1.1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture

Prolia is indicated for the 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. In postmenopausal women with osteoporosis, Prolia reduces the incidence of vertebral, nonvertebral, and hip fractures [see Clinical Studies (14.1)].

1.2 Treatment to Increase Bone Mass in Men with Osteoporosis

Prolia is indicated for treatment to increase bone mass in men 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 [see Clinical Studies (14.2)].

1.3 Treatment of Glucocorticoid-Induced Osteoporosis

Prolia is indicated for the treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months. High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy [see Clinical Studies (14.3)].

1.4 Treatment of Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

Prolia is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer. In these patients Prolia also reduced the incidence of vertebral fractures [see Clinical Studies (14.4)].

1.5 Treatment of Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for Breast 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 [see Clinical Studies (14.5)].

2.1 Pregnancy Testing Prior to Initiation of Prolia

Pregnancy must be ruled out prior to administration of Prolia. Perform pregnancy testing in all females of reproductive potential prior to administration of Prolia. Based on findings in animals, Prolia can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1, 8.3)].

2.2 Laboratory Testing in Patients with Advanced Chronic Kidney Disease Prior to Initiation of Prolia

In patients with advanced chronic kidney disease [i.e., estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2], including dialysis-dependent patients, evaluate for the presence of chronic kidney disease mineral and bone disorder (CKD-MBD) with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25 (OH)2 vitamin D prior to decisions regarding Prolia treatment. Consider also assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate the underlying bone disease that may be present [see Warnings and Precautions (5.1)].

2.3 Recommended Dosage

Prolia should be administered by a healthcare professional.

The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Prolia via subcutaneous injection in the upper arm, the upper thigh, or the abdomen. All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily [see Warnings and Precautions (5.1)].

If a dose of Prolia is missed, administer the injection as soon as the patient is available. Thereafter, schedule injections every 6 months from the date of the last injection.

2.4 Preparation and Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Prolia is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter.

Prior to administration, Prolia may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Prolia in any other way [see How Supplied/Storage and Handling (16)].

Instructions for Administration of Prolia Prefilled Syringe with Needle Safety Guard

IMPORTANT: In order to minimize accidental needlesticks, the Prolia single-dose prefilled syringe will have a green safety guard; manually activate the safety guard after the injection is given.

DO NOT slide the green safety guard forward over the needle before administering the injection; it will lock in place and prevent injection.

Activate the green safety guard (slide over the needle) after the injection.

Step 1: Remove Gray Needle Cap

Remove needle cap.

Step 2: Administer Subcutaneous Injection

	Choose an injection site. The recommended injection sites for Prolia include: the upper arm OR the upper thigh OR the abdomen.

Insert needle and inject all the liquid subcutaneously. Do not administer into muscle or blood vessel.

DO NOT put gray needle cap back on needle.

Step 3: Immediately Slide Green Safety Guard Over Needle

With the needle pointing away from you.

Hold the prefilled syringe by the clear finger grip with one hand. Then, with the other hand, grasp the green safety guard by its base and gently slide it towards the needle until the green safety guard locks securely in place and/or you hear a "click". DO NOT grip the green safety guard too firmly - it will move easily if you hold and slide it gently.

	Hold clear finger grip.
	Gently slide green safety guard over needle and lock securely in place. Do not grip green safety guard too firmly when sliding over needle.

Immediately dispose of the syringe and needle cap in the nearest sharps container. DO NOT put the needle cap back on the used syringe.

5.1 Severe Hypocalcemia and Mineral Metabolism Changes

Prolia can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Prolia. Adequately supplement all patients with calcium and vitamin D [see Dosage and Administration (2.1), Contraindications (4), and Adverse Reactions (6.1)].

In patients without advanced chronic kidney disease who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, treatment with other calcium-lowering drugs), assess serum calcium and mineral levels (phosphorus and magnesium) 10 to14 days after Prolia injection. In some postmarketing cases, hypocalcemia persisted for weeks or months and required frequent monitoring and intravenous and/or oral calcium replacement, with or without vitamin D.

5.2 Drug Products with Same Active Ingredient

Prolia contains the same active ingredient (denosumab) found in Xgeva. Patients receiving Prolia should not receive Xgeva.

5.3 Hypersensitivity

Clinically significant hypersensitivity including anaphylaxis has been reported with Prolia. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy, and discontinue further use of Prolia [see Contraindications (4), Adverse Reactions (6.2)].

