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Generic Name: Denosumab
Class: Bone Resorption Inhibitors
Chemical Name: Anti-(human osteoclast differentiation factor) (human monoclonal AMG162 heavy chain), disulfide with human monoclonal AMG162 light chain immunoglobulin G2 dimer.
Molecular Formula: C6404H9912N1724O2004S50
CAS Number: 615258-40-7

Warning(s)

REMS:

FDA approved a REMS for denosumab to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of denosumab and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Bone resorption inhibitor; fully human monoclonal antibody specific for receptor activator of nuclear factor kappa-B ligand (RANKL); RANKL inhibitor.1 2 10 25

Uses for Prolia

Osteoporosis (Prolia)

Treatment of osteoporosis in postmenopausal women and men at high risk of fracture, defined as history of osteoporotic fracture or multiple risk factors for fracture.1 3 4 26

Treatment of osteoporosis in postmenopausal women and men who have failed or are intolerant of other available osteoporosis therapies.1 4

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Bone Loss Associated with Androgen Deprivation Therapy (Prolia)

Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer.1 17

Bone Loss Associated with Aromatase Inhibitor Therapy (Prolia)

Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.1 18

Bone Metastases of Solid Tumors (Xgeva)

Prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors.2 19 20 21

Not indicated for prevention of SREs in patients with multiple myeloma.2

Giant Cell Tumor of Bone (Xgeva)

Treatment of giant cell tumor of bone in adults and skeletally mature adolescents if the disease is unresectable or surgical resection likely to result in severe morbidity.2 28 29

Prolia Dosage and Administration

General

  • Correct preexisting hypocalcemia prior to initiating denosumab.1 2

  • All patients receiving denosumab (Prolia) for treatment of osteoporosis or treatment of bone loss associated with androgen deprivation or aromatase inhibitor therapy should receive 1 g of calcium and at least 400 units of vitamin D daily.1

  • Patients receiving denosumab (Xgeva) for prevention of SREs or treatment of giant cell tumor of bone should receive calcium, vitamin D, and magnesium supplementation as necessary.2

Administration

Sub-Q Administration

Administer by sub-Q injection into upper arm, upper thigh, or abdomen;1 2 do not inject into muscle or blood vessels.1

Manufacturer states Prolia should be administered by a health-care professional.1

Prior to administration, may warm to room temperature by allowing drug to stand in original packaging at room temperature (≤25°C) for approximately 15–30 minutes.1 2 Do not warm using any other method.1 2

Solution should appear clear, colorless to pale yellow; may contain trace amounts of translucent to white proteinaceous particles.1 2 Do not use if solution is discolored, cloudy, or contains many particles or foreign matter.1 2

Single-use prefilled syringe (Prolia): Remove gray needle cap and inject entire solution.1 After injection is complete, activate needle guard by pointing needle away from body and gently sliding green safety guard toward needle until locked securely in place.1 The needle cap contains dry natural rubber (latex) and should not be handled by individuals sensitive to latex.1 (See Latex Sensitivity under Cautions.)

Single-use vial (Prolia, Xgeva): Use 27-gauge needle to withdraw and inject entire vial contents.1 2 Do not re-enter vial; discard any remaining solution along with the vial.1 2

Dosage

Pediatric Patients

Giant Cell Tumor of Bone (Xgeva)
Treatment in Skeletally Mature Adolescents
Sub-Q

120 mg once every 4 weeks; during first month of treatment, give additional 120-mg dose on day 8 and 15.2

Adults

Osteoporosis (Prolia)
Treatment in Postmenopausal Women at High Risk for Fracture
Sub-Q

60 mg once every 6 months.1

Administer a missed dose as soon as patient is available; give subsequent doses every 6 months from date of last dose.1

Treatment in Men at High Risk for Fracture
Sub-Q

60 mg once every 6 months.1

Administer a missed dose as soon as patient is available; give subsequent doses every 6 months from date of last dose.1

Bone Loss Associated with Androgen Deprivation Therapy (Prolia)
Treatment in Men with Nonmetastatic Prostate Cancer at High Risk for Fracture
Sub-Q

60 mg once every 6 months.1

Administer a missed dose as soon as patient is available; give subsequent doses every 6 months from date of last dose.1

Bone Loss Associated with Adjuvant Aromatase Inhibitor Therapy (Prolia)
Treatment in Women with Breast Cancer at High Risk for Fracture
Sub-Q

60 mg once every 6 months.1

Administer a missed dose as soon as patient is available; give subsequent doses every 6 months from date of last dose.1

Bone Metastases of Solid Tumors (Xgeva)
Prevention of SREs
Sub-Q

120 mg once every 4 weeks.2

Giant Cell Tumor of Bone (Xgeva)
Sub-Q

120 mg once every 4 weeks; during first month of treatment, give additional 120-mg dose on day 8 and 15.2

Special Populations

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment.1 2

Renal Impairment

Dosage adjustment not necessary in patients with renal impairment.1 27 However, those with severe renal impairment (Clcr <30 mL/minute) or receiving dialysis are at greater risk of developing hypocalcemia.1 2 (See Hypocalcemia and Mineral Metabolism under Cautions.)

Cautions for Prolia

Contraindications

  • Prolia: Hypocalcemia (correct preexisting hypocalcemia prior to initiating denosumab), pregnancy, history of systemic hypersensitivity to denosumab or any component in the product.1

  • Xgeva: Hypocalcemia (correct preexisting hypocalcemia prior to initiating denosumab), hypersensitivity to denosumab or any component of the product.2

Warnings/Precautions

Choice of Denosumab Products

Commercially available as Prolia and Xgeva;1 2 these products labeled by FDA for different indications.1 2 (See Uses.)

Do not use Prolia and Xgeva concomitantly.1 2

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm when administered during pregnancy.1 2 (See Pregnancy under Cautions.)

Denosumab (Prolia) contraindicated during pregnancy.1 If pregnancy occurs during denosumab treatment, the woman should discontinue the drug and contact her clinician.1

If denosumab (Xgeva) used in females of childbearing potential, use highly-effective contraception during and for at least 5 months after last dose.2 If pregnancy occurs during denosumab treatment for prevention of skeletal-related events (SREs) related to bone metastases from solid tumors or for treatment of giant cell tumor of bone, consider benefits and risks of continuing treatment with the drug.2

If denosumab (Prolia, Xgeva) used during pregnancy or if pregnancy confirmed or suspected during treatment, inform woman of possible risk to the fetus;1 2 risk may be greatest during second and third trimesters.1 2

Not known if denosumab is present in seminal fluid.1 2 While risk of fetal harm may be low, inform men receiving denosumab who have pregnant partners about potential fetal exposure to the drug during unprotected sexual intercourse.1 2

Sensitivity Reactions

Hypersensitivity

Systemic hypersensitivity reactions (e.g., anaphylaxis, hypotension, dyspnea, throat tightness, facial and upper airway edema, lip swelling, rash, pruritus, urticaria) reported.1 2

If anaphylaxis or other clinically important hypersensitivity reaction occurs, discontinue denosumab and initiate appropriate therapy.1 2 Do not reinitiate the drug in such patients.1 2

Latex Sensitivity

Prolia: Some packaging components (i.e., needle cap) of prefilled syringes contain natural latex proteins in the form of dry natural rubber (latex),1 and should not be handled by individuals sensitive to latex.1 5 6 7

Some individuals may be hypersensitive to natural latex proteins;5 6 7 rarely, hypersensitivity reactions to natural latex proteins have been fatal.6 7

Hypocalcemia and Mineral Metabolism

Decreased serum calcium concentrations can occur;1 2 preexisting hypocalcemia may be exacerbated.1

Severe, symptomatic hypocalcemia (including some fatalities) reported.2

Correct preexisting hypocalcemia prior to initiating denosumab.1 2

All patients receiving Prolia should receive calcium and vitamin D supplementation daily.1 Patients receiving Xgeva should receive calcium, vitamin D, and magnesium supplementation as necessary.2 (See General under Dosage and Administration.)

In patients receiving Prolia who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g., history of hypocalcemia, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment, receiving dialysis), clinical monitoring of calcium, phosphorus, and magnesium highly recommended.1

In patients receiving denosumab (Xgeva) for prevention of SREs or treatment of giant cell tumor of bone, monitor calcium concentrations; monitor more frequently in those receiving concomitant therapy with other drugs that may also reduce serum calcium concentrations.2

Risk of hypocalcemia is greater in patients with severe renal impairment (Clcr <30 mL/minute) or receiving dialysis.1 2 Monitor such patients for symptoms of hypocalcemia and ensure adequate calcium and vitamin D supplementation.1 (See Renal Impairment under Cautions.)

