between week 16 and 24 at the discretion of the medical and 
surgical oncologist as shown on Table 2.  
 
 
5.2.3 Treatment Duration 
 
5.2.3.1 Phase I 
Patients will receive treatment for at least until week 8 as long as there are no DLTs in the 
first 4 weeks, or significant toxicities requiring treatment discontinuation in the judgment of the 
treating investigator, and no evidence of clinical progression.  At week 8, if tumor assessment 
by scans show evidence or response by RECIST 1.1 criteria (applies only to patients with 


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measurable disease), they will be allowed to stay on treatment as long as there is no 
evidence of progression or significant toxicities up to a maximum of 1 year.  This maximum 
timeframe is due to concerns about HCQ toxicity, which could be duration-dependent.  
Patients who show progression or stability of disease at week 8 will come off study and can 
continue standard treatment (standard dose palbociclib and letrozole) or alternate therapy at 
the discretion of the treating physician. 
 
5.2.3.2 Phase II 
Following the study schema (Figure 2) patients are expected to complete 28 days of study 
treatment followed by surgery 
, with an off study visit after surgery, and 
will be monitored for adverse events up to 30 days after the last dose of study drug.  
 
Patients whose tumors at T1 biopsy show Ki67 > 10% will be required to come off study and 
per standard of care would typically be recommended to proceed to definitive surgery or 
standard neoadjuvant chemotherapy.  All other patients will continue on study therapy and at 
T2 (week 5, or day 29), will proceed with definitive surgery or undergo a research biopsy and 
continue with standard of care neoadjuvant endocrine therapy or chemotherapy as clinically 
indicated. 
 
5.2.4 End of treatment visit and Follow up assessments  
Patients who discontinue study treatment, will be followed for 30 days after stopping the study 
drugs for assessment of safety (i.e., assessment of AEs and/or serious AEs [SAEs] and 
concomitant medications) and resolution of any treatment related toxicity. Patients continuing 
to experience toxicity at this point following discontinuation of treatment will continue to be 
followed at least every 4 weeks until resolution or determination, in the clinical judgment of the 
investigator, that no further improvement is expected. 
 
5.2.5 Early discontinuation 
Patients who come off trial early will be asked to return for the off-study assessments as 
detailed in Tables 1 and 2. In the event of a continuing AE, the patient will be asked to return 
for follow-up until resolution or stabilization of the AE. 
 
5.2.6 Review of Systems and Physical Exam 
A full review of systems that covers all of the domains and systems represented in CTCAE  
V 4.03 toxicity criteria will be performed at screening/baseline. Subsequent physical exams 
may be limited and should be focused on sites of disease to explore clinical signs and 
symptoms. 
 
5.2.7 Laboratory Assessments 
CBC/differential, electrolytes, BUN, creatinine, glucose, albumin, AST, ALT, total bilirubin, 
alkaline phosphatase, PT, PTT, and Urinalysis. 
5.2.8 Imaging assessments Phase I 
Tumor response will be assessed according to RECIST Version 1.1 using standard contrast-
enhanced computed tomographic scanning of the chest, abdomen and pelvis. In the case of 
iodine contrast allergy or reaction, either non-contrast-enhanced or MRI scanning can be 
performed. Patients should have at least one documented measurable lesion (per RECIST 
v1.1) or in the absence of measurable disease, have at least one lytic or mixed (blastic/lytic) 
bone lesion at study entry. 


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Imaging assessments will be performed at screening within 28 days prior to first dose of study 
treatment, at 8 weeks (+/- 1 week) from day one of study treatment and subsequently every 
8-12 weeks (+/- 2 weeks) thereafter.
Tumor response should be assessed using the same imaging method throughout the study. 
 
5.2.9 Imaging assessments Phase II 
Methods for ultrasound evaluation and volumetric measure of response  
Grayscale and power Doppler ultrasound will be performed on the breast and regional nodal 
basins using a Philips iU22 system or Sonoline Antares systems equipped with a 5- to 13-
MHz broadband linear transducer. Ultrasound images of the index tumors and index nodes 
will be captured in the longitudinal and transverse planes with three dimensions measured. 
The size of the index tumors and index nodes will be reported in three dimensions to allow for 
volumetric calculation. The percent change in volume will then be calculated and reported to 
determine response. 
 
 
5.3 Correlative Biomarker Studies 
 
5.3.1 Biopsies, Tissue Handling and Analysis 
All biopsies on Phase I are optional and will be done with appropriate image guidance.  
Biopsies for Phase II are mandatory and will be done under ultrasound guidance by a 
member of the research team using standard of care imaging-guided biopsy.  Local 
anesthesia and hemostasis protocols will be used as per standard protocol.  Core needles of 
18 of 16G size will be used and 3-4 core biopsies will be obtained. The first core will be 
placed in standard 10% formalin, and all other cores will be placed in a cryovial and snap 
frozen in liquid nitrogen. 
All of the correlative studies (unless otherwise indicated) will be performed in the laboratory of 
Dr. Khandan Keyomarsi located in the Zayed building at 6565 MD Anderson Blvd, Houston, 
Texas, 77030.  For all the correlative analysis we will use tumor tissues collected from the 
biopsies and at surgical resections.  
Cyclin E, and Rb immunohistochemistry (IHC) assays.   FFPE tumor tissue slides will be 
prepared from paraffin imbedded blocks per standard methodologies and subjected to IHC 
analysis with 2 different antibodies: cyclin E and Rb:  
Cyclin E: the anti-human C-19 polyclonal antibody (Santa Cruz Biologicals) at 1:2000 dilution 
will be used to stain each slide. Each slide will be scored for percent nuclear and percent 
cytoplasmic positive staining. Only tumor cells with greater than 5% nuclear or cytoplasmic 
positivity are considered as cyclin E positive. Nuclear and cytoplasmic staining scores are 
assigned according to the staining intensity (0 = no staining, 1 = blush staining, 2 = weak 
staining, 3 = intermediate staining and 4= strong staining). The nuclear and cytoplasmic 
scores are then combined, and four immunophenotypes are identified. First, breast tumors 
will be considered to be negative for cyclin E when staining is not detected in the nuclei or 
cytoplasm (phenotype 1). Second, in cases determined to be cyclin E+, if the nuclear staining 
score exceeded the cytoplasmic score, cyclin E expression is defined as predominantly 
nuclear (phenotype 2). Third, when the nuclear and cytoplasmic staining scores are equal, 


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cyclin E expression is considered to be both nuclear and cytoplasmic (phenotype 3). Fourth, if 
the cytoplasmic staining score is higher than the nuclear score, cyclin E expression is 
considered to be predominantly cytoplasmic (phenotype 4).  
Rb: The anti-human Clone 4H1 mouse monoclonal antibody (Cell Signaling Technology, 
Denvers, MA) at 1:100 dilution will be used to stain each slide. Each slide will be scored 
separately for intensity of staining and percentage of positive cells. Staining intensity will be 
scored as follows: 0, no staining; 1, weak positive (faint yellow staining); 2, intermediate 
positive; and 3, strong positive (brown staining). The number of positive cells will visually be 
evaluated and stratified as follows: <1%, 0 (negative); 1 to <5% positive cells, 1 (weak); 5-
50% positive cells, 2 (moderate); >50% positive cells, 3 (strong). The sum of the staining 
intensity and percentage of positive cell scores will be used to determine the staining index for 
each section, with a minimum score of 0 and maximum score of 6; scores  >1 will be defined 
as Rb positivity.  
 
5.3.2 Whole Blood/Plasma Biospecimens 
Blood specimens (Phase II only) will be collected as shown on Table 2 at baseline, days 15 
and 29 
be collected on days 43, 57 and every 4 weeks thereafter until surgery. Each blood draw will 
be to collect three tubes  one for plasma (8 mL CPT top) and the other for serum (6 mLred 
top) and one for whole blood (6 mLlavender).  Blood will be processed immediately following 
collections  tubes will be gently inverted and kept at room temperature prior to centrifuging, 
and clotted tube (red top) will have serum aspirated, while the green top tube will have 
plasma aspirated  both being aliquoted in 0.5 mL cryovials and placed in a -20 C freezer 
(and stored long term at -80 C). A laboratory protocol contains additional details. 
 
5.3.3 Ki67 Tumor Assay and Scoring 
CLIA-approved Ki67 staining will be performed using anti-Ki67 rabbit monoclonal antibody 
(
clone MIB-1, DAKO) in the diagnostic Immunohistochemistry Laboratory of 
Department of Pathology using an established protocol. Briefly this protocol includes de-
paraffinization (30 minutes at 72°C)and rehydration with antigen retrieval performed at 100°C 
for 20 minutes with Tris-EDTA buffer, pH 6.0.   
Endogenous peroxidase is blocked with 3% peroxide for 5 minutes. Primary anti-Ki-67 
antibody (Dako, clone MIB-1) is applied at 1:100 dilution for 15 minutes. Post primary 
antibody detection is carried out using a commercial polymer system (Bond Polymer Refine 
Detection, Leica), and stain development is achieved by incubation with DAB and DAB 
Enhancer (Leica).   
 
Ki67 staining will be evaluated in whole tissue sections without focusing on the hot spots. The 
staining will be quantitatively assessed by automated image analysis using the Aperio 
ScanScope AT2 scanner (Leica Biosystems, Inc., 1700 Leider Lane, Buffalo Grove IL, 
60089).  All Ki67 immunostained slides will be scanned at 20 X magnification.  As Ki67 is a 
nuclear stain, the Genie nuclear v9.1 algorithm will be used to create a custom-made 
classifier.  A color graphic phase of image analysis is afterward performed using red, orange, 
and yellow  (high, medium, and low reaction, respectively) to represent positive cells, and 
blue to represent negative ones.  A curvature threshold adjustment is made to de-cluster or 


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break up large groups of closely apposed nuclei when needed. The original factory algorithm 
is also adjusted to avoid false positives by lowering the Cytoplasmic Intensity settings. All 
algorithm adjustments are tested to assure accurate detection of positive and negative 
nuclei.
 
5.4 Banked Biospecimens 
Leftover blood and tumor samples which are not consumed for planned study testing will be retained 
for potential additional testing at a later date (i.e. if newer technologies become available) under the 
same objectives. Samples will be retained at a secure storage facility (in the laboratory of Dr. 
Keyomarsi located in the Zayed building at 6565 MD Anderson Blvd, Houston, Texas, 77030) in case 
there is need for retesting or additional testing. Samples will be stored for up to 10 years or until 
termination of this study. These may be used for future studies only as approved by the MD 
Anderson IRB and the Principal Investigator. 
 
 
6.0
.INVESTIGATIONAL AND NON  INVESTIGATIONAL AGENTS 
6.1 Palbociclib 
 
6.1.1 Description of palbociclib 
Palbociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6, which are downstream of 
signaling pathways that lead to cellular proliferation. In vitro, palbociclib reduces cellular 
proliferation of ER-positive breast cancer cell lines by blocking progression of the cell from G1 
into S phase of the cell cycle. Treatment of breast cancer cell lines with the combination of 
palbociclib and endocrine therapies leads to decreased retinoblastoma protein (Rb) 
phosphorylation resulting in reduced E2F expression and signaling, and increased growth 
arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast 
cancer cell lines with the combination of palbociclib and antiestrogens leads to increased cell 
senescence, which was sustained for up to 6 days following drug removal. In vivo studies 
using a patient-derived ER-positive breast cancer xenograft model demonstrated that the 
combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, 
downstream signaling and tumor growth compared to each drug alone (Pfizer Pharma United 
States product insert (USPI), (2015). Highlights of Prescribing Information; IBRANCE® 
(palbociclib) for oral use. New York: Pfizer, Inc.  details are contained in the package insert
in Appendix A). 
Complete information for palbociclib may be found in the single reference safety document 
(SRSD), which for this study is the Pfizer Investigator Brochure for Palbociclib (PD-0332991). 
 
6.1.2 Source of palbociclib 
Palbociclib will be provided by Pfizer Inc. Palbociclib commercial supply will be supplied as 75 
mg capsules in High Density Polyethylene (HDPE) bottles, labeled according to 
investigational pharmacy procedures. 
 
6.1.3 Preparation and dispensing 
Qualified site personnel will provide adequate palbociclib supplies for patient to take home 
until next scheduled visit. 
Patients will receive a drug diary to document dosing. The completed diary must be returned 


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to the site at the next study visit. 
6.1.4 Dosing of palbociclib and dose adjustments for palbociclib (holding, discontinuation)
Patients should be instructed to swallow palbociclib capsules whole and not to manipulate or 
chew them prior to swallowing. No capsule should be ingested if it is broken, cracked, or 
otherwise not intact. Patients should be encouraged to take their dose at approximately the 
same time each day. Patients should be instructed to record daily administration in the patient 
diary. 
Patients should take palbociclib with food.  
 
day. 
 
and to resume treatment the next day as prescribed. 
 
Patients who inadvertently take 1 extra dose during a day must be instructed to skip the 
 
 
Dose adjustments and patient discontinuation criteria are as follows: 
 
 
Palbociclib will be held for grade 3 or 4 neutropenia, and CBC/diff will be checked in one 
week intervals, with treatment resumed at the same dose when neutropenia has 
the dose will be lowered to 75 mg by mouth twice a week. 
 
Once palbociclib dose has been lowered, it will not be re-escalated. If criteria for another 
dose reduction are met, the patient must be permanently discontinued 
 
discontinuation 
 
For 
-hematologic toxicity attributed to palbociclib, palbociclib will be held 
until the toxicity in question resolves to 
the patient. 
 
Any patient with liver 
permanently discontinued 
 
6.2 Hydroxychloroquine 
 
6.2.1 Description of hydroxychloroquine (HCQ): 
Hydroxychloroquine (HCQ) is a small molecule drug that is indicated for the suppressive 
treatment and treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. 
ovale, and susceptible strains of P. falciparum. It is also indicated for the treatment of discoid 
and systemic lupus erythematosus, and rheumatoid arthritis, and often used for overlap 
connective tissue disorders. Although the exact mechanism of action is unknown, it may be 
based on ability of HCQ to bind to and alter DNA. HCQ has also has been found to be taken 
up into the acidic food vacuoles of the parasite in the erythrocyte. This increases the pH of the 
acid vesicles, interfering with vesicle functions and possibly inhibiting phospholipid 


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metabolism. In suppressive treatment, HCQ inhibits the erythrocytic stage of development of 
plasmodia. In acute attacks of malaria, it interrupts erythrocytic schizogony of the parasite. Its 
ability to concentrate in parasitized erythrocytes may account for their selective toxicity 
against the erythrocytic stages of plasmodia infection. As an anti-rheumatic, HCQ is thought 
to act as a mild immunosuppressant, inhibiting the production of rheumatoid factor and acute 
phase reactants. It also accumulates in white blood cells, stabilizing lysosomal membranes 
and inhibiting the activity of many enzymes, including collagenase and the proteases that 
cause cartilage breakdown.  
 
HCQ is also known to inhibit autophagy, a cellular process that may also lead to resistance to 
several cancer drugs, and as such, several trials have been conducted and shown safety of 
HCQ combined with several antineoplastic agents.34-37 However, no trials have tested HCQ in 
this setting and with the rationale and drug combination proposed in this trial. Additional detail 
is provided in the package insert in Appendix B. 
 
6.2.2 Source and dispensing of hydroxychloroquine 
Generic HCQ as 200 mg tablets will be obtained from a commercial source, Quality 
Prescription Drugs (Suite #245, 7360 137th Street, Surrey, and B.C. V3W), a Canada-based 
company that uses U.S. sources that is both CIPA certified and Pharmacy Checker approved. 
The drug will be ordered for direct delivery to the Investigational Pharmacy at MD Anderson in 
batches to maintain at least a 3 months of supply on hand and will be dispensed as an 
investigational drug with standard logging of drug acquisition, dispensation and final 
accounting for disposition.  Unused or returned drug will be destroyed. Drug will be dispensed 
to patients with the name and dosage drug, date dispensed, name of patients, name of study 
and instructions for use. 
 
 
 
6.2.3 Dosing of hydroxychloroquine and dose adjustments for hydroxychloroquine  
HCQ will be given by mouth at the assigned dose for the Phase I dose escalation and Phase II 
fixed dose parts of the trial The dose of 400 mg daily was chosen as the starting dose for the 
Phase I portion as this is the usual dose used clinically and has been combined with 
endocrine and other and cancer therapies at this does in prior studies.P34-37P There will be no 
dose adjustments for HCQ, and any grade 3 toxicity that is attributed to HCQ will require 
discontinuation of drug and for the patient to come off study. Subsequent treatment will be as 
per standard of care. For patients on the Phase I portion, any Grade III toxicity attributed to 
HCQ will also be counted as a dose-limiting toxicity if occurring in the first 28 days. 
 
 
6.3 Letrozole 
Letrozole at the standard approved dose of 2.5 mg by mouth daily continuous dosing will be 
prescribed as standard of care for neoadjuvant endocrine 
trozole.  If the patient is felt to 
be having unacceptable toxicities due to letrozole, then treatment will be stopped and the patient will 
come off study.  Subsequent treatment will be as per standard of care. Additional details are provided 
in the package insert in Appendix C. 
 


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6.4 Concomitant Medications
In general, the use of any concomitant medication or therapies deemed necessary for the care of the 
patient is permitted with the exception of strong CYP3A inhibitors or inducers.  
7.0 ADVERSE EVENT MONITORING AND REPORTING
7.1 Definition of an Adverse Event
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal laboratory values 
or test results constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy.
7.2 Serious Adverse Event (SAE) Reporting
view of either the 
investigator or the sponsor, it results in any of the following outcomes:
Death
A life-threatening adverse drug experience 
any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death.
Inpatient hospitalization or prolongation of existing hospitalization
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions.
A congenital anomaly/birth defect.
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse drug experience when, based upon appropriate medical judgment, 


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they may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the Principal 
Investigator or the IND Sponsor, IND Office. 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
Texas M. D. Anderson Cancer Center Institutional Review Board Policy for Investigators on Reporting 
Serious Unanticipated Adverse Events for Drug
protocol, all SAEs, expected or unexpected, must be reported to the IND Office, regardless of 
attribution (within 5 working days of knowledge of the event). 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have a 
written report submitted within 24 hours (next working day) of knowledge of the event to the Safety 
Project Manager in the IND Office.   
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety reporting to the 
IND Office and MDACC IRB.  
Serious adverse events will be captured from the time of the first protocol-specific intervention, until 30 
days after the last dose of drug, unless the participant withdraws consent. Serious adverse events must 
be followed until clinical recovery is complete and laboratory tests have returned to baseline, 
progression of the event has stabilized, or there has been acceptable resolution of the event. 
Additionally, any serious adverse events that occur after the 30 day time period that are related to the 
study treatment must be reported to the IND Office. This may include the development of a secondary 
malignancy. 
Reporting to FDA: 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager IND 
Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
 
 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after informed consent is 
obtained and starting protocol intervention and ends 30 days following the last administration of study 
treatment or study discontinuation/termination, whichever is earlier.  
 


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After this period, only SAEs that are attributed to prior study treatment will be reported. All AEs, 
regardless of attribution, will be collected during Phase I and II studies for at least 30 days after last 
dose of the study drugs. 
7.3 Recording of Adverse Events 
 
Medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered a serious adverse drug experience when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32).  
 
Important medical events as defined above, may also be considered serious adverse events.  
 
Any important medical event can and should be reported as an SAE if deemed appropriate by 
the Principal Investigator. All events occurring during the conduct of a protocol and meeting 
the definition of a SAE must be reported to the IRB in accordance with the timeframes and 
procedures o
Review Board Policy for Investigators on Reporting Serious Unanticipated Adverse Events for 
unexpected, must be reported to the IND Office, regardless of attribution (within 5 working 
days of knowledge of the event).  
Serious adverse events will be captured in the RedCap electronic system from the time of the first 
protocol specific intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. It is the responsibility of the PI and the research 
team to ensure serious adverse events are reported according to the Code of Federal 
Regulations, 
Institutional Review Board policy. 
This study will be performed in compliance with the principles of International Conference on 
Harmonization (ICH) Good Clinical Practices (GCP) Guideline. 
 
7.4 Assessment of Adverse Events 
 
The PI or designee will be responsible for assigning attribution of adverse events to the study agent.  
As far as possible, each adverse event should be evaluated using CTCAE V 4.03 criteria to 
determine: 
 The severity grade (mild, moderate, severe) or grade (1-4). 
 Its relationship to the study drug(s) (suspected/not suspected). 
 Its duration (start and end dates or if continuing at the final exam). 
 Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; study drug 
permanently discontinued due to this adverse event; concomitant medications taken; non-drug 
therapy given; hospitalization/prolonged hospitalization. 
 Whether it constitutes a serious adverse events (SAE). 


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All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be 
reported appropriately.   
Expected AEs are those AEs that are listed or characterized in the Package Insert (PI) or current 
 
includes AEs for which the specificity or severity is not consistent with the description in the PI or 
. 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for subjects 
enrolled. 
7.5 Communications between the Investigator and Supporting Company Pfizer 
 
SAEs that occur after completion of the reporting time period as defined above are reportable to 
Pfizer if the Investigator suspects a causal relationship between the Pfizer product and the SAE. Of 
note, Pfizer is supporting the study only with provision of palbociclib. 
 
-866-997-8322 (See 
Appendix G in PDOL for Pfizer Reportable Events Fax Form). 
 
8.0  STATISTICAL CONSIDERATIONS 
 
Phase I: 
For the phase I portion, a 3+3 design will be used with 3 to 6 patients for each dose escalation cohort 
(depending on whether a DLT is seen) and 6 patients in the final (RP2D) cohort to assess the 
primary endpoint of safety and the determination of RP2D.38 Therefore a minimum of 12 and 
maximum of 18 patients will be enrolled.  This total does not include patients who may need to be 
replaced if not evaluable for DLT (see Section 3.3). 
 