5.4 Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab [see Adverse Reactions (6.1)]. A routine oral exam should be performed by the prescriber prior to initiation of Prolia treatment. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Prolia in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and comorbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Prolia. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. The risk of ONJ may increase with duration of exposure to Prolia.

For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment.

Patients who are suspected of having or who develop ONJ while on Prolia should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia therapy should be considered based on individual benefit-risk assessment.

5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Atypical low energy or low trauma fractures of the shaft have been reported in patients receiving Prolia [see Adverse Reactions (6.1)]. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with antiresorptive agents.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral, and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture.

During Prolia treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Prolia therapy should be considered, pending a benefit-risk assessment, on an individual basis.

5.6 Multiple Vertebral Fractures (MVF) Following Discontinuation of Prolia Treatment

Following discontinuation of Prolia treatment, fracture risk increases, including the risk of multiple vertebral fractures. Treatment with Prolia results in significant suppression of bone turnover and cessation of Prolia treatment results in increased bone turnover above pretreatment values 9 months after the last dose of Prolia. Bone turnover then returns to pretreatment values 24 months after the last dose of Prolia. In addition, bone mineral density (BMD) returns to pretreatment values within 18 months after the last injection [see Clinical Pharmacology (12.2), Clinical Studies (14.1)].

New vertebral fractures occurred as early as 7 months (on average 19 months) after the last dose of Prolia. Prior vertebral fracture was a predictor of multiple vertebral fractures after Prolia discontinuation. Evaluate an individual's benefit-risk before initiating treatment with Prolia.

If Prolia treatment is discontinued, patients should be transitioned to an alternative antiresorptive therapy [see Adverse Reactions (6.1)].

5.7 Serious Infections

In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Prolia group than in the placebo group [see Adverse Reactions (6.1)]. Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more frequent in patients treated with Prolia. Endocarditis was also reported more frequently in Prolia-treated patients. The incidence of opportunistic infections was similar between placebo and Prolia groups, and the overall incidence of infections was similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.

Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. Consider the benefit-risk profile in such patients before treating with Prolia. In patients who develop serious infections while on Prolia, prescribers should assess the need for continued Prolia therapy.

5.8 Dermatologic Adverse Reactions

In a large clinical trial of over 7800 women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate in the Prolia group compared to the placebo group. Most of these events were not specific to the injection site [see Adverse Reactions (6.1)]. Consider discontinuing Prolia if severe symptoms develop.

5.9 Musculoskeletal Pain

In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Prolia [see Adverse Reactions (6.2)]. The time to onset of symptoms varied from one day to several months after starting Prolia. Consider discontinuing use if severe symptoms develop [see Patient Counseling Information (17)].

5.10 Suppression of Bone Turnover

In clinical trials in women with postmenopausal osteoporosis, treatment with Prolia resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry [see Clinical Pharmacology (12.2), Clinical Studies (14.1)]. The significance of these findings and the effect of long-term treatment with Prolia are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with Prolia may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. Monitor patients for these consequences.

5.11 Hypercalcemia in Pediatric Patients with Osteogenesis Imperfecta

Prolia is not approved for use in pediatric patients. Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products, including Prolia. Some cases required hospitalization [see Use in Specific Populations (8.4)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

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 resulting in hospitalization, life-threatening events, and fatal cases
• 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
• Multiple vertebral fractures following discontinuation of Prolia
• Cutaneous and mucosal lichenoid drug eruptions (e.g., lichen planus-like reactions)
• Alopecia
• Vasculitis (e.g. ANCA positive vasculitis, leukocytoclastic vasculitis)
• Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Based on findings in animals, Prolia can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of Prolia have not been established in pediatric patients.

In one multicenter, open-label study conducted in 153 pediatric patients with osteogenesis imperfecta, aged 2 to 17 years, evaluating fracture risk reduction, efficacy was not established.

Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products, including Prolia. Some cases required hospitalization and were complicated by acute renal injury [see Warnings and Precautions (5.11)]. Clinical studies in pediatric patients with osteogenesis imperfecta were terminated early due to the occurrence of life-threatening events and hospitalizations due to hypercalcemia.

Based on results from animal studies, Prolia may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years.

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. Of the patients in the glucocorticoid-induced osteoporosis study, 355 patients (47%) were ≥ 65 years old, while 132 patients (17%) 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.

Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported postmarketing. In clinical studies, patients with advanced chronic kidney disease (i.e., eGFR < 30 mL/min/1.73 m2), including dialysis-dependent patients, were at greater risk of developing hypocalcemia. The presence of underlying chronic kidney disease-mineral bone disorder (CKD-MBD, renal osteodystrophy) markedly increases the risk of hypocalcemia. Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk. Consider the benefits and risks to the patient when administering Prolia to patients with advanced chronic kidney disease. Monitor calcium and mineral levels (phosphorus and magnesium). Adequate intake of calcium and vitamin D is important in patients with advanced chronic kidney disease including dialysis-dependent patients [see Dosage and Administration (2.2),Warnings and Precautions (5.1), Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

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 [P1NP]) 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, the mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg∙day/mL (SD = 101 mcg∙day/mL). The mean maximum denosumab concentration (Cmax) was 6.75 mcg/mL (SD = 1.89 mcg/mL). No accumulation or change in denosumab pharmacokinetics with time is observed with multiple dosing of 60 mg subcutaneously administered once every 6 months.

12.6 Immunogenicity

The observed incidence of anti-drug antibody is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of Prolia or denosumab products.

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.

There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of denosumab.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

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

In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and increased 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.

14.1 Treatment of 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 Hip Fractures

The incidence of hip fracture was 1.2% for placebo-treated women compared to 0.7% for Prolia-treated women at year 3. The age-adjusted absolute risk reduction of hip fractures was 0.3% with a relative risk reduction of 40% at 3 years (p = 0.04) ( see Figure 1).

Figure 1. Cumulative Incidence of Hip Fractures Over 3 Years

N = number of subjects randomized

14.2 Treatment to Increase Bone Mass in Men with Osteoporosis

The efficacy and safety of Prolia in the treatment to increase bone mass in men with osteoporosis was demonstrated in a 1-year, randomized, double-blind, placebo-controlled trial. Enrolled men had a baseline BMD T-score between -2.0 and -3.5 at the lumbar spine or femoral neck. Men with a BMD T-score between -1.0 and -3.5 at the lumbar spine or femoral neck were also enrolled if there was a history of prior fragility fracture. Men with other diseases (such as rheumatoid arthritis, osteogenesis imperfecta, and Paget's disease) or on therapies that may affect bone were excluded from this study. The 242 men enrolled in the study ranged in age from 31 to 84 years with a mean age of 65 years. Men were randomized to receive SC injections of either placebo (n = 121) or Prolia 60 mg (n = 121) once every 6 months. All men received at least 1000 mg calcium and at least 800 IU vitamin D supplementation daily.

14.3 Treatment of Glucocorticoid-Induced Osteoporosis

The efficacy and safety of Prolia in the treatment of patients with glucocorticoid-induced osteoporosis was assessed in the 12-month primary analysis of a 2-year, randomized, multicenter, double-blind, parallel-group, active-controlled study (NCT 01575873) of 795 patients (70% women and 30% men) aged 20 to 94 years (mean age of 63 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent) for < 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-initiating subpopulation; n = 290) or ≥ 3 months prior to study enrollment and planning to continue treatment for a total of at least 6 months (glucocorticoid-continuing subpopulation, n = 505). Enrolled patients < 50 years of age were required to have a history of osteoporotic fracture. Enrolled patients ≥ 50 years of age who were in the glucocorticoid-continuing subpopulation were required to have a baseline BMD T-score of ≤ -2.0 at the lumbar spine, total hip, or femoral neck; or a BMD T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of osteoporotic fracture.

Patients were randomized (1:1) to receive either an oral daily bisphosphonate (active-control, risedronate 5 mg once daily) (n = 397) or Prolia 60 mg subcutaneously once every 6 months (n = 398) for one year. Randomization was stratified by gender within each subpopulation. Patients received at least 1000 mg calcium and 800 IU vitamin D supplementation daily.

14.4 Treatment of Bone Loss in Men with Prostate Cancer

The efficacy and safety of Prolia in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) were demonstrated in a 3-year, randomized (1:1), double-blind, placebo-controlled, multinational study. Men less than 70 years of age had either a BMD T-score at the lumbar spine, total hip, or femoral neck between -1.0 and -4.0, or a history of an osteoporotic fracture. The mean baseline lumbar spine BMD T-score was -0.4, and 22% of men had a vertebral fracture at baseline. The 1468 men enrolled ranged in age from 48 to 97 years (median 76 years). Men were randomized to receive subcutaneous injections of either placebo (n = 734) or Prolia 60 mg (n = 734) once every 6 months for a total of 6 doses. Randomization was stratified by age (< 70 years vs. ≥ 70 years) and duration of ADT at trial entry (≤ 6 months vs. > 6 months). Seventy-nine percent of patients received ADT for more than 6 months at study entry. All men received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.