Osteonecrosis of the Jaw (ONJ)

ONJ reported in patients receiving denosumab (Prolia, Xgeva).1 2 May occur spontaneously, but generally associated with tooth extraction and/or local infection with delayed healing.1 ONJ may manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion.2

Risk factors for ONJ include invasive dental procedures (e.g., tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and comorbidities (e.g., preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures).1

Perform routine oral examination and appropriate preventative dentistry prior to initiating denosumab,1 2 especially in patients with risk factors for ONJ.1 All patients should maintain good oral hygiene during denosumab treatment.1 2

Avoid invasive dental procedures during denosumab treatment.2 If invasive dental procedures are required, use clinical judgment of the prescriber and/or oral surgeon and assessment of risks and benefits to guide the management plan.1

If ONJ develops or is suspected, refer patient to dentist or oral surgeon.1 2 Extensive dental surgery to treat ONJ may exacerbate the condition.1 2 Consider discontinuing denosumab based on patient-specific risk-benefit assessment.1

Atypical Subtrochanteric and Diaphyseal Femoral Fracture

Atypical low energy or low trauma fractures of the femur reported in patients receiving denosumab (Prolia, Xgeva).1 2 Such fractures can occur anywhere along femoral shaft from just below lesser trochanter to above supracondylar flare and have transverse or short oblique orientation without evidence of comminution.1 2

May be bilateral and often occur with minimal or no trauma to affected area.1 2 Many patients report dull or aching thigh pain weeks to months before a complete fracture occurs.1 2 Some patients were also receiving glucocorticoid (prednisone) treatment at time of fracture.1 2

Advise patients receiving denosumab to report new or unusual pain in the thigh, hip, or groin.1 2 Evaluate patients with such symptoms to rule out incomplete femur fracture; also evaluate contralateral limb for fracture.1 2

Consider interrupting denosumab treatment pending assessment of risks and benefits of the drug for the individual patient.1 2

Suppression of Bone Turnover

Significant suppression of bone remodeling reported in clinical trials of denosumab (Prolia) in postmenopausal women with osteoporosis.1 4

Denosumab treatment results in reduction in biochemical bone turnover markers4 and bone formation rates (as shown by tetracycline labeling).1

Long-term effects of the degree of bone remodeling suppression seen with denosumab are unknown.1 Because these effects may contribute to adverse outcomes, such as ONJ, atypical fractures, and delayed fracture healing, monitor patients for such events.1

Immunogenicity and Antibody Formation

Denosumab-binding antibodies (preexisting, transient, and developing antibodies) reported rarely in postmenopausal women with osteoporosis receiving up to 5 years of denosumab (Prolia) and in patients with osseous metastases receiving up to 3 years of denosumab (Xgeva) in dosages ranging from 30–180 mg every 4 or 12 weeks.1 2 Not reported in patients who received denosumab (Xgeva) for treatment of giant cell tumor of bone.2

Denosumab-neutralizing antibodies not reported to date, and antibody formation does not appear to affect denosumab pharmacokinetics, toxicity, or efficacy.1 2

Serious Infections

May increase risk of infection.1

Serious skin infections (e.g., cellulitis, erysipelas), endocarditis, and infections of the abdomen, urinary tract, and ear reported in a clinical trial evaluating denosumab (Prolia) in postmenopausal women with osteoporosis;1 some infections required hospitalization.1

Patients receiving concomitant immunosuppressive agents or with impaired immune systems may be at greater risk of serious infections.1 Assess need for continued denosumab treatment in patients who develop serious infections.1

Dermatologic Reactions

Adverse epidermal and dermal events (e.g., dermatitis, eczema, rash) reported in a clinical trial evaluating denosumab (Prolia) in postmenopausal women with osteoporosis; most reactions were not specific to the injection site.1

Consider discontinuing denosumab if severe dermatologic symptoms develop.1

Specific Populations

Pregnancy

Prolia: Category X.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Xgeva: Category D.2 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Fetal loss, stillbirths, postnatal mortality, and evidence of absent lymph nodes, abnormal bone growth, and decreased neonatal growth reported in reproduction studies in monkeys.1 2

Encourage women who become pregnant while receiving denosumab to enroll in manufacturer's pregnancy surveillance program at 800-772-6436.1 2

Lactation

Not known whether distributed into milk.1 2 Discontinue nursing or drug.1 2

Studies in pregnant mice indicate denosumab exposure during pregnancy may impair maternal mammary gland development and lactation.1 2

Pediatric Use

Prolia: Safety and efficacy not established for any indication in pediatric patients.1

Xgeva: Safety and efficacy established for treatment of giant cell tumor of bone in skeletally mature adolescents.2 Safety and efficacy not established for any other indication in pediatric patients.2

May impair bone growth in children with open growth plates and may inhibit eruption of dentition.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults,1 2 but increased sensitivity cannot be ruled out.1

Hepatic Impairment

No pharmacokinetic studies performed in patients with hepatic impairment.1 2

Renal Impairment

Pharmacokinetics not affected by renal impairment;1 2 27 dosage adjustment not necessary.1 27

Patients with severe renal impairment (Clcr <30 mL/minute) or receiving dialysis are at greater risk of hypocalcemia.1 2 27 Consider risks and benefits of denosumab in such patients.1 Clinical monitoring of calcium, phosphorus, and magnesium highly recommended, and adequate calcium and vitamin D supplementation is important.1 (See Hypocalcemia and Mineral Metabolism under Cautions.)

Common Adverse Effects

Prolia for treatment of osteoporosis: Back pain,1 extremity pain,1 musculoskeletal pain,1 hypercholesterolemia,1 cystitis (postmenopausal women)1 or back pain,1 arthralgia,1 nasopharyngitis (men).1

Prolia for treatment of bone loss associated with androgen deprivation or aromatase inhibitor therapy: Arthralgia,1 back pain,1 extremity pain,1 musculoskeletal pain.1 Cataracts also reported in men receiving denosumab for bone loss associated with androgen deprivation therapy.1

Xgeva for prevention of SREs in patients with bone metastases: Fatigue/asthenia,2 hypophosphatemia,2 nausea,2 dyspnea,2 diarrhea,2 hypocalcemia,2 cough,2 headache.2

Xgeva for treatment of giant cell tumor of bone: Arthralgia,2 headache,2 nausea,2 back pain,2 fatigue,2 extremity pain.2

Interactions for Prolia

Drugs Metabolized by Hepatic Enzymes

Clinically important drug interactions not expected when denosumab used concomitantly with drugs metabolized by CYP3A4 in postmenopausal women with osteoporosis.1

Drugs Affecting Serum Calcium Concentrations

Monitor serum calcium concentrations more frequently than usual in patients receiving concomitant therapy with other drugs that may also reduce serum calcium concentrations.2 (See Hypocalcemia and Mineral Metabolism under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Antineoplastic agents

No evidence that chemotherapy and/or hormone therapy affect denosumab pharmacokinetics or pharmacodynamics2

Immunosuppressive agents

Possible increased risk of serious infections1

Assess risks and benefits of denosumab in patients receiving immunosuppressive agents1

Midazolam

No clinically important effect on midazolam pharmacokinetics in postmenopausal women with osteoporosis1

Prolia Pharmacokinetics

Absorption

Bioavailability

Approximately 61–62% following sub-Q administration.2 11

Prolonged absorption phase;12 median time to peak serum concentrations after single 60-mg sub-Q dose is 10 days (range 3–21 days).1

Characterization of other monoclonal antibodies indicates that absorption is probably mediated by the lymphatic system.3 14

Onset

Studies in postmenopausal women with osteoporosis indicate reduction in bone resorption biomarkers observed within 3 days after a 60-mg dose; maximal reductions observed by 1 month.1

Duration

Studies in postmenopausal women with osteoporosis indicate effect on bone resorption markers partially attenuated at the end of each 6-month dosing interval.1 Bone mineral density (BMD) and levels of bone resorption markers return to baseline within 12 months after discontinuing denosumab.1

Distribution

Extent

Not known whether distributed into milk.1 2

Elimination

Elimination Route

Clearance may occur via reticuloendothelial system; renal excretion not expected.3 14