Phase II: 
The Phase II portion will be performed in a different population of patients (early stage) in the pre-
operative setting.  In order to obtain qualitative information about the dose responsiveness of HCQ 
when added to letrozole and palbociclib, Part 1 of the Phase II portion will enroll 6 patients at an HCQ 
dose of 400 mg (if in fact, the RP2D is 600 or 800 mg).  Following this, Part 2 will be conducted at the 
RP2D for HCQ based on the primary endpoint of proportion of patients achieving tumoral CCCA, with 
the formal statistical plan using a 2-stage Simon optimal design and looking to increase the CCCA 
rate from 50% with low dose palbociclib + letrozole to 75% after the addition of HCQ. This design 
requires 11 patients in the first stage and 14 patients in the 2nd stage. It would stop after the 1st 
stage if no more than 6 patients show CCCA by tumor biopsy after HCQ treatment and declared the 
treatment as promising if at least 17 out of 25 total evaluable patients exhibit CCCA.  
 


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This design has alpha = 4%, 81% power, and a probability of 0.73 of terminating after the 1st stage if 
the true CCCA rate=50%.  For the group of patients at the RP2D, we therefore plan a sample size of 
30 patients over 12-15 months, accounting for patient dropout (including those with Ki67 >10% at 
T1). We have a large eligible patient population and have led national accruals in other multi-center 
neoadjuvant endocrine trials in post-menopausal women (e.g. ALTERNATE Trial). In addition, recent 
local experience of conducting window of opportunity trials in this setting have demonstrated the 
feasibility of accrual at a rate of ~2 patients per month. Thus, we expect to achieve accrual goals. 
 
8.1  IND Office Reporting 
 
The Investigator is responsible for completing toxicity/efficacy summary reports and submitting them 
to the IND office 
Medical Affairs and Safety Group for review.  These should be submitted as follows:  
 
 
Phase I: 
After the first 3 evaluable patients, complete 1 cycle of study treatment, and every 3 evaluable 
patients thereafter, IND Office approval must be obtained prior to advancing/changing dose levels. 
 
 
Phase II: 
After the first 6 evaluable patients complete 4 weeks of study treatment, and every 6 patients 
thereafter. 
 
A copy of the cohort summ
 
 
 
9.0  INSTITUTIONAL REVIEW, CONSENT, MEDICAL MONITORING AND RECORD-
KEEPING AND SAFETY MONITORING 
 
9.1 Informed Consent 
 
The informed consent documents must be 
representative before his or her participation in the study.  The case history for each subject shall 
document that informed consent was obtained prior to participation in the study.  A copy of the 
informed consent document must be provided to the subject or the subject's legally authorized 
representative.  If applicable, it will be provided in a certified translation of the local language. 
 
file and must be available for verification 
by study monitors at any time. 
 
 
 


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9.2 Institutional Review Board Approval 
 
This protocol, the informed consent document, and relevant supporting information must be 
submitted to the IRB for review and must be approved before the study is initiated.  The study will be 
conducted in accordance with FDA, applicable national and local health authorities, and IRB 
requirements. 
 
The Principal Investigator is responsible for keeping the IRB apprised of the progress of the study 
and of any changes made to the protocol as deemed appropriate, but in any case, the IRB must be 
updated at least once a year.  The Principal Investigator must also keep the IRB informed of any 
significant AEs. 
 
Investigators are required to promptly notify their respective IRB of all adverse drug reactions that are 
both serious and unexpected.  This generally refers to SAEs that are not already identified in the 
ule or study 
drug by the investigator.  Some IRBs may have other specific AE requirements to which investigators 
are expected to adhere.  Investigators must immediately forward to their IRB any written safety report 
or update provided by Pfizer (e.g., IND 
and updates, etc.). 
 
9.3 Confidentiality 
 
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the ICF (or separate authorization to use and disclose personal health 
information) signed by the patient or unless permitted or required by law. Medical information may be 
for treatment purposes. Data generated by this study must be available for 
inspection upon request by representatives of the FDA and other regulatory agencies as applicable.
 
9.4  Study Medical Monitoring Requirements 
 
This clinical research study will be monitored internally (by the PI) and externally (by the MDACC 
IRB).  In terms of internal review, the PI will continuously monitor and tabulate AEs.  Appropriate 
reporting to the MDACC IRB will be made.  The PI of this study will also continuously monitor the 
conduct, data, and safety of this study to ensure that: 
 
Interim and safety analyses occur as scheduled, 
 
Stopping rules for toxicity and/or response are met, 
 
Risk/benefit ratio is not altered to the detriment of the subjects, 
 
Appropriate internal monitoring of AEs and outcomes is done, 
 
Over-accrual does not occur, 
 
Under-accrual is addressed with appropriate amendments or actions, and 
 
Data are being appropriately collected in a reasonably timely manner. 
 
Routine monitoring will be carried out via a periodic team conference among investigators during 
which toxicity data, including all SAEs, will be reviewed and other issues relevant to the study such 
as interim assessment of accrual, outcome, and compliance with study guidelines, will be discussed.  


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Monitoring will be carried out on an ongoing basis.  The severity, relatedness, and whether or not the 
event is expected will be reviewed. Data will be housed and analyzed on a Redcap database using 
our institutional and Departmental protocols for data entry and verification. 
9.5  Data Collection 
 
The study coordinator and investigators are responsible for ensuring that the eligibility checklist 
is completed in a legible and timely manner for every patient enrolled in the study, and that data are 
recorded on the appropriate forms and in a timely manner.  Any errors on source data should be 
lined through, but not obliterated, with the correction inserted, initialed, and dated by the study 
coordinator or PI.  All source documents will be available for inspection by the FDA and the MD 
Anderson IRB. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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28. Jones RL, Salter J, A'Hern R, et al. The prognostic significance of Ki67 before and after 
neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. 116:53-68, 2009. 
29. Polychronis A, Sinnett HD, Hadjiminas D, et al. Preoperative gefitinib versus gefitinib and 
anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-
factor-receptor positive primary breast cancer: a double-blind placebo-controlled phase II 
randomized trial. Lancet Oncol. 6:383-91, 2005. 
30. Baselga J, Semiglazov V, van Dam, et al. Phase II randomized study of neoadjuvant everolimus 
plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive 
breast cancer. J Clin Oncol. 27:2630-7, 2009. 
31. Smith IE, Walsh G, Skene A, et al. A phase II placebo-controlled trial of neoadjuvant anastrozole 
alone or with gefitinib in early breast cancer. J Clin Oncol. 25:3816-22, 2007. 
32. Marmor MF, Kellner U, Lai TY, et al. Recommendations on screening for chloroquine and 
hydroxychloroquine retinopathy (2016 Revision). Ophthalmology. 123:1386-94, 2016 
33. Pfizer Pharma. (2015). Highlights of prescribing information. IBRANCE (palbociclib). Retrieved 
from: http://www.Accessdata.fda.gov/drugsatfda_docs/label/2015/207103s000lbl.pdf. Accessed
November 16, 2015 


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34. Mahalingam D, Mita M, Sarantopoulos J, et al. Combined autophagy and HDAC inhibition: a 
phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of 
hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced 
solid tumors. Autophagy. 10:1403-14, 2014.
35. Rangwala R, Chang YC, Hu J, et al. Combined MTOR and autophagy inhibition: phase I trial of 
hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma. 
Autophagy. 10:1391-1402, 2014.  
36. Rangwala R, Leone R, Chang YC, et al. Phase I trial of hydroxychloroquine with dose-intense 
temozolomide in patients with advanced solid tumors and melanoma. Autophagy. 10:1369-79, 
2014. 
37. Rosenfeld MR, Ye X, Supko JG, et al. A phase I/II trial of hydroxychloroquine in conjunction with 
radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed 
glioblastoma multiform. Autophagy. 10:1359-68, 2014. 
38. Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in Phase I cancer clinical trials. J Natl 
Cancer Inst. 101:708-20, 2009. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX A - Palbociclib (Ibrance) Highlights of Prescribing Information 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use IBRANCE safely and 
effectively. See full prescribing information for IBRANCE. 
 
IBRANCE® (palbociclib) capsules, for oral use Initial U.S. Approval: 2015 
 
--------------------------- RECENT MAJOR CHANGES -------------------------- 
Indications and Usage (1) 03/2017 
Dosage and Administration (2.1, 2.2) 03/2017 
Warnings and Precautions (5.1, 5.2) 03/2017 Warnings and Precautions, Pulmonary Embolism (5) 
Removed 03/2017 
 
--------------------------- INDICATIONS AND USAGE--------------------------- 
IBRANCE is a kinase inhibitor indicated for the treatment of hormone receptor (HR)-positive, human 
epidermal growth factor receptor 2 
(HER2)-negative advanced or metastatic breast cancer in combination with: 
 
an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or 
 
fulvestrant in women with disease progression following endocrine therapy. (1) 
 
-----------------------DOSAGE AND ADMINISTRATION ---------------------- 
IBRANCE capsules are taken orally with food in combination with an aromatase inhibitor or 
fulvestrant. (2) 
 
Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 
days off treatment. (2.1) 
 
Dosing interruption and/or dose reductions are recommended based on individual safety and 
tolerability. (2.2) 
 
--------------------- DOSAGE FORMS AND STRENGTHS--------------------- 
Capsules: 125 mg, 100 mg, and 75 mg. (3) 
 
------------------------------ CONTRAINDICATIONS ----------------------------- 
None. (4) 
 


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----------------------- WARNINGS AND PRECAUTIONS ---------------------- 
Neutropenia: Monitor complete blood count prior to start of IBRANCE therapy and at the 
beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. 
(2.2, 5.1) 
 
Embryo-Fetal Toxicity: IBRANCE can cause fetal harm. Advise patients of potential risk to a 
fetus and to use effective contraception. (5.2, 8.1, 8.3) 
 
------------------------------ ADVERSE REACTIONS ----------------------------- 
ropenia, infections, leukopenia, fatigue, 
nausea, stomatitis, anemia, alopecia, diarrhea, thrombocytopenia, rash, vomiting, decreased 
appetite, asthenia, and 
pyrexia. (6) 
 
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 
1-800-FDA-1088 or www.fda.gov/medwatch. 
 
------------------------------ DRUG INTERACTIONS------------------------------ 
 
CYP3A Inhibitors: Avoid concurrent use of IBRANCE with strong CYP3A inhibitors. If the 
strong inhibitor cannot be avoided, reduce the IBRANCE dose. (2.2, 7.1) 
 
CYP3A Inducers: Avoid concurrent use of IBRANCE with strong CYP3A inducers. (7.2) 
 
CYP3A Substrates: The dose of sensitive CYP3A4 substrates with narrow therapeutic indices 
may need to be reduced when given concurrently with IBRANCE. (7.3) 
 
----------------------------USE IN SPECIFIC POPULATIONS------------------ 
 
Lactation: Advise not to breastfeed. (8.2) 
 
See 17 for PATIENT COUNSELING INFORMATION and 
FDA-approved patient labeling. 
 
Revised: 03/312017 
 
 
 
 
 
 


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FULL PRESCRIBING INFORMATION: CONTENTS* 
1. INDICATIONS AND USAGE 
2. DOSAGE AND ADMINISTRATION 
1. Recommended Dose and Schedule 
2. Dose Modification 
3. DOSAGE FORMS AND STRENGTHS 
4. CONTRAINDICATIONS 
5. WARNINGS AND PRECAUTIONS 
1. Neutropenia 
2. Embryo-Fetal Toxicity 
6. ADVERSE REACTIONS 
1. Clinical Studies Experience 
7. DRUG INTERACTIONS 
1. Agents That May Increase Palbociclib Plasma Concentrations 
2. Agents That May Decrease Palbociclib Plasma Concentrations 
3. Drugs That May Have Their Plasma Concentrations Altered by Palbociclib 
8. USE IN SPECIFIC POPULATIONS 
1. Pregnancy 
2. Lactation 
3. Females and Males of Reproductive Potential 
4. Pediatric Use 
5. Geriatric Use 
6. Hepatic Impairment 
7. Renal Impairment 
1. OVERDOSAGE 
2. DESCRIPTION 
3. CLINICAL PHARMACOLOGY 
1. Mechanism of Action 
2. Pharmacodynamics 
3. Pharmacokinetics 
4. NONCLINICAL TOXICOLOGY 
1. Carcinogenesis, Mutagenesis, Impairment of Fertility 


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5.
CLINICAL STUDIES
1.
HOW SUPPLIED/STORAGE AND HANDLING
2.
PATIENT COUNSELING INFORMATION
o
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
1. INDICATIONS AND USAGE
IBRANCE is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic 
breast cancer in combination with:
an aromatase inhibitor as initial endocrine based therapy in 
postmenopausal women; or
fulvestrant in women with disease progression following endocrine 
therapy.
2.
DOSAGE AND ADMINISTRATION
1.
Recommended Dose and Schedule
The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive 
days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be 
taken with food [see Clinical Pharmacology (12.3)].
administer the recommended dose of an aromatase inhibitor when given with IBRANCE. Please refer 
to the Full Prescribing Information for the aromatase inhibitor being used.
When given with IBRANCE, the recommended dose of fulvestrant is 500 mg administered on Days 1, 
15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant.
Patients should be encouraged to take their dose of IBRANCE at approximately the same time each 
day.
If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed 
dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not 
chew, crush, or open them prior to swallowing). Capsules should not be ingested if they are broken, 
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Pre/perimenopausal women treated with the combination IBRANCE plus fulvestrant therapy should 
be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical 
practice standards. 
 
2. Dose Modification 
The recommended dose modifications for adverse reactions are listed in Tables 1, 2, and 3. 
1. Table 1. Recommended Dose Modification for Adverse Reactions 
Dose Level 
Dose 
Recommended starting dose 
125 mg/day 
First dose reduction 
100 mg/day 
Second dose reduction 
75 mg/day* 
If further dose reduction below 75 mg/day is required, discontinue. 
 
Monitor complete blood counts prior to the start of IBRANCE therapy and at the beginning of 
each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. 
 
For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor 
complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle 
and as clinically indicated. 
CTCAE Grade 
Dose Modifications 
Grade 1 or 2 
No dose adjustment is required. 
Grade 3 
Day 1 of cycle: 
Withhold IBRANCE, repeat complete blood count monitoring within 1 
 same dose.
 
Day 15 of first 2 cycles: 
If Grade 3 on Day 15, continue IBRANCE at current dose to complete 
cycle and repeat complete blood count on Day 22. 
If Grade 4 on Day 22, see Grade 4 dose modification guidelines below. 
 
Consider dose reduction in cases of prolonged (>1 week) recovery from 
Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of 
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Grade 3 
neutropenia with fever 
infection 
At any time: 
next lower 
dose. 
Grade 4 
At any time: 
 next lower 
dose. 
 
2. Table 2. Dose Modification and Management  Hematologic Toxicities 
Grading according to CTCAE 4.0. 
CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal. 
a. Table applies to all hematologic adverse reactions except lymphopenia (unless associated with 
clinical events, e.g., opportunistic infections). 
b. Absolute neutrophil count (ANC): Grade 1: ANC < LLN - 1500/mm3; Grade 2: ANC 1000 - 
<1500/mm3; Grade 3: ANC 500 - <1000/mm3; Grade 4: ANC <500/mm3. 
 
3. Table 3. Dose Modification and Management  Non-Hematologic Toxicities 
CTCAE Grade 
Dose Modifications 
Grade 1 or 2 
No dose adjustment is required. 
-hematologic toxicity (if 
persisting despite optimal medical 
treatment) 
Withhold until symptoms resolve to: 
Resume at the next lower dose. 
 
 
 
 
Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events. 
Refer to the Full Prescribing Information for coadministered endocrine therapy dose adjustment 
guidelines in the event of toxicity and other relevant safety information or contraindications. 
4. Dose Modifications for Use With Strong CYP3A Inhibitors 
 
Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant 
medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A 
inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, 
increase the IBRANCE dose (after 3 to 5 half-lives of the inhibitor) to the dose used prior to the 
initiation of the strong CYP3A inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 
 


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3. 
DOSAGE FORMS AND STRENGTHS 
125 mg capsules: opaque, hard gelatin capsules, size 0, with caramel cap and body, printed with 
 
 
100 mg capsules: opaque, hard gelatin capsules, size 1, with caramel cap and light orange body, 
 
 
75 mg capsules: opaque, hard gelatin capsules, size 2, with light orange cap and body, printed with 
 
 
1. CONTRAINDICATIONS 
None.
 
2. WARNINGS AND PRECAUTIONS 
1. Neutropenia 
Neutropenia was the most frequently reported adverse reaction in Study 1 (PALOMA-2) with an 
incidence of 80% and Study 2 (PALOMA-
neutrophil counts was reported in 66% of patients receiving IBRANCE plus letrozole in Study 1 and 
66% of patients receiving IBRANCE plus fulvestrant in Study 2. In Study 1 and 2, the median time to 
ia 
was 7 days [see Adverse Reactions (6.1)]. 
 
Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each cycle, 
as well as on Day 15 of the first 2 cycles, and as clinically indicated. Dose interruption, dose 
reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 
4 neutropenia [see Dosage and Administration (2.2)]. 
 
Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across Studies 1 
and 2. One death due to neutropenic sepsis was observed in Study 2. Physicians should inform 
patients to promptly report any episodes of fever [see Patient Counseling Information (17)]. 
 
2. Embryo-Fetal Toxicity 
Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm 
when administered to a pregnant woman. In animal reproduction studies, administration of palbociclib 
to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal 
e human clinical exposure based on area under the curve (AUC). 
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use effective contraception during treatment with IBRANCE and for at least 3 weeks after the last 
dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1)].
 
 
ADVERSE REACTIONS 
The following topic is described below and elsewhere in the labeling: Neutropenia [see Warnings and 
Precautions (5.1)].  
 
3. Clinical Studies Experience 
 
Because clinical trials are conducted under varying conditions, the adverse reaction rates observed 
cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical 
practice. 
 
Study 1: IBRANCE plus Letrozole 
 
5. Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic 
breast cancer for initial endocrine based therapy 
 
The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus placebo plus letrozole was 
evaluated in Study 1 (PALOMA-2). The data described below reflect exposure to IBRANCE in 444 
out of 666 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 
dose of IBRANCE plus letrozole in Study 1. The median duration of treatment for IBRANCE plus 
letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was 
13.8 months. 
 
Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving 
IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1. 
 
Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (9.7%) patients 
receiving IBRANCE plus letrozole and in 13 of 222 (5.9%) patients receiving placebo plus letrozole. 
Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus 
letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%). 
 
letrozole arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea, 
alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased 
appetite, dry skin, pyrexia, and dysgeusia. 


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The most frequently reported Grade >
letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia. 
 
plus 
letrozole in Study 1 are listed in Table 4. 
6. 
 
 
IBRANCE plus Letrozole 
(N=444) 
Placebo plus Letrozole (N=222)
Adverse Reaction 
All Grades
% 
Grade 3
% 
Grade 4 
% 
All Grades
% 
Grade 3 
% 
Grade 4 
% 
Infections and infestations 
 
Infections 
60b 
6 
1 
42 
3 
0 
Blood and lymphatic system disorders 
 
Neutropenia Leukopenia 
Anemia Thrombocytopenia 
80 
39 
24 
16 
56 
24 
5 
1 
10 
1 
<1 
<1 
6 
2 
9 
1 
1 
0 
2 
0 
1 
0 
0 
0 
Metabolism and nutrition disorders 
 
Decreased appetite 
15 
1 
0 
9 
0 
0 
Nervous system disorders 
 
Dysgeusia 
10 
0 
0 
5 
0 
0 
Gastrointestinal disorders 
 
Stomatitis 
Nausea Diarrhea Vomiting 
30 
35 
26 
16 
1 
<1 
1 
1 
0 
0 
0 
0 
14 
26 
19 
17 
0 
2 
1 
1 
0 
0 
0 
0 
Skin and subcutaneous tissue disorders 
 
Alopecia Rash Dry skin 
33d18 
12 
N/A 1 
0 
N/A 0 
0 
16e12 
6 
N/A 1 
0 
N/A 0 
0 
General disorders and administration site conditions 
 
Fatigue Asthenia Pyrexia 
37 
17 
2 
2 
0 
0 
28 
12 
1 
0 
0 
0 


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12 
0 
0 
9 
0 
0 
 
Grading according to CTCAE 4.0. 
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not 
applicable; 
a. Infections includes all reported preferred terms (PTs) that are part of the System Organ Class 
Infections and infestations. 
b. Most common infections (>1%) include: nasopharyngitis, upper respiratory tract infection, urinary 
tract infection, oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, 
conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth 
infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract 
infection viral, and folliculitis. 
c. Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal 
inflammation, 
oral pain, oral discomfort, oropharyngeal pain, and stomatitis. 
d. Grade 1 events  30%; Grade 2 events  3%. 
e. Grade 1 events  15%; Grade 2 events  1%. 
f. Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash 
papular, dermatitis, dermatitis acneiform, and toxic skin eruption. 
 
Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving 
IBRANCE plus letrozole in Study 1 included alanine aminotransferase increased (9.9%), aspartate 
aminotransferase increased (9.7%), epistaxis (9.2%), lacrimation increased (5.6%), dry eye (4.1%), 
vision blurred (3.6%), and febrile neutropenia (2.5%). 
 
 
7. Table 5. Laboratory Abnormalities in Study 1 
 
IBRANCE plus Letrozole 
(N=444) 
Placebo plus Letrozole 
(N=222) 
Laboratory 
Abnormality 
All 
Grades 
% 
Grade 3
% 
Grade 4 
% 
All 
Grades 
% 
Grade 3
% 
Grade 4 
% 
WBC decreased 
97 
35 
1 
25 
1 
0 
Neutrophils decreased 95 
56 
12 
20 
1 
1 
Anemia 
78 
6 
0 
42 
2 
0 
Platelets decreased 
63 
1 
1 
14 
0 
0 


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Aspartate 
aminotransferase 
increased
52 
3 
0 
34 
1 
0 
Alanine 
aminotransferase 
increased 
43 
2 
<1 
30 
0 
0 
N=number of patients; WBC=white blood cells. 
 
Study 2: IBRANCE plus Fulvestrant 
 
8. Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have 
had disease progression on or after prior adjuvant or metastatic endocrine 
therapy 
 
The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was 
evaluated in Study 2 (PALOMA-3). The data described below reflect exposure to IBRANCE in 345 
out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who 
received at least 1 dose of IBRANCE plus fulvestrant in Study 2. The median duration of treatment 
for IBRANCE plus fulvestrant was 10.8 months while the median duration of treatment for placebo 
plus fulvestrant arm was 4.8 months. 
 
Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving 
IBRANCE plus fulvestrant. No dose reduction was allowed for fulvestrant in Study 2. 
 