14.5 Treatment of Bone Loss in Women with Breast Cancer

The efficacy and safety of Prolia in the treatment of bone loss in women receiving adjuvant aromatase inhibitor (AI) therapy for breast cancer was assessed in a 2-year, randomized (1:1), double-blind, placebo-controlled, multinational study. Women had baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip, or femoral neck, and had not experienced fracture after age 25. The mean baseline lumbar spine BMD T-score was -1.1, and 2.0% of women had a vertebral fracture at baseline. The 252 women enrolled ranged in age from 35 to 84 years (median 59 years). Women were randomized to receive subcutaneous injections of either placebo (n = 125) or Prolia 60 mg (n = 127) once every 6 months for a total of 4 doses. Randomization was stratified by duration of adjuvant AI therapy at trial entry (≤ 6 months vs. > 6 months). Sixty-two percent of patients received adjuvant AI therapy for more than 6 months at study entry. All women received at least 1000 mg calcium and 400 IU vitamin D supplementation daily.

How Supplied

Prolia injection is a clear, colorless to pale yellow solution supplied in a single-dose prefilled syringe with a safety guard. The prefilled syringe is not made with natural rubber latex.

Storage and Handling

Store Prolia in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Prior to administration, Prolia may be allowed to reach room temperature (up to 25°C/77°F) in the original container. Once removed from the refrigerator, Prolia must not be exposed to temperatures above 25°C/77°F and must be used within 14 days. If not used within the 14 days, Prolia should be discarded. Do not use Prolia after the expiry date printed on the label. Protect Prolia from direct light and heat.

Avoid vigorous shaking of Prolia.

Hypocalcemia

Advise the patient to adequately supplement with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving Prolia [see Warnings and Precautions (5.1), Use in Specific Populations (8.6)]. Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcemia.

Severe Hypocalcemia in Patients with Advanced Chronic Kidney Disease

Advise patients with advanced chronic kidney disease, including those who are dialysis-dependent, about the symptoms of hypocalcemia and the importance of maintaining serum calcium levels with adequate calcium and activated vitamin D supplementation. Advise these patients to have their serum calcium measured weekly for the first month after Prolia administration and monthly thereafter [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6)]

Drug Products with Same Active Ingredient

Advise patients that denosumab is also marketed as Xgeva, and if taking Prolia, they should not receive Xgeva [see Warnings and Precautions (5.2)].

Hypersensitivity

Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions that they should not receive denosumab (Prolia or Xgeva) [see Warnings and Precautions (5.3), Contraindications (4)].

Osteonecrosis of the Jaw

Advise patients to maintain good oral hygiene during treatment with Prolia and to inform their dentist prior to dental procedures that they are receiving Prolia. Patients should inform their physician or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery [see Warnings and Precautions (5.4)].

Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Advise patients to report new or unusual thigh, hip, or groin pain [see Warnings and Precautions (5.5)].

Multiple Vertebral Fractures (MVF) Following Discontinuation of Prolia Treatment

Advise patients not to interrupt Prolia therapy without talking to their physician [see Warnings and Precautions (5.6)].

Serious Infections

Advise patients to seek prompt medical attention if they develop signs or symptoms of infections, including cellulitis [see Warnings and Precautions (5.7)].

Dermatologic Adverse Reactions

Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatological reactions (such as dermatitis, rashes, and eczema) [see Warnings and Precautions (5.8)].

Musculoskeletal Pain

Inform patients that severe bone, joint, and/or muscle pain have been reported in patients taking Prolia. Patients should report severe symptoms if they develop [see Warnings and Precautions (5.9)].

Pregnancy/Nursing

Counsel females of reproductive potential to use effective contraceptive measure to prevent pregnancy during treatment and for at least 5 months after the last dose of Prolia. Advise the patient to contact their physician immediately if pregnancy does occur during these times. Advise patients not to take Prolia while pregnant or breastfeeding. If a patient wishes to start breastfeeding after treatment, advise her to discuss the appropriate timing with her physician [see Contraindications (4), Use in Specific Populations (8.1)].

Schedule of Administration

Advise patients that if a dose of Prolia is missed, the injection should be administered as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection.