Investigator Brochure Bone 2.0 2013-08-23 English

Product: Denosumab (AMG 162)
Investigator’s Brochure
Date: 23 August 2013 Page 1 of 45
INVESTIGATOR’S BROCHURE
Denosumab (AMG 162)
Bone Loss
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Superseded
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Do not share this brochure with unauthorized individuals
Sponsor: Amgen Inc.

One Amgen Center Drive
Thousand Oaks, CA 91320-1799
(805) 447-1000
Edition: 2.0
Date: 23 August 2013
Data Cutoff Date for Safety Reporting: 01 June 2013
Supersedes: Edition 1.1
CONFIDENTIALITY STATEMENT
This document contains confidential information that is the
property of Amgen Inc. and must not be disclosed to anyone
other than the recipient clinical investigator(s) and members
of the institutional review board and independent ethics
committee. This information cannot be used for any
purpose other than the evaluation or conduct of the clinical
investigation without the prior written consent of Amgen Inc.
1. TABLE OF CONTENTS
Page
1. TABLE OF CONTENTS.............................................................................................2
1.1 List of Tables..................................................................................................3
1.2 List of Figures.................................................................................................3
1.3 List of Appendices..........................................................................................3
1.4 List of Abbreviations and Definition of Terms................................................4
2. SUMMARY.................................................................................................................5
2.1 Denosumab and the RANK/RANKL Pathway................................................5
Superseded
2.2 Nonclinical Experience With Denosumab......................................................5
2.3 Clinical Experience With Denosumab............................................................6
3. INTRODUCTION........................................................................................................9
3.1 Denosumab....................................................................................................9
3.2 Indications and Treatment Settings Under Investigation...............................9
3.2.1 Postmenopausal Osteoporosis......................................................9
3.2.2 Bones Loss Associated With Hormone-ablation Therapy..................9
3.2.3 Male Osteoporosis.......................................................................10
3.2.4 Glucocorticoid-induced Osteoporosis..........................................11
4. PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES

AND FORMULATION..............................................................................................13
5. NONCLINICAL STUDIES........................................................................................14
5.1 Nonclinical Pharmacology............................................................................14
5.2 Summary of Nonclinical Pharmacokinetics and Drug Metabolism..............15
5.3 Summary of Toxicology................................................................................16
6. EFFECTS IN HUMANS............................................................................................18
6.1 Pharmacodynamics and Pharmacokinetics of Denosumab in
Humans........................................................................................................18
6.2 Effects of Denosumab in Subjects With Postmenopausal Osteoporosis......19
6.3 Effects of Denosumab in Subjects With Bone Loss Associated
With Hormone-ablation Therapy..................................................................19
6.4 Effects of Denosumab in Subjects With Male Osteoporosis........................20
6.4.1 Efficacy of Denosumab in Men With Osteoporosis.....................20
6.4.2 Safety of Denosumab in Men With Osteoporosis........................22
6.5 Effects of Denosumab in Subjects With Glucocorticoid-induced Osteoporosis......24
6.6 Registration and Marketing Experience With Denosumab..........................25
7. ADDITIONAL INFORMATION FOR THE INVESTIGATOR....................................36
8. REFERENCES.........................................................................................................37
9. APPENDICES..........................................................................................................39
1.1 List of Tables

Table 6-1. Summary of Marketing Experience with Denosumab......................................26
Table 9-1. Serious Adverse Events Considered by the Investigator and/or
Superseded
Amgen to be Related to Denosumab (60 mg Q6M) in
Unblinded Data From Denosumab Clinical Studies
(Summarized by MedDRA System Organ Class and Preferred
Term).........................................................................................................42
Table 9-2. Serious Adverse Events Considered by the Investigator and/or
Amgen to be Related to Denosumab (120 mg Q4W) in
Unblinded Data From Denosumab Clinical Studies
(Summarized by MedDRA System Organ Class and Preferred
Term).........................................................................................................44
1.2 List of Figures

Figure 1. Study 20080098 Bone Mineral Density Percent Change From
Baseline at Month 12 by Anatomical Site Least Squares
Means and 95% CIs From ANCOVA (Primary Efficacy
Analysis Set, LOCF)..................................................................................21
1.3 List of Appendices

Appendix A. Denosumab Development Core Safety Information.....................................40
Appendix B. Serious Adverse Events Considered by the Investigator and/or
Amgen to be Related to Denosumab........................................................41
1.4 List of Abbreviations and Definition of Terms
Term / Abbreviation Definition/Explanation
ANCOVA analysis of covariance
BMD bone mineral density
BSAP bone-specific alkaline phosphatase
CI confidence interval
CL clearance
CTX1 C-telopeptide of type 1 collagen
DCSI Development Core Safety Information
DXA dual X-ray absorptiometry
Superseded
EU European Union
Fc crystallizable fragment of immunoglobulins
FcRn Fc neonatal receptor
GIOP glucocorticoid-induced osteoporosis
IgG2 immunoglobulin G type 2
IV intravenous or intravenously
Kd dissociation equilibrium constant
MedDRA Medical Dictionary for Regulatory Activities
ONJ osteonecrosis of the jaw
OPG osteoprotegerin
OPG-Fc OPG linked to an immunoglobulin crystallizable fragment
Q6M 6-monthly (every 6 months)
Q4W 4-weekly (every 4 weeks)
QD once daily
RANK-Fc RANK linked to an immunoglobulin crystallizable fragment
RANKL RANK ligand; in older literature citations, this molecule was
referred to as OPG ligand or TRANCE.
SC subcutaneous or subcutaneously
SPC Summary of Product Characteristics
SRE skeletal-related event
TK toxicokinetics
TNF tumor necrosis factor
TRAIL tumor necrosis factor-related apoptosis-inducing ligand
uNTx/Cr creatinine-adjusted urinary N-telopeptide
US United States
USPI United States Prescribing Information
Vss volume of distribution at steady-state
2. SUMMARY
2.1 Denosumab and the RANK/RANKL Pathway
Denosumab is a fully human monoclonal immunoglobulin G type 2 (IgG2) antibody that
binds with high affinity (dissociation equilibrium constant [Kd] = 3 x 10-12 M) and
specificity to RANK ligand (RANKL) and neutralizes the activity of human RANKL,
similar to the action of endogenous osteoprotegerin (OPG). Denosumab is highly
specific because it binds only to RANKL and not to other members of the tumor necrosis
factor (TNF) family, including TNF, TNF, TNF-related apoptosis-inducing ligand
Superseded
(TRAIL), or CD40 ligand (Elliott et al, 2006; Kostenuik et al, 2009). By blocking RANKL,
denosumab inhibits osteoclast formation, function, and survival, thereby decreasing
bone resorption and increasing bone mass and strength in both cortical and trabecular
bone.
2.2 Nonclinical Experience With Denosumab

The biologic effects of denosumab have been assessed in numerous in vitro and in vivo
models and nonclinical pharmacodynamic, pharmacokinetic, and toxicology studies
conducted in mice, rats, and cynomolgus monkeys. Since the biological activity of
denosumab in animals is specific to nonhuman primates, evaluation of genetically
engineered (knockout) mice or use of other biological inhibitors of the RANK/RANKL
pathway, such as OPG linked to an immunoglobulin crystallizable fragment (OPG-Fc)
and RANK linked to an immunoglobulin crystallizable fragment (RANK-Fc), were used to
evaluate the pharmacodynamic properties of denosumab in rodent models. These
studies show that denosumab is a potent inhibitor of bone resorption via inhibition of
RANKL. The toxicological effects observed in animal studies were attributable to the
pharmacological activity of denosumab.
In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss,

stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes,
abnormal bone growth, and decreased neonatal growth.
2.3 Clinical Experience With Denosumab
Postmenopausal Osteoporosis
In the United States (US), European Union (EU), and a number of other regions, Prolia 
(denosumab, 60 mg every 6 months [Q6M]) is currently approved for the treatment of
postmenopausal women with osteoporosis at increased or high risk for fracture. See
Section 6.6 for information on the marketing experience and regions of approval.
Detailed information on the nonclinical effects of denosumab and its clinical effects in
this patient population is provided in the current country-specific prescribing information
Superseded
for Prolia. The EU Summary of Product Characteristics (SPC) and US Prescribing
Information (USPI) provide detailed product information for investigators in the EU
regions, the US, and in regions where Prolia is not currently approved.
Link to EU SPC:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicine
s/001120/human_med_001324.jsp&mid=WC0b01ac058001d124
Link to USPI:
http://pi.amgen.com/united_states/prolia/prolia_pi.pdf
Bones Loss Associated With Hormone-ablation Therapy

