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Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength 
returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still 
apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph 
nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in 
one recovery animal.  There was no evidence of maternal harm prior to labor; adverse maternal effects 
occurred infrequently during labor.  Maternal mammary gland development was normal.  There was no 
fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 
50 mg/kg was evaluated.

 
In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node 
agenesis and led to postnatal impairment of dentition and bone growth.  Pregnant RANKL knockout mice 
showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Use in 
Specific Populations (8.3) and Nonclinical Toxicology (13.2)].  
 
8.3 

Nursing Mothers 

 
It is not known whether Prolia is excreted into human milk.  Measurable concentrations of denosumab 
were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of 
denosumab (≤ 0.5% milk:serum ratio).  Because many drugs are excreted in human milk and because of 
the potential for serious adverse reactions in nursing infants from Prolia, a decision should be made 
whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to 
the mother. 
 
Maternal exposure to Prolia during pregnancy may impair mammary gland development and lactation 
based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown 
altered maturation of the maternal mammary gland, leading to impaired lactation postpartum.  However in 
cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland 
development was normal, with no impaired lactation.  Mammary gland histopathology at 6 months of age 
was normal in female offspring exposed to denosumab in utero; however, development and lactation have 
not been fully evaluated [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.2)]. 
 
8.4 

Pediatric Use 

 
Prolia is not recommended in pediatric patients.  The safety and effectiveness of Prolia in pediatric 
patients have not been established.  
 
Treatment with Prolia may impair bone growth in children with open growth plates and may inhibit 
eruption of dentition.  In neonatal rats, inhibition of RANKL (the target of Prolia therapy) with a 
construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of 
bone growth and tooth eruption.  Adolescent primates treated with denosumab at doses 10 and 50 times 
(10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered every 
6 months, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with 
the pharmacological activity of denosumab.  
 
Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, an absence of 
axillary, inguinal, mandibular, and mesenteric lymph nodes, reduced hematopoiesis, tooth malalignment, 
and decreased neonatal growth.  Some bone abnormalities recovered once exposure was ceased following 
birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth [see Use in 
Specific Populations (8.1)].    
 
 

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8.5 

Geriatric Use 

 
Of the total number of patients in clinical studies of Prolia, 9943 patients (76%) were ≥ 65 years old, 
while 3576 (27%) were ≥ 75 years old.  Of the patients in the osteoporosis study in men, 133 patients 
(55%) were ≥ 65 years old, while 39 patients (16%) were ≥ 75 years old.  No overall differences in safety 
or efficacy were observed between these 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. 
 
8.6 

Renal Impairment 

 
No dose adjustment is necessary in patients with renal impairment.  
 
In clinical studies, patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving 
dialysis were at greater risk of developing hypocalcemia.  Consider the benefit-risk profile when 
administering Prolia to patients with severe renal impairment or receiving dialysis.  Clinical monitoring of 
calcium and mineral levels (phosphorus and magnesium) is highly recommended.  Adequate intake of 
calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis 
[see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)]. 
 
8.7 

Hepatic Impairment 

 
No clinical studies have been conducted to evaluate the effect of hepatic impairment on the 
pharmacokinetics of Prolia. 
 
10 

OVERDOSAGE  

 
There is no experience with overdosage with Prolia.   
 
11 

DESCRIPTION  

 
Prolia (denosumab) is a human IgG2 monoclonal antibody with affinity and specificity for human 
RANKL (receptor activator of nuclear factor kappa-B ligand).  Denosumab has an approximate molecular 
weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.  
 
Prolia is a sterile, preservative-free, clear, colorless to pale yellow solution.  
 
Each 1 mL single-use prefilled syringe of Prolia contains 60 mg denosumab (60 mg/mL solution), 
4.7% sorbitol, 17 mM acetate, 0.01% polysorbate 20, Water for Injection (USP),

and sodium hydroxide to 

a pH of 5.2.   
 
Each 1 mL single-use vial of Prolia contains 60 mg denosumab (60 mg/mL solution), 4.7% sorbitol, 
17 mM acetate, Water for Injection (USP),

and sodium hydroxide to a pH of 5.2.   

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12 

CLINICAL PHARMACOLOGY 

 
12.1 

Mechanism of Action 

 
Prolia binds to RANKL, a transmembrane or soluble protein essential for the formation, function, and 
survival of osteoclasts, the cells responsible for bone resorption.  Prolia prevents RANKL from activating 
its receptor, RANK, on the surface of osteoclasts and their precursors.  Prevention of the RANKL/RANK 
interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and 
increasing bone mass and strength in both cortical and trabecular bone. 
 
12.2 

Pharmacodynamics 

 
In clinical studies, treatment with 60 mg of Prolia resulted in reduction in the bone resorption marker 
serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring 
by 1 month.  CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of 
patients 1 to 3 months after dosing of Prolia.  At the end of each dosing interval, CTX reductions were 
partially attenuated from a maximal reduction of 



 87% to 



 45% (range: 45% to 80%), as serum 

denosumab levels diminished, reflecting the reversibility of the effects of Prolia on bone remodeling.  
These effects were sustained with continued treatment.  Upon reinitiation, the degree of inhibition of CTX 
by Prolia was similar to that observed in patients initiating Prolia treatment.   
 
Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, 
subsequent reductions in bone formation markers (i.e. osteocalcin and procollagen type 1 N-terminal 
peptide [PlNP]) were observed starting 1 month after the first dose of Prolia.  After discontinuation of 
Prolia therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but 
returned to baseline levels within 12 months.   
 
12.3 

Pharmacokinetics 

 
In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following 
a single subcutaneously administered Prolia dose of 60 mg after fasting (at least for 12 hours), the mean 
maximum denosumab concentration (C

max

) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL).  

The median time to maximum denosumab concentration (T

max

) was 10 days (range: 3 to 21 days).  After 

C

max

, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 

25.4 days (SD = 8.5 days; n = 46).  The mean area-under-the-concentration-time curve up to 16 weeks 
(AUC

0-16 weeks

) of denosumab was 316 mcg



day/mL (SD = 101 mcg



day/mL). 

 
No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple 
dosing of 60 mg subcutaneously administered once every 6 months.   
 
Prolia pharmacokinetics were not affected by the formation of binding antibodies.  
 
A population pharmacokinetic analysis was performed to evaluate the effects of demographic 
characteristics.  This analysis showed no notable differences in pharmacokinetics with age (in 
postmenopausal women), race, or body weight (36 to 140 kg). 
 
Seminal Fluid Pharmacokinetic Study 
Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age 
range: 43-65 years).  After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) 
C

max

 values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81.9) ng/mL, 

respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels.  

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The median (range) T

max

 values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 

49) days, respectively.  Amongst the subjects, the highest denosumab concentration in seminal fluid was 
301 ng/mL at 22 days post-dose.  On the first day of measurement (10 days post-dose), nine of eleven 
subjects had quantifiable concentrations in semen.  On the last day of measurement (106 days post-dose), 
five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) 
seminal fluid concentration of 21.1 (±36.5) ng/mL across all subjects (n = 12). [see Use in Specific 
Populations (8.1)].

 
Drug Interactions 
In a study of 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered two 
weeks after a single dose of denosumab (60 mg subcutaneous injection), which approximates the T

max

 of 

denosumab.  Denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by 
cytochrome P450 3A4 (CYP3A4).  This indicates that denosumab should not alter the pharmacokinetics 
of drugs metabolized by CYP3A4 in postmenopausal women with osteoporosis.  
 
Specific Populations 
Gender: Mean serum denosumab concentration-time profiles observed in a study conducted in healthy 
men ≥ 50 years were similar to those observed in a study conducted in postmenopausal women using the 
same dose regimen.   
 
Age: The pharmacokinetics of denosumab were not affected by age across all populations studied whose 
ages ranged from 28 to 87 years.  
  
Race: The pharmacokinetics of denosumab were not affected by race.  
 
Renal Impairment: In a study of 55 patients with varying degrees of renal function, including patients on 
dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose 
adjustment for renal impairment is not necessary.  
 
Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment 
on the pharmacokinetics of denosumab.

 
13 

NONCLINICAL TOXICOLOGY 

 
13.1 

Carcinogenesis, Mutagenesis, Impairment of Fertility  

 
Carcinogenicity 
The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.  
  
Mutagenicity 
The genotoxic potential of denosumab has not been evaluated.   
 
Impairment of Fertility 
Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 
13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once 
every 6 months, based on body weight (mg/kg). 
 
13.2 

Animal Toxicology and/or Pharmacology 

 
Denosumab is an inhibitor of osteoclastic bone resorption via inhibition of RANKL.  
 

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In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and 
increased bone mineral density (BMD) and strength of cancellous and cortical bone at doses 50-fold 
higher than the recommended human dose of 60 mg administered once every 6 months, based on body 
weight (mg/kg).  Bone tissue was normal with no evidence of mineralization defects, accumulation of 
osteoid, or woven bone.  
 
Because 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, namely OPG-Fc, provided additional information on the pharmacodynamic properties of 
denosumab.  RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an 
absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development 
during pregnancy).  Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of 
tooth eruption.  A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also 
showed reduced bone growth, altered growth plates, and impaired tooth eruption.  These changes were 
partially reversible in this model when dosing with the RANKL inhibitors was discontinued.  
 
14 

CLINICAL STUDIES 

 
14.1 

Postmenopausal Women with Osteoporosis  

 
The efficacy and safety of Prolia in the treatment of postmenopausal osteoporosis was demonstrated in a 
3-year, randomized, double-blind, placebo-controlled trial.  Enrolled women had a baseline BMD T-score 
between -2.5 and -4.0 at either the lumbar spine or total hip.  Women with other diseases (such as 
rheumatoid arthritis, osteogenesis imperfecta, and Paget’s disease) or on therapies that affect bone were 
excluded from this study.  The 7808 enrolled women were aged 60 to 91 years with a mean age of 
72 years.  Overall, the mean baseline lumbar spine BMD T-score was -2.8, and 23% of women had a 
vertebral fracture at baseline.  Women were randomized to receive subcutaneous injections of either 
placebo (N = 3906) or Prolia 60 mg (N = 3902) once every 6 months.  All women received at least 
1000 mg calcium and 400 IU vitamin D supplementation daily.   

The primary efficacy variable was the incidence of new morphometric (radiologically-diagnosed) 
vertebral fractures at 3 years.  Vertebral fractures were diagnosed based on lateral spine radiographs  
(T4-L4) using a semiquantitative scoring method.  Secondary efficacy variables included the incidence of 
hip fracture and nonvertebral fracture, assessed at 3 years.  

Effect on Vertebral Fractures 
Prolia significantly reduced the incidence of new morphometric vertebral fractures at 1, 2, and 3 years 
(p < 0.0001), as shown in Table 2.  The incidence of new vertebral fractures at year 3 was 7.2% in the 
placebo-treated women compared to 2.3% for the Prolia-treated women.  The absolute risk reduction was 
4.8% and relative risk reduction was 68% for new morphometric vertebral fractures at year 3.