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SYSTEM ORGAN CLASS 
    Preferred Term 

Prolia 

(N = 3886) 

n (%) 

Placebo 

(N = 3876) 

n (%) 

Pharyngitis 

91 (2.3) 

78 (2.0) 

Herpes zoster 

79 (2.0) 

72 (1.9) 

 
METABOLISM AND NUTRITION DISORDERS 

Hypercholesterolemia 

280 (7.2) 

236 (6.1) 

MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 

Back pain 

1347 (34.7) 

1340 (34.6) 

Pain in extremity 

453 (11.7) 

430 (11.1) 

Musculoskeletal pain 

297 (7.6) 

291 (7.5) 

Bone pain 

142 (3.7) 

117 (3.0) 

Myalgia 

114 (2.9) 

94 (2.4) 

Spinal osteoarthritis 

82 (2.1) 

64 (1.7) 

 
NERVOUS SYSTEM DISORDERS 

Sciatica 

178 (4.6) 

149 (3.8) 

 
PSYCHIATRIC DISORDERS 

Insomnia 

126 (3.2) 

122 (3.1) 

 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 

Rash 

96 (2.5) 

79 (2.0) 

Pruritus 

87 (2.2) 

82 (2.1) 

 
Hypocalcemia 
Decreases in serum calcium levels to less than 8.5 mg/dL at any visit were reported in 0.4% women in the 
placebo group and 1.7% women in the Prolia group.  The nadir in serum calcium level occurs at 
approximately day 10 after Prolia dosing in subjects with normal renal function.  
 
In clinical studies, subjects with impaired renal function were more likely to have greater reductions in 
serum calcium levels compared to subjects with normal renal function.  In a study of 55 subjects with 
varying degrees of renal function, serum calcium levels < 7.5 mg/dL or symptomatic hypocalcemia were 
observed in 5 subjects.  These included no subjects in the normal renal function group, 10% of subjects in 
the creatinine clearance 50 to 80 mL/min group, 29% of subjects in the creatinine clearance < 30 mL/min 
group, and 29% of subjects in the hemodialysis group.  These subjects did not receive calcium and 
vitamin D supplementation.  In a study of 4550 postmenopausal women with osteoporosis, the mean 
change from baseline in serum calcium level 10 days after Prolia dosing was -5.5% in subjects with 
creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance ≥ 30 mL/min.   
 

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Serious Infections  
Receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed on activated T and B 
lymphocytes and in lymph nodes.  Therefore, a RANKL inhibitor such as Prolia may increase the risk of 
infection.   
 
In the clinical study of 7808 postmenopausal women with osteoporosis, the incidence of infections 
resulting in death was 0.2% in both placebo and Prolia treatment groups.  However, the incidence of 
nonfatal serious infections was 3.3% in the placebo and 4.0% in the Prolia groups.  Hospitalizations due 
to serious infections in the abdomen (0.7% placebo vs. 0.9% Prolia), urinary tract (0.5% placebo vs. 
0.7% Prolia), and ear (0.0% placebo vs. 0.1% Prolia) were reported.  Endocarditis was reported in no 
placebo patients and 3 patients receiving Prolia. 
 
Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more 
frequently in patients treated with Prolia (< 0.1% placebo vs. 0.4% Prolia).  
 
The incidence of opportunistic infections was similar to that reported with placebo. 
 
Dermatologic Reactions  
A significantly higher number of patients treated with Prolia developed epidermal and dermal adverse 
events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 
10.8% of the Prolia groups (p < 0.0001).  Most of these events were not specific to the injection site 
[see Warnings and Precautions (5.7)]. 
 
Osteonecrosis of the Jaw 
ONJ has been reported in the osteoporosis clinical trial program in patients treated with Prolia 
[see Warnings and Precautions (5.4)]. 
 
Atypical Subtrochanteric and Diaphyseal Fractures 
In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with 
Prolia.  The duration of Prolia exposure to time of atypical femoral fracture diagnosis was as early as 2½ 
years [see Warnings and Precautions (5.5)]. 
 
Pancreatitis 
Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Prolia groups.  
Of these reports, 1 patient in the placebo group and all 8 patients in the Prolia group had serious events, 
including one death in the Prolia group.  Several patients had a prior history of pancreatitis.  The time 
from product administration to event occurrence was variable. 
 
New Malignancies 
The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Prolia groups.  New 
malignancies related to the breast (0.7% placebo vs. 0.9% Prolia), reproductive system (0.2% placebo vs. 
0.5% Prolia), and gastrointestinal system (0.6% placebo vs. 0.9% Prolia) were reported.  A causal 
relationship to drug exposure has not been established. 
 
Treatment to Increase Bone Mass in Men with Osteoporosis 
 
The safety of Prolia in the treatment of men with osteoporosis was assessed in a 1-year randomized, 
double-blind, placebo-controlled study.  A total of 120 men were exposed to placebo and 120 men were 
exposed to Prolia administered subcutaneously once every 6 months as a single 60 mg dose.

 All men 

were instructed to take at least 1000 mg of calcium and 800 IU of vitamin D supplementation per day. 
 

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The incidence of all-cause mortality was 0.8% (n = 1) in the placebo group and 0.8% (n = 1) in the Prolia 
group.  The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the 
Prolia group.  The percentage of patients who withdrew from the study due to adverse events was 0% and 
2.5% for the placebo and Prolia groups, respectively. 
 
Adverse reactions reported in ≥ 5% of men with osteoporosis and more frequently with Prolia than in the 
placebo-treated patients were: back pain (6.7% placebo vs. 8.3% Prolia), arthralgia (5.8% placebo 
vs. 6.7% Prolia), and nasopharyngitis (5.8% placebo vs. 6.7% Prolia). 

Serious Infections  
Serious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the Prolia 
group.  
 
Dermatologic Reactions  
Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 4 patients 
(3.3%) in the placebo group and 5 patients (4.2%) in the Prolia group. 
 
Osteonecrosis of the Jaw 
No cases of ONJ were reported. 
 
Pancreatitis 
Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the Prolia 
group.   
 
New Malignancies 
New malignancies were reported in no patients in the placebo group and 4 (3.3%) patients (3 prostate 
cancers, 1 basal cell carcinoma) in the Prolia group.

 
Treatment of Bone Loss in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer or 
Adjuvant Aromatase Inhibitor Therapy for Breast Cancer  
 
The safety of Prolia in the treatment of bone loss in men with nonmetastatic prostate cancer receiving 
androgen deprivation therapy (ADT) was assessed in a 3-year, randomized, double-blind, placebo-
controlled, multinational study of 1468 men aged 48 to 97 years.  A total of 725 men were exposed to 
placebo and 731 men were exposed to Prolia administered once every 6 months as a single 60 mg 
subcutaneous dose.  All men were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D 
supplementation per day. 
 
The incidence of serious adverse events was 30.6% in the placebo group and 34.6% in the Prolia group.  
The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the 
placebo and Prolia groups, respectively. 
 
The safety of Prolia in the treatment of bone loss in women with nonmetastatic breast cancer receiving 
aromatase inhibitor (AI)  therapy was assessed in a 2-year, randomized, double-blind, placebo-controlled, 
multinational study of 252 postmenopausal women aged 35 to 84 years.  A total of 120 women were 
exposed to placebo and 129 women were exposed to Prolia administered once every 6 months as a single 
60 mg subcutaneous dose.  All women were instructed to take at least 1000 mg of calcium and 400 IU of 
vitamin D supplementation per day. 
 

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The incidence of serious adverse events was 9.2% in the placebo group and 14.7% in the Prolia group.

The percentage of patients who withdrew from the study due to adverse events was 4.2% and 0.8% for the 
placebo and Prolia groups, respectively. 
 
Adverse reactions reported in ≥ 10% of Prolia-treated patients receiving ADT for prostate cancer or 

adjuvant AI therapy for breast cancer, and more frequently than in the placebo-treated patients were: 
arthralgia (13.0% placebo vs. 14.3% Prolia) and back pain (10.5% placebo vs. 11.5% Prolia).  Pain in 
extremity (7.7% placebo vs. 9.9% Prolia) and musculoskeletal pain (3.8% placebo vs. 6.0% Prolia)

have 

also been reported in clinical trials.  Additionally in Prolia-treated men with nonmetastatic prostate cancer 
receiving ADT, a greater incidence of cataracts was observed (1.2% placebo vs. 4.7% Prolia).  
Hypocalcemia (serum calcium < 8.4 mg/dL) was reported only in Prolia-treated patients (2.4% vs. 0%) at 
the month 1 visit.  