In the US and a number of other regions, Prolia is currently approved for the treatment of
bone loss due to hormone ablation therapy in men with prostate cancer at high risk for
fracture and in women with breast cancer at high risk for fracture. In the EU and a
number of other regions, Prolia is currently approved for the treatment of bone loss
associated with hormone ablation in men with prostate cancer at high risk for fracture. In
these regions, the treatment of bone loss associated with hormone ablation in women
with breast cancer at high risk of fracture is subsumed by the postmenopausal
osteoporosis indication. See Section 6.6 for information on the marketing experience
and regions of approval.
for Prolia. The EU SPC and USPI provide detailed product information for investigators
in the EU regions, the US, and in regions where Prolia is not currently approved.
Link to EU SPC:
Link to USPI:
Superseded
Male Osteoporosis
Denosumab has been evaluated in a randomized, double-blind, placebo-controlled study
in men with low bone mass (phase 3 Study 20080098 [n = 242]). In this study
denosumab significantly increased mean bone mineral density (BMD) at the lumbar
spine compared with placebo at month 12 (Section 6.4).
A similar incidence of adverse events, serious adverse events, and fatal adverse events
was observed in the denosumab and placebo treatment groups. The safety profile
observed in this study was consistent with that observed in previous bone loss studies.
No new safety risks associated with denosumab treatment were identified.
Glucocorticoid-induced Osteoporosis
Denosumab is being evaluated for treatment of glucocorticoid-induced osteoporosis
(GIOP) in men and women initiating or receiving long-term systemic glucocorticoids at a
daily dosage equivalent to 7.5 mg or greater of prednisone. Study 20101217 is an
ongoing, phase 3, randomized, double-blind, active-controlled study to evaluate the
efficacy and safety of denosumab compared with risedronate in men and women
receiving glucocorticoids (Section 6.5). Since this study is not yet complete, results are
not currently available.
Clinical Experience With Denosumab for Advanced Malignancies Involving Bone

Denosumab has also gained marketing approval in the US, EU, and a number of other
regions under the proprietary name XGEVA® (denosumab, 120 mg every 4 weeks
[Q4W]) for the prevention of skeletal-related events (SREs) in patients with bone
metastases from solid tumors.
for XGEVA. The EU SPC and USPI provide detailed product information for
Superseded
investigators in the EU regions, the US, and in regions where XGEVA is not currently
approved.
Link to EU SPC:
Link to USPI:
http://pi.amgen.com/united_states/xgeva/xgeva_pi.pdf
3. INTRODUCTION
3.1 Denosumab
Denosumab is a fully human monoclonal IgG2 antibody to RANKL that binds with high
affinity (Kd 3 x 10-12 M) and specificity to the soluble and cell membrane-bound forms of
human RANKL. Denosumab has an approximate molecular weight of 147 kDa and is
produced in genetically engineered mammalian (Chinese hamster ovary) cells.
Denosumab is formulated for subcutaneous (SC) injection and is administered at a dose
of 60 mg Q6M for bone loss indications.
Superseded
3.2 Indications and Treatment Settings Under Investigation
3.2.1 Postmenopausal Osteoporosis
Denosumab is approved in the US, EU, and a number of other regions for the treatment
of postmenopausal women with osteoporosis at increased or high risk for fracture. See
Section 6.6 for information on the marketing experience and regions of approval.
Detailed information on the nonclinical effects of denosumab, and its clinical effects in
for denosumab (60 mg administered Q6M). The EU SPC and USPI provide detailed
product information for investigators in the EU regions, the US, and in regions where
denosumab is not currently approved.
Link to EU SPC:
Link to USPI:
3.2.2 Bones Loss Associated With Hormone-ablation Therapy

Denosumab is approved in the US and a number of other regions for the treatment of
bone loss due to hormone ablation therapy in men with prostate cancer at high risk for
fracture and in women with breast cancer at high risk for fracture. Denosumab is
approved in the EU and a number of other regions for the treatment of bone loss
associated with hormone ablation in men with prostate cancer at high risk for fracture. In
these regions, the treatment of bone loss associated with hormone ablation in women
with breast cancer at high risk of fracture is subsumed by the postmenopausal
osteoporosis indication. See Section 6.6 for information on the marketing experience
and regions of approval.
Detailed information on the nonclinical effects of denosumab, and its clinical effects in
for denosumab (60 mg administered Q6M). The EU SPC and USPI provide detailed
product information for investigators in the EU regions, the US, and in regions where
denosumab is not currently approved.
Superseded
Link to EU SPC:
Link to USPI:
3.2.3 Male Osteoporosis

Osteoporosis is a systemic skeletal disease characterized by a decrease in bone mass
greater than expected for an individual’s sex, age, and race. Age-related osteoporosis
causes loss in both trabecular and cortical bone and micro-architectural deterioration.
These changes increase bone fragility and susceptibility to fracture (NIH Consensus
Development Panel on Osteoporosis Prevention, Diagnosis and Therapy, 2001).
Although osteoporosis and osteoporotic fractures are most commonly associated with
postmenopausal women, osteoporosis in men is an important clinical and public health
issue. An estimated 2 million men in the US have osteoporosis, and over 12 million
more are at risk (National Osteoporosis Foundation, 2011; Looker et al, 1997).
Osteoporosis is largely due to increased bone resorption, resulting from increased

recruitment, activation, and/or activity of osteoclasts driven by cytokines that regulate
osteoclasts including RANKL (Rodan and Martin, 2000), which leads to structural
damage predisposing a patient to fracture (Teitelbaum, 2000). Denosumab blocks the
differentiation, activation, and survival of osteoclasts and thus has the potential to correct
the negative effect of bone resorption on the skeleton, protect against bone loss, and
reduce the risk for fracture in the setting of osteoporosis. Amgen has conducted a
randomized, double-blind, placebo-controlled study to compare the effects of
denosumab 60 mg SC Q6M with placebo on lumbar spine BMD in men with low BMD
(Section 6.4).
3.2.4 Glucocorticoid-induced Osteoporosis

Glucocorticoid therapy is commonly used to treat a variety of chronic inflammatory
conditions such as giant cell arteritis, polymyalgia rheumatica, rheumatoid arthritis,
asthma, chronic obstructive pulmonary disease, and dermatologic conditions. The
prevalence of oral glucocorticoid use is estimated at approximately 0.2% to 1% in the
Superseded
general population, with higher rates in the elderly (Saag, 2003; van Staa et al, 2000).
The anti-inflammatory and immunosuppressive properties of glucocorticoids have
promoted their extensive use; however, the side effects of these drugs are significant.
Therapeutic use of glucocorticoids leads to decreased intestinal calcium absorption
(Patschan et al, 2001), hypercalciuria (Reid, 1997; Suzuki et al, 1983), secondary
hyperparathyroidism (Suzuki et al, 1983), decreased sex hormone levels
(Patschan et al, 2001), increased resorption and impairment of bone formation
(Canalis et al, 2004; Patschan et al, 2001), and increased RANKL and decreased
osteoprotegerin expression (Sasaki et al, 2001; Hofbauer et al, 1999). As a
consequence of these side effects, glucocorticoid use can lead to GIOP, a serious
skeletal disorder that is associated with fractures (Canalis et al, 2007).
In patients initiating oral glucocorticoid therapy, a rapid decline in BMD begins within the
first 3 months of glucocorticoid use and peaks at 6 months, followed by a slower, steady
decline with continued use (Lane and Lukert, 1998). Thus, the aim of GIOP therapy is to
stop the rapid bone loss that occurs in patients who have recently initiated systemic
glucocorticoid therapy and plan to continue on the therapy for some time and to stop the
slower, continued bone loss that occurs in patients who are already receiving
chronic/long-term glucocorticoid therapy.
Preliminary nonclinical and clinical evaluations suggest that denosumab can effectively
mitigate bone loss associated with long-term glucocorticoid therapy. In a GIOP murine
model, treatment with denosumab inhibited cortical bone loss without impairing
biomechanical strength (Hofbauer et al, 2007). In Study 20040144, a phase 2
dose-ranging study in subjects with rheumatoid arthritis, a subset of subjects (n = 74)
were coadministered denosumab and glucocorticoid therapy (Dore et al, 2010). In this
study, subjects who received denosumab 180 or 60 mg Q6M had greater increases in
BMD at month 12 at all anatomic sites measured compared with subjects who received
placebo. Amgen is currently conducting a phase 3, randomized, double-blind,
active-controlled study to evaluate the efficacy and safety of denosumab compared with
risedronate in men and women receiving oral glucocorticoid therapy (Section 6.5).
Superseded
4. PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES AND

FORMULATION
Detailed information on the physical and chemical description of denosumab, available
dosage forms, and drug supply and storage information is provided in the current
country-specific prescribing information for denosumab. The EU SPC and USPI provide
detailed product information for investigators in the EU regions, the US, and in regions
where denosumab is not currently approved.
Link to EU SPC:
Superseded
Link to USPI:
For applicable investigations, the denosumab placebo product contains the same
deliverable volume and excipients without the active ingredient.
5. NONCLINICAL STUDIES
5.1 Nonclinical Pharmacology
Denosumab binds both the soluble and cell membrane-bound forms of human RANKL
with high affinity, but does not bind other members of the TNF family, including TNF,
TNF, TRAIL, or CD40 ligand (Kostenuik et al, 2009).
RANKL inhibition is associated with well-mineralized bone (Capparelli et al, 2003) that
has favorable biomechanical quality, as demonstrated by increased bone mass and
bone strength in rats treated with OPG-Fc (Ross et al, 2001) and in cynomolgus
Superseded
monkeys treated with denosumab (Atkinson et al, 2005).
The pharmacologic action of recombinant RANKL inhibitors is reversible; in rats, the

clearance of OPG-Fc was associated with the progressive recovery of osteoclast
numbers (Capparelli et al, 2003). The clearance of denosumab was also associated
with the recovery of osteoclasts and bone resorption in cynomolgus monkeys
(Kostenuik et al, 2011).
Treatment of adult, ovariectomized monkeys with long-term (16-month) denosumab

treatment (25 or 50 mg/kg monthly) was associated with significant gains in the mass
and density of cancellous and cortical bone (Ominsky et al, 2011). Additionally, serum
C-telopeptide of type 1 collagen (CTX1), serum bone-specific alkaline phosphatase
(BSAP), and creatinine-adjusted urinary N-telopeptide (uNTx/Cr) were significantly
reduced by denosumab treatment throughout the study.
Genetic ablation of RANKL in knockout mice, and lifelong inhibition of RANKL by OPG in
transgenic rats, was associated with deleterious changes in long bone growth, geometry
and/or strength (Ominsky et al, 2009; Li et al, 2000; Kong et al, 1999). RANKL knockout
mice, but not OPG transgenic rats, also exhibited failure of tooth eruption
(Kong et al, 1999; Ominsky et al, 2009). Nonclinical pharmacology studies in neonatal
rats administered RANKL inhibitors also resulted in reduced bone growth, altered growth
plates, and impaired tooth eruption. All of these changes were partially reversible when
dosing of RANKL inhibitors was discontinued. Studies in mice suggest absence of
RANKL during pregnancy may interfere with maturation of the mammary gland leading
to impaired lactation post-partum. However, this was not seen in pregnant cynomolgus
monkeys treated with monthly doses of 50 mg/kg denosumab throughout pregnancy
(Bussiere et al, 2013).
In summary, RANKL inhibition with denosumab was associated with rapid and significant
gains in the mass, density, and strength of cancellous and cortical bone consistent with
the expected pharmacodynamic effects of an antiresorptive therapy. Nonclinical
pharmacology data also suggest that the use of denosumab in the rapidly growing
skeleton carries potential risks from widened growth plates, decreased bone growth,
decreased bone toughness, and impaired dentition.
Superseded
5.2 Summary of Nonclinical Pharmacokinetics and Drug Metabolism
The single-dose pharmacokinetics and multiple-dose toxicokinetics (TK) of denosumab
following intravenous (IV) or SC administration were evaluated in mice, rats, and
cynomolgus monkeys. In addition, tissue distribution (by solid scintillation counting) and
quantitative whole body autoradiography studies were conducted in cynomolgus
monkeys following SC administration of denosumab.
In mice and rats, species in which denosumab does not bind RANKL, the
IV pharmacokinetics of denosumab were linear over the dose range of approximately
0.1 to 10 mg/kg, with low clearance (CL) and a volume of distribution at steady-state
(Vss) that indicated a lack of extensive extravascular distribution. Approximately 6- and
15-fold higher CL was observed in knock-in mice that express a chimeric form of RANKL
to which denosumab binds and knock-out mice lacking expression of the Fc neonatal
receptor (FcRn), respectively, indicating important roles of RANKL and FcRn in
denosumab disposition.
In cynomolgus monkeys, the IV pharmacokinetics of denosumab were nonlinear over

the dose range of 0.0016 to 1 mg/kg (with approximately 16-fold lower CL at the highest
relative to lowest dose) but were approximately dose-linear for doses  1 mg/kg. At all
doses, the Vss indicated a lack of extensive extravascular distribution. The SC
pharmacokinetics of denosumab were also nonlinear in monkeys over the dose range of
0.0016 to 1 mg/kg, but were approximately dose-linear between 1 and 3 mg/kg.
In tissue distribution and quantitative whole-body autoradiography studies in cynomolgus

125
monkeys, radioactivity following SC administration of I-labeled denosumab was widely
distributed. In general, systemic (serum) radioactivity was largely (> 85%)
acid-precipitable, indicating that the majority of circulating radioactivity was most likely
the intact antibody and iodinated peptide fragments. Concentrations of radioactivity in
bone (eg, femur or lumbar vertebrae) and bone marrow were much less than (generally
< 10%) those in serum and declined in parallel, indicating no specific uptake or
sequestration in bone.
The multiple-dose TK of denosumab was evaluated for up to 16 months in cynomolgus

monkeys for once weekly or monthly SC doses ranging from 1 to 50 mg/kg. Exposure
Superseded
following the first dose increased approximately dose-proportionally, indicating linear
pharmacokinetics over this dose range. No sex difference in denosumab TK was
observed. The development of antidrug antibodies led to decreased exposure relative to
exposure after the first dose and to animals that were antibody negative. In
antibody-negative animals, no evidence of time-dependent changes in denosumab TK
was observed.
5.3 Summary of Toxicology

Nonclinical studies assessing the safety of denosumab included in vitro tissue
cross-reactivity studies, assessment of acute effects on the cardiovascular and
respiratory system in cynomolgus monkeys, repeated-dose toxicity studies in
cynomolgus monkeys up to 1 year in duration, and reproductive and embryo-fetal toxicity
studies in cynomolgus monkeys. No toxicologically significant effects were observed
with administration of denosumab once monthly for 1 year at doses of 1, 10, and
50 mg/kg; however, abnormal growth plates were observed, which is consistent with the
pharmacological action of denosumab. Denosumab had no effect on male or female
fertility, and was not an embryo-fetal or a maternal toxicant when administered to
cynomolgus monkeys during the first trimester of pregnancy (lymph nodes were not
examined in this study).
In another study, pregnant cynomolgus monkeys were given monthly SC injections of

0 (control) or 50 mg/kg/dose denosumab from approximately gestation day 20 until
parturition (up to 6 doses). Administration of denosumab resulted in effects on the
pregnant females and their offspring. There were increased stillbirths and postnatal
mortality; abnormal bone growth resulting in reduced bone strength, reduced
hematopoiesis, and tooth malalignment (with no effect on tooth eruption); absence of

peripheral lymph nodes; and decreased neonatal growth. There was no evidence of
maternal harm prior to labor and adverse maternal effects occurred infrequently during
labor. Following a recovery period from birth out to 6 months of age, the effects on bone
strength and quality returned to normal; some denosumab-related effects persisted
(absent/decreased size of lymph nodes, extramedullary hematopoiesis, and dental
dysplasia). There were no adverse effects on tooth eruption and minimal to moderate
mineralization in multiple tissues was seen in 1 recovery animal. Maternal mammary
gland development was normal. Very low concentrations of denosumab were present in
Superseded
the maternal milk of cynomologus monkeys up to 1 month after the last dose of
denosumab (≤ 0.5% milk:serum ratio). In general, the effects observed in mothers and
infants were consistent with the pharmacological action of denosumab as a monoclonal
antibody against RANKL and an inhibitor of osteoclastic bone resorption.
6. EFFECTS IN HUMANS
Regulatory authorization for the commercial use of denosumab (Prolia) for the treatment
of postmenopausal women with osteoporosis at increased or high risk for fracture and
for the treatment of bone loss due to hormone ablation therapy in men with prostate
cancer at high risk for fracture and, in some regions, women with breast cancer at high
risk for fracture is based on an extensive clinical database. This clinical database, which
also includes studies conducted to support regulatory authorization of denosumab for
advanced cancer indications (XGEVA, 120 mg Q4W), consists of 53 clinical studies
(39 completed and 14 ongoing) in healthy adults and patients with osteoporosis
Superseded
(approximately 14,300 subjects), bone loss associated with hormone-ablation therapy
(approximately 5,500 subjects), rheumatoid arthritis (approximately 200 subjects),
advanced cancer (multiple myeloma and advanced malignancies involving bone
[approximately 12,300 subjects]), and giant cell tumor of the bone (approximately
500 subjects) collected between June 2001 and May 2013.
Detailed product information on the effects of denosumab (60 mg Q6M) in the treatment
of postmenopausal women with osteoporosis at increased or high risk for fracture and
cancer at high risk for fracture and, in some regions, in women with breast cancer at
high risk for fracture is provided in the product label (Section 3.2.1). Additional
supportive information on these indications and detailed information on indications still
under investigation are provided in Section 6.2 to Section 6.5.
6.1 Pharmacodynamics and Pharmacokinetics of Denosumab in

Humans
Information describing key pharmacokinetic and pharmacodynamic properties of
denosumab following SC administration over a wide dose range is summarized in the
approved product labeling (Section 3.2.1).
Bioequivalence studies demonstrate that denosumab supplied in a 60 mg/mL prefilled

syringe is bioequivalent to denosumab supplied in a 60 mg/mL vial.
6.2 Effects of Denosumab in Subjects With Postmenopausal
Osteoporosis
Denosumab (60 mg Q6M) is currently approved for the treatment of postmenopausal
women with osteoporosis at increased or high risk for fracture. Detailed information on
the clinical effects of denosumab in this patient population is provided in the current
country-specific prescribing information for Prolia. The EU SPC and USPI provide
Link to EU SPC:
Superseded
Link to USPI:
6.3 Effects of Denosumab in Subjects With Bone Loss Associated With

Hormone-ablation Therapy
Denosumab (60 mg Q6M) is currently approved in the US and a number of other regions
cancer at high risk for fracture and in women with breast cancer at high risk for fracture.
Denosumab is currently approved in the EU and a number of other regions for the
treatment of bone loss associated with hormone ablation in men with prostate cancer at
high risk for fracture. In these regions, the treatment of bone loss associated with
hormone ablation in women with breast cancer at high risk of fracture is subsumed by
the postmenopausal osteoporosis indication. Detailed information on the clinical effects
of denosumab in this patient population is provided in the current country-specific
prescribing information for Prolia. The EU SPC and USPI provide detailed product
information for investigators in the EU regions, the US, and in regions where denosumab
is not currently approved.
Link to EU SPC:
Link to USPI:
6.4 Effects of Denosumab in Subjects With Male Osteoporosis

Study 20080098 was a randomized, double-blind, placebo-controlled study to compare
the effects of denosumab 60 mg SC Q6M with placebo on lumbar spine BMD in men
Superseded
with low BMD. The study included a 12-month double-blind, placebo-controlled
treatment phase (primary analysis phase) followed by a 12-month open-label treatment
phase during which all subjects received denosumab. In total, 240 subjects received
either denosumab (n = 120) or placebo (n = 120) during the 12-month double-blind
phase of the study. A total of 228 subjects (94%) (111 denosumab/denosumab
[long-term], 117 placebo/denosumab [crossover]) entered the open-label treatment
phase, 1 of whom (in the crossover group) never received denosumab in this phase.
6.4.1 Efficacy of Denosumab in Men With Osteoporosis

Denosumab significantly increased lumbar spine BMD compared with placebo at
month 12. The mean difference in lumbar spine BMD between treatment groups was
4.8% (p < 0.0001; 95% confidence interval [CI]: 4.0%, 5.6%) (Figure 1).
Denosumab significantly increased BMD at all other skeletal sites measured, with mean
differences compared with placebo of 2.0%, 2.2%, 2.3%, and 0.9% at total hip, femoral
neck, trochanter, and distal radius, respectively (Figure 1).
Figure 1. Study 20080098 Bone Mineral Density Percent Change From Baseline at
Month 12 by Anatomical Site
Least Squares Means and 95% CIs From ANCOVA
(Primary Efficacy Analysis Set, LOCF)
Lumbar Spine Total Hip Femoral Neck Trochante Distal Radius
r
9.0
Placebo Denosumab
8.0
Percent Change from Baseline at Month 12 (LS Mean and CI)
7.0
*
6.0
Superseded
5.0
4.0 *
3.0 * *
2.0
*
1.0
0.0
-1.0
Point estimates and nominal 95% confidence intervals are based on an analysis of covariance
(ANCOVA) model with treatment as main effect and level of baseline BMD T-score as covariate
* p < 0.05
Source: Study 20080098 Primary Analysis CSR, Figure 14-2.501
Treatment with denosumab also significantly decreased median serum CTX1

concentration compared with placebo at day 15.
A total of 29 subjects (17 denosumab, 12 placebo) were enrolled in a bone biopsy

substudy. Overall, bone biopsy results showed normal bone histology. After 12 months
of denosumab treatment, there was evidence of normal lamellar bone, normal
mineralization, and normal osteoid in both treatment groups. There was no evidence of
osteomalacia, marrow fibrosis, or woven bone. Denosumab did not impair matrix
mineralization.
In accordance with denosumab’s mechanism of action, evaluation of histomorphometric

parameters showed changes consistent with decreased bone remodeling in subjects
treated with denosumab compared with placebo. Decreased bone remodeling led to
reductions in tetracycline uptake and therefore labeling. As a consequence, a reduction
in single and double labels was observed in a number of biopsies in the denosumab
group. Evaluation of dynamic bone histomorphometry in the subset of samples in which
double or single labels were present showed changes consistent with decreased
remodeling in subjects treated with denosumab.
6.4.2 Safety of Denosumab in Men With Osteoporosis

During the double-blind treatment phase, the subject incidences of adverse events,
Superseded
serious adverse events, and fatal adverse events were similar between treatment
groups. A total of 86 subjects (72%) in the denosumab group and 84 subjects (70%) in
the placebo group reported  1 adverse event during the first 12 months of the study.
The most frequently reported adverse events ( 5% in either treatment group
[denosumab, placebo]) were back pain (8%, 7%), arthralgia (7%, 6%), nasopharyngitis
(7%, 6%), and constipation (0%, 6%). Most of the adverse events in both groups were
categorized as being of mild-to-moderate severity. The incidence of treatment-related
adverse events was 1.7% in the denosumab group and 5.0% in the placebo group.
Serious adverse events were reported for 9.2% of subjects in the denosumab group and
8.3% of subjects in the placebo group. The only serious adverse events reported in
more than 1 subject per treatment group were prostate cancer, reported for 3 subjects
(2.5%) in the denosumab group (with 2 of 3 cases being detected within the first 3 weeks
of the study) and no subjects in the placebo group; and “arterial thrombosis limb,”
reported for 2 subjects (1.7%) in the denosumab group and no subjects in the placebo
group. All other serious adverse events were reported in a single subject per treatment
group (< 1%).
Two deaths were reported: myocardial infarction in a subject receiving denosumab and
basilar artery thrombosis in a subject receiving placebo.
In the denosumab and placebo groups, 3 subjects (2.5%) and 0 subjects, respectively,
had adverse events leading to investigational product discontinuation. None of the
adverse events leading to investigational product discontinuation were considered
related to treatment.
A number of adverse events are of interest for the denosumab clinical development
program either based on their possible association with antiresorptive activity or RANKL
inhibition, reactivity to monoclonal antibody administration, or because of results from
previous denosumab studies. These events include hypocalcemia; osteonecrosis of the
jaw (ONJ); adverse events potentially associated with hypersensitivity; infections,
including serious adverse events of skin infections; new primary malignancies;
cardiovascular adverse events; fracture healing complications, atypical femoral
fractures; eczema; and acute pancreatitis.
Superseded
There were no adverse events of hypocalcemia, adjudicated-positive ONJ, fracture
healing complications, or atypical femoral fractures during the 12-month double-blind
treatment phase. Events potentially associated with hypersensitivity, infection events,
and acute pancreatitis events were balanced between treatment groups. One
nonserious adverse event of skin infection was reported for a subject receiving placebo.
There were no adverse events of skin infection in the denosumab group.
Malignancy adverse events were reported for 4 subjects (3.3%) in the denosumab group
and no subjects in the placebo group. The events consisted of prostate cancer in
3 subjects (2.5%) and basal cell carcinoma in 1 subject (0.8%). None of the events was
considered by the investigator to be related to the investigational product. In 2 of the
3 subjects with prostate cancer, diagnoses were made within the first 3 weeks of
denosumab treatment, indicating that the cancers were likely pre-existing and present at
baseline.
Adverse events in the Medical Dictionary for Regulatory Activities (MedDRA) system
organ class of cardiac disorders were reported for 8 subjects (6.7%) in the denosumab
group and 3 subjects (2.5%) in the placebo group. Four subjects in the denosumab
group reported adverse events coded to the preferred term angina pectoris. Upon
further clinical review, 2 of the cases of angina pectoris were identified as angina
tonsillitis that had been incorrectly coded to angina pectoris due to differences in
verbatim reporting across geographic regions. The subjects who experienced the
2 remaining cases of angina pectoris had a history of cardiovascular disease. The
incidence of serious cardiac adverse events was similar between treatment groups. The
incidence of vascular disorders adverse events and serious adverse events was also
similar between treatment groups.
Eczema was reported for 2 subjects (1.7%) in the denosumab group and no subjects in
the placebo group. The events were mild or moderate in severity and resolved within
7 weeks of onset; both subjects continued denosumab administration without evidence
of recurrence.
During the open-label treatment phase, subject incidences of adverse events

(63.1% long-term, 51.7% crossover), serious adverse events (8.1% long-term,
Superseded
4.3% crossover), fatal adverse events (0.9% long-term, 0% crossover), and adverse
events leading to investigational product discontinuation (0% both groups) were the
same or lower than the incidences during the 12-month double-blind phase.
Hypocalcemia, ONJ, fracture healing complications, atypical femoral fractures, eczema,
acute pancreatitis, osteonecrosis outside the jaw, and binding antidenosumab antibodies
were not reported during the open-label treatment phase. Rates of infection, skin
infection, malignancy, cardiovascular events, cataracts, and adverse events potentially
associated with hypersensitivity did not appear to increase over time.
6.5 Effects of Denosumab in Subjects With Glucocorticoid-induced

Osteoporosis
To evaluate the effect of denosumab in GIOP, Amgen is conducting a phase 3,
randomized, double-blind, active-controlled study (Study 20101217) in men and women
who are receiving oral glucocorticoid therapy. Two subpopulations
(glucocorticoid-continuing and glucocorticoid-initiating) will be evaluated in this study.
Approximately 776 subjects will be enrolled. Subjects will be randomized in a 1:1 ratio to
receive either:
 SC denosumab 60 mg Q6M and oral placebo for risedronate once daily (QD) for
24 months
 oral risedronate 5 mg QD and SC placebo for denosumab Q6M for 24 months
The primary objective in the glucocorticoid-continuing subpopulation of men and women

treated with chronic glucocorticoid therapy (≥ 7.5 mg daily prednisone or its equivalent
for ≥ 3 months and are planning to continue treatment for a total of at least 6 months) is
to demonstrate that treatment with SC denosumab 60 mg Q6M is not inferior to
Date: 23 August 2013 Page 25 of
treatment with oral risedronate 5 mg QD with respect to the percent change from
baseline in lumbar spine BMD by dual X-ray absorptiometry (DXA) at 12 months.
The primary objective in the glucocorticoid-initiating subpopulation of men and women

treated with glucocorticoid therapy (≥ 7.5 mg daily prednisone or its equivalent for
< 3 months and are planning to continue treatment for a total of at least 6 months) is to
demonstrate that treatment with SC denosumab 60 mg Q6M is not inferior to treatment
with oral risedronate 5 mg QD with respect to the percent change from baseline in
lumbar spine BMD by DXA at 12 months.
Superseded
Results are not yet available for this study.
6.6 Registration and Marketing Experience With Denosumab

Table 6-1 provides the approval dates and indications for the various regions where
denosumab (60 mg) has been approved by the corresponding regulatory agencies as of
26 May 2013.
Table 6-1. Summary of Marketing Experience with Denosumab
Region/Country Approval Date Indication
a
Europe 26 May 2010 Treatment of osteoporosis in postmenopausal women at
increased risk of fracturesb.
Treatment of bone loss associated with hormone ablation
in men with prostate cancer at increased risk of fractures.
United States 01 June 2010 Treatment of postmenopausal women with osteoporosis
at high risk for fracture, defined as a history of
osteoporotic fracture, or multiple risk factors for fracture;
or patients who have failed or are intolerant to other
available osteoporosis therapy.
16 September 2011 Prolia is indicated as a treatment to increase bone mass
Superseded
in men at high risk for fracture receiving androgen
deprivation therapy for nonmetastatic prostate cancer.
Prolia is indicated as a treatment to increase bone mass
in women at high risk for fracture receiving adjuvant
aromatase inhibitor therapy for breast cancer.
20 September 2012 Treatment to increase bone mass in men with
osteoporosis at high risk of fracture.
Australia 02 June 2010 Treatment of osteoporosis in postmenopausal women.
Treatment of HALT prostate cancer.
Switzerland 03 August 2010 Treatment of osteoporosis in postmenopausal women for
prevention of vertebral and non vertebral fractures.
Concomitant treatment of women with breast cancer
undergoing adjuvant therapy with aromatase inhibitors
and concomitant treatment of men with prostate
carcinoma undergoing hormone ablation therapy who are
at increased risk of fracture.
Canada 06 August 2010 Treatment of postmenopausal women with osteoporosis
at high risk for fracture, defined as a history of
osteoporotic fracture, or multiple risk factors for fracture;
available osteoporosis therapy.
21 November 2012 Treatment to increase bone mass in men with
osteoporosis at high risk for fracture, defined as a history
of osteoporotic fractures, or multiple risk factors for
fracture; or patients who have failed or are intolerant to
other available osteoporosis therapy.
Page 1 of 10
a
Includes 28 European Union members + 3 European Economic Area countries.
b
In the corresponding CHMP opinion dated 18 March 2010, the CHMP determined that women who are
receiving aromatase inhibitor (AI) therapy for breast cancer are by definition postmenopausal and AI use is
considered to be a factor that can increase fracture risk; therefore, a separate indication was not warranted
and women who are at an increased risk of fractures are included in the scope of the PMO indication.
c
GlaxoSmithKline (GSK) owns the licensing rights
d
Daiichi Sankyo owns the licensing rights..

c
Macau 18 November 2010 Treatment of osteoporosis in postmenopausal women at
increased risk of fractures and treatment of bone loss
associated with hormone ablation in men with prostate
cancer at increased risk of fractures.
Croatiaa 13 April 2011 Treatment of osteoporosis in postmenopausal women at
increased risk of fractures. Prolia significantly reduces
the risk of vertebral, non vertebral and hip fractures.
in men with prostate cancer at increased risk of fractures
(see Section 5.1 of CDS). In men with prostate cancer
Superseded
receiving hormone ablation, Prolia significantly reduces
the risk of vertebral fractures.
Peruc 15 April 2011 Treatment of osteoporosis in postmenopausal women at
Mexico 18 April 2011 Treatment of osteoporosis in postmenopausal women.
In postmenopausal women with osteoporosis, Prolia
increases bone mineral density and reduces the
incidence of hip, vertebral, and non-vertebral fractures.
Treatment of bone loss in patients undergoing hormone
ablation for prostate or breast cancer. In patients with
prostate cancer, Prolia reduces the incidence of vertebral
fractures.
Argentinac 18 May 2011 Treatment of osteoporosis in postmenopausal women at
Page 2 of 10
a
b
c
GlaxoSmithKline (GSK) owns the licensing rights.
d
Daiichi Sankyo owns the licensing rights.

c
Macedonia 27 May 2011 Treatment of osteoporosis in postmenopausal women at
Israelc 12 June 2011 Treatment of osteoporosis in postmenopausal women at
Superseded
Hong Kongc 22 July 2011 Treatment of postmenopausal women with osteoporosis
at high risk for fracture
the risk of vertebral fractures
Colombiac 29 July 2011 Treatment of postmenopausal women with osteoporosis
at high risk for fracture
New Zealand 11 August 2011 Treatment of osteoporosis in postmenopausal women.
c
Taiwan 29 August 2011 Treatment of postmenopausal women with osteoporosis
at high risk for fracture.
Treatment of bone loss in men at high risk for fracture
receiving androgen deprivation therapy for non-
metastatic prostate cancer
Explanation:
In any one of the following situations: those with a
history of osteoporotic fracture, or multiple risk factors for
fracture; or those who have failed or are intolerant to
other available osteoporosis therapy.
In postmenopausal women with osteoporosis, PROLIA
reduces the incidence of vertebral, non-vertebral, and hip
fractures.
Page 3 of 10
a
b
c
d

c
Chile 15 September 2011 Postmenopausal Osteoporosis: PROLIA is indicated for
the treatment of osteoporosis in postmenopausal
women. In postmenopausal women with osteoporosis,
PROLIA increases bone mineral density (BMD) and
reduces the incidence of hip, vertebral and non-vertebral
fractures.
Bone Loss in Patients Undergoing Hormone Ablation for
Cancer: PROLIA is indicated for the treatment of bone
loss in patients undergoing hormone ablation for prostate
or breast cancer. In patients with prostate cancer,
Superseded
PROLIA reduces the incidence of vertebral fractures.
Serbiac 16 September 2011 Treatment of osteoporosis in postmenopausal women at
In men with prostate cancer receiving hormone ablation,
Prolia significantly reduces the risk of vertebral fractures.
Singaporec 27 September 2011 PROLIA is indicated for the treatment of postmenopausal
women with osteoporosis at high risk of fracture, defined
as a history of osteoporotic fracture, or multiple risk
factors for fracture; or patients who have failed or are
intolerant to other available osteoporosis therapy. In
postmenopausal women with osteoporosis, PROLIA
reduces the incidence of vertebral, nonvertebral, and hip
fractures.
Russia 14 October 2011 Treatment of postmenopausal osteoporosis.
Treatment of bone loss in women with breast cancer
undergoing therapy with aromatase inhibitors and in men
with prostate cancer undergoing hormone ablation
therapy.
22 August 2012 Treatment of senile osteoporosis in men.
Page 4 of 10
a
b
c
d

c
Brazil 24 October 2011 Postmenopausal Osteoporosis: PROLIA is indicated for
fractures.
Superseded
Bosnia and 04 November 2011 Treatment of osteoporosis in postmenopausal women at
Herzegovinac increased risk of fractures. Prolia significantly reduces
Georgiac 09 November 2011 Postmenopausal Osteoporosis: PROLIA is indicated for
fractures.
Azerbaijanc 05 December 2011 Treatment of osteoporosis in postmenopausal women at
increased risk of fractures. In postmenopausal women
with osteoporosis, PROLIA increases bone mineral
density (BMD) and reduces the incidence of hip,
vertebral and non-vertebral fractures.
in men with prostate cancer or breast cancer. In patients
with prostate cancer, PROLIA reduces the incidence of
vertebral fractures.
Page 5 of 10
a
b
c
d

c
Philippines 22 December 2011 Treatment of post-menopausal women with osteoporosis
at high risk of fracture, defined as a history of
osteoporotic fracture, or multiple risk factors for fracture,
available therapy; reduces the incidence of vertebral,
non-vertebral and hip fractures in women with
osteoporosis.
Albaniac 23 December 2011 Treatment of osteoporosis in postmenopausal women at
the risk of vertebral and hip fractures.
Superseded
Armeniac 28 December 2011 Treatment of osteoporosis in postmenopausal women at
increased risk of fractures. In postmenopausal women
prostate cancer, PROLIA reduces the incidence of
Uruguayc 01 February 2012 Treatment of osteoporosis in postmenopausal women at
increased risk of fractures.
Malaysiac 23 February 2012 Postmenopausal Osteoporosis
PROLIA is indicated for the treatment of osteoporosis in
postmenopausal women at increased risk of fracture. In
postmenopausal women with osteoporosis, PROLIA
increases bone mineral density (BMD) and reduces the
incidence of hip, vertebral and non-vertebral fractures.
Cancer
PROLIA is indicated for the treatment of bone loss in
patients undergoing hormone ablation for prostate or
aromatase inhibitor treatment for breast cancer. In
patients with prostate cancer, PROLIA reduces the
incidence of vertebral fractures.
Page 6 of 10
a
b
c

c
Ukraine 23 February 2012 Treatment of osteoporosis in postmenopausal women at
increased risk of fractures (vertebral, non-vertebral and
hip fractures).
in men with prostate cancer at increased risk of vertebral
fractures.
Jordan 04 March 2012 Treatment of osteoporosis in postmenopausal women at
Superseded
(see section 5.1 of CDS). In men with prostate cancer
Kazakhstanc 11 March 2012 Postmenopausal Osteoporosis
PROLIA is indicated for the treatment of osteoporosis in
postmenopausal women. In postmenopausal women
Cancer
breast cancer. In patients with prostate cancer, PROLIA
reduces the incidence of vertebral fractures
Panamac 28 March 2012 Treatment of osteoporosis in postmenopausal women at
increased risk of fractures. Treatment of bone loss
associated with hormone ablation in men with prostate
cancer at increased risk of fractures.
Page 7 of 10
a
b
c
d
c
Ecuador 10 May 2012 Postmenopausal Osteoporosis: PROLIA is indicated for
fractures.
Superseded
Costa Ricac 18 June 2012 Postmenopausal Osteoporosis: PROLIA is indicated for
fractures.
Moldovac 23 July 2012 PROLIA is indicated for the treatment of osteoporosis in
postmenopausal women. In postmenopausal women
breast cancer. In patients with prostate cancer, PROLIA
reduces the incidence of vertebral fractures.
Kuwait 05 August 2012 Treatment of osteoporosis in postmenopausal women at
(see section 5.1). In men with prostate cancer receiving
hormone ablation, Prolia significantly reduces the risk of
Page 8 of 10
a
b
c
d

Morocco 14 November 2012 Treatment of osteoporosis in postmenopausal women at
Bahrain 23 December 2012 Treatment of osteoporosis in women after the
menopause (postmenopausal), reducing the risk of
Superseded
spinal, non-spinal and hip fractures.
Treatment of bone loss that results from a reduction in
hormone (testosterone) level cause by surgery or
treatment with medicines in patients with prostate
cancer.
Bangladeshc 24 December 2012 Postmenopausal osteoporosis
Bone loss in patients undergoing hormone ablation for
cancer (prostate or breast cancer)
Qatar 24 January 2013 Treatment of osteoporosis in postmenopausal women at
the risk of vertebral, non vertebral and hip fractures
Japand 25 March 2013 Osteoporosis
c
Lebanon 16 April 2013 Treatment of osteoporosis in post-menopausal women
ablation for prostate or breast cancer
Thailandc 01 May 2013 Treatment of osteoporosis in postmenopausal women.
In postmenopausal women with osteoporosis, PROLIA
increases bone mineral density (BMD) and reduces the
incidence of hip, vertebral and non-vertebral fractures.
prostate cancer, PROLIA reduces the incidence of
vertebral fractures
Page 9 of 10
a
b
c
d

Oman 05 May 2013 Treatment of osteoporosis in postmenopausal women at
Saudi Arabia 12 May 2013 Treatment of osteoporosis in postmenopausal women at
Superseded
Turkey 12 May 2013 Treatment of postmenopausal women with osteoporosis

who are at high risk for fracture.
Treatment of osteoporosis in patients at high risk for
fracture, who are receiving adjuvant aromatase inhibitor
therapy for breast cancer or hormone ablation therapy for
non-metastatic prostate cancer.
Page 10 of 10
a
b
c
d
Source: Prolia Periodic Safety Update Report No. 6

7. ADDITIONAL INFORMATION FOR THE INVESTIGATOR

Please refer to the complete safety information for the postmenopausal osteoporosis
and bone loss due to hormone-ablation therapy indications as provided in the current
country-specific prescribing information for denosumab. The EU SPC and USPI provide
Link to EU SPC:
Superseded
Link to USPI:
Please refer to the complete safety information for the male osteoporosis and GIOP
indications as detailed in the Development Core Safety Information Sheet (DCSI) for
denosumab (60 mg Q6M) (Appendix A).
Table 9-1 and Table 9-2, provided in Appendix B, present a summary of all serious
adverse events considered by the investigator and/or Amgen to be at least possibly
related to investigational product (denosumab 60 mg Q6M and denosumab 120 mg
Q4W, respectively) that were reported to Amgen as of 01 June 2013 for subjects with
unblinded treatment assignments. Inclusion of these events in Table 9-1 and Table 9-2
does not imply that a causal relationship to denosumab has been established.
8. REFERENCES
Atkinson J, Cranmer P, Saunders T, et al. AMG 162, a fully human RANKL antibody,
increases bone mass and bone strength in cynomolgus monkeys. J Bone Min Res.
2005;20(suppl 1):S294.
Bussiere JL, Boyce R, Pyrah I, et al. Reproductive toxicity of denosumab in cynomolgus
monkeys. Repro Toxicol. In press.
Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis:
pathophysiology and therapy. Osteoporos Int. 2007;18:1319-1328.
Canalis E, Bilezikian JP, Angeli A, Giustina A. Perspectives on glucocorticoid-induced
osteoporosis. Bone. 2004;34:593-598.
Superseded
Capparelli C, Morony S, Warmington K, et al. Sustained antiresorptive effects after a
single treatment with human recombinant osteoprotegerin (OPG): a pharmacodynamic
and pharmacokinetic analysis in rats. J Bone Miner Res. 2003;18:852-858.
Dore RK, Cohen SB, Lane NE, et al. Effects of denosumab on bone mineral density and
bone turnover in patients with rheumatoid arthritis receiving concurrent glucocorticoids or
bisphosphonates. Ann Rheum Dis. 2010;69:872-875.
Elliott R, Kostenuik P, Chen C, et al. Denosumab is a selective inhibitor of human
receptor activator of NF- ligand that blocks osteoclast formation in vitro and in vivo.
Eur J Ca Suppl. 2006;4:62.
Hofbauer LC, Zeitz U, Schoppet M, et al. RANK ligand inhibition by denosumab
prevents cortical bone loss in a murine mouse model of glucocorticoid-induced
osteoporosis. J Bone Miner Res. 2007;22:S4.
Hofbauer LC, Gori F, Riggs BL, et al. Stimulation of osteoprotegerin ligand and
inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage
cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis.
Endocrinology. 1999;140:4382-4389.
Kong Y-Y, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis,
lymphocyte development and lymph node organogenesis. Nature. 1999;315-323.
Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah I, Ominsky MS. Decreased bone
remodeling and porosity are associated with improved bone strength in ovariectomized
cynomolgus monkeys treated with denosumab, a full human RANKL antibody. Bone.
2011;49:151-161.
Kostenuik PJ, Nguyen HQ, McCabe J, et al. Denosumab, a Fully Human Monoclonal
Antibody to RANKL, Inhibits Bone Resorption and Increases BMD in Knock-In Mice That
Express Chimeric (Murine/Human) RANKL. J Bone Miner Res. 2009;24:182-195.
Lane NE, Lukert B. The science and therapy of glucocorticoid-induced bone loss.
Endocrinol Metab Clin North Am. 1998;27:465-483.
Li J, Sarosi I, Yan XQ, et al. RANK is the intrinsic hematopoietic cell surface receptor
that controls osteoclastogenesis, and regulation of bone mass and calcium metabolism.
Proc Natl Acad Sci USA. 2000;97:1566-1571.
Looker AC, Orwoll ES, Johnston CC Jr, et al. Prevalence of low femoral bone density in
older U.S. adults from NHANES III. J Bone Miner Res. 1997;12:1761-1768.
National Osteoporosis Foundation. National Osteoporosis Foundation website.
http://www.nof.org/aboutosteoporosis/formen/whatmenneedtoknow. Accessed
September 9, 2011.
NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis and
Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785-795.
Ominsky MS, Stouch B, Schroeder J, et al. Denosumab, a fully human RANKL
antibody, reduced bone turnover markers and increased trabecular and cortical bone
mass, density, and strength in ovariectomized cynomolgus monkeys. Bone.
2011;49:162-173.
Superseded
Ominsky MS, Stolina M, Li X, et al. One year of transgenic overexpression of
osteoprotegerin in rats suppressed bone resorption and increased vertebral bone
volume, density and strength. J Bone Miner Res. 2009;23:1234-1246.
Patschan D, Loddenkemper K, Buttgereit F. Molecular mechanisms of
glucocorticoid-induced osteoporosis. Bone. 2001;29:498-505.
Reid IR. Glucocorticoid osteoporosis--mechanisms and management. Eur J Endocrinol.
1997;137:209-17.
Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science.
2000;289:1508-1514.
Ross AB, Bateman TA, Kostenuik PJ, et al. The effects of osteoprotegerin on the
mechanical properties of rat bone. J Materials Sci: Materials Med. 2001;12:583-588.
Saag KG. Glucocorticoid-induced osteoporosis. Endocrinol Metab Clin North Am.
2003;32:135-157.
Sasaki N, Kusano E, Ando Y, Yano K, Tsuda E, Asano Y. Glucocorticoid decreases
circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced
osteoporosis. Nephrol Dial Transplant. 2001;16:479-482.
Suzuki Y, Ichikawa Y, Saito E, Homma M. Importance of increased urinary calcium
excretion in the development of secondary hyperparathyroidism of patients under
glucocorticoid therapy. Metabolism. 1983;32:151-156.
Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289:1504-1508.
van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Oral corticosteroids and
fracture risk: relationship to daily and cumulative doses. Rheumatology.
2000;39:1383-1389.
9. APPENDICES
Appendix A contains a summary of key safety-related information for denosumab for the
male osteoporosis and GIOP indications. This appendix is used by internal Amgen
personnel to assess expectedness for regulatory reporting purposes in denosumab
clinical studies.
Appendix B provides a tabular summary of unblinded serious adverse events considered

by the investigators and/or Amgen to be related to denosumab from completed or
ongoing denosumab clinical studies as of 01 June 2013. Tabular summaries of serious
Superseded
adverse events for denosumab administered at a dose of 60 mg Q6M (bone loss
indications) and 120 mg Q4W (oncology indications) are provided.
Appendix A. Denosumab Development Core Safety Information

The DCSI includes possible risks for the male osteoporosis and GIOP indications. The
safety profile in these subjects is still being defined. For information regarding Dosage
and Method of Administration, Contraindications, Special Warnings and Precautions for
Use, Pregnancy and Breast-Feeding, Effects on Ability to Drive and Use Machines,
Adverse Drug Reactions, Overdose, Abuse and Dependence, Pediatric Use, Geriatric
Use, Renal Impairment, and Hepatic Impairment, investigators should reference the
current country-specific prescribing information for denosumab (Prolia). The EU SPC
Superseded
and USPI provide detailed product information for investigators in the EU regions, the
US, and in regions where denosumab is not currently approved.
Link to EU SPC:
Link to USPI:
Appendix B. Serious Adverse Events Considered by the Investigator and/or

Amgen to be Related to Denosumab
Superseded
Table 9-1. Serious Adverse Events Considered by the Investigator and/or Amgen
to be Related to Denosumab (60 mg Q6M) in Unblinded Data From Denosumab
Clinical Studies
(Summarized by MedDRA System Organ Class and Preferred Term)
Blood and lymphatic system disorders

Leukocytosis, Leukopenia, Neutropenia, Pancytopenia Cardiac disorders
Acute myocardial infarction, Angina pectoris, Angina unstable, Arrhythmia, Atrial fibrillation, Cardiac failure, Cardiac failure congesti
Ear and labyrinth disorders Deafness unilateral, Vertigo
Eye disorders
Retinal detachment, Retinal haemorrhage Gastrointestinal disorders
Superseded
Abdominal pain, Colitis, Colitis ischaemic, Diverticulum intestinal haemorrhagic, Gastritis, Gastrointestinal haemorrhage, Intestinal o
General disorders and administration site conditions Asthenia, Chills, Death, Feeling hot, Malaise, Pyrexia
Hepatobiliary disorders
Autoimmune hepatitis, Cholecystitis acute, Cholelithiasis, Hepatic function abnormal, Hyperplastic cholecystopathy
Infections and infestations
Appendicitis, Cellulitis, Liver abscess, Lower respiratory tract infection, Lung infection, Mycobacterium avium complex infection, Ost
Injury, poisoning and procedural complications
Atypical femoral fracture, Fall, Femoral neck fracture, Femur fracture, Hip fracture, Postoperative wound complication, Pubis fractu
Page 1 of 2
Source: Argus Safety database as of 01 June 2013. MedDRA Version 16.0
to be Related to Denosumab (60 mg Q6M) in Unblinded Data From Denosumab
Clinical Studies
System Organ Class
Preferred Terms
Metabolism and nutrition disorders
Cachexia, Decreased appetite, Hypocalcaemia,
Musculoskeletal and connective tissue disorders
Arthralgia, Bone disorder, Fracture delayed union, Lumbar spinal stenosis, Muscle
spasms, Musculoskeletal pain, Osteoarthritis, Osteonecrosis, Osteonecrosis of jaw,
Spinal column stenosis
Superseded
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign soft tissue neoplasm, Brain neoplasm, Breast cancer, Breast cancer stage III,
Carcinoid tumour pulmonary, Cervix carcinoma, Chronic lymphocytic leukaemia, Colon
cancer, Endometrial adenocarcinoma, Follicle centre lymphoma, follicular grade I, II, III,
Hypergammaglobulinaemia benign monoclonal, Intraductal proliferative breast lesion,
Invasive ductal breast carcinoma, Invasive lobular breast carcinoma, Lentigo maligna,
Lung adenocarcinoma, Mantle cell lymphoma stage IV, Metastases to lung, Metastatic
squamous cell carcinoma, Myeloproliferative disorder, Neuroendocrine carcinoma,
Oesophageal squamous cell carcinoma, Ovarian cancer, Pancreatic carcinoma, Plasma
cell myeloma, Squamous cell carcinoma of skin, Squamous cell carcinoma of the oral
cavity
Nervous system disorders
Cerebral infarction, Cerebrovascular accident, Dizziness, Epilepsy, Guillain-Barre
syndrome, Headache, Ischaemic stroke, Mononeuropathy multiplex, Subarachnoid
haemorrhage, Transient global amnesia, Transient ischaemic attack
Renal and urinary disorders
Acute prerenal failure, Cystitis interstitial
Reproductive system and breast disorders
Adenomyosis, Endometrial hyperplasia
Respiratory, thoracic and mediastinal disorders
Dyspnoea paroxysmal nocturnal, Pulmonary embolism
Skin and subcutaneous tissue disorders
Drug eruption, Pruritus, Pruritus generalised, Rash pruritic
Vascular disorders
Aortic stenosis, Deep vein thrombosis, Hypertension, Peripheral ischaemia, Temporal
arteritis, Vasculitis
Page 2 of 2
to be Related to Denosumab (120 mg Q4W) in Unblinded Data From Denosumab
Clinical Studies
System Organ Class
Preferred Terms
Blood and lymphatic system disorders
Anaemia, Disseminated intravascular coagulation, Pancytopenia, Thrombocytopenia
Cardiac disorders
Atrial fibrillation, Bradycardia, Cardiac arrest, Cardiac failure, Cardiac failure acute,
Cardiac failure congestive, Palpitations
Endocrine disorders
Superseded
Hypothyroidism
Eye disorders
Arteriosclerotic retinopathy, Blindness unilateral, Cataract, Macular oedema, Retinal vein
occlusion, Vision blurred
Gastrointestinal disorders
Colitis, Dental alveolar anomaly, Diarrhoea, Duodenal ulcer, Gastritis, Gingival disorder,
Gingival erosion, Loose tooth, Mouth ulceration, Nausea, Oesophageal ulcer, Oral
disorder, Pancreatitis, Periodontal disease, Tooth disorder, Vomiting
General disorders and administration site conditions
Asthenia, Chest discomfort, Chest pain, Death, Fatigue, General physical health
deterioration, Generalised oedema, Mucosal inflammation, Multi-organ failure, Oedema
peripheral, Pyrexia
Hepatobiliary disorders
Acute hepatic failure, Hepatic failure, Hepatic function abnormal, Hepatitis toxic
Immune system disorders
Anaphylactic reaction, Hypersensitivity
Infections and infestations
Abscess jaw, Abscess oral, Acute sinusitis, Alveolar osteitis, Atypical pneumonia,
Bacteraemia, Cellulitis, Chronic sinusitis, Gingival abscess, Lobar pneumonia, Lower
respiratory tract infection, Lung infection, Osteomyelitis, Osteomyelitis acute,
Osteomyelitis chronic, Pneumonia, Skin infection, Tooth abscess
Injury, poisoning and procedural complications
Atypical femur fracture, Hip fracture, Lower limb fracture
Investigations
Blood creatinine increased, Blood pressure increased, Bone density decreased,
Creatinine renal clearance decreased, Weight decreased
Page 1 of 2
to be Related to Denosumab (120 mg Q4W) in Unblinded Data From Denosumab
Clinical Studies
System O
Metabolism and nutrition disorders

Decreased appetite, Dehydration, Electrolyte imbalance, Hypocalcaemia, Hypophosphataemia
Musculoskeletal and connective tissue disorders
Arthralgia, Back pain, Bone disorder, Bone pain, Exostosis of jaw, Exposed bone in jaw, Fractured nonunion, Jaw disorder, Muscle fa
Superseded
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia, Benign hydatidiform mole, Bone giant cell tumour, Colon cancer, Lung adenocarcinoma, Malignant n
Nervous system disorders
Cerebral infarction, Complex partial seizures, Dizziness, Embolic stroke, Headache, Ischaemic stroke, Syncope
Pregnancy, puerperium and perinatal conditions Molar abortion
Psychiatric disorders
Adjustment disorder, Confusional state, Insomnia, Mental status changes,Suicide attempt Renal and urinary disorders
Haematuria, Renal failure, Renal failure acute, Urinary tract obstruction Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema, Acute respiratory distress syndrome, Dyspnoea, Dyspnoea exertional, Hypoxia, Lung infiltration, Pneumo
Skin and subcutaneous tissue disorders
Angioedema, Drug eruption, Purpura, Rash, Skin ulcer Vascular disorders
Aneurysm, Deep vein thrombosis, Hypotension
Page 2 of 2

Investigator Brochure Bone 2.0 2013-08-23 English

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Investigator Brochure Bone 2.0 2013-08-23 English

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Product: Denosumab (AMG 162)

DO NOT PHOTOCOPY THIS DOCUMENT

Sponsor: Amgen Inc.

Date: 23 August 2013

Data Cutoff Date for Safety Reporting: 01 June 2013

Supersedes: Edition 1.1

4. PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES

7. ADDITIONAL INFORMATION FOR THE INVESTIGATOR....................................36

1.1 List of Tables

1.2 List of Figures

1.3 List of Appendices

2.2 Nonclinical Experience With Denosumab

In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss,

Bones Loss Associated With Hormone-ablation Therapy

Clinical Experience With Denosumab for Advanced Malignancies Involving Bone

3.2.2 Bones Loss Associated With Hormone-ablation Therapy

3.2.3 Male Osteoporosis

Osteoporosis is largely due to increased bone resorption, resulting from increased

3.2.4 Glucocorticoid-induced Osteoporosis

4. PHYSICAL, CHEMICAL, AND PHARMACEUTICAL PROPERTIES AND

The pharmacologic action of recombinant RANKL inhibitors is reversible; in rats, the

Treatment of adult, ovariectomized monkeys with long-term (16-month) denosumab

In cynomolgus monkeys, the IV pharmacokinetics of denosumab were nonlinear over

In tissue distribution and quantitative whole-body autoradiography studies in cynomolgus

The multiple-dose TK of denosumab was evaluated for up to 16 months in cynomolgus

5.3 Summary of Toxicology

In another study, pregnant cynomolgus monkeys were given monthly SC injections of

hematopoiesis, and tooth malalignment (with no effect on tooth eruption); absence of

6.1 Pharmacodynamics and Pharmacokinetics of Denosumab in

Bioequivalence studies demonstrate that denosumab supplied in a 60 mg/mL prefilled

6.3 Effects of Denosumab in Subjects With Bone Loss Associated With

6.4 Effects of Denosumab in Subjects With Male Osteoporosis

6.4.1 Efficacy of Denosumab in Men With Osteoporosis

Treatment with denosumab also significantly decreased median serum CTX1

A total of 29 subjects (17 denosumab, 12 placebo) were enrolled in a bone biopsy

In accordance with denosumab’s mechanism of action, evaluation of histomorphometric

6.4.2 Safety of Denosumab in Men With Osteoporosis

During the open-label treatment phase, subject incidences of adverse events

6.5 Effects of Denosumab in Subjects With Glucocorticoid-induced

The primary objective in the glucocorticoid-continuing subpopulation of men and women

The primary objective in the glucocorticoid-initiating subpopulation of men and women

6.6 Registration and Marketing Experience With Denosumab

Region/Country Approval Date Indication

Region/Country Approval Date Indication

Region/Country Approval Date Indication

Region/Country Approval Date Indication

Region/Country Approval Date Indication

Table 6-1. Summary of Marketing Experience with Denosumab

Region/Country Approval Date Indication

Table 6-1. Summary of Marketing Experience with Denosumab

Region/Country Approval Date Indication

Table 6-1. Summary of Marketing Experience with Denosumab

Region/Country Approval Date Indication

Turkey 12 May 2013 Treatment of postmenopausal women with osteoporosis

Source: Prolia Periodic Safety Update Report No. 6

7. ADDITIONAL INFORMATION FOR THE INVESTIGATOR

Appendix B provides a tabular summary of unblinded serious adverse events considered

Appendix A. Denosumab Development Core Safety Information

Appendix B. Serious Adverse Events Considered by the Investigator and/or

Blood and lymphatic system disorders

Metabolism and nutrition disorders

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