Permanent discontinuation associated with an adverse reaction occurred in 19 of 345 (6%) patients 
receiving IBRANCE plus fulvestrant, and in 6 of 172 (3%) patients receiving placebo plus fulvestrant. 
Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant 
included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%). 
fulvestrant arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, 
anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and 
pyrexia. 
 
fulvestrant in descending frequency were neutropenia and leukopenia. 
 
plus fulvestrant in Study 2 are listed in Table 6. 
9. 
 


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Adverse Reaction 
IBRANCE plus Fulvestrant 
(N=345) 
Placebo plus Fulvestrant 
(N=172) 
All 
Grades 
Grade 3 
Grade 4 
All 
Grades 
Grade 3 
Grade 4 
% 
% 
% 
% 
% 
% 
Infections and infestations 
Infections 
47b 
3 
1 
31 
3 
0 
Blood and lymphatic system disorders 
Neutropenia Leukopenia 
Anemia 
Thrombocytopenia 
83 
53 
30 
23 
55 
30 
4 
2 
11 
1 
0 
1 
4 
5 
13 
0 
1 
1 
2 
0 
0 
1 
0 
0 
Metabolism and nutrition disorders 
Decreased appetite 
16 
1 
0 
8 
1 
0 
Gastrointestinal disorders 
Nausea Stomatitis 
Diarrhea Vomiting 
34 
28 
24 
19 
0 
1 
0 
1 
0 
0 
0 
0 
28 
13 
19 
15 
1 
0 
1 
1 
0 
0 
0 
0 
Skin and subcutaneous tissue disorders 
Alopecia Rash 
18d17 
N/A 1 
N/A 0 
6e 
6 
N/A 0 
N/A 0 
General disorders and administration site conditions 
Fatigue Pyrexia 
41 
13 
2 
<1 
0 
0 
29 
5 
1 
0 
0 
0 
 
Grading according to CTCAE 4.0. 
CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not 
applicable. 
a. Infections includes all reported preferred terms (PTs) that are part of the System Organ Class 
Infections and infestations. 
b. Most common infections (>1%) include: nasopharyngitis, upper respiratory tract infection, urinary 
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infection, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes, 
respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, 
and paronychia. 
c. Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal 
inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis. 
d. Grade 1 events  17%; Grade 2 events  1%. 
e. Grade 1 events  6%. 
f. Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, 
dermatitis, dermatitis acneiform, toxic skin eruption. 
 
Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving 
IBRANCE plus fulvestrant in Study 2 included asthenia (7.5%), aspartate aminotransferase increased 
(7.5%), dysgeusia (6.7%), epistaxis (6.7%), lacrimation increased (6.4%), dry skin (6.1%), alanine 
aminotransferase increased (5.8%), vision blurred (5.8%), dry eye (3.8%), and febrile 
neutropenia (0.9%). 
10. Table 7. Laboratory Abnormalities in Study 2 
 
Laboratory Abnormality
IBRANCE plus Fulvestrant 
(N=345) 
Placebo plus Fulvestrant 
(N=172) 
All Grades 
% 
Grade 3
% 
Grade 4 
% 
All Grades
% 
Grade 3 
% 
Grade 4 
% 
WBC decreased 
99 
45 
1 
26 
0 
1 
Neutrophils decreased 
96 
56 
11 
14 
0 
1 
Anemia 
78 
3 
0 
40 
2 
0 
Platelets decreased 
62 
2 
1 
10 
0 
0 
Aspartate 
aminotransferase 
increased 
43 
4 
0 
48 
4 
0 
Alanine aminotransferase 
increased 
36 
2 
0 
34 
0 
0 
 
N=number of patients; WBC=white blood cells. 
 
3. DRUG INTERACTIONS 
 
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In 
vivo, palbociclib is a time-dependent inhibitor of CYP3A. 
 


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0. Agents That May Increase Palbociclib Plasma Concentrations Effect of CYP3A 
Inhibitors 
Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of 
palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors 
(e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole). Avoid grapefruit or 
grapefruit juice during IBRANCE treatment. If coadministration of IBRANCE with a strong CYP3A 
inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration (2.2) and 
Clinical Pharmacology (12.3)]. 
 
1. Agents That May Decrease Palbociclib Plasma Concentrations Effect of CYP3A 
Inducers 
Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib 
in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, 
 [see Clinical Pharmacology (12.3)]. 
 
2. Drugs That May Have Their Plasma Concentrations Altered by Palbociclib 
 
Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma 
exposure by 61%, in healthy subjects, compared to administration of midazolam alone. The dose of 
the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, 
dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) 
may need to be reduced, as IBRANCE may increase its exposure [see Clinical Pharmacology (12.3)]. 
 
 
4. USE IN SPECIFIC POPULATIONS 
 
0. Pregnancy Risk Summary 
Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm 
when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available 
data in pregnant women to inform the drug-associated risk. In animal reproduction studies, 
administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in 
embryofetal toxicity at maternal exposures that were 4 times the human clinical exposure based on 
AUC [see Data]. Advise pregnant women of the potential risk to a fetus. 
 
The estimated background risk of major birth defects and miscarriage for the indicated population is 
unknown. In the U.S. general population, the estimated background risk of major birth defects and 
miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. 
 
11. Data 


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Animal Data
 
In a fertility and early embryonic development study in female rats, palbociclib was administered 
orally for 15 days before mating through to Day 7 of pregnancy, which did not cause embryo toxicity 
at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human 
exposure (AUC) at the recommended dose. 
 
In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of 
palbociclib up to 300 mg/kg/day and 20 mg/kg/day, respectively, during the period of organogenesis. 
The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body 
(increased incidence of a rib present at the seventh cervical vertebra). At the maternally toxic dose of 
20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small 
phalanges in the forelimb. At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal 
systemic exposures were approximately 4 and 9 times the human exposure (AUC) at the 
recommended dose, respectively. 
 
CDK4/6 double knockout mice have been reported to die in late stages of fetal development 
(gestation Day 14.5 until birth) due to severe anemia. However, knockout mouse data may not be 
predictive of effects in humans due to differences in degree of target inhibition. 
 
1. Lactation Risk Summary 
There is no information regarding the presence of palbociclib in human milk, its effects on milk 
production, or the breastfed infant. Because of the potential for serious adverse reactions in 
breastfed infants from IBRANCE, advise a lactating woman not to breastfeed during treatment with 
IBRANCE and for 3 weeks after the last dose. 
2. Females and Males of Reproductive Potential Pregnancy Testing 
Based on animal studies, IBRANCE can cause fetal harm when administered to a pregnant woman 
[see Use in Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy 
test prior to starting treatment with IBRANCE. 
 
12. Contraception 
 
Females 
 
IBRANCE can cause fetal harm when administered to a pregnant woman [see Use in Specific 
Populations (8.1)]. Advise females of reproductive potential to use effective contraception during 
treatment with IBRANCE and for at least 3 weeks after the last dose. 
 


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Males
Because of the potential for genotoxicity, advise male patients with female partners of reproductive 
potential to use effective contraception during treatment with IBRANCE and for 3 months after the 
last dose [see Nonclinical Toxicology (13.1)]. 
 
13. Infertility 
 
Males
 
Based on animal studies, IBRANCE may impair fertility in males of reproductive potential [see 
Nonclinical Toxicology (13.1)]. 
 
3. Pediatric Use 
 
The safety and efficacy of IBRANCE in pediatric patients have not been studied. 
Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes 
in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation, 
chronic progressive nephropathy) and adipose tissue (atrophy) were identified in a 27 week repeat-
dose toxicology study in rats that were immature at the beginning of the studies and were most 
exposure [AUC] at the recommended dose). Some of these findings (glycosuria/hyperglycemia, 
pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present with lower incidence 
and severity in a 15 week repeat-dose toxicology study in immature rats. Altered glucose metabolism 
or associated changes in the pancreas, eye, kidney and adipose tissue were not identified in a 27-
week repeat-dose toxicology study in rats that were mature at the beginning of the study and in dogs 
in repeat-dose toxicology studies up to 39 weeks duration. 
 
Toxicities in teeth independent of altered glucose metabolism were observed in rats. Administration 
of 100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] at 
the recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast 
degeneration/necrosis, mononuclear cell infiltrate). Other toxicities of potential concern to pediatric 
patients have not been evaluated in juvenile animals. 
4. Geriatric Use 
 
Of 444 patients who received IBRANCE i
 
differences in safety or effectiveness of IBRANCE were observed between these patients and 
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5. Hepatic Impairment 
 
Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had 
LN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and 
any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The 
pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic 
impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)]. 
 
Review the Full Prescribing Information for the aromatase inhibitor or fulvestrant for dose 
modifications related to hepatic impairment. 
 
6. Renal Impairment 
 
Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had 
impairment 
exposure 
of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe 
renal impairment [see Clinical Pharmacology (12.3)]. 
 
 
1. OVERDOSAGE 
 
There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of 
general supportive measures. 
 
2. DESCRIPTION 
 
IBRANCE capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase 
inhibitor. The molecular formula for palbociclib is C24H29N7O2. The molecular weight is 
447.54 daltons. The chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl) pyridin-2
yl] amino} pyrido [2, 3-d] pyrimidin-7(8H)-one, and its structural formula is: 


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Palbociclib is a yellow to orange powder with pKa of 7.4 (the secondary piperazine nitrogen) and 
3.9 (the pyridine nitrogen). At or below pH 4, palbociclib behaves as a high-solubility compound. 
Above pH 4, the solubility of the drug substance reduces significantly. 
Inactive ingredients: Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, 
colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells. The light orange, light 
orange/caramel, and caramel opaque capsule shells contain gelatin, red iron oxide, yellow iron oxide, 
and titanium dioxide; the printing ink contains shellac, titanium dioxide, ammonium hydroxide, 
propylene glycol, and simethicone. 
 
3. CLINICAL PHARMACOLOGY 
 
1. Mechanism of Action 
 
Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are 
downstream of signaling pathways which lead to cellular proliferation. In vitro, palbociclib reduced 
cellular proliferation of estrogen receptor (ER)-positive breast cancer cell lines by blocking 
progression of the cell from G1 into S phase of the cell cycle. Treatment of breast cancer cell lines 
with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma (Rb) protein 
phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest 
compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines 
with the combination of palbociclib and antiestrogens led to increased cell senescence compared to 
each drug alone, which was sustained for up to 6 days following palbociclib removal and was greater 
if antiestrogen treatment was continued. In vivo studies using a patient-derived ER-positive breast 
cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the 
inhibition of Rb phosphorylation, downstream signaling, and tumor growth compared to each drug 
alone. 
 


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Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an 
anti- estrogen in vitro did not become senescent and resumed proliferation following palbociclib 
withdrawal. 
 
2. Pharmacodynamics Cardiac Electrophysiology 
The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time- 
matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding 
pharmacokinetic data in 77 patients with breast cancer. Palbociclib had no large effect on QTc (i.e. > 
20 ms) at 125 mg once daily (Schedule 3/1). 
 
3. Pharmacokinetics 
 
The pharmacokinetics (PK) of palbociclib were characterized in patients with solid tumors including 
advanced breast cancer and in healthy subjects. 
 
14. Absorption 
 
The mean maximum observed concentration (Cmax) of palbociclib is generally observed between 6 
to 12 hours (time to reach maximum concentration, Tmax) following oral administration. The mean 
absolute bioavailability of IBRANCE after an oral 125 mg dose is 46%. In the dosing range of 25 mg 
to 225 mg, the AUC and Cmax increased proportionally with dose in general. Steady state was 
achieved within 8 days following repeated once daily dosing. With repeated once daily administration, 
palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5 to 4.2). 
 
Food effect: Palbociclib absorption and exposure were very low in approximately 13% of the 
population under the fasted condition. Food intake increased the palbociclib exposure in this small 
subset of the 
population, but did not alter palbociclib exposure in the rest of the population to a clinically relevant 
extent. Therefore, food intake reduced the intersubject variability of palbociclib exposure, which 
supports administration of IBRANCE with food. Compared to IBRANCE given under overnight fasted 
conditions, the population average area under the concentration-time curve from zero to infinity 
(AUCINF) and Cmax of palbociclib increased by 21% and 38%, respectively, when given with high-
fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from 
protein, carbohydrate, and fat, respectively), by 12% and 27%, respectively, when given with low-fat, 
low-calorie food (approximately 400 to 500 calories with 120, 250, and 28 to 35 calories from protein, 
carbohydrate, and fat, respectively), and by 13% and 24%, respectively, when moderate-fat, 
standard calorie food (approximately 500 to 700 calories with 75 to 105, 250 to 350 and 175 to 245 
calories from protein, carbohydrate, and fat, respectively) was given 1 hour before and 2 hours after 
IBRANCE dosing. 
 
15. Distribution 


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Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no
concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The geometric 
mean apparent volume of distribution (Vz/F) was 2583 L with a coefficient of variation (CV) of 26%. 
 
16. Metabolism 
 
In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans. 
Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, the primary 
metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and 
glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug-derived 
entity in plasma (23%). The major circulating metabolite was a glucuronide conjugate of palbociclib, 
although it only represented 1.5% of the administered dose in the excreta. Palbociclib was 
extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces 
and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-
related component, accounting for 26% of the administered dose. In vitro studies with human 
hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A 
and SULT2A1 are mainly involved in the metabolism of palbociclib. 
 
17. Elimination 
 
The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the 
mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced 
breast cancer. In 6 healthy male subjects given a single oral dose of [14C]palbociclib, a median of 
91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) 
was the major route of excretion, with 17.5% of the dose recovered in urine. The majority of the 
material was excreted as metabolites. 
 
18. Age, Gender, and Body Weight 
 
Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 
female patients, age range from 22 to 89 years, and body weight range from 37.9 to 123 kg), gender 
had no effect on the exposure of palbociclib, and age and body weight had no clinically important 
effect on the exposure of palbociclib. 
19. Pediatric Population 
 
Pharmacokinetics of IBRANCE have not been evaluated in patients <18 years of age. 
 
20. Drug Interactions 
 


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In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the metabolism 
of palbociclib. Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing 
to steady state in humans. In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 
2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant 
concentrations. 
 
CYP3A Inhibitors: Data from a drug interaction trial in healthy subjects (N=12) indicate that 
coadministration of multiple 200 mg daily doses of itraconazole with a single 125 mg IBRANCE dose 
increased palbociclib AUCINF and the Cmax by approximately 87% and 34%, respectively, relative 
to a single 125 mg IBRANCE dose given alone [see Drug Interactions (7.1)]. 
 
CYP3A Inducers: Data from a drug interaction trial in healthy subjects (N=15) indicate that 
coadministration of multiple 600 mg daily doses of rifampin, a strong CYP3A inducer, with a single 
125 mg IBRANCE dose decreased palbociclib AUCINF and Cmax by 85% and 70%, respectively, 
relative to a single 125 mg IBRANCE dose given alone. Data from a drug interaction trial in healthy 
subjects (N=14) indicate that coadministration of multiple 400 mg daily doses of modafinil, a 
moderate 
CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUCINF and Cmax by 
32% and 11%, respectively, relative to a single 125 mg IBRANCE dose given alone [see Drug 
Interactions (7.2)]. 
 
CYP3A Substrates: Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg 
dosing to steady state in humans. In a drug interaction trial in healthy subjects (N=26), 
coadministration of midazolam with multiple doses of IBRANCE increased the midazolam 
AUCINF and the Cmax values by 61% and 37%, respectively, as compared to administration of 
midazolam alone [see Drug Interactions (7.3)]. 
 
Gastric pH Elevating Medications: In a drug interaction trial in healthy subjects, coadministration of a 
single 125 mg dose of IBRANCE with multiple doses of the proton pump inhibitor (PPI) rabeprazole 
under fed conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCINF 
(13% decrease), when compared to a single dose of IBRANCE administered alone. Given the 
reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, the 
effect of these classes of acid-reducing agents on palbociclib exposure under fed conditions is 
expected to be minimal. Under fed conditions there is no clinically relevant effect of PPIs, H2-
receptor antagonists, or local antacids on palbociclib exposure. In another healthy subject study, 
coadministration of a single dose of IBRANCE with multiple doses of the PPI rabeprazole under 
fasted conditions decreased palbociclib AUCINF and Cmax by 62% and 80%, respectively, when 
compared to a single dose of IBRANCE administered alone. 
 
Letrozole: Data from a clinical trial in patients with breast cancer showed that there was no drug 
interaction between palbociclib and letrozole when the 2 drugs were coadministered. 
 


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Fulvestrant: Data from a clinical trial in patients with breast cancer showed that there was no clinically 
relevant drug interaction between palbociclib and fulvestrant when the 2 drugs were coadministered.
Goserelin: Data from a clinical trial in patients with breast cancer showed that there was no clinically 
relevant drug interaction between palbociclib and goserelin when the 2 drugs were coadministered. 
 
Anastrozole or exemestane: No clinical data are available to evaluate drug interactions between 
anastrozole or exemestane and palbociclib. A clinically significant drug interaction between 
anastrozole or exemestane and palbociclib is not expected based on analyses of the effects of 
anastrozole, exemestane and palbociclib on or by metabolic pathways or transporter systems. 
 
Effect of Palbociclib on Transporters: In vitro evaluations indicated that palbociclib has a low potential 
to inhibit the activities of drug transporters P-glycoprotein (P-gp), breast cancer resistance protein 
(BCRP), organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, and organic 
anion transporting polypeptide (OATP)1B1, OATP1B3 at clinically relevant concentrations. 
 
Effect of Transporters on Palbociclib: Based on in vitro data, P-gp and BCRP mediated transport are 
unlikely to affect the extent of oral absorption of palbociclib at therapeutic doses. 
 
4. NONCLINICAL TOXICOLOGY 
 
1. Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
Carcinogenicity studies have not been conducted with palbociclib. 
 
Palbociclib was aneugenic in Chinese Hamster Ovary cells in vitro and in the bone marrow of male 
reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte 
chromosome aberration assay. 
 
In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to 
300 mg/kg/day (approximately 4 times human clinical exposure based on AUC) and no adverse 
effects were observed in the female reproductive tissues in repeat-dose toxicity studies up to 300 
mg/kg/day in the rat and 3 mg/kg/day in the dog (approximately 6 times and similar to human 
exposure [AUC], at the recommended dose, respectively). 
 
The adverse effects of palbociclib on male reproductive function and fertility were observed in the 
repeat-dose toxicology studies in rats and dogs and a male fertility study in rats. In repeat-dose 
toxicology studies, palbociclib-related findings in the testis, epididymis, prostate, and seminal vesicle 
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gs included decreased organ weight, atrophy or 
degeneration, hypospermia, intratubular cellular debris, and decreased secretion. Partial reversibility 
of male reproductive organ effects was observed in the rat and dog following a 4- and 12-week non-
dosing 
times, respectively, the exposure [AUC] in humans at the recommended dose. In the fertility and 
early embryonic development study in male rats, palbociclib caused no effects on mating but resulted 
in a slight decrease in fertility in association with lower sperm motility and density at 100 mg/kg/day 
with projected exposure levels [AUC] of 20 times the exposure in humans at the recommended dose.
 
21. 14 CLINICAL STUDIES Study 1: IBRANCE plus Letrozole 
22. Patients with ER-positive, HER2-negative advanced or metastatic breast cancer for initial 
endocrine based therapy 
Study 1 (PALOMA-2) was an international, randomized, double-blind, parallel-group, multicenter 
study of IBRANCE plus letrozole versus placebo plus letrozole conducted in postmenopausal women 
with 
ER-positive, HER2-negative advanced breast cancer who had not received previous systemic 
treatment for their advanced disease. A total of 666 patients were randomized 2:1 to IBRANCE plus 
letrozole or placebo plus letrozole. Randomization was stratified by disease site (visceral versus non-
visceral), disease-
treatment to disease recurrence versus >12 months from the end of adjuvant treatment to disease 
recurrence), and nature of prior (neo) adjuvant anticancer therapies (prior hormonal therapies versus 
no prior hormonal therapy). IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive 
days followed by 
7 days off treatment. Patients received study treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever 
occurred first. The major efficacy outcome of the study was investigator-assessed progression-free 
survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST). 
 
Patients enrolled in this study had a median age of 62 years (range 28 to 89). The majority of 
patients were White (78%), and most patients had an Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 or 1 (98%). Forty-eight percent of patients had received chemotherapy 
and 56% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their 
diagnosis of advanced breast cancer. Thirty-seven percent of patients had no prior systemic therapy 
in the neoadjuvant or adjuvant setting. The majority of patients (97%) had metastatic disease. 
Twenty-three percent of patients had bone only disease, and 49% of patients had visceral disease. 
 
Major efficacy results from Study 1 are summarized in Table 8 and Figure 1. Consistent results were 
observed across patient subgroups of disease-free interval (DFI), disease site, and prior therapy. The 
treatment effect of the combination on PFS was also supported by an independent review of 
radiographs. The overall survival (OS) data were not mature at the time of the final PFS analysis 
(20% of patients had died). Patients will continue to be followed for the final analysis. 
 


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23. Table 8. Efficacy Results  Study 1 (Investigator Assessment, Intent-to-Treat Population) 
IBRANCE 
plus Letrozole 
Placebo plus Letrozole 
Progression-free survival for ITT 
N=444 
N=222 
Number of PFS events (%) 
194 (43.7) 
137 (61.7) 
Median progression-free survival (months, 
95% CI) 
24.8 (22.1, NE) 
14.5 (12.9, 17.1) 
Hazard ratio (95% CI) and p-value 
0.576 (0.463, 0.718), p<0.0001 
Objective Response for patients with 
measurable disease 
N=338 
N=171 
Objective response rate* (%, 95% CI) 
55.3 (49.9, 60.7) 
44.4 (36.9, 52.2) 
 
 
*Response based on confirmed responses 
CI=confidence interval; ITT=Intent-to-Treat; N=number of patients; NE=not estimable. 
24. Figure 1. Kaplan-Meier Plot of Progression-Free Survival  Study 1 (Investigator 
Assessment, Intent-to-Treat Population) 
 


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Study 2: IBRANCE plus Fulvestrant 
 
25. Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have 
had disease progression on or after prior adjuvant or metastatic endocrine 
therapy 
 
Study 2 (PALOMA-3) was an international, randomized, double-blind, parallel group, multicenter 
study of IBRANCE plus fulvestrant versus placebo plus fulvestrant conducted in women with HR-
positive, HER2-negative advanced breast cancer, regardless of their menopausal status, whose 
disease progressed on or after prior endocrine therapy. A total of 521 pre/postmenopausal women 
were randomized 2:1 to IBRANCE plus fulvestrant or placebo plus fulvestrant and stratified by 
documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus 
postmenopausal), and presence of visceral metastases. IBRANCE was given orally at a dose of 125 
mg daily for 21 consecutive days followed by 7 days off treatment. Pre/perimenopausal women were 
enrolled in the study and received the LHRH agonist goserelin for at least 4 weeks prior to and for the 
duration of Study 2. Patients continued to receive assigned treatment until objective disease 
progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, 
whichever occurred first. The major efficacy outcome of the study was investigator-assessed PFS 
evaluated according to RECIST 1.1. 
 
Patients enrolled in this study had a median age of 57 years (range 29 to 88). The majority of 
patients on study were White (74%), all patients had an ECOG PS of 0 or 1, and 80% were 
postmenopausal. All patients had received prior systemic therapy, and 75% of patients had received 
a previous chemotherapy regimen. Twenty-five percent of patients had received no prior therapy in 
the metastatic disease setting, 60% had visceral metastases, and 23% had bone only disease. 
 
The results from the investigator-assessed PFS from Study 2 are summarized in Table 9 and Figure 
2. Consistent results were observed across patient subgroups of disease site, sensitivity to prior 
hormonal therapy and menopausal status. The overall survival (OS) data were not mature at the time 
of the final PFS analysis (11% of patients had died). Patients will continue to be followed for the final 
analysis.
 


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Table 9. Efficacy Results  Study 2 (Investigator Assessment, Intent-to-Treat Population) 
 
 
 
Figure 2. Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, Intent-to-
Treat Population)  Study 2 
 
 


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16.  HOW SUPPLIED/STORAGE AND HANDLING 
IBRANCE is supplied in the following strengths and package configurations: 
 
IBRANCE Capsules 
Package 
Configuration 
Capsule 
Strength (mg) 
NDC 
Capsule Description 
Bottles of 21 
capsules 
125 
NDC 0069-0189-21
opaque, hard gelatin capsules, size 0, 
with caramel cap and body, printed with 
 
 
IBRANCE Capsules 
Package 
Configuration 
Capsule 
Strength (mg) 
NDC 
Capsule Description 
 
 
 
Bottles of 21 
capsules 
100 
NDC 0069-0188-21 
opaque, hard gelatin capsules, size 1, 
with caramel cap and light orange body, 
 
Bottles of 21 
capsules 
75 
NDC 0069-0187-21 
opaque, hard gelatin capsules, size 2, 
with light orange cap and body, printed 
 
 
Store at 20 oC to 25 oC (68 oF to 77 oF); excursions permitted between 15 oC to 30 oC (59 oF to 
86 oF).  
[see USP Controlled Room Temperature]. 
 
17.  PATIENT COUNSELING INFORMATION 
Advise the patient to read the FDA-approved patient labeling (Patient 
Information). Myelosuppression/Infection 
 
Advise patients to immediately report any signs or symptoms of myelosuppression or 
infection, 
such as fever, chills, dizziness, shortness of breath, weakness, or any increased tendency to bleed 
and/or to bruise [see Warnings and Precautions (5.1)]. 
 


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Drug Interactions 
Grapefruit may interact with IBRANCE. Patients should not consume grapefruit products while 
on treatment with IBRANCE. 
 
Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers. 
 
Advise patients to inform their health care providers of all concomitant medications, including 
prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug 
Interactions (7)]. 
 
Dosing and Administration 
 
Advise patients to take IBRANCE with food. 
 
If the patient vomits or misses a dose, an additional dose should not be taken. The next 
prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed 
whole (do not chew, crush, or open them prior to swallowing). No capsule should be ingested 
if it is broken, cracked, or otherwise not intact. 
 
Pregnancy, Lactation, and Fertility 
 
Embryo-Fetal Toxicity 
o 
Advise females of reproductive potential of the potential risk to a fetus and to use 
effective contraception during treatment with IBRANCE therapy and for at least 3 
weeks after the last dose. Advise females to inform their healthcare provider of a 
known or suspected pregnancy [see Warnings and Precautions (5.2) and Use in 
Specific Populations (8.1 and 8.3)]. 
o 
Advise male patients with female partners of reproductive potential to use effective 
contraception during treatment with IBRANCE and for at least 3 months after the last 
dose [see Use in Specific Populations (8.3)]. 
 
Lactation: Advise women not to breastfeed during treatment with IBRANCE and for 3 weeks 
after the last dose [see Use in Specific Populations (8.2)]. 
 
n updated. For full prescribing information, please 
visit www.IBRANCE.com. 
 
 
 
LAB-0723-2.1 
 
 


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PATIENT INFORMATION 
IBRANCE® (EYE-brans) (palbociclib) 
Capsules
What is the most important information I should know about IBRANCE? IBRANCE may 
cause serious side effects, including: 
Low white blood cell counts (neutropenia). Low white blood cell counts are very common when 
taking 
IBRANCE and may cause serious infections that can lead to death. Your healthcare provider should 
check your white blood cell counts before and during treatment. 
If you develop low white blood cell counts during treatment with IBRANCE, your healthcare provider 
may stop your treatment, decrease your dose, or may tell you to wait to begin your treatment cycle. 
Tell your healthcare provider right away if you have signs and symptoms of low white blood cell 
counts or infections such as fever and chills. 
 
effects. 
What is IBRANCE? 
IBRANCE is a prescription medicine used to treat hormone receptor (HR)-positive, human 
epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of 
the body (metastatic) in combination with: 
 
an aromatase inhibitor as the first hormonal based therapy in women who have gone 
through menopause, or 
 
fulvestrant in women with disease progression following hormonal therapy. It is not known if 
IBRANCE is safe and effective in children. 
What should I tell my healthcare provider before taking IBRANCE? 
Before you take IBRANCE, tell your healthcare provider if you: 
 
have fever, chills, or any other signs or symptoms of infection. 
 
have liver or kidney problems. 
 
have any other medical conditions. 
 
are pregnant, or plan to become pregnant. IBRANCE can harm your unborn baby. 
o 
Females who are able to become pregnant and who take IBRANCE should use 
effective birth control during treatment and for at least 3 weeks after stopping 
IBRANCE. 
o 
Males who are taking IBRANCE, with female partners who can become pregnant 
should use effective birth control during treatment with IBRANCE for 3 months after 
the final dose of IBRANCE. 
o 
Talk to your healthcare provider about birth control methods that may be right for you 
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o 
If you become pregnant or think you are pregnant, tell your healthcare provider right 
away. 
are breastfeeding or plan to breastfeed. It is not known if IBRANCE passes into your breast 
milk. You and your healthcare provider should decide if you will take IBRANCE or 
breastfeed. You should not do both. 
Tell your healthcare provider about all of the medicines you take, including prescription and 
over-the-counter medicines, vitamins, and herbal supplements. IBRANCE and other medicines may 
affect each other causing side effects. 
Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist 
when you get a new medicine. 
How should I take IBRANCE? 
 
Take IBRANCE exactly as your healthcare provider tells you. 
 
Take IBRANCE with food. 
 
Swallow IBRANCE capsules whole. Do not chew, crush or open IBRANCE capsules before 
swallowing them. 
 
Do not take any IBRANCE capsules that are broken, cracked, or that look damaged. 
 
Avoid grapefruit and grapefruit products during treatment with IBRANCE. Grapefruit may 
increase the amount of IBRANCE in your blood. 
 
Do not change your dose or stop taking IBRANCE unless your healthcare provider tells you.
 
If you miss a dose of IBRANCE or vomit after taking a dose of IBRANCE, do not take 
another dose on that day. Take your next dose at your regular time. 
 
If you take too much IBRANCE, call your healthcare provider right away or go to the nearest 
hospital emergency room. 
 


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What are the possible side effects of IBRANCE? 
 
Common side effects of IBRANCE when used with either letrozole or fulvestrant include: 
 
Low red blood cell counts and low platelet counts are common with IBRANCE. Call your 
healthcare provider right away if you develop any of these symptoms during treatment: 
o 
dizziness o bleeding or bruising more easily 
o 
shortness of breath  
o 
nosebleeds 
o 
weakness 
 
 i
 
 
diarrhea 
 
hair thinning or hair loss  
 
tiredness  
 
vomiting 
 
nausea  
 
rash 
 
sore mouth  
 
loss of appetite 
 
abnormalities in liver blood tests 
BRANCE may cause fertility problems in males. This may affect your ability to father a child. Talk 
to your healthcare provider if this is a concern for you. 
Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 
These are not all of the possible side effects of IBRANCE. For more information, ask your 
healthcare provider or pharmacist. 
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-
FDA-1088. 
How should I store IBRANCE? 
 
Store IBRANCE at 68 °F to 77 °F (20 °C to 25 °C). 
Keep IBRANCE and all medicines out of the reach of children. 
General information about the safe and effective use of IBRANCE 
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information 
leaflet. Do not use IBRANCE for a condition for which it was not prescribed. Do not give IBRANCE 
to other people, even if they have the same symptoms you have. It may harm them. 


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If you would like more information, talk with your healthcare provider. You can ask your pharmacist 
or healthcare provider for more information about IBRANCE that is written for health professionals.
For more information, go to www.IBRANCE.com or call 1-800-438-1985.
What are the ingredients in IBRANCE? 
Active ingredient: palbociclib 
Inactive ingredients: Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, 
colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells. 
Light orange, light orange/caramel and caramel opaque capsule shells contain: gelatin, red iron 
oxide, yellow iron oxide, and titanium dioxide. 
Printing ink contains: shellac, titanium dioxide, ammonium hydroxide, propylene glycol, and 
simethicone. 
 
LAB-0724-2.1 
This Patient Information has been approved by the U.S. Food and Drug Administration.  
 
 


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APPENDIX B - Hydroxychloroquine (Plaquenil) Package Insert 
 
PLAQUENIL® 
HYDROXYCHLOROQUINE SULFATE, USP 
 
 
 
26. DESCRIPTION 
Hydroxychloroquine sulfate is a colorless crystalline solid, soluble in water to at least 20 percent; 
chemically the drug is 2-[[4-[(7-Chloro-4-quinolyl) amino]pentyl] ethylamino] ethanol sulfate (1:1). 
PLAQUENIL (hydroxychloroquine sulfate) tablets contain 200 mg hydroxychloroquine sulfate, 
equivalent to 155 mg base, and are for oral administration. 
Inactive Ingredients: Dibasic Calcium Phosphate, Hydroxypropyl Methylcellulose, Magnesium 
Stearate, Polyethylene glycol 400, Polysorbate 80, Starch, Titanium Dioxide. 
 
 
27. ACTIONS 
The drug possesses antimalarial actions and also exerts a beneficial effect in lupus erythematosus 
(chronic discoid or systemic) and acute or chronic rheumatoid arthritis. The precise mechanism of 
action is not known. 
 
 
28. INDICATIONS 
PLAQUENIL is indicated for the suppressive treatment and treatment of acute attacks of malaria due 
to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also 
indicated for the treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis. 
 
 
29. CONTRAlNDICATIONS 
Use of this drug is contraindicated (1) in the presence of retinal or visual field changes attributable to 
any 4-aminoquinoline compound, (2) in patients with known hypersensitivity to 4- aminoquinoline 
compounds, and (3) for long-term therapy in children. 
WARNING 
PHYSICIANS SHOULD COMPLETELY FAMILIARIZE THEMSELVES WITH THE 
COMPLETE CONTENTS OF THIS LEAFLET BEFORE PRESCRIBING 
HYDROXYCHLOROQUINE. 


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30. WARNINGS, General
PLAQUENIL is not effective against chloroquine-resistant strains of P. falciparum. 
Children are especially sensitive to the 4-aminoquinoline compounds. A number of fatalities have 
been reported following the accidental ingestion of chloroquine, sometimes in relatively small doses 
(0.75 g or 1 g in one 3-year-old child). Patients should be strongly warned to keep these drugs out 
of the reach of children. 
Use of PLAQUENIL in patients with psoriasis may precipitate a severe attack of psoriasis. When 
used in patients with porphyria the condition may be exacerbated. The preparation should not be 
used in these conditions unless in the judgment of the physician the benefit to the patient outweighs 
the possible hazard. 
Usage in Pregnancy
Usage of this drug during pregnancy should be avoided except in the 
suppression or treatment of malaria when in the judgment of the physician the benefit outweighs the 
possible hazard. It should be noted that radioactively-tagged chloroquine administered 
intravenously to pregnant, pigmented CBA mice passed rapidly across the placenta. It accumulated 
selectively in the melanin structures of the fetal eyes and was retained in the ocular tissues for five 
months after the drug had been eliminated from the rest of the body. 
 
 
31. PRECAUTIONS, General 
Antimalarial compounds should be used with caution in patients with hepatic disease or alcoholism 
or in conjunction with known hepatotoxic drugs. 
Periodic blood cell counts should be made if patients are given prolonged therapy. If any severe 
blood disorder appears which is not attributable to the disease under treatment, discontinuation of 
the drug should be considered. The drug should be administered with caution in patients having G-
6-PD (glucose-6-phosphate dehydrogenase) deficiency. 
 
 
32. OVERDOSAGE 
The 4-aminoquinoline compounds are very rapidly and completely absorbed after ingestion, and in 
accidental overdosage, or rarely with lower doses in hypersensitive patients, toxic symptoms may 
occur within 30 minutes. These consist of headache, drowsiness, visual disturbances, 
cardiovascular collapse, and convulsions, followed by sudden and early respiratory and cardiac 
arrest. The electrocardiogram may reveal atrial standstill, nodal rhythm, prolonged intraventricular 
conduction time, and progressive bradycardia leading to ventricular fibrillation and/or arrest. 
Treatment is symptomatic and must be prompt with immediate evacuation of the stomach by 
emesis (at home, before transportation to the hospital) or gastric lavage until the stomach is 
completely emptied. If finely powdered, activated charcoal is introduced by the stomach tube, after 
lavage, and within 30 minutes after ingestion of the tablets, it may inhibit further intestinal absorption 
of the drug.  To be effective, the dose of activated charcoal should be at least five times the 
estimated dose of hydroxychloroquine ingested.  Convulsions, if present, should be controlled 
before attempting gastric lavage. If due to cerebral stimulation, cautious administration of an 
ultrashort-acting barbiturate may be tried but, if due to anoxia, it should be corrected by oxygen 
administration, artificial respiration or, in shock with hypotension, by vasopressor therapy.  Because 
of the importance of supporting respiration, 


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tracheal intubation or tracheostomy, followed by gastric lavage, may also be necessary. Exchange 
transfusions have been used to reduce the level of 4-aminoquinoline drug in the blood. 
 
A patient who survives the acute phase and is asymptomatic should be closely observed for at least 
six hours. Fluids may be forced, and sufficient ammonium chloride (8 g daily in divided doses for 
adults) may be administered for a few days to acidify the urine to help promote urinary excretion in 
cases of both overdosage and sensitivity. 
 
 
33. Actions 
Like chloroquine phosphate, USP, PLAQUENIL is highly active against the erythrocytic forms of P. 
vivax and malariae and most strains of P. falciparum (but not the gametocytes of P. falciparum). 
PLAQUENIL does not prevent relapses in patients with vivax or malariae malaria because it is not 
effective against exo-erythrocytic forms of the parasite, nor will it prevent vivax or malariae infection 
when administered as a prophylactic. It is highly effective as a suppressive agent in patients with 
vivax or malariae malaria, in terminating acute attacks, and significantly lengthening the interval 
between treatment and relapse. In patients with falciparum malaria, it abolishes the acute attack 
and effects complete cure of the infection, unless due to a resistant strain of P. falciparum. 
34. Indications 
PLAQUENIL is indicated for the treatment of acute attacks and suppression of malaria. 
35. Warning 
In recent years, it has been found that certain strains of P. falciparum have become resistant to 4-
aminoquinoline compounds (including hydroxychloroquine) as shown by the fact that normally 
adequate doses have failed to prevent or cure clinical malaria or parasitemia. 
Treatment with quinine or other specific forms of therapy is therefore advised for patients infected 
with a resistant strain of parasites. 
36. Adverse Reactions 
Following the administration in doses adequate for the treatment of an acute malarial attack, mild 
and transient headache, dizziness, and gastrointestinal complaints (diarrhea, anorexia, nausea, 
abdominal cramps and, on rare occasions, vomiting) may occur. 
Cardiomyopathy has been rarely reported with high daily dosages of hydroxychloroquine. 
37. Dosage and Administration 
One tablet of 200 mg of hydroxychloroquine sulfate is equivalent to 155 mg base. 
Malaria: Suppression
 In adults, 400 mg (=310 mg base) on exactly the same day of each week. 
In infants and children, the weekly suppressive dosage is 5 mg, calculated as base, per kg of body 
weight, but should not exceed the adult dose regardless of weight. 


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If circumstances permit, suppressive therapy should begin two weeks prior to exposure. However, 
failing this, in adults an initial double (loading) dose of 800 mg (=620 mg base), or in children 10 mg 
base/kg may be taken in two divided doses, six hours apart. The suppressive therapy should be 
continued for eight weeks after leaving the endemic area. 
Treatment of the acute attack
 In adults, an initial dose of 800 mg (= 620 mg base) followed by 400 
mg (=310 mg base) in six to eight hours and 400 mg (=310 mg base) on each of two consecutive 
days (total 2 g hydroxychloroquine sulfate or 1.55 g base). An alternative method, employing a single 
dose of 800 mg (=620 mg base), has also proved effective. 
The dosage for adults may also be calculated on the basis of body weight; this method is preferred 
for infants and children. A total dose representing 25 mg of base per kg of body weight is 
administered in three days, as follows: 
First dose: 10 mg base per kg (but not exceeding a single dose of 620 mg base). 
Second dose: 5 mg base per kg (but not exceeding a single dose of 310 mg base) 6 hours after first 
dose. 
Third dose: 5 mg base per kg 18 hours after second dose. Fourth dose: 5 mg base per kg 24 hours 
after third dose. 
For radical cure of vivax and malariae malaria concomitant therapy with an 8- aminoquinoline 
compound is necessary. 
 
 
 
 
38. Indications 
PLAQUENIL is useful in patients with the following disorders who have not responded satisfactorily to 
drugs with less potential for serious side effects: lupus erythematosus (chronic discoid and systemic) 
and acute or chronic rheumatoid arthritis. 
39. Warnings 
PHYSICIANS SHOULD COMPLETELY FAMILIARIZE THEMSELVES WITH THE COMPLETE 
CONTENTS OF THIS LEAFLET BEFORE PRESCRlBlNG PLAQUENIL. 
Irreversible retinal damage has been observed in some patients who had received long- term or high-
dosage 4-aminoquinoline therapy for discoid and systemic lupus erythematosus, or rheumatoid 
arthritis.  Retinopathy has been reported to be dose-related. 
When prolonged therapy with any Antimalarial compound is contemplated, initial (base line) and 
periodic (every three months) ophthalmologic examinations (including visual acuity, expert slit-lamp, 
funduscopic, and visual field tests) should be performed. 
If there is any indication of abnormality in the visual acuity, visual field, or retinal macular areas (such 
as pigmentary changes, loss of foveal reflex), or any visual symptoms (such as light flashes and 
streaks) which are not fully explainable by difficulties of accommodation or corneal opacities, the drug 
should be discontinued immediately and the patient closely observed 
LUPUS ERYTHEMATOSUS AND 
RHEUMATOID ARTHRITIS 


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for possible progression. Retinal changes (and visual disturbances) may progress even after 
cessation of therapy. 
All patients on long-term therapy with this preparation should be questioned and examined 
periodically, including the testing of knee and ankle reflexes, to detect any evidence of muscular 
weakness.  If weakness occurs, discontinue the drug. 
In the treatment of rheumatoid arthritis, if objective improvement (such as reduced joint swelling, 
increased mobility) does not occur within six months, the drug should be discontinued. Safe use of 
the drug in the treatment of juvenile arthritis has not been established. 
 
 
40. Precautions 
Dermatologic reactions to PLAQUENIL may occur and, therefore, proper care should be exercised 
when it is administered to any patient receiving a drug with a significant tendency to produce 
dermatitis. 
The methods recommended for early diagnosi
 
(1) funduscopic examination of the macula for fine pigmentary disturbances or loss of the foveal 
reflex and (2) examination of the central visual field with a small red test object for pericentral or 
paracentral scotoma or determination of retinal thresholds to red. Any unexplained visual 
symptoms, such as light flashes or streaks should also be regarded with suspicion as possible 
manifestations of retinopathy. 
If serious toxic symptoms occur from overdosage or sensitivity, it has been suggested that 
ammonium chloride (8 g daily in divided doses for adults) be administered orally three or four days a 
week for several months after therapy has been stopped, as acidification of the urine increases 
renal excretion of the 4-aminoquinoline compounds by 20 to 90 percent. However, caution must be 
exercised in patients with impaired renal function and/or metabolic acidosis. 
 
 
41. Adverse Reactions 
Not all of the following reactions have been observed with every 4-aminoquinoline compound during 
long-term therapy, but they have been reported with one or more and should be borne in mind when 
drugs of this class are administered. Adverse effects with different compounds vary in type and 
frequency. 
CNS Reactions: Irritability, nervousness, emotional changes, nightmares, psychosis, headache, 
dizziness, vertigo, tinnitus, nystagmus, nerve deafness, convulsions, ataxia. 
Neuromuscular Reactions: Skeletal muscle palsies or skeletal muscle myopathy or 
neuromyopathy leading to progressive weakness and atrophy of proximal muscle groups which may 
be associated with mild sensory changes, depression of tendon reflexes and abnormal nerve 
conduction. 
Ocular Reactions: 
A. Ciliary body: Disturbance of accommodation with symptoms of blurred vision. This reaction is 
dose-related and reversible with cessation of therapy. 


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B. Cornea: Transient edema, punctate to lineal opacities, decreased corneal sensitivity. The corneal 
changes, with or without accompanying symptoms (blurred vision, halos around lights, 
photophobia), are fairly common, but reversible. Corneal deposits may appear as early as three 
weeks following initiation of therapy. 
The incidence of corneal changes and visual side effects appears to be considerably lower with 
hydroxychloroquine than with chloroquine. 
C. Retina: Macula
-
appearance), loss of foveal reflex, increased macular recovery time following exposure to a 
bright light (photo-stress test), elevated retinal threshold to red light in macular, paramacular, and 
peripheral retinal areas. 
Other fundus changes include optic disc pallor and atrophy, attenuation of retinal arterioles, fine 
granular pigmentary disturbances in the peripheral retina and prominent choroidal patterns in 
advanced stage. 
D. Visual field defects: Pericentral or paracentral scotoma, central scotoma with decreased visual 
acuity, rarely field constriction, abnormal color vision. 
The most common visual symptoms attributed to the retinopathy are: reading and seeing difficulties 
(words, letters, or parts of objects missing), photophobia, blurred distance vision, missing or blacked 
out areas in the central or peripheral visual field, light flashes and streaks. 
Retinopathy appears to be dose related and has occurred within several months (rarely) to several 
years of daily therapy; a small number of cases have been reported several years after antimalarial 
drug therapy was discontinued.  It has not been noted during prolonged use of weekly doses of the 
4-aminoquinoline compounds for suppression of malaria. 
Patients with retinal changes may have visual symptoms or may be asymptomatic (with or without 
visual field changes). Rarely scotomatous vision or field defects may occur without obvious retinal 
change. 
Retinopathy may progress even after the drug is discontinued. In a number of patients, early 
retinopathy (macular pigmentation sometimes with central field defects) diminished or regressed 
completely after therapy was discontinued. Paracentral scotoma to red targets (sometimes called 
of therapy. 
A small number of cases of retinal changes have been reported as occurring in patients who 
received only hydroxychloroquine. These usually consisted of alteration in retinal pigmentation 
which was detected on periodic ophthalmologic examination; visual field defects were also present 
in some instances. A case of delayed retinopathy has been reported with loss of vision starting one 
year after administration of hydroxychloroquine had been discontinued. 
Dermatologic Reactions: Bleaching of hair, alopecia, pruritus, skin and mucosal pigmentation, 
photosentivity, and skin eruptions (urticarial, morbilliform, lichenoid, maculopapular, purpuric, 
erythema annulare centrifugum, Stevens-Johnson syndrome, acute generalized exanthematous 
pustulosis, and exfoliative dermatitis). 
Hematologic Reactions: Various blood dyscrasias such as aplastic anemia, agranulocytosis, 
leukopenia, anemia, thrombocytopenia (hemolysis in individuals with glucose- 6-phosphate 
dehydrogenase (G-6-PD) deficiency). 


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Gastrointestinal Reactions: Anorexia, nausea, vomiting, diarrhea, and abdominal cramps.  
Isolated cases of abnormal liver function and fulminant hepatic failure. 
Allergic reactions: Urticaria, angioedema and bronchospasm have been reported.
Miscellaneous Reactions: Weight loss, lassitude, exacerbation or precipitation of porphyria and 
nonlight-sensitive psoriasis. 
Cardiomyopathy has been rarely reported with high daily dosages of hydroxychloroquine. 
 
 
42. Dosage and Administration 
One tablet of hydroxychloroquine sulfate, 200 mg, is equivalent to 155 mg base. 
Lupus erythematosus
Initially, the average adult dose is 400 mg (=310 mg base) once or twice 
daily. This may be continued for several weeks or months, depending on the response of the 
patient. For prolonged maintenance therapy, a smaller dose, from 200 mg to 400 mg (=155 mg to 
310 mg base) daily will frequently suffice. 
The incidence of retinopathy has been reported to be higher when this maintenance dose is 
exceeded. 
Rheumatoid arthritis
The compound is cumulative in action and will require several weeks to 
exert its beneficial therapeutic effects, whereas minor side effects may occur relatively early. 
Several months of therapy may be required before maximum effects can be obtained. If objective 
improvement (such as reduced joint swelling, increased mobility) does not occur within six months, 
the drug should be discontinued. Safe use of the drug in the treatment of juvenile rheumatoid 
arthritis has not been established. 
Initial dosage
In adults, from 400 mg to 600 mg (=310 mg to 465 mg base) daily, each dose to be 
taken with a meal or a glass of milk. In a small percentage of patients, troublesome side effects may 
require temporary reduction of the initial dosage. Later (usually from five to ten days), the dose may 
gradually be increased to the optimum response level, often without return of side effects. 
Maintenance dosage
When a good response is obtained (usually in four to twelve weeks), the 
dosage is reduced by 50 percent and continued at a usual maintenance level of 200 mg to 400 mg 
(=155 mg to 310 mg base) daily, each dose to be taken with a meal or a glass of milk. The 
incidence of retinopathy has been reported to be higher when this maintenance dose is exceeded.
Should a relapse occur after medication is withdrawn, therapy may be resumed or continued on an 
intermittent schedule if there are no ocular contraindications. 
Corticosteroids and salicylates may be used in conjunction with this compound, and they can 
generally be decreased gradually in dosage or eliminated after the drug has been used for several 
weeks.  When gradual reduction of steroid dosage is indicated, it may be done by reducing every 
four to five days the dose of cortisone by no more than from 5 mg to 15 mg; of hydrocortisone from 
5 mg to 10 mg; of prednisolone and prednisone from 1 mg to 2.5 mg; of methylprednisolone and 
triamcinolone from 1 mg to 2 mg; and of dexamethasone from 0.25 mg to 0.5 mg. 


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43. HOW SUPPLIED 
PLAQUENIL tablets are white, to off-white, film 
in black ink. Each tablet contains 200 mg 
hydroxychloroquine sulfate (equivalent to 155 mg 
base).  Bottles of 100 tablets (NDC 0024-1562-10). 
Dispense in a tight, light-resistant container as 
defined in the USP/NF. Store at room temperature up 
to 30° C (86° F). 
sanofi-aventis U.S. LLC, Bridgewater, NJ 08807 
 
Revised October 2006 
 
©2006 sanofi-aventis U.S. LLC 
 
 


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APPENDIX C 
Letrozole Package Insert 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to 
use FEMARA safely and effectively. See full prescribing 
information for FEMARA. 
Femara (letrozole) tablets, for oral 
use Initial U.S. Approval: 1997 
----------------------------RECENT MAJOR CHANGES-------------------------- 
Contraindications (4)
7/201
7 
Warnings and Precautions, Embryo-Fetal Toxicity (5.6)
7/201
7 
----------------------------INDICATIONS AND USAGE--------------------------- 
Femara is an aromatase inhibitor indicated for: 
 Adjuvant treatment of postmenopausal women with hormone 
receptor positive early breast cancer (1.1) 
 Extended adjuvant treatment of postmenopausal women with early 
breast cancer who have received prior standard adjuvant tamoxifen 
therapy (1.2) 
 First and second-line treatment of postmenopausal women with 
hormone receptor positive or unknown advanced breast cancer 
(1.3)
-------------------------DOSAGE AND ADMINISTRATION--------------------- 
Femara tablets are taken orally without regard to meals (2): 
 Recommended dose: 2.5.mg once daily (2.1) 
 Patients with cirrhosis or severe hepatic impairment: 2.5 mg 
every other day (2.5, 5.3) 
-----------------------DOSAGE FORMS AND STRENGTHS-------------------
-
2.5 mg tablets (3) 
--------------------------------CONTRAINDICATIONS----------------------------- 
 Pregnancy (4) 
 Known hypersensitivity to the active substance, or to any of the 
excipients (4) 
-----------------------WARNINGS AND PRECAUTIONS----------------------- 
 Decreases in bone mineral density may occur. Consider bone 
mineral density monitoring (5.1) 
 Increases in total cholesterol may occur. Consider cholesterol 
monitoring. (5.2) 
 Fatigue, dizziness and somnolence may occur. Exercise 
caution when operating machinery (5.4) 
 Embryo-Fetal toxicity: Can cause fetal harm when 
administered to pregnant women. Obtain a pregnancy test in 
females of reproductive potential. Advise females of 
reproductive potential to use effective contraception (5.6, 8.1,
8.3) 
------------------------------ADVERSE REACTIONS-------------------------------
The most common adverse reactions (greater than 20%) were hot 
flashes, arthralgia; flushing, asthenia, edema, arthralgia, headache, 
dizziness, hypercholesterolemia, sweating increased, bone pain; and 
musculoskeletal (6). 
 
To report SUSPECTED ADVERSE REACTIONS, contact Novartis 
Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-
FDA- 1088 or www.fda.gov/medwatch. 
------------------------------USE IN SPECIFIC POPULATIONS-----------------
 Lactation: Advise not to breastfeed. (8.2) 
See 17 for PATIENT COUNSELING INFORMATION. 
 
Revised: 11/2017
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
1 
INDICATIONS AND USAGE 
1.1
Adjuvant Treatment of Early Breast Cancer 
1.2
Extended Adjuvant Treatment of Early Breast Cancer 
1.3
First and Second-Line Treatment of Advanced Breast 
Cancer
2 
DOSAGE AND ADMINISTRATION 
2.1
Recommended Dose 
2.2
Use in Adjuvant Treatment of Early Breast Cancer 
2.3
Use in Extended Adjuvant Treatment of Early Breast 
Cancer
2.4
Use in First and Second-Line Treatment of Advanced 
Breast Cancer 
2.5 
Use in Hepatic Impairment 
2.6 
Use in Renal Impairment 
3 
DOSAGE FORMS AND STRENGTHS 
4 
CONTRAINDICATIONS 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Bone Effects 
5.2 
Cholesterol 
5.3 
Hepatic Impairment 
5.4 
Fatigue and Dizziness 
5.5 
Laboratory Test Abnormalities 
5.6 
Embryo-Fetal Toxicity 
6 
ADVERSE REACTIONS 
6.1 
Clinical Trials Experience 
6.2 
Postmarketing Experience 


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7 
DRUG INTERACTIONS 
8 
USE IN SPECIFIC POPULATIONS 
8.1
Pregnancy 
8.2 
Lactation 
8.3 
Females and Males of Reproductive Potential 
8.4 
Pediatric Use 
8.5 
Geriatric Use 
10 
OVERDOSAGE 
11 
DESCRIPTION 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
12.2 
Pharmacodynamics 
12.3 
Pharmacokinetics 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 
CLINICAL STUDIES 
14.1 
Updated Adjuvant Treatment of Early Breast Cancer 
14.2 
Extended Adjuvant Treatment of Early Breast Cancer, 
Median Treatment Duration of 24 Months 
14.3 
Updated Analyses of Extended Adjuvant Treatment of
Early Breast Cancer, Median Treatment Duration of 60
Months 
14.4 
First-Line Treatment of Advanced Breast Cancer 
14.5 
Second-Line Treatment of Advanced Breast Cancer 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
17 
PATIENT COUNSELING INFORMATION 
 
*Sections or subsections omitted from the full prescribing information 
are not listed 
 


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44. 
FULL PRESCRIBING INFORMATION 
 
1
INDICATIONS AND USAGE 
1.1 
Adjuvant Treatment of Early Breast Cancer 
Femara (letrozole) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor 
positive early breast cancer. 
1.2 
Extended Adjuvant Treatment of Early Breast Cancer 
Femara is indicated for the extended adjuvant treatment of early breast cancer in postmenopausal women, 
who have received 5 years of adjuvant tamoxifen therapy. The effectiveness of Femara in extended 
adjuvant treatment of early breast cancer is based on an analysis of disease-free survival in patients treated 
with Femara for a median of 60 months [see Clinical Studies (14.2, 14.3)]. 
1.3 
First and Second-Line Treatment of Advanced Breast Cancer 
Femara is indicated for first-line treatment of postmenopausal women with hormone receptor positive or 
unknown, locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced 
breast cancer in postmenopausal women with disease progression following antiestrogen therapy [see Clinical 
Studies (14.4, 14.5)]. 
 
2
DOSAGE AND ADMINISTRATION 
2.1 
Recommended Dose 
The recommended dose of Femara is one 2.5 mg tablet administered once a day, without regard to meals. 
2.2 
Use in Adjuvant Treatment of Early Breast Cancer 
In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. In both the adjuvant study 
and the post approval adjuvant study, median treatment duration was 5 years. Treatment should be 
discontinued at relapse [see Clinical Studies (14.1)]. 
2.3 
Use in Extended Adjuvant Treatment of Early Breast Cancer 
In the extended adjuvant setting, the optimal treatment duration with Femara is not known. The planned 
duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up 
of 62 months, the median treatment duration for Femara was 60 months. Seventy-one (71%) percent of patients 
were treated for at least 3 years and 58% of patients completed at least 
4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies 
(14.2)].
2.4 
Use in First and Second-Line Treatment of Advanced Breast Cancer 
In patients with advanced disease, treatment with Femara should continue until tumor progression is evident [see 
Clinical Studies (14.4, 14.5)]. 
2.5 
Use in Hepatic Impairment 
No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although Femara 
blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. 
The dose of Femara in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see 


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Warnings and Precautions (5.3)]. The recommended dose of Femara for such patients is 2.5 mg administered 
every other day. The effect of hepatic impairment on Femara exposure in noncirrhotic cancer patients with 
elevated bilirubin levels has not been determined. 
2.6 
Use in Renal Impairment 
No dosage adjustment is required for patients with renal impairment if creatinine clearance is greater than or equal to 10 
mL/min [see Clinical Pharmacology (12.3)]. 
 
3
DOSAGE FORMS AND STRENGTHS 
2.5 mg tablets: dark yellow, film-coated, round, slightly biconvex, with beveled edges (imprinted with the 
letters FV on one side and CG on the other side). 
 
4
CONTRAINDICATIONS 
Pregnancy: Letrozole can cause fetal harm [see Use in Specific Populations (8.1)]. 
Known hypersensitivity to the active substance, or to any of the excipients [see Adverse Reactions (6)]. 


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5 
WARNINGS AND PRECAUTIONS 
5.1
Bone Effects
Use of Femara may cause decreases in bone mineral density (BMD). Consideration should be given to 
monitoring BMD. Results of a safety study to evaluate safety in the adjuvant setting comparing the effect on 
lumbar spine (L2-L4) BMD of adjuvant treatment with letrozole to that with tamoxifen showed at 24 months 
a median decrease in lumbar spine BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% 
in the tamoxifen arm (difference = 4.4%) (P <0.0001) [see Adverse Reactions (6)]. Updated results from the 
BMD substudy (MA-17B) in the extended adjuvant setting demonstrated that at 2 years patients receiving 
letrozole had a median decrease from baseline of 3.8% in hip BMD compared to a median decrease of 2.0% 
in the placebo group. The changes from baseline in lumbar spine BMD in letrozole and placebo treated 
groups were not significantly different [see Adverse Reactions (6)]. 
In the adjuvant trial (BIG 1-98) the incidence of bone fractures at any time after randomization was 14.7% for 
letrozole and 11.4% for tamoxifen at a median follow-up of 96 months. The incidence of osteoporosis was 
5.1% for letrozole and 2.7% for tamoxifen [see Adverse Reactions (6)]. In the extended adjuvant trial (MA-
17), the incidence of bone fractures at any time after randomization was 13.3% for letrozole and 7.8% for 
placebo at a median follow-up of 62 months. The incidence of new osteoporosis was 14.5% for letrozole and 
7.8% for placebo [see Adverse Reactions (6)]. 
5.2
Cholesterol 
Consideration should be given to monitoring serum cholesterol. In the adjuvant trial (BIG 1-98), 
hypercholesterolemia was reported in 52.3% of letrozole patients and 28.6% of tamoxifen patients. Grade 3-4 
hypercholesterolemia was reported in 0.4% of letrozole patients and 0.1% of tamoxifen patients. Also in the 
adjuvant setting, an increase of greater than or equal to 1.5 x upper limit of normal (ULN) in total cholesterol 
(generally nonfasting) was observed in patients on monotherapy who had baseline total serum cholesterol 
within the normal range (i.e., less than =1.5 x ULN) in 155/1843 (8.4%) patients on letrozole vs 71/1840 
(3.9%) patients on tamoxifen Lipid lowering medications were required for 29% of patients on letrozole and 
20% on tamoxifen [see Adverse Reactions (6)]. 
5.3
Hepatic Impairment 
Subjects with cirrhosis and severe hepatic impairment who were dosed with 2.5 mg of Femara experienced 
approximately twice the exposure to Femara as healthy volunteers with normal liver function [see Clinical 
Pharmacology (12.3)]. Therefore, a dose reduction is recommended for this patient population. The effect of 
hepatic impairment on Femara exposure in cancer patients with elevated bilirubin levels has not been 
determined [see Dosage and Administration (2.5)]. 
5.4
Fatigue and Dizziness 
Because fatigue, dizziness, and somnolence have been reported with the use of Femara, caution is advised 
when driving or using machinery until it is known how the patient reacts to Femara use. 
5.5
Laboratory Test Abnormalities 
No dose-related effect of Femara on any hematologic or clinical chemistry parameter was evident. Moderate 
decreases in lymphocyte counts, of uncertain clinical significance, were observed in some patients receiving 
Femara 2.5 mg. This depression was transient in about half of those affected. Two patients on Femara 
developed thrombocytopenia; relationship to the study drug was unclear. Patient withdrawal due to laboratory 
abnormalities, whether related to study treatment or not was infrequent. 


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5.6 
Embryo-Fetal Toxicity 
Based on post-marketing reports, findings from animal studies and the mechanism of action, Femara can cause 
fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during 
pregnancy resulted in cases of spontaneous abortions and congenital birth defects. Letrozole caused embryo-
fetal toxicities in rats and rabbits at maternal exposures that were below the maximum recommended human 
dose (MHRD) on a mg/m2 basis. Advise pregnant women of the potential risk to a fetus. Advise females of 
reproductive potential to use effective contraception during therapy with Femara and for at least 3 weeks after 
the last dose [see Adverse Reactions (6.2), Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology 
(12.1)]. 
 
6
ADVERSE REACTIONS 
The following adverse reactions are discussed in greater detail in other sections of the labeling. 
Bone effects [see Warnings and Precautions (5.1)] 
Increases in cholesterol [see Warnings and Precautions (5.2)] 
Fatigue and Dizziness [see Warnings and Precautions (5.4)] 


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6.1 
Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in 
the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and 
may not reflect the rates observed in practice. 
Adjuvant Treatment of Early Breast Cancer 
In study, BIG 1-98, the median treatment duration of adjuvant treatment was 60 months and the median 
duration of follow-up for safety was 96 months for patients receiving Femara and tamoxifen. 
Certain adverse reactions were prospectively specified for analysis (see Table 1), based on the known 
pharmacologic properties and side effect profiles of the two drugs. 
Adverse reactions were analyzed irrespective of whether a symptom was present or absent at baseline. Most 
adverse reactions reported (approximately 75% of patients who reported AEs) were Grade 1 or Grade 2 applying 
the Common Toxicity Criteria (CTC) Version 2.0/Common Terminology Criteria for Adverse Events (CTCAE), 
Version 3.0. Table 1 describes adverse reactions (Grades 1-4 and Grades 3-4) irrespective of relationship to study 
treatment in the adjuvant trial for the monotherapy arms analysis (safety population). 
45. 
Table 1: Patients with Adverse Reactions (CTC Grades 1-4,) in the Adjuvant Study  Monotherapy 
Arms Analysis (Median Follow-up 96 Months; Median Treatment 60 Months) 
 
Grades 1-4 
 
 
Grades 3-4 
 
 
Femara 
Tamoxifen 
Femara 
Tamoxifen 
Adverse Reactions 
N=2448 
N=2447 
N=2448 
N=2447 
 
n (%)  
n (%)  
n (%)  
n (%) 
Patients with any adverse reaction 
2309 
(94.3) 
2212 
(90.4) 
636 
(26.0) 
606 
(24.8)
Hypercholesterolemia* 
1280 
(52.3) 
700 
(28.6) 
11 
(0.4) 
6 
(0.2)
Hot flashes* 
819 
(33.5) 
929 
(38.0) 
- 
- 
- 
-
Arthralgia/arthritis* 
621 
(25.4) 
504 
(20.6) 
84 
(3.4) 
50 
(2.0)
Bone fractures1 
361 
(14.7) 
280 
(11.4) 
- 
- 
- 
-
Night sweats*
356 
(14.5) 
426 
(17.4) 
- 
- 
- 
-
Weight increase* 
317 
(12.9) 
378 
(15.4) 
27 
(1.1) 
39 
(1.6)
Nausea* 
284 
(11.6) 
277 
(11.3) 
6 
(0.2) 
9 
(0.4)
Bone fractures**2 
249 
(10.2) 
175 
(7.2) 
- 
- 
- 
-
Fatigue (lethargy, malaise, 
asthenia)* 
235 
(9.6) 
250 
(10.2) 
6 
(0.2) 
7 
(0.3)
Myalgia*
221 
(9.0) 
212 
(8.7) 
18 
(0.7) 
14 
(0.6)
Vaginal bleeding* 
129 
(5.3) 
320 
(13.1) 
1 
(<0.1) 
8 
(0.3)
Edema* 
164 
(6.7) 
160 
(6.5) 
3 
(0.1) 
1 
(<0.1)
Weight decrease 
140 
(5.7) 
129 
(5.3) 
8 
(0.3) 
5 
(0.2)
Osteoporosis** 
126 
(5.1) 
67 
(2.7) 
10 
(0.4) 
5 
(0.2)
Back pain
125 
(5.1) 
136 
(5.6) 
7 
(0.3) 
11 
(0.4)
Bone pain 
123 
(5.0) 
109 
(4.5) 
6 
(0.2) 
4 
(0.2)
Depression 
119 
(4.9) 
114 
(4.7) 
16 
(0.7) 
14 
(0.6)


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Vaginal irritation*
112
(4.6)
77
(3.1)
2
(<0.1)
2
(<0.1)
Headache* 
105 
(4.3) 
94 
(3.8) 
8 
(0.3) 
4 
(0.2)
Pain in extremity 
103 
(4.2) 
79 
(3.2) 
6 
(0.2) 
4 
(0.2)
Osteopenia*
87 
(3.6) 
76 
(3.1) 
0 
- 
3 
(0.1)
Dizziness/light-headedness* 
84 
(3.4) 
80 
(3.3) 
1 
(<0.1) 
6 
(0.2)
Alopecia 
83 
(3.4) 
84 
(3.4) 
- 
- 
- 
-
Vomiting* 
80 
(3.3) 
80 
(3.3) 
3 
(0.1) 
5 
(0.2)
Cataract* 
49 
(2.0) 
54 
(2.2) 
16 
(0.7) 
17 
(0.7)
Constipation* 
49 
(2.0) 
71 
(2.9) 
3 
(0.1) 
1 
(<0.1)


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Myocardial infarction1 
42 
(1.7) 
28 
(1.1) 
- 
- 
- 
-
Breast pain*
37 
(1.5) 
43 
(1.8) 
1 
(<0.1) 
- 
-
Anorexia* 
20 
(0.8) 
20 
(0.8) 
1 
(<0.1) 
1 
(<0.1)
Endometrial proliferation 
disorders*
14 
(0.6) 
86 
(3.5) 
0 
- 
14 
(0.6)
Ovarian cyst* 
11 
(0.4) 
18 
(0.7) 
4 
(0.2) 
4 
(0.2)
Endometrial 
hyperplasia/cancer**1 
11 
(0.4) 
72 
(2.9) 
- 
- 
- 
-
Endometrial 
hyperplasia/cancer**,3 
6/1909 
(0.3) 
57/1943 
(2.9) 
- 
- 
- 
-
Other endometrial disorders* 
2 
(<0.1) 
3 
(0.1) 
0 
- 
0 
-
Myocardial infarction**2 
24 
(1.0) 
12 
(0.5) 
- 
- 
- 
-
Myocardial ischemia 
6 
(0.2) 
9 
(0.4) 
- 
- 
- 
-
Cerebrovascular accident/TIA**1 
74 
(3.0) 
68 
(2.8) 
- 
- 
- 
-
Cerebrovascular accident/TIA**2 
51 
(2.1) 
47 
(1.9) 
- 
- 
- 
-
Angina requiring surgery**1 
35 
(1.4) 
33 
(1.3) 
- 
- 
- 
-
Angina requiring surgery**2 
25 
(1.0) 
25 
(1.0) 
- 
- 
- 
-
Thromboembolic event**1 
79 
(3.2) 
113 
(4.6) 
- 
- 
- 
-
Thromboembolic event**2 
51 
(2.1) 
89 
(3.6) 
- 
- 
- 
-
Cardiac failure1 
39 
(1.6) 
34 
(1.4) 
- 
- 
- 
-
Cardiac failure2 
27 
(1.1) 
15 
(0.6) 
- 
- 
- 
-
Hypertension1 
160 
(6.5) 
175 
(7.2) 
- 
- 
- 
-
Hypertension2 
138 
(5.6) 
139 
(5.7) 
- 
- 
- 
-
Other cardiovascular**1 
172 
(7.0) 
174 
(7.1) 
- 
- 
- 
-
Other cardiovascular**2 
120 
(4.9) 
119 
(4.9) 
- 
- 
- 
-
Second primary malignancy1 
129 
(5.3) 
150 
(6.1) 
- 
- 
- 
-
Second primary malignancy2 
54 
(2.2) 
79 
(3.2) 
- 
- 
- 
-
* Target events pre-specified for analysis 
** Events pre-printed on CRF 
1At median follow-up of 96 months (i.e. any time after randomization) for Femara (range up to 144 months) and 95 months for 
tamoxifen (range up to 143 months ) 
2At median treatment duration of 60 months (i.e. during treatment + 30 days after discontinuation of treatment) for Femara and 
tamoxifen (range up to 68 months) 
3Excluding women who had undergone hysterectomy before study entry 
TIA = Transient ischemic attack 
Note: Cardiovascular events (including cerebrovascular and thromboembolic events), skeletal and urogenital/endometrial events and 
second primary malignancies were collected life -long. All of these events were assumed to be of CTC Grade 3 to 5 and were not 
individually graded 
When considering all grades during study treatment, a higher incidence of events was seen for Femara 
regarding fractures (10.1% vs 7.1%), myocardial infarctions (1.0% vs 0.5%), and arthralgia (25.2% vs 
20.4%) (Femara vs tamoxifen respectively). A higher incidence was seen for tamoxifen regarding 
thromboembolic events (2.1% vs 3.6%), endometrial hyperplasia/cancer (0.3% vs 2.9%), and endometrial 
proliferation disorders (0.3% vs 1.8%) (Femara vs tamoxifen respectively). 


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At a median follow-up of 96 months, a higher incidence of events was seen for Femara (14.7%) than for 
tamoxifen (11.4%) regarding fractures. A higher incidence was seen for tamoxifen compared to Femara 
regarding thromboembolic events (4.6% vs 3.2%), and endometrial hyperplasia or cancer (2.9% vs 0.4%) 
(tamoxifen vs Femara, respectively).
Bone Study: Results of a safety trial in 263 postmenopausal women with resected receptor positive early 
breast cancer in the adjuvant setting comparing the effect on lumbar spine (L2-L4) BMD of adjuvant 
treatment with letrozole to that with tamoxifen showed at 24 months a median decrease in lumbar spine 
BMD of 4.1% in the letrozole arm compared to a median increase of 0.3% in the tamoxifen arm (difference = 
4.4%) (P <0.0001). No patients with a normal BMD at baseline became osteoporotic over the 2 years and 
only 1 patient with osteopenia at baseline (T score of -1.9) developed 


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osteoporosis during the treatment period (assessment by central review). The results for total hip BMD 
were similar, although the differences between the two treatments were less pronounced. During the 2 
year period, fractures were reported by 4 of 103 patients (4%) in the letrozole arm, and 6 of 97 patients 
(6%) in the tamoxifenarm.
Lipid Study: In a safety trial in 263 postmenopausal women with resected receptor positive early breast 
cancer at 24 months comparing the effects on lipid profiles of adjuvant letrozole to tamoxifen, 12% of 
patients on letrozole had at least one total cholesterol value of a higher CTCAE grade than at baseline 
compared with 4% of patients on tamoxifen. In another postapproval randomized, multicenter, open label, 
study of letrozole vs anastrozole in the adjuvant treatment of postmenopausal women with hormone 
receptor and node positive breast cancer (FACE, NCT00248170), the median duration of treatment was 60 
months for both treatment arms. Table 2 describes adverse reactions (Grades 1-4 and Grades 3-4) 
irrespective of relationship to study treatment in the adjuvant study (safety population). 
Table 2: Adverse Reactions (CTC Grades 1-4), Occurring in at least 5% of Patients in Either Treatment 
Arm, by Preferred Term (Safety set) 
 
 
 
Adverse Reactions 
Letrozole 
N = 2049 
n (%) 
Anastrozole 
N = 2062 
n (%) 
 
Grade 3/4 
n (%) 
All grades 
n (%) 
Grade 3/4 
n (%) 
All grades 
n (%) 
Patients with at least one AR
628 (30.6)
2049 (100.0)
591 (28.7)
2062 (100.0)
Arthralgia 
80 (3.9) 
987 (48.2) 
69 (3.3) 
987 (47.9) 
Hot flush 
17 (0.8) 
666 (32.5) 
9 (0.4) 
666 (32.3) 
Fatigue 
8 (0.4) 
345 (16.8) 
10 (0.5) 
343 (16.6) 
Osteoporosis 
5 (0.2) 
223 (10.9) 
11 (0.5) 
225 (10.9) 
Myalgia 
16 (0.8) 
233 (11.4) 
15 (0.7) 
212 (10.3) 
Back pain 
11 (0.5) 
212 (10.3) 
17 (0.8) 
193 (9.4) 
Osteopenia 
4 (0.2) 
203 (9.9) 
1 (0.0) 
173 (8.4) 
Pain in extremity 
9 (0.4) 
168 (8.2) 
3 (0.1) 
174 (8.4) 
Lymphoedema 
5 (0.2) 
159 (7.8) 
2 (0.1) 
179 (8.7) 
Insomnia
7 (0.3) 
160 (7.8) 
3 (0.1) 
149 (7.2) 
Hypercholesterolaemia 
2 (0.1) 
155 (7.6) 
1 (0.0) 
151 (7.3) 
Hypertension 
25 (1.2) 
156 (7.6) 
20 (1.0) 
149 (7.2) 
Depression 
16 (0.8) 
147 (7.2) 
13 (0.6) 
137 (6.6) 
Bone pain 
10 (0.5) 
138 (6.7) 
9 (0.4) 
122 (5.9) 
Nausea 
6 (0.3) 
137 (6.7) 
5 (0.2) 
152 (7.4) 
Headache 
3 (0.1) 
130 (6.3) 
5 (0.2) 
168 (8.1) 
Alopecia 
2 (0.1) 
127 (6.2) 
0 (0.0) 
134 (6.5) 
Musculoskeletal pain 
6 (0.3) 
123 (6.0) 
9 (0.4) 
147 (7.1) 
Radiation skin injury 
11 (0.5) 
120 (5.9) 
6 (0.3) 
88 (4.3) 
Dyspnoea
16 (0.8) 
118 (5.8) 
10 (0.5) 
96 (4.7) 
Cough
1 (0.0) 
106 (5.2) 
1 (0.0) 
120 (5.8) 
Musculoskeletal stiffness 
2 (0.1) 
102 (5.0) 
2 (0.1) 
84 (4.1) 
Dizziness
2 (0.2) 
94 (4.6) 
7 (0.3) 
109 (5.3) 
The following adverse reactions were also identified in less than 5% of the 2049 patients treated with letrozole 


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and not included in the table: fall, vertigo, hyperbilirubinemia, jaundice, and chest pain. 
Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months
In study MA-17, the median duration of extended adjuvant treatment was 24 months and the median 
duration of follow-up for safety was 28 months for patients receiving Femara and placebo. 
Table 3 describes the adverse reactions occurring at a frequency of at least 5% in any treatment group 
during treatment. Most adverse reactions reported were Grade 1 and Grade 2 based on the CTC Version 
2.0. In the extended adjuvant setting, the reported drug-related adverse reactions that were significantly 
different from placebo were hot flashes, arthralgia/arthritis, and myalgia. 
Table 3: Adverse Reactions Occurring in at least 5% of Patients in either Treatment Arm 


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Number (%) of Patients with Grade 1-4 
Adverse Reactions
Number (%) of Patients with Grade 3-4 
Adverse Reactions
 
Femara 
Placebo 
Femara 
Placebo 
N=2563
N=2573
N=2563
N=2573
Any Adverse Reactions 
2232 (87.1) 
2174 (84.5) 
419 (16.3) 
389 (15.1) 
Vascular Disorders 
1375 (53.6) 
1230 (47.8) 
59 (2.3) 
74 (2.9) 
Flushing 
1273 (49.7) 
1114 (43.3) 
3 (0.1) 
0 
General Disorders 
1154 (45) 
1090 (42.4) 
30 (1.2) 
28 (1.1) 
Asthenia 
862 (33.6) 
826 (32.1) 
16 (0.6) 
7 (0.3) 
Edema NOS 
471 (18.4) 
416 (16.2) 
4 (0.2) 
3 (0.1) 
Musculoskeletal Disorders 
978 (38.2) 
836 (32.5) 
71 (2.8) 
50 (1.9) 
Arthralgia 
565 (22) 
465 (18.1) 
25 (1) 
20 (0.8) 
Arthritis NOS 
173 (6.7) 
124 (4.8) 
10 (0.4) 
5 (0.2) 
Myalgia 
171 (6.7) 
122 (4.7) 
8 (0.3) 
6 (0.2) 
Back Pain 
129 (5) 
112 (4.4) 
8 (0.3) 
7 (0.3) 
Nervous System Disorders 
863 (33.7) 
819 (31.8) 
65 (2.5) 
58 (2.3) 
Headache 
516 (20.1) 
508 (19.7) 
18 (0.7) 
17 (0.7) 
Dizziness 
363 (14.2) 
342 (13.3) 
9 (0.4) 
6 (0.2) 
Skin Disorders 
830 (32.4) 
787 (30.6) 
17 (0.7) 
16 (0.6) 
Sweating Increased 
619 (24.2) 
577 (22.4) 
1 (<0.1) 
0 
Gastrointestinal Disorders 
725 (28.3) 
731 (28.4) 
43 (1.7) 
42 (1.6) 
Constipation 
290 (11.3) 
304 (11.8) 
6 (0.2) 
2 (<0.1) 
Nausea 
221 (8.6) 
212 (8.2) 
3 (0.1) 
10 (0.4) 
Diarrhea NOS 
128 (5) 
143 (5.6) 
12 (0.5) 
8 (0.3) 
Metabolic Disorders 
551 (21.5) 
537 (20.9) 
24 (0.9) 
32 (1.2) 
Hypercholesterolemia 
401 (15.6) 
398 (15.5) 
2 (<0.1) 
5 (0.2) 
Reproductive Disorders 
303 (11.8) 
357 (13.9) 
9 (0.4) 
8 (0.3) 
Vaginal Hemorrhage 
123 (4.8) 
171 (6.6) 
2 (<0.1) 
5 (0.2) 
Vulvovaginal Dryness 
137 (5.3) 
127 (4.9) 
0 
0 
Psychiatric Disorders 
320 (12.5) 
276 (10.7) 
21 (0.8) 
16 (0.6) 
Insomnia 
149 (5.8) 
120 (4.7) 
2 (<0.1) 
2 (<0.1) 
Respiratory Disorders 
279 (10.9) 
260 (10.1) 
30 (1.2) 
28 (1.1) 
Dyspnea 
140 (5.5) 
137 (5.3) 
21 (0.8) 
18 (0.7) 
Investigations 
184 (7.2) 
147 (5.7) 
13 (0.5) 
13 (0.5) 
Infections and Infestations 
166 (6.5) 
163 (6.3) 
40 (1.6) 
33 (1.3) 
Renal Disorders 
130 (5.1) 
100 (3.9) 
12 (0.5) 
6 (0.2) 
Based on a median follow-up of patients for 28 months,the incidence of clinical fractures from the core 
randomized study in patients who received Femara was 5.9% (152) and placebo was 5.5% (142). The incidence 
of self-reported osteoporosis was higher in patients who received Femara 6.9% (176) than in patients who 
received placebo 5.5% (141). Bisphosphonates were administered to 21.1% of the patients who received Femara 
and 18.7% of the patients who received placebo. 
The incidence of cardiovascular ischemic events from the core randomized study was comparable between 
patients who received Femara 6.8% (175) and placebo 6.5% (167). 
A patient-reported measure that captures treatment impact on important symptoms associated with estrogen 
deficiency demonstrated a difference in favor of placebo for vasomotor and sexual symptom domains. 


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Bone Substudy: [see Warnings and Precautions (5.1)]
Lipid Substudy: In the extended adjuvant setting, based on a median duration of follow-up of 62 months, there 
was no significant difference between Femara and placebo in total cholesterol or in any lipid fraction at any 
time over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed [see 
Warnings and Precautions (5.2)]. 
45.9 
Updated Analysis, Extended Adjuvant Treatment of Early Breast Cancer, Median 
Treatment Duration of 60 Months 
The extended adjuvant treatment trial (MA-17) was unblinded early [see Adverse Reactions (6)]. At the 
updated (final analysis), overall the side effects seen were consistent to those seen at a median treatment 
duration of 24 months. 
During treatment or within 30 days of stopping treatment (median duration of treatment 60 months) a higher 
rate of fractures was observed for Femara (10.4%) compared to placebo (5.8%), as also a higher rate of 
osteoporosis (Femara 12.2% vs placebo 6.4%). 
Based on 62 months median duration of follow-up in the randomized letrozole arm in the safety population 
the incidence of new fractures at any time after randomization was 13.3% for letrozole and 7.8% for 
placebo. The incidence of new osteoporosis was 14.5% for letrozole and 7.8% for placebo. 
During treatment or within 30 days of stopping treatment (median duration of treatment 60 months), the 
incidence of cardiovascular events was 9.8% for Femara and 7.0% for placebo. 
Based on 62 months median duration of follow-up in the randomized letrozole arm in the safety 
population the incidence of cardiovascular disease at any time after randomization was 14.4% for 
letrozole and 9.8% for placebo. 
Lipid substudy: In the extended adjuvant setting (MA-17), based on a median duration of follow-up of 62 
months, there was no significant difference between Femara and placebo in total cholesterol or in any lipid 
fraction over 5 years. Use of lipid lowering drugs or dietary management of elevated lipids was allowed 
[see Warnings and Precautions (5.2)]. 
45.10 
First-Line Treatment of Advanced Breast Cancer 
In study P025 a total of 455 patients were treated for a median time of exposure of 11 months in the Femara arm 
(median 6 months in the tamoxifen arm). The incidence of adverse reactions was similar for Femara and 
tamoxifen. The most frequently reported adverse reactions were bone pain, hot flushes, back pain, nausea, 
arthralgia and dyspnea. Discontinuations for adverse reactions other than progression of tumor occurred in 
10/455 (2%) of patients on Femara and in 15/455 (3%) of patients on tamoxifen. 
Adverse reactions that were reported in at least 5% of the patients treated with Femara 2.5 mg or tamoxifen 
20 mg in the first-line treatment study are shown in Table 4. 
46. 
Table 4: Adverse Reactions Occurring in at least 5% of Patients in either Treatment Arm 
 
Adverse
Femara
Tamoxifen
Reactions
2.5 mg 
20 mg 
(N=455) 
(N=455) 
% 
% 
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Fatigue 
13 
13 
Chest Pain 
8 
9 
Edema Peripheral 
5 
6 
Pain NOS 
5 
7 
Weakness 
6 
4 
Investigations 
Weight Decreased 
7 
5 
Vascular Disorders 
Hot Flushes 
19 
16 
Hypertension 
8 
4 
Gastrointestinal Disorders 
Nausea 
17 
17 
Constipation 
10 
11 
Diarrhea 
8 
4 
Vomiting 
7 
8 
Infections/Infestations 
Influenza 
6 
4 
Urinary Tract Infection NOS 
6 
3 
Injury, Poisoning and Procedural Complications 
Post-Mastectomy Lymphedema 
7 
7 
Metabolism and Nutrition Disorders 
Anorexia 
4 
6 
Musculoskeletal and Connective Tissue Disorders 
Bone Pain 
22 
21 
Back Pain 
18 
19 
Arthralgia 
16 
15 
Pain in Limb 
10 
8 
Nervous System Disorders 
Headache NOS 
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7 


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Psychiatric Disorders
Insomnia 
7 
4 
Reproductive System and Breast Disorders 
Breast Pain 
7 
7 
Respiratory, Thoracic and Mediastinal Disorders 
 
 
Dyspnea 
18 
17 
Cough 
13 
13 
Chest Wall Pain 
6 
6 
Other less frequent (less than or equal to 2%) adverse reactions considered consequential for both treatment 
groups, included peripheral thromboembolic events, cardiovascular events, and cerebrovascular events. 
Peripheral thromboembolic events included venous thrombosis, thrombophlebitis, portal vein thrombosis and 
pulmonary embolism. Cardiovascular events included angina, myocardial infarction, myocardial ischemia, and 
coronary heart disease. Cerebrovascular events included transient ischemic attacks, thrombotic or hemorrhagic 
strokes and development of hemiparesis. 
46.9 
Second-Line Treatment of Advanced Breast Cancer 
Study discontinuations in the megestrol acetate comparison study (AR/BC2) for adverse reactions other than 
progression of tumor were 5/188 (2.7%) on Femara 0.5 mg, in 4/174 (2.3%) on Femara 2.5 mg, and in 15/190 
(7.9%) on megestrol acetate. There were fewer thromboembolic events at both Femara doses than on the 
megestrol acetate arm (0.6% vs 4.7%). There was also less vaginal bleeding (0.3% vs 3.2%) on Femara than on 
megestrol acetate. In the aminoglutethimide comparison study (AR/BC3), discontinuations for reasons other 
than progression occurred in 6/193 (3.1%) on 0.5 mg Femara, 7/185 (3.8%) on 2.5 mg Femara, and 7/178 
(3.9%) of patients on aminoglutethimide. 
Comparisons of the incidence of adverse reactions revealed no significant differences between the high and 
low dose Femara groups in either study. Most of the adverse reactions observed in all treatment groups were 
mild to moderate in severity and it was generally not possible to distinguish adverse reactions due to treatment 
intercurrent illness. 
Adverse reactions that were reported in at least 5% of the patients treated with Femara 0.5 mg, Femara 2.5 mg, 
megestrol acetate, or aminoglutethimide in the two controlled trials AR/BC2 and AR/BC3 are shown in Table 5. 
47. 
Table 5: Adverse Reactions Occurring at a Frequency of at Least 5% of Patients in Either 
Treatment Arm 
 
Adverse 
Pooled 
Pooled 
megestrol 
Reactions 
Femara 
Femara 
acetate 
aminoglutethimide 
2.5 mg 
0.5 mg 
160 mg 
500 mg 
(N=359) 
(N=380) 
(N=189) 
(N=178) 
% 
% 
% 
% 
Body as a Whole 
 
 
 
 
Chest Pain 
 
6 
 
3 
 
7 
 
3 
Peripheral Edema1 
5 
5 
8 
3 
Asthenia 
4 
5 
4 
5 
Weight Increase 
2 
2 
9 
3 
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Hypertension
5
7
5
6
Digestive System 
Nausea
13
15
9
14
Vomiting 
7 
7 
5 
9 
Constipation 
6 
7 
9 
7 
Diarrhea 
6 
5 
3 
4 
Pain-Abdominal 
6 
5 
9 
8 
Anorexia 
5 
3 
5 
5 
Dyspepsia 
3 
4 
6 
5 
Infections/Infestations 
Viral Infection 
6 
5 
6 
3 
Lab Abnormality 
Hypercholesterolemia 
3 
3 
0 
6 
Musculoskeletal System 
Musculoskeletal2 
21 
22 
30 
14 
Arthralgia 
8 
8 
8 
3 
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Headache
9
12
9
7
Somnolence 
3 
2 
2 
9 
Dizziness
3
5
7
3
Respiratory System 
Dyspnea 
7 
9 
16 
5 
Coughing 
6 
5 
7 
5 
Skin and Appendages 
Hot Flushes 
6 
5 
4 
3 
Rash3
5 
4 
3 
12 
Pruritus 
1 
2 
5 
3 
1Includes peripheral edema, leg edema, dependent edema, edema 
2Includes musculoskeletal pain, skeletal pain, back pain, arm pain, leg pain 
3Includes rash, erythematous rash, maculopapular rash, psoriasiform rash, vesicular rash 
Other less frequent (less than 5%) adverse reactions considered consequential and reported in at least 3 patients 
treated with Femara, included hypercalcemia, fracture, depression, anxiety, pleural effusion, alopecia, increased 
sweating and vertigo. 
47.9 
First and Second-Line Treatment of Advanced Breast Cancer 
In the combined analysis of the first- and second-line metastatic trials and postmarketing experiences other 
adverse reactions that were reported were cataract, eye irritation, palpitations, cardiac failure, tachycardia, 
dysesthesia (including hypesthesia/paresthesia), arterial thrombosis, memory impairment, irritability, 
nervousness, urticaria, increased urinary frequency, leukopenia, stomatitis cancer pain, pyrexia, vaginal 
discharge, appetite increase, dryness of skin and mucosa (including dry mouth), and disturbances of taste and 
thirst. 
6.2 
Postmarketing Experience 
The following adverse reactions have been identified during postapproval use of Femara. Because these 
reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably 
estimate their frequency or establish a causal relationship to drug exposure. 
 
Eye Disorders:  blurred vision 
 
Hepatobiliary Disorders: increased hepatic enzymes, hepatitis 
 
Immune System Disorders: anaphylactic reactions, hypersensitivity reactions 
 
Nervous System Disorders: carpal tunnel syndrome, trigger finger 
 
Pregnancy: spontaneous abortions, congenital birth defects 
 
Skin and subcutaneous disorders: angioedema, toxic epidermal necrolysis, erythema multiforme 
 
7
DRUG INTERACTIONS 
47.9.1.1
Tamoxifen 
Coadministration of Femara and tamoxifen 20 mg daily resulted in a reduction of letrozole plasma levels of 
38% on average (study P015). Clinical experience in the second-line breast cancer trials (AR/BC2 and 
AR/BC3) indicates that the therapeutic effect of Femara therapy is not impaired if Femara is administered 
immediately after tamoxifen. 


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47.9.1.2
Cimetidine 
A pharmacokinetic interaction study with cimetidine (study P004) showed no clinically significant 
effect on letrozole pharmacokinetics. 
47.9.1.3
Warfarin 
An interaction study (P017) with warfarin showed no clinically significant effect of letrozole on warfarin 
pharmacokinetics. 
 
47.9.1.4
Other anticancer agents 
There is no clinical experience to date on the use of Femara in combination with other anticancer agents. 


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8
USE IN SPECIFIC POPULATIONS 
8.1
Pregnancy
Risk Summary 
Based on postmarketing reports, findings from animal studies and the mechanism of action, Femara can cause 
fetal harm and is contraindicated for use in pregnant women. In post-marketing reports, use of letrozole during 
pregnancy resulted in cases of spontaneous abortions and congenital birth defects; however, the data are 
insufficient to inform a drug-associated risk [see Contraindications (4), Warnings and Precautions (5.6), Adverse 
Reactions (6.2), and Clinical Pharmacology (12.1)]. 
In animal reproduction studies, administration of letrozole to pregnant animals during organogenesis resulted in 
increased post- implantation pregnancy loss and resorption, fewer live fetuses, and fetal malformation affecting 
the renal and skeletal systems in rats and rabbits at doses approximately 0.1 times the daily maximum 
recommended human dose (MRHD) on a mg/m2 basis (see Data). 
The background risk of major birth defects and miscarriage for the indicated population is unknown. However, 
the background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-
20% of clinically recognized pregnancies. 
Data 
Animal Data
In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole 
starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-
0.003 mg/kg/day (approximately 0.01 times the maximum recommended human dose on a mg/m2 basis). 
In an embryo-fetal developmental toxicity study in rats, daily administration of oral letrozole during the period 
a mg/m2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorptions and 
postimplantation loss, decreased numbers of live fetuses and fetal anomalies including absence and shortening of 
renal papilla, dilation of ureter, edema and incomplete ossification of frontal skull and metatarsals. Letrozole was 
teratogenic to rats at a dose of 0.03 mg/kg (approximately 0.01 times the maximum recommended human dose 
on a mg/m2 basis) and caused fetal domed head and cervical/centrum vertebral fusion. 
In the embryo-fetal development toxicity study in rabbits, daily administration of oral letrozole during the period 
a mg/m2 basis) resulted in embryo-fetal toxicity including intrauterine mortality, increased resorption, increased 
postimplantation loss and decreased numbers of live fetuses. Fetal anomalies included incomplete ossification of 
the skull, sternebrae, and fore- and hind legs. 
8.2 
Lactation 
Risk Summary 
It is not known if letrozole is present in human milk. There are no data on the effects of letrozole on the breastfed 
infant or milk production. Exposure of lactating rats to letrozole was associated with impaired reproductive 
performance of the male offspring (see Data). Because of the potential for serious adverse reactions in breastfed 
infants from Femara, advise lactating women not to breastfeed while taking Femara and for at least 3 weeks after 
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Data
Animal Data
In a postnatal developmental toxicity study in lactating rats, letrozole was administered orally at doses of 1, 
0.003, 0.03 or 0.3 mg/kg/day on day 0 through day 20 of lactation. The reproductive performance of the male 
offspring was impaired at letrozole dose as low as 0.003 mg/kg/day (approximately 0.01 times the maximum 
recommended human dose on a mg/m2 basis), as reflected by decreased mating and pregnancy ratios. There were 
no effects on the reproductive performance of female offspring. 
 
8.3
Females and Males of Reproductive Potential 
Pregnancy Testing 
Based on animal studies, Femara can cause fetal harm when administered to a pregnant woman [see Use in 
Specific Populations (8.1)]. Females of reproductive potential should have a pregnancy test prior to starting 
treatment with Femara. 
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Based on animal studies, Femara can cause fetal harm when administered to a pregnant woman [see Use in 
Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during 
treatment with Femara and for at least 3 weeks after the last dose. 
Infertility 
Females 
Based on studies in female animals, Femara may impair fertility in females of reproductive potential [see Nonclinical 
Toxicology (13.1)]. 
Males 
Based on studies in male animals, Femara may impair fertility in males of reproductive potential [see Nonclinical 
Toxicology (13.1)]. 
8.4 
Pediatric Use 
The safety and effectiveness in pediatric patients have not been established. 
Letrozole administration to young (postnatal day 7) rats for 12 weeks duration at 0.003, 0.03, 0.3 mg/kg/day by 
oral gavage resulted in adverse skeletal/growth effects (bone maturation, bone mineral density) and 
neuroendocrine and reproductive developmental perturbations of the hypothalamic-pituitary axis. Administration 
of 0.3 mg/kg/day resulted in AUC values that were similar to the AUC in adult patients receiving the 
recommended dose of 2.5 mg/day. Decreased fertility was accompanied by hypertrophy of the hypophysis and 
testicular changes that included degeneration of the seminiferous tubular epithelium and atrophy of the female 
reproductive tract. Young rats in this study were allowed to recover following discontinuation of letrozole 
treatment for 42 days. 
Histopathological changes were not reversible at clinically relevant exposures. 
8.5 
Geriatric Use 
The median age of patients in all studies of first-line and second-line treatment of metastatic breast cancer was 
64-65 years. About 1/3 of the patients were greater than or equal to 70 years old. In the first-line study, patients 
greater than or equal to 70 years of age experienced longer time to tumor progression and higher response rates 
than patients less than 70. 
For the extended adjuvant setting (MA-17), more than 5,100 postmenopausal women were enrolled in the 
clinical study. In total, 41% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. 
In the extended adjuvant setting, no overall differences in safety or efficacy were observed between these older 
patients and younger patients, and other reported clinical experience has not identified differences in responses 
between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 
In the adjuvant setting (BIG 1-98), more than 8,000 postmenopausal women were enrolled in the clinical study. 
In total, 36% of patients were aged 65 years or older at enrollment, while 12% were 75 or older. More adverse 
reactions were generally reported in elderly patients irrespective of study treatment allocation. However, in 
comparison to tamoxifen, no overall differences with regards to the safety and efficacy profiles were observed 
between elderly patients and younger patients. 
 
10 
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Isolated cases of Femara overdose have been reported. In these instances, the highest single dose ingested was 
62.5 mg or 25 tablets. While no serious adverse reactions were reported in these cases, because of the limited 
data available, no firm recommendations for treatment can be made. However, emesis could be induced if the 
patient is alert. In general, supportive care and frequent monitoring of vital signs are also appropriate. In single-
dose studies, the highest dose used was 30 mg, which was well tolerated; in multiple-dose trials, the largest dose 
of 10 mg was well tolerated. 
Lethality was observed in mice and rats following single oral doses that were equal to or greater than 2,000 
mg/kg (about 4,000 to 8,000 times the daily maximum recommended human dose on a mg/m2 basis); death 
was associated with reduced motor activity, ataxia and dyspnea. Lethality was observed in cats following 
single IV doses that were equal to or greater than 10 mg/kg (about 50 times the daily maximum recommended 
human dose on a mg/m2 basis); death was preceded by depressed blood pressure and arrhythmias. 
 
11 
DESCRIPTION 
Femara tablets for oral administration contains 2.5 mg of letrozole, a nonsteroidal aromatase inhibitor (inhibitor 
of estrogen synthesis). It is chemically described as 4
-(1H-1, 2, 4-Triazol-1-ylmethylene) dibenzonitrile, and 
its structural formula is 


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Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, 
slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical 
formula C17H11N5, and a melting range of 184°C to 185°C. 
Femara is available as 2.5 mg tablets for oral administration. 
Inactive Ingredients: Colloidal silicon dioxide, ferric oxide, hydroxypropyl methylcellulose, lactose 
monohydrate, magnesium stearate, maize starch, microcrystalline cellulose, polyethylene glycol, sodium 
starch glycolate, talc, and titanium dioxide. 
 
12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
The growth of some cancers of the breast is stimulated or maintained by estrogens. Treatment of breast cancer 
thought to be hormonally responsive (i.e., estrogen and/or progesterone receptor positive or receptor unknown) 
has included a variety of efforts to decrease estrogen levels (ovariectomy, adrenalectomy, hypophysectomy) or 
inhibit estrogen effects (antiestrogens and progestational agents). These interventions lead to decreased tumor 
mass or delayed progression of tumor growth in some women. 
In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which 
converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The 
suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be 
achieved by specifically inhibiting the aromatase enzyme. 
Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of 
androgens to estrogens. In adult nontumor- and tumor-bearing female animals, letrozole is as effective as 
ovariectomy in reducing uterine weight, elevating serum LH, and causing the regression of estrogen-dependent 
tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum FSH. Letrozole 
selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or 
glucocorticoid synthesis. 
Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit 
of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. Treatment of women with 
letrozole significantly lowers serum estrone, estradiol and estrone sulfate and has not been shown to 
significantly affect adrenal corticosteroid synthesis, aldosterone synthesis, or synthesis of thyroid hormones. 


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12.2 
Pharmacodynamics 
In postmenopausal patients with advanced breast cancer, daily doses of 0.1 mg to 5 mg Femara (letrozole) 
suppress plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline with 
maximal suppression achieved within two- three days. Suppression is dose-related, with doses of 0.5 mg and 
higher giving many values of estrone and estrone sulfate that were below the limit of detection in the assays. 
Estrogen suppression was maintained throughout treatment in all patients treated at 0.5 mg or higher. 
Letrozole is highly specific in inhibiting aromatase activity. There is no impairment of adrenal steroidogenesis. 
No clinically-relevant changes were found in the plasma concentrations of cortisol, aldosterone, 11-
deoxycortisol, 17-hydroxy-progesterone, ACTH or in plasma renin activity among postmenopausal patients 
treated with a daily dose of Femara 0.1 mg to 5 mg. The ACTH stimulation test performed after 6 and 12 weeks 
of treatment with daily doses of 0.1, 0.25, 0.5, 1, 2.5, and 5 mg did not indicate any attenuation of aldosterone or 
cortisol production. Glucocorticoid or mineralocorticoid supplementation is, therefore, not necessary. 
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone) among 
healthy postmenopausal women after 0.1, 0.5, and 2.5 mg single doses of Femara or in plasma concentrations 
of androstenedione among postmenopausal patients treated with daily doses of 0.1 mg to 5 mg. This indicates 
that the blockade of estrogen biosynthesis does not lead to accumulation of androgenic precursors. Plasma 
levels of LH and FSH were not affected by letrozole in patients, nor was thyroid function as evaluated by TSH 
levels, T3 uptake, and T4 levels. 


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12.3 
Absorption and Distribution: Letrozole is rapidly and completely absorbed from the gastrointestinal tract and 
absorption is not affected by food. It is metabolized slowly to an inactive metabolite whose glucuronide 
conjugate is excreted renally, representing the major clearance pathway. About 90% of radiolabeled letrozole is 
-life is about 2 days and steady-state plasma 
concentration after daily 2.5 mg dosing is reached in 2-6 weeks. Plasma concentrations at steady state are 1.5 to 
2 times higher than predicted from the concentrations measured after a single dose, indicating a slight non-
linearity in the pharmacokinetics of letrozole upon daily administration of 2.5 mg. These steady-state levels are 
maintained over extended periods, however, and continuous accumulation of letrozole does not occur. Letrozole 
is weakly protein bound and has a large volume of distribution (approximately 1.9 L/kg). 
Elimination 
Metabolism and Excretion: Metabolism to a pharmacologically-inactive carbinol metabolite (4,4'-methanol-
bisbenzonitrile) and renal excretion of the glucuronide conjugate of this metabolite is the major pathway of 
letrozole clearance. Of the radiolabel recovered in urine, at least 75% was the glucuronide of the carbinol 
metabolite, about 9% was two unidentified metabolites, and 6% was unchanged letrozole. 
In human microsomes with specific CYP isozyme activity, CYP3A4 metabolized letrozole to the carbinol 
metabolite while CYP2A6 formed both this metabolite and its ketone analog. In human liver microsomes, 
letrozole inhibited CYP2A6 and CYP2C19, however, the clinical significance of these findings is unknown. 
Specific Populations 
Pediatric, Geriatric and Race: In the study populations (adults ranging in age from 35 to greater than 80 years), 
no change in pharmacokinetic parameters was observed with increasing age. Differences in letrozole 
pharmacokinetics between adult and pediatric populations have not been studied. Differences in letrozole 
pharmacokinetics due to race have not been studied. 
Renal Impairment: In a study of volunteers with varying renal function (24-hour creatinine clearance: 9 to 116 
mL/min), no effect of renal function on the pharmacokinetics of single doses of 2.5 mg of Femara was found. In 
addition, in a study (AR/BC2) of 347 patients with advanced breast cancer, about half of whom received 2.5 mg 
Femara and half 0.5 mg Femara, renal impairment (calculated creatinine clearance: 20 to 50 mL/min) did not 
affect steady-state plasma letrozole concentrations. 
Hepatic Impairment: In a study of subjects with mild to moderate non-metastatic hepatic dysfunction (e.g., 
cirrhosis, Child-Pugh classification A and B), the mean area under curve (AUC) values of the volunteers 
with moderate hepatic impairment were 37% higher than in normal subjects, but still within the range seen in 
subjects without impaired function. 
In a pharmacokinetic study, subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh 
classification C, which included bilirubins about 2-11 times ULN with minimal to severe ascites) had two-fold 
increase in exposure (AUC) and 47% reduction in systemic clearance. Breast cancer patients with severe hepatic 
impairment are thus expected to be exposed to higher levels of letrozole than patients with normal liver function 
receiving similar doses of this drug [see Dosage and Administration (2.5)]. 
 


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13 
NONCLINICAL TOXICOLOGY 
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
A conventional carcinogenesis study in mice at doses of 0.6 to 60 mg/kg/day (about 1 to 100 times the daily 
maximum recommended human dose on a mg/m2  basis) administered by oral gavage for up to 2 years revealed a 
dose-related increase in the incidence of benign ovarian stromal tumors. The incidence of combined 
hepatocellular adenoma and carcinoma showed a significant trend in females when the high dose group was 
excluded due to low survival. In a separate study, plasma AUC0-12hr levels in mice at 60 mg/kg/day were 55 times 
higher than the AUC0-24hr level in breast cancer patients at the recommended dose. The carcinogenicity study in 
rats at oral doses of 0.1 to 10 mg/kg/day (about 0.4 to 40 times the daily maximum recommended human dose on 
a mg/m2 basis) for up to 2 years also produced an increase in the incidence of benign ovarian stromal tumors at 
10 mg/kg/day. Ovarian hyperplasia was observed in females at doses equal to or greater than 0.1 mg/kg/day. At 
10 mg/kg/day, plasma AUC0-24hr levels in rats were 80 times higher than the level in breast cancer patients at the 
recommended dose. The benign ovarian stromal tumors observed in mice and rats were considered to be related 
to the pharmacological inhibition of estrogen synthesis and may be due to increased luteinizing hormone 
resulting from the decrease in circulating estrogen. 
Femara (letrozole) was not mutagenic in in vitro tests (Ames and E.coli bacterial tests) but was observed to be a 
potential clastogen in 
in vitro assays (CHO K1 and CCL 61 Chinese hamster ovary cells). Letrozole was not clastogenic in vivo 
(micronucleus test in rats). 
In a fertility and early embryonic development toxicity study in female rats, oral administration of letrozole 
starting 2 weeks before mating until pregnancy day 6 resulted in an increase in pre-
0.03 mg/kg/day (approximately 0.1 times the maximum recommended human dose on a mg/m2 basis). In repeat-
dose toxicity studies, administration of letrozole caused sexual 


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inactivity in females and atrophy of the reproductive tract in males and females at doses of 0.6, 0.1 and 0.03 
mg/kg in mice, rats and dogs, respectively (approximately 1, 0.4 and 0.4 times the daily maximum recommended 
human dose on a mg/m2 basis, respectively). 
 
14 
CLINICAL STUDIES 
14.1 
Updated Adjuvant Treatment of Early Breast Cancer 
In a multicenter study (BIG 1-98, NCT00004205) enrolling over 8,000 postmenopausal women with 
resected, receptor- positive early breast cancer, one of the following treatments was randomized in a 
double-blind manner: 
Option 1: 
A. tamoxifen for 5 years 
B. Femara for 5 years 
C. tamoxifen for 2 years followed by Femara for 3 years 
D. Femara for 2 years followed by tamoxifen for 3 
years Option 2: 
A. tamoxifen for 5 years 
B. Femara for 5 years 
The study in the adjuvant setting, BIG 1-98 was designed to answer two primary questions: whether Femara 
for 5 years was superior to Tamoxifen for 5 years (Primary Core Analysis) and whether switching endocrine 
treatments at 2 years was superior to continuing the same agent for a total of 5 years (Sequential 
Treatments Analysis). Selected baseline characteristics for the study population are shown in Table 6. 
The primary endpoint of this trial was disease-free survival (DFS) (i.e., interval between randomization and 
earliest occurrence of a local, regional, or distant recurrence, or invasive contralateral breast cancer, or death 
from any cause). The secondary endpoints were overall survival (OS), systemic disease-free survival (SDFS), 
invasive contralateral breast cancer, time to breast cancer recurrence (TBR) and time to distant metastasis 
(TDM). 
The Primary Core Analysis (PCA) included all patients and all follow-up in the monotherapy arms in both 
randomization options, but follow-up in the two sequential treatments arms was truncated 30 days after 
switching treatments. The PCA was conducted at a median treatment duration of 24 months and a median 
follow-up of 26 months. Femara was superior to tamoxifen in all endpoints except overall survival and 
contralateral breast cancer [e.g., DFS: hazard ratio, HR 0.79; 95% CI (0.68, 0.92); P=0.002; SDFS: HR 0.83; 
95% CI (0.70, 0.97); TDM: HR 0.73; 95% CI (0.60, 0.88); OS: HR 0.86; 95% CI (0.70, 1.06). 
In 2005, based on recommendations by the independent Data Monitoring Committee, the tamoxifen arms 
were unblinded and patients were allowed to complete initial adjuvant therapy with Femara (if they had 
received tamoxifen for at least 2 years) or to start extended adjuvant treatment with Femara (if they had 
received tamoxifen for at least 4.5 years) if they remained alive and disease-free. In total, 632 patients 
crossed to Femara or another aromatase inhibitor. Approximately 70% (448) of these 632 patients crossed to 
Femara to complete initial adjuvant therapy and most of these crossed in years 3 to 4. All of these patients 
were in Option 1. A total of 184 patients started extended adjuvant therapy with Femara (172 patients) or with 


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another aromatase inhibitor (12 patients). To explore the impact of this selective crossover, results from 
analyses censoring follow-up at the date of the selective crossover (in the tamoxifen arm) are presented for 
the MAA. 
The PCA allowed the results of Femara for 5 years compared with tamoxifen for 5 years to be reported in 2005 
after a median follow- up of only 26 months. The design of the PCA is not optimal to evaluate the effect of 
Femara after a longer time (because follow-up was truncated in two arms at around 25 months). The MAA 
(ignoring the two sequential treatment arms) provided follow-up equally as long in each treatment and did not 
over-emphasize early recurrences as the PCA did. The MAA thus provides the clinically appropriate updated 
efficacy results in answer to the first primary question, despite the confounding of the tamoxifen reference arm 
by the selective crossover to Femara. The updated results for the MAA are summarized in Table 7. Median 
follow-up for this analysis is 73 months. 
The Sequential Treatments Analysis (STA) addresses the second primary question of the study. The primary 
analysis for the STA was from switch (or equivalent time-point in monotherapy arms) + 30 days (STA-S) with a 
two-sided test applied to each pair-wise comparison at the 2.5% level. Additional analyses were conducted 
from randomization (STA-R) but these comparisons (added in light of changing medical practice) were under-
powered for efficacy. 
Table 6: Adjuvant Study - Patient and Disease Characteristics (ITT Population) 


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Primary Core Analysis (PCA) 
Monotherapy Arms Analysis (MAA) 
Femara 
Tamoxifen 
Femara 
Tamoxifen 
N=4003
N=4007
N=2463
N=2459
Characteristic 
n (%) 
n (%) 
n (%) 
n (%) 
Age (median, years) 
61 
61 
61 
61 
Age range (years) 
38-89 
39-90 
38-88 
39-90 
Hormone receptor status (%) 
ER+ and/or PgR+ 
99.7 
99.7 
99.7 
99.7 
Both unknown 
0.3 
0.3 
0.3 
0.3 
Nodal status (%) 
Node negative 
52 
52 
50 
52 
Node positive 
41 
41 
43 
41 
Nodal status unknown 
7 
7 
7 
7 
Prior adjuvant chemotherapy (%) 
24 
24 
24 
24 
 
 
Table 7: Updated Adjuvant Study Results - Monotherapy Arms Analysis (Median Follow-up 73 Months)
 
 
 
Femara 
N=2463 
Tamoxifen 
N=2459 
Hazard ratio  
 
 
Events 
(%) 
5-year 
rate 
Events 
(%) 
5-year 
rate 
(95% CI) 
P 
Disease-free survival1 
ITT 
445 (18.1) 
87.4 
500 (20.3) 
84.7 
0.87 (0.76, 0.99) 
0.03 
Censor 
445 
87.4 
483 
84.2 
0.84 (0.73, 0.95) 
0 positive nodes 
ITT 
165 
92.2 
189 
90.3 
0.88 (0.72, 1.09) 
1-3 positive nodes 
ITT 
151 
85.6 
163 
83.0 
0.85 (0.68, 1.06) 
>=4 positive nodes 
ITT 
123 
71.2 
142 
62.6 
0.81 (0.64, 1.03) 
Adjuvant chemotherapy 
ITT 
119 
86.4 
150 
80.6 
0.77 (0.60, 0.98) 
No chemotherapy 
ITT 
326 
87.8 
350 
86.1 
0.91 (0.78, 1.06) 
Systemic DFS2 
ITT 
401 
88.5 
446 
86.6 
0.88 (0.77,1.01) 
Time to distant metastasis3 
ITT 
257 
92.4 
298 
90.1 
0.85 (0.72, 1.00) 
Adjuvant chemotherapy 
ITT 
84 
- 
109 
- 
0.75 (0.56-1.00) 
No chemotherapy 
ITT 
173 
- 
189 
- 
0.90 (0.73,1.11) 
Distant DFS4
ITT 
385 
89.0 
432 
87.1 
0.87 (0.76,1.00) 
Contralateral breast cancer 
ITT 
34 
99.2 
44 
98.6 
0.76 (0.49, 1.19) 
Overall survival 
ITT 
303 
91.8 
343 
90.9 
0.87 (0.75, 1.02) 
Censor 
303 
91.8 
338 
90.1 
0.82 (0.70, 0.96) 
0 positive nodes 
ITT 
107 
95.2 
121 
94.8 
0.90 (0.69.1.16) 
1-3 positive nodes 
ITT 
99 
90.8 
114 
90.6 
0.81(0.62,1.06) 
>=4 positive nodes 
ITT 
92 
80.2 
104 
73.6 
0.86 (0.65, 1.14) 
Adjuvant chemotherapy 
ITT 
76 
91.5 
96 
88.4 
0.79 (0.58, 1.06) 
No chemotherapy 
ITT 
227 
91.9 
247 
91.8 
0.91 (0.76, 1.08) 
Definition of: 
1Disease-free survival: Interval from randomization to earliest event of invasive loco-regional recurrence, distant metastasis, 
invasive contralateral breast cancer, or death without a prior event. 
2Systemic disease-free survival: Interval from randomization to invasive regional recurrence, distant metastasis, or death without a 
prior cancer event. 
3Time to distant metastasis: Interval from randomization to distant metastasis. 
4Distant disease-free survival: Interval from randomization to earlier event of relapse in a distant site or death from any cause. 
ITT analysis ignores selective crossover in tamoxifen arms. 
Censored analysis censors follow-up at the date of selective crossover in 632 patients who crossed to Femara or another aromatase 
inhibitor after the tamoxifen arms were unblinded in 2005.
 


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Figure 1 shows the Kaplan-Meier curves for Disease-Free Survival Monotherapy Analysis
Figure 1: Disease-Free Survival (Median follow-up 73 months, ITT 
Approach)
DFS events defined as loco-regional recurrence, distant metastasis, invasive contralateral breast cancer, or death from any cause 
(i.e., definition excludes second non-breast primary cancers).
The medians of overall survival for both arms were not reached for the MAA. There was no statistically 
significant difference in overall survival. The hazard ratio for survival in the Femara arm compared to the 
tamoxifen arm was 0.87, with 95% CI (0.75, 1.02) (see Table 7).
There were no significant differences in DFS, OS, SDFS, and Distant DFS from switch in the Sequential 
Treatments Analysis with respect to either monotherapy (e.g., [tamoxifen 2 years followed by] Femara 3 years 
versus tamoxifen beyond 2 years, DFS HR 0.89; 97.5% CI 0.68, 1.15 and [Femara 2 years followed by] 
tamoxifen 3 years versus Femara beyond 2 years, DFS HR 0.93; 97.5% CI
0.71, 1.22).


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There were no significant differences in DFS, OS, SDFS, and Distant DFS from randomization in the Sequential 
Treatments Analyses. 
14.2 
Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment Duration of 24 Months 
A double-blind, randomized, placebo-controlled trial (MA-17, NCT00003140) of Femara was performed in 
over 5,100 postmenopausal women with receptor-positive or unknown primary breast cancer who were 
disease free after 5 years of adjuvant treatment with tamoxifen. 
The planned duration of treatment for patients in the study was 5 years, but the trial was terminated early 
because of an interim analysis showing a favorable Femara effect on time without recurrence or contralateral 
breast cancer. At the time of unblinding, women had been followed for a median of 28 months, 30% of patients 
had completed 3 or more years of follow-up and less than 1% of patients had completed 5 years of follow-up. 
Selected baseline characteristics for the study population are shown in Table 8. 
 
48. 
Table 8: Selected Study Population Demographics (Modified ITT Population) 
 
Baseline Status
Femara
Placebo
 
N=2582 
N=2586 
Hormone Receptor Status (%)
 
 
ER+ and/or PgR+ 
98 
98 
Both Unknown 
2 
2 
Nodal Status (%) 
 
 


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Node Negative
50
50
Node Positive
46
46
Nodal Status Unknown
4
4
Chemotherapy 
46 
46 
 
Table 9 shows the study results. Disease-free survival was measured as the time from randomization to the 
earliest event of loco- regional or distant recurrence of the primary disease or development of contralateral 
breast cancer or death. DFS by hormone receptor status, nodal status and adjuvant chemotherapy were similar to 
the overall results. Data were premature for an analysis of survival. 
 
49. 
Table 9: Extended Adjuvant Study Results 
 
 
Femara
N = 2582 
Placebo
N = 2586 
Hazard Ratio
(95% CI) 
P-Value
Disease Free Survival (DFS)1 Events
122 (4.7%) 
193 (7.5%) 
0.62 (0.49, 0.78)2 
0.00003 
Local Breast Recurrence 
9 
22 
 
 
Local Chest Wall Recurrence 
2 
8 
 
 
Regional Recurrence 
7 
4 
 
 
Distant Recurrence 
55 
92 
0.61 (0.44 - 0.84) 
0.003 
Contralateral Breast Cancer 
19 
29 
 
 
Deaths Without Recurrence or Contralateral Breast 
Cancer 
30 
38 
 
 
CI = confidence interval for hazard ratio. Hazard ratio of less than 1.0 indicates difference in favor of Femara (lesser risk of recurrence); hazard 
ratio greater than 1.0 indicates difference in favor of placebo (higher risk of recurrence with Femara). 
1First event of loco-regional recurrence, distant relapse, contralateral breast cancer or death from any cause. 
2Analysis stratified by receptor status, nodal status and prior adjuvant chemotherapy (stratification factors as at randomization). P-value based on 
stratified log-rank test.
 
 
 
14.3 
Updated Analyses of Extended Adjuvant Treatment of Early Breast Cancer, Median Treatment
Duration of 60 Months 
 
Table 10: Update of Extended Adjuvant Study Results 
 
 
Femara 
N = 2582 
(%) 
Placebo 
N = 2586 
(%) 
Hazard Ratio1 
(95% CI) 
P-Value2 


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Disease Free Survival (DFS) events3 
344 (13.3) 
402 (15.5) 
0.89 (0.77, 1.03) 
0.12 
Breast cancer recurrence
(Protocol definition of DFS events4) 
209
286
0.75 (0.63, 0.89)
0.001
Local Breast Recurrence 
15 
44 
 
 
Local Chest Wall Recurrence 
6 
14 
 
 
Regional Recurrence 
10 
8 
 
 
Distant Recurrence 
140 
167 
 
 
Distant Recurrence (first or subsequent events) 
Contralateral Breast Cancer 
142 
 
37 
169 
 
53 
0.88 (0.70,1.10) 
0.246 
Deaths Without Recurrence or 
Contralateral 
Breast Cancer 
135
116
 
 


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1Adjusted by receptor status, nodal status and prior chemotherapy
2Stratified log-rank test, stratified by receptor status, nodal status and prior chemotherapy
3DFS events defined as earliest of loco-regional recurrence, distant metastasis, contralateral breast cancer or 
death from any cause, and ignoring switches to Femara in 60% of the placebo arm. 
4Protocol definition does not include deaths from any cause 
Updated analyses were conducted at a median follow-up of 62 months. In the Femara arm, 71% 
of the patients were treated for a least 3 years and 58% of patients completed at least 4.5 years 
of extended adjuvant treatment. After the unblinding of the study at a median follow-up of 28 
months, approximately 60% of the selected patients in the placebo arm opted to switch to 
Femara. 
In this updated analysis shown in Table 10 Femara significantly reduced the risk of breast 
cancer recurrence or contralateral breast cancer compared with placebo (HR 0.75; 95% CI 0.63, 
0.89; P=0.001). However, in the updated DFS analysis (interval between randomization and 
earliest event of loco-regional recurrence, distant metastasis, contralateral breast cancer, or 
death from any cause) the treatment difference was heavily diluted by 60% of the patients in the 
placebo arm switching to Femara and accounting for 64% of the total placebo patient-years of 
follow-up. Ignoring these switches, the risk of DFS event was reduced by a non-significant 
11% (HR 0.89; 95% CI 0.77, 1.03). There was no significant difference in distant disease-free 
survival or overall survival. 
14.4 
First-Line Treatment of Advanced Breast Cancer 
A randomized, double-blind, multinational trial (P025) compared Femara 2.5 mg with 
tamoxifen 20 mg in 916 postmenopausal patients with locally advanced (Stage IIIB or loco-
regional recurrence not amenable to treatment with surgery or radiation) or metastatic breast 
cancer. Time to progression (TTP) was the primary endpoint of the trial. Selected baseline 
characteristics for this study are shown in Table 11. 


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50.
Table 11: Selected Study Population Demographics 
Baseline Status
Femara
Tamoxifen
 
N=458 
N=458 
Stage of Disease
 
 
IIIB 
6% 
7% 
IV 
93% 
92% 
Receptor Status 
 
 
ER and PgR Positive 
38% 
41% 
ER or PgR Positive 
26% 
26% 
Both Unknown 
34% 
33% 
ER- or PgR-/Other Unknown 
<1% 
0 
Previous Antiestrogen Therapy 
 
 
Adjuvant 
19% 
18% 
None 
81% 
82% 
Dominant Site of Disease 
 
 
Soft Tissue 
25% 
25% 
Bone 
32% 
29% 
Viscera
43%
46%
Femara was superior to tamoxifen in TTP and rate of objective tumor response (see Table 12). 
Table 12 summarizes the results of the trial, with a total median follow-up of approximately 32 
months. (All analyses are unadjusted and use 2-sided P-values.) 


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51.
Table 12: Results of First-Line Treatment of Advanced Breast Cancer 
Femara
Tamoxifen
Hazard or Odds
 
2.5 mg
20 mg
Ratio (95% CI)
 
N=453 
N=454 
P-Value (2-Sided) 
 
 
Median Time to Progression 
 
 
9.4 months 
 
 
6.0 months 
 
 
0.72 (0.62, 0.83)1 
 
 
 
P <0.0001 
Objective Response Rate 
 
 
 
(CR + PR) 
145 (32%) 
95 (21%) 
1.77 (1.31, 2.39)2 
 
 
 
P=0.0002 
(CR) 
42 (9%) 
15 (3%) 
2.99 (1.63, 5.47)2 
 
 
 
P=0.0004 
Duration of Objective Response 
 
 
 
Median 
18 months 
16 months 
 
 
(N=145) 
(N=95) 
 
Overall Survival 
35 months 
32 months 
 
 
(N=458) 
(N=458) 
P=0.51363 
1Hazard ratio 
2Odds ratio 
3Overall log-rank test 
Figure 2 shows the Kaplan-Meier curves for TTP. 


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52. 
Figure 2: Kaplan-Meier Estimates of Time to Progression (Study 
P025)
Table 13 shows results in the subgroup of women who had received prior antiestrogen adjuvant 
therapy, Table 14, results by disease site and Table 15, the results by receptor status. 
53.
Table 13: Efficacy in Patients Who Received Prior Antiestrogen Therapy 
Variable
Femara
Tamoxifen
 
2.5 mg 
20 mg 
 
N=84 
N=83 
Median Time to Progression (95% CI) 
8.9 months (6.2, 12.5) 
5.9 months (3.2, 6.2) 
Hazard Ratio for TTP (95% CI) 
0.60 (0.43, 0.84) 
Objective Response Rate 
 
 
(CR + PR) 
22 (26%) 
7 (8%) 
Odds Ratio for Response (95% CI) 
3.85 (1.50, 9.60) 
Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater than 
1 or odds ratio less than 1 favors tamoxifen. 
 


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Table 14: Efficacy by Disease Site 
 
Femara
Tamoxifen
 
2.5 mg 
20 mg 
Dominant Disease Site
 
 
Soft Tissue: 
N=113 
N=115 
Median TTP 
12.1 months 
6.4 months 
Objective Response Rate 
50% 
34% 
Bone: 
N=145 
N=131 
Median TTP 
9.5 months 
6.3 months 
Objective Response Rate 
23% 
15% 
Viscera: 
N=195 
N=208 
Median TTP 
8.3 months 
4.6 months 
Objective Response Rate
28%
17%
Table 15: Efficacy by Receptor Status 
Variable
Femara
Tamoxifen
 
2.5 mg 
20 mg 
Receptor Positive 
N=294 
N=305 
 
Median Time to Progression (95% CI)
9.4 months (8.9, 11.8) 
6.0 months 
(5.1, 8.5) 
Hazard Ratio for TTP (95% CI) 
0.69 (0.58, 0.83) 
 
Objective Response Rate (CR+PR) 
97 (33%) 
66 (22%) 
Odds Ratio for Response 95% CI) 
1.78 (1.20, 2.60) 
 
Receptor Unknown 
N=159 
N=149 
 
Median Time to Progression (95% CI) 
9.2 months (6.1, 12.3) 
6.0 months 
(4.1, 6.4) 
Hazard Ratio for TTP (95% CI) 
0.77 (0.60, 0.99) 
 
Objective Response Rate (CR+PR) 
48 (30%) 
29 (20%) 
Odds Ratio for Response (95% CI) 
1.79 (1.10, 3.00) 
 
 


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Hazard ratio less than 1 or odds ratio greater than 1 favors Femara; hazard ratio greater 
than 1 or odds ratio less than 1 favors tamoxifen.
Figure 3 shows the Kaplan-Meier curves for survival.
54. Figure 3: Survival by Randomized Treatment Arm 
 
Legend: Randomized Femara: n=458, events 57%, median overall survival 35 
months (95% CI 32 to 38 months) Randomized tamoxifen: n=458, events 57%, 
median overall survival 32 months (95% CI 28 to 37 months) Overall log-rank 
P=0.5136 (i.e., there was no significant difference between treatment arms in overall 
survival). 
The median overall survival was 35 months for the Femara group and 32 months for the 
tamoxifen group, with a P-value 0.5136. Study design allowed patients to cross over upon 
progression to the other therapy. Approximately 50% of patients crossed over to the opposite 
treatment arm and almost all patients who crossed over had done so by 36 months. The median 
time to crossover was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara). 
In patients who did not cross over to the opposite treatment arm, median survival was 35 
months with Femara (n=219, 95% CI 29 to 43 months) vs 20 months with tamoxifen (n=229, 
95% CI 16 to 26 months). 
14.5 
Second-Line Treatment of Advanced Breast Cancer 
Femara was initially studied at doses of 0.1 mg to 5.0 mg daily in six noncomparative trials 
(AR/BC1, P01, AR/ST1, AR/PS1, AR/ES1 and NJO-03) in 181 postmenopausal 


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estrogen/progesterone receptor positive or unknown advanced breast cancer patients previously 
treated with at least antiestrogen therapy. Patients had received other hormonal therapies and 
also may have received cytotoxic therapy. Eight (20%) of forty patients treated with Femara 2.5 
mg daily in trials achieved an objective tumor response (complete or partial response). 
Two large randomized, controlled, multinational (predominantly European) trials (AR/BC2, 
AR/BC3) were conducted in patients with advanced breast cancer who had progressed despite 
antiestrogen therapy. Patients were randomized to Femara 0.5 mg daily, Femara 
2.5 mg daily, or a comparator [megestrol acetate 160 mg daily in one study (AR/BC2); and 
aminoglutethimide 250 mg twice a day with corticosteroid supplementation in the other 
study (AR/BC3)]. In each study over 60% of the patients had received therapeutic 
antiestrogens, and about one-fifth of these patients had an objective response. The megestrol 
acetate controlled study was double- blind; the other study was open label. Selected baseline 
characteristics for each study are shown in Table 16. 
55.
Table 16: Selected Study Population Demographics 
Parameter
megestrol acetate
aminoglutethimide
 
study 
study 
No. of Participants 
552 
557 
Receptor Status 
 
 
ER/PR Positive 
57% 
56% 
ER/PR Unknown 
43% 
44% 
Previous Therapy 
 
 
Adjuvant Only 
33% 
38% 
Therapeutic +/- Adj. 
66% 
62% 
Sites of Disease 
 
 
Soft Tissue 
56% 
50% 
Bone 
50% 
55% 
Viscera 
40% 
44% 
Confirmed objective tumor response (complete response plus partial response) was the primary 
endpoint of the trials. Responses were measured according to the Union Internationale Contre le 
Cancer (UICC) criteria and verified by independent, blinded review. All responses were 
confirmed by a second evaluation 4 to 12 weeks after the documentation of the initial response. 
Table 17 shows the results for the first trial (AR/BC2), with a minimum follow-up of 15 
months, which compared Femara 0.5 mg, Femara 2.5 mg, and megestrol acetate 160 mg 


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daily. (All analyses are unadjusted.)
56.
Table 17: Megestrol Acetate Study Results 
Femara
Femara
megestrol
0.5 mg 
2.5 mg 
acetate 
 
N=188 
N=174 
N=190 
Objective Response (CR + PR)
22 (11.7%) 
41 (23.6%) 
31 (16.3%) 
Median Duration of Response 
552 days 
(Not reached) 
561 days 
Median Time to Progression 
154 days 
170 days 
168 days 
Median Survival 
633 days 
730 days 
659 days 
Odds Ratio for Response 
Femara 2.5: Femara 0.5=2.33 
Femara 2.5: megestrol=1.58 
(95% CI: 1.32, 4.17); P=0.004* 
(95% CI: 0.94, 2.66); P=0.08* 
Relative Risk of Progression 
Femara 2.5: Femara 0.5=0.81 
Femara 2.5: megestrol=0.77 
 
(95% CI: 0.63, 1.03); P=0.09* 
(95% CI: 0.60, 0.98); P=0.03* 
*Two-sided P-value 
The Kaplan-Meier curves for progression for the megestrol acetate study are shown in Figure 4. 
Figure 4: Kaplan-Meier Estimates of Time to Progression (Megestrol Acetate Study). 
The results for the study comparing Femara to aminoglutethimide (AR/BC3), with a minimum 
follow-up of 9 months, are shown in Table 18 (Unadjusted analyses are used). 
57.
Table 18: Aminoglutethimide Study Results 


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Femara
Femara
0.5 mg 
2.5 mg 
aminoglutethimide 
 
N=193 
N=185 
N=179 
Objective Response (CR + PR)
34 (17.6%) 
34 (18.4%) 
22 (12.3%) 
Median Duration of Response 
619 days 
706 days 
450 days 
Median Time to Progression 
103 days 
123 days 
112 days 
Median Survival 
636 days 
792 days 
592 days 
Odds Ratio for Response 
Femara 2.5: 
Femara 2.5: 
Femara 0.5=1.05 
aminoglutethimide=1.61 
(95% CI: 0.62, 1.79); P=0.85* 
(95% CI: 0.90, 2.87); P=0.11* 
Relative Risk of Progression 
Femara 2.5: 
Femara 2.5: 
Femara 0.5=0.86 
aminoglutethimide=0.74 
 
(95% CI: 0.68, 1.11); P=0.25* 
(95% CI: 0.57, 0.94); P=0.02* 
*Two-sided P-value 
The Kaplan-Meier curves for progression for the aminoglutethimide study is shown in Figure 5. 
58. 
Figure 5: Kaplan-Meier Estimates of Time to Progression 
(Aminoglutethimide Study) 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
Packaged in HDPE bottles with a safety screw cap. 
2.5 mg tablets 
Bottles of 30 tablets...................................................................................NDC 0078-
0249-15 
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP 


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Controlled Room Temperature]. 
17 
PATIENT COUNSELING INFORMATION 
58.9.1 
Embryo-Fetal Toxicity 
Advise females of reproductive potential of the potential risk to a fetus and to use effective 
contraception during Femara therapy and for at least 3 weeks after the last dose. Advise females to 
contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during 
treatment with Femara [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 
8.3)]. 
58.9.2 
Lactation 
Advise women not to breastfeed during Femara treatment and for at least 3 weeks after the last dose 
[see Use in Specific Populations (8.2)]. 
58.9.3 
Infertility 
Advise females and males of reproductive potential of the potential for reduced fertility from Femara 
[see Use in Specific Populations (8.3)]. 
58.9.4 
Fatigue and Dizziness 
Since fatigue and dizziness have been observed with the use of Femara and somnolence was 
uncommonly reported, caution is advised when driving or using machinery. 
58.9.5 
Bone Effects 
Consideration should be given to monitoring 
bone mineral density. Distributed by: 
Novartis Pharmaceuticals Corporation 
East Hanover, New Jersey, 07936 
© Novartis 
T2017-106