 
6.2 

Postmarketing Experience 

 
Because postmarketing 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. 
 
The following adverse reactions have been identified during post approval use of Prolia: 



  Drug-related hypersensitivity reactions: anaphylaxis, rash, urticaria, facial swelling, and erythema   



  Hypocalcemia: severe symptomatic hypocalcemia  



  Musculoskeletal pain, including severe cases 



  Parathyroid Hormone (PTH): Marked elevation in serum PTH in patients with severe renal 

impairment (creatinine clearance < 30 mL/min) or receiving dialysis. 

 
6.3 

Immunogenicity 

 
Denosumab is a human monoclonal antibody.  As with all therapeutic proteins, there is potential for 
immunogenicity.  Using an electrochemiluminescent bridging immunoassay, less than 1% (55 out of 
8113) of patients treated with Prolia for up to 5 years tested positive for binding antibodies (including 
pre-existing, transient

, 

and developing antibodies).  None of the patients tested positive for 

neutralizing antibodies, as was assessed using a chemiluminescent cell-based in vitro biological assay.  
No evidence of altered pharmacokinetic profile, toxicity profile, or clinical response was associated 
with binding antibody development.  
 
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.  
Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result 
may be influenced by several factors, including assay methodology, sample handling, timing of sample 
collection, concomitant medications, and underlying disease.  For these reasons, comparison of antibodies 
to denosumab with the incidence of antibodies to other products may be misleading. 
 
7 

DRUG INTERACTIONS 

 
In subjects with postmenopausal osteoporosis, Prolia (60 mg subcutaneous injection) did not affect the 
pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4), indicating 
that it should not affect the pharmacokinetics of drugs metabolized by this enzyme in this population 
[see Clinical Pharmacology (12.3)].   
 
 

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8 

USE IN SPECIFIC POPULATIONS 

 
8.1 

Pregnancy  

 
Pregnancy Category X 
 
Risk Summary 
Prolia may cause fetal harm when administered to a pregnant woman based on findings in animals.  In 
utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and 
postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased 
neonatal growth.  Prolia is contraindicated in women who are pregnant.  If this drug is used during 
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of 
the potential hazard to a fetus. 
 
Women who become pregnant during Prolia treatment are encouraged to enroll in Amgen’s Pregnancy 
Surveillance Program.  Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to 
enroll. 
 
Clinical Considerations 
The effects of Prolia on the fetus are likely to be greater during the second and third trimesters of 
pregnancy.  Monoclonal antibodies, such as denosumab, are transported across the placenta in a linear 
fashion as pregnancy progresses, with the largest amount transferred during the third trimester.  If the 
patient becomes pregnant during Prolia therapy, treatment should be discontinued and the patient should 
consult their physician. 
 
Prolia was present at low concentrations (approximately 2% of serum exposure) in the seminal fluid of 
male subjects given Prolia.  Following vaginal intercourse, the maximum amount of Prolia delivered to a 
female partner would result in exposures approximately 11,000 times lower than the prescribed 60 mg 
subcutaneous dose. 
 
The no-effect dose for denosumab-induced teratogenicity is unknown.  However, a C

max

 of 22.9 ng/mL 

was identified in cynomolgus monkeys as a level in which no biologic effects (NOEL) of denosumab 
were observed (no inhibition of RANKL).  Using the highest seminal fluid concentration measured in 
men, and assuming 100% vaginal and placental transfer from a 6-mL ejaculate per day, female and fetal 
exposure via seminal fluid would be up to 0.6 ng/mL per day.  Thus, the potential amount of fetal 
exposure when a man treated with Prolia has unprotected sexual intercourse with a pregnant partner is at 
least 38-times lower than the NOEL in monkeys.  Therefore, it is unlikely that a female partner or fetus 
would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid [see 
Clinical Pharmacology (12.3)]. 
 
Animal Data 
The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and 
genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene 
removal (a “knockout mouse”).  In cynomolgus monkeys dosed subcutaneously with denosumab 
throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, 
stillbirths, and postnatal mortality.  Other findings in offspring included absence of axillary, inguinal, 
mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced 
hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth.  At birth out to 
1 month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels).