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
Brands: Prolia, Xgeva

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 Denosumab

Osteoporosis (Prolia)

Treatment of osteoporosis in postmenopausal women at high risk of fracture, defined as history of osteoporotic fracture or multiple risk factors for fracture.^{1 3 4}

Treatment of osteoporosis in postmenopausal women who have failed or are intolerant of other available osteoporosis therapies.^{1 4}

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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

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

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 use any other method to warm the drug.^{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

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

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

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 However, those with severe renal impairment (Cl_cr <30 mL/minute) or receiving dialysis are at greater risk of developing hypocalcemia.^{1 2} (See Hypocalcemia and Mineral Metabolism under Cautions.)

Cautions for Denosumab

Contraindications

• Prolia: Hypocalcemia; correct preexisting hypocalcemia prior to initiating denosumab.¹

• Xgeva: Manufacturer states none.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

Hypocalcemia and Mineral Metabolism

Decreased serum calcium concentrations (including severe hypocalcemia) can occur;^{1 2} preexisting hypocalcemia may be exacerbated.¹

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.)

Clinical monitoring of calcium, phosphorus, and magnesium highly recommended 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).¹ Monitor calcium concentrations as necessary in patients receiving Xgeva; monitor more frequently in patients 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 (Cl_cr <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.)

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

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

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}

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

Sensitivity Reactions

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}

Specific Populations

Pregnancy

Prolia, Xgeva: Category C.^{1 2}

Use during pregnancy only if potential benefits justify potential risks to fetus.^{1 2}

Women who become pregnant during denosumab treatment are encouraged to enroll in the 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, Xgeva: Safety and efficacy not established.^{1 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} dosage adjustment not necessary.¹

Patients with severe renal impairment (Cl_cr <30 mL/minute) or receiving dialysis are at greater risk of hypocalcemia.^{1 2} 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.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

Interactions for Denosumab

No formal drug interaction studies to date.^{1 2}

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.)

Antineoplastic Agents

No evidence that antineoplastic treatment (chemotherapy and/or hormone therapy) affects systemic exposure or pharmacodynamic effects of denosumab.²

Bisphosphonates

No evidence that prior IV bisphosphonate therapy affects systemic exposure or pharmacodynamic effects of denosumab.²

Immunosuppressive Agents

Concomitant use with immunosuppressive agents may increase the risk of serious infections.¹ Assess risks and benefits to guide use of denosumab in patients receiving immunosuppressive agents.¹ (See Serious Infections under Cautions.)

Denosumab 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

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}

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 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 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} (See Pregnancy 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 02/2013. 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