Half-life

Approximately 25–28 days.1 2

Special Populations

Pharmacokinetics not evaluated in patients with hepatic impairment;1 pharmacokinetics not affected by renal impairment.1 27

Studies using denosumab (Prolia) dosage of 60 mg once every 6 months indicate pharmacokinetics not affected by body weight.1 Studies using denosumab (Xgeva) dosage of 120 mg once every 4 weeks indicate steady-state exposure is lower in 120-kg patients compared with 66-kg patients.2

Stability

Storage

Parenteral

Injection for Sub-Q Use

2–8ºC; do not freeze.1 2 Protect from direct light and heat.1 2

Use within 14 days after removal from refrigerator.1 2 Do not expose to temperatures >25ºC.1 2

Do not shake vigorously.1 2

Actions

  • Denosumab, a fully human monoclonal IgG2 antibody, is a bone resorption inhibitor.1 2 10 25

  • Denosumab is specific for and binds to RANKL, and acts as a RANKL inhibitor preventing interaction with its receptor (RANK).1 2 10 25 The interaction between RANK and RANKL is integral to normal bone resorption process.10 As a result, denosumab inhibits osteoclast formation, function, and survival and, ultimately, bone resorption.1 10

  • In postmenopausal women with osteoporosis, denosumab increases BMD and reduces incidence of vertebral, nonvertebral, and hip fractures.1 4

  • In patients with bone loss associated with androgen deprivation or aromatase inhibitor therapy, denosumab increases BMD;1 17 18 also reduces incidence of vertebral fractures in men with prostate cancer receiving androgen deprivation therapy.1 17

  • In patients with solid tumors and metastases to the bone, denosumab delays time to first SRE.2 19 20 21

  • Effects of denosumab are considered reversible since bone turnover markers and BMD return to baseline within 12 months after the drug is discontinued.1 10 12

  • In giant cell tumors of bone, stromal cells express RANKL and osteoclast-like giant cells express RANK receptor;2 signaling through the RANK receptor contributes to osteolysis and tumor growth.2 Denosumab (Xgeva) prevents RANKL from activating the receptor on the surfaces of osteoclasts, their precursors, and osteoclast-like giant cells.2

Advice to Patients

  • Denosumab (Prolia) medication guide must be provided to the patient each time the drug is administered; importance of reading the medication guide prior to initiating therapy and prior to each subsequent dose.1 8 16 (See REMS.)

  • Importance of receiving adequate calcium and vitamin D supplementation during denosumab therapy, and importance of seeking medical attention if signs or symptoms of hypocalcemia develop (e.g., spasms, twitches, muscle cramps, numbness or tingling in fingers, toes, or near mouth).1 2 16

  • Advise patients to seek prompt medical attention if they develop symptoms of hypersensitivity (e.g., rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension, respiratory tract edema).1 2 Advise such patients they should not receive further doses of denosumab.1 2

  • Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis (e.g., fever, chills, severe abdominal pain, frequent or urgent need to urinate or burning feeling when urinating, skin that is red, swollen, hot, or tender to touch).1 16

  • Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatologic reactions (e.g., redness, itching, rash, dry skin, blisters that ooze or crust, peeling skin).1 16

  • Importance of maintaining good oral hygiene during denosumab treatment; importance of informing dentist about denosumab treatment prior to dental procedures.1 2 Advise patients to inform clinician or dentist if persistent pain and/or slow healing of mouth or jaw occurs after dental surgery or if symptoms of ONJ (pain, numbness, swelling of or drainage from the jaw, mouth, or teeth) occur at any time.1 2

  • Advise patients to report new or unusual thigh, hip, or groin pain since these may be symptoms of atypical femoral fracture.1 2

  • Advise patients that denosumab is commercially available as Prolia and Xgeva; patients should not receive concomitant treatment with both drugs.1 2 16

  • Importance of informing clinician about latex allergy.1 (See Latex Sensitivity under Cautions.)

  • Inform patients receiving denosumab (Prolia) for treatment of osteoporosis or bone loss associated with androgen deprivation or aromatase inhibitor therapy that if a dose is missed, the dose should be given as soon as convenient and subsequent dose should be scheduled for 6 months from date of last dose.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2 Advise male patients with pregnant partners about potential fetal exposure to denosumab during unprotected sex.1 Advise female patients with reproductive potential to use highly effective contraception during and for at least 5 months after last dose of denosumab (Xgeva).2 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 2

  • Importance of informing patients of other important precautionary information.1 2 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Denosumab

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

60 mg/mL

Prolia

Amgen

120 mg/1.7 mL

Xgeva

Amgen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Xgeva 120MG/1.7ML Solution (AMGEN): 2/$1,900.01 or 5/$5,499.85

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 2, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Amgen. Prolia (denosumab) injection for subcutaneous use prescribing information. Thousand Oaks, CA. 2013 Jul.

2. Amgen. Xgeva (denosumab) injection for subcutaneous use prescribing information. Thousand Oaks, CA. 2013 Aug.

3. Lewiecki EM. Denosumab--an emerging treatment for postmenopausal osteoporosis. Expert Opin Biol Ther. 2010; 10:467-76. [PubMed 20095877]

4. Cummings SR, San Martin J, McClung MR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009; 361:756-65. [PubMed 19671655]

5. Food and Drug Administration. Amended economic impact analysis of final rule requiring use of labeling on natural rubber containing devices. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1998; 63:50660-704.

6. Food and Drug Administration. Latex-containing devices; user labeling. 21 CFR Part 801. Proposed rule. (Docket No. 96N-0119) Fed Regist. 1996; 61:32617-21.

7. Food and Drug Administration. Natural rubber-containing medical devices; user labeling. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1997; 62:51021-30.

8. Prolia™ (denosumab) injection risk evaluation and mitigation strategy (REMS). From FDA website. Accessed Nov 16, 2012.

10. Romas E. Clinical applications of RANK-ligand inhibition. Intern Med J. 2009; 39:110-6. [PubMed 19356186]

11. Rodriguez, RD, Sutjandra L, Peterson MC, et al. Population pharmacokinetic meta-analysis of denosumab in healthy and cancer subjects and postmenopausal women with osteopenia or osteoporosis. The AAPS Journal.2009;11(S1).

12. Bekker PJ, Holloway DL, Rasmussen AS et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004; 19:1059-66. [PubMed 15176987]

13. Amgen. Prolia Postmarketing Active Safety Surveillance Program. Available at www.proliasafety.com. Accessed August 26, 2010.

14. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004; 93:2645-68. [PubMed 15389672]

15. Food and Drug Administration Center for Drug Evaluation and Research. Summary review (application number 125320). From FDA website.

16. Amgen. Prolia (denosumab) injection medication guide. Thousand Oaks, CA. 2013 Jul.

17. Smith MR, Egerdie B, Hernández Toriz N et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009; 361:745-55. [PubMed 19671656]

18. Ellis GK, Bone HG, Chlebowski R et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008; 26:4875-82. [PubMed 18725648]

19. Stopeck AT, Lipton A, Body JJ et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010; 28:5132-9. [PubMed 21060033]

20. Henry DH, Costa L, Goldwasser F et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011; 29:1125-32. [PubMed 21343556]

21. Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011; 377:813-22. [PubMed 21353695]

22. Food and Drug Administration. List of orphan designations and approvals. From FDA web site.

23. Safety study of denosumab in subjects with recurrent or unresectable giant cell tumor of bone (NCT 00680992). From ClinicalTrials.gov website. Accessed 2011 Nov 17.

24. Ellis GK, Bone HG, Chlebowski R et al. Effect of denosumab on bone mineral density in women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: subgroup analyses of a phase 3 study. Breast Cancer Res Treat. 2009; 118:81-7. [PubMed 19308727]

25. Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011; 48:677-92. [PubMed 21145999]

26. Orwoll E, Teglbjaerg CS, Langdahl BL et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012; 97:3161-9. [PubMed 22723310]

27. Block GA, Bone HG, Fang L et al. A single-dose study of denosumab in patients with various degrees of renal impairment. J Bone Miner Res. 2012; 27:1471-9. [PubMed 22461041]

28. Thomas D, Henshaw R, Skubitz K et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase 2 study. Lancet Oncol. 2010; 11:275-80. [PubMed 20149736]

29. Chawla S, Henshaw R, Seeger L et al. Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study. Lancet Oncol. 2013; :. [PubMed 23867211]

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