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Denosumab

Class: Bone Resorption Inhibitors
ATC Class: M05BX04
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

Medically reviewed by Drugs.com. Last updated on Aug 26, 2019.

Warning

Risk Evaluation and Mitigation Strategy (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 https://www.accessdata.fda.gov/scripts/cder/rems/.

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

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 following failure of or intolerance to other available osteoporosis therapies.1 4

In addition to adequate intake of calcium/vitamin D and other lifestyle modifications (e.g., exercise, avoidance of excessive alcohol and tobacco use), experts recommend that pharmacologic therapy for osteoporosis be considered in postmenopausal women and men (≥50 years of age) with high risk of fractures (generally those who have experienced a previous hip or vertebral fracture or who have low bone mineral density [BMD]); pharmacologic therapy also may be considered in postmenopausal women and men (≥50 years of age) with low bone mass, although there is less evidence supporting overall fracture risk reduction in such patients.105 106

Use of a drug with proven antifracture efficacy is recommended; experts generally recommend denosumab as one of several first-line drugs that may be used.105 106

Individualize choice of therapy based on potential benefits (with respect to fracture risk reduction) and adverse effects of therapy, patient preferences, comorbidities, and risk factors.105 106

Glucocorticoid-induced Osteoporosis

Treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture, defined as a history of osteoporotic fracture or multiple risk factors for fracture.1 30

Treatment of glucocorticoid-induced osteoporosis in men and women following failure of or intolerance to other osteoporosis therapies.1

Manufacturer recommends use in patients who are either initiating or continuing long-term (≥6 months) systemic glucocorticoid therapy in a dosage equivalent to ≥7.5 mg daily of prednisone.1

American College of Rheumatology (ACR) recommends optimizing calcium and vitamin D intake and lifestyle modifications (e.g., diet, smoking cessation, weight-bearing or resistance-training exercise) in all patients receiving long-term glucocorticoid therapy; in addition, pharmacologic therapy with an oral bisphosphonate is recommended in patients at moderate-to-high risk of fracture.622 Oral bisphosphonates generally are preferred because of their demonstrated antifracture benefits, safety, and cost; denosumab is suggested as an alternative.622

Bone Loss Associated with Androgen Deprivation Therapy

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

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

Multiple Myeloma and Bone Metastases of Solid Tumors

Prevention of skeletal-related events (SREs) in patients with multiple myeloma or bone metastases from solid tumors.2 19 20 21 31

Giant Cell Tumor of Bone

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

Hypercalcemia Associated with Malignancy

Treatment of bisphosphonate-refractory hypercalcemia of malignancy.2 32

Denosumab Dosage and Administration

General

  • Correct preexisting hypocalcemia prior to initiating denosumab.1 2

  • All patients receiving denosumab 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 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 administer IV or by IM or intradermal injection.1 2

Available as 60-mg/mL solution (Prolia) in single-use prefilled syringes for treatment of osteoporosis or treatment of bone loss associated with androgen deprivation or aromatase inhibitor therapy.1 Manufacturer states Prolia should be administered by a health-care professional.1

Available as 120-mg/1.7-mL solution (Xgeva) in single-use vials for prevention of SREs in patients with multiple myeloma or bone metastases from solid tumors, for treatment of bisphosphonate-refractory hypercalcemia of malignancy, or for treatment of giant cell tumor of bone.2

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: 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: Use 27-gauge needle to withdraw and inject entire vial contents.2 Do not re-enter vial; discard any remaining solution along with the vial.2

Dosage

Pediatric Patients

Giant Cell Tumor of Bone
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 day 15.2

Adults

Osteoporosis
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

Glucocorticoid-induced Osteoporosis
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
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
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

Multiple Myeloma or Bone Metastases of Solid Tumors
Prevention of SREs
Sub-Q

120 mg once every 4 weeks.2

Giant Cell Tumor of Bone
Sub-Q

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

Hypercalcemia Associated with Malignancy
Sub-Q

120 mg once every 4 weeks; during first month of treatment, give additional 120-mg dose on day 8 and day 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 and also see Renal Impairment under Cautions.)

Cautions for Denosumab

Contraindications

  • Hypocalcemia (correct preexisting hypocalcemia prior to initiating denosumab).1 2

  • History of clinically important hypersensitivity (e.g., systemic hypersensitivity) to denosumab or any component in the formulation.1 2

  • Prolia also contraindicated in pregnant women.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

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 Sub-Q Administration under Dosage and Administration.)

Do not use Prolia and Xgeva concomitantly.1 2

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 2 Fetal loss, stillbirths, postnatal mortality, and evidence of absent lymph nodes, abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia, tooth malalignment, and decreased neonatal growth reported in reproduction studies in monkeys; some bone abnormalities recovered once drug exposure ceased following birth.1 2

Perform pregnancy testing prior to initiation of denosumab therapy in women with reproductive potential.1 2 (See Contraindications under Cautions.) Women with reproductive potential should use effective contraceptive methods during denosumab therapy and for ≥5 months after the last dose.1 2

If used during pregnancy, apprise patient of potential fetal risk.2

The manufacturer states that condom use during sexual encounters is not necessary by men receiving Prolia.1 Denosumab is present in low concentrations in seminal fluid after administration of a single 60-mg dose; the manufacturer states that it is unlikely that a female partner or a partner's fetus would be exposed to pharmacologically relevant concentrations.1 (See Distribution under Pharmacokinetics.)

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

Some packaging components (i.e., needle cap) of Prolia 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

Hypocalcemia that lasted for weeks or months and required frequent monitoring and IV and/or oral calcium replacement therapy, with or without vitamin D supplementation, reported in some patients.1

Correct preexisting hypocalcemia prior to initiating denosumab.1 2

Patients receiving denosumab for treatment of osteoporosis or for treatment of bone loss associated with androgen deprivation or aromatase inhibitor therapy: All such patients should receive calcium and vitamin D supplementation daily.1 (See General under Dosage and Administration.) In those 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 within 14 days of denosumab administration is highly recommended.1

Patients receiving denosumab for prevention of SREs or treatment of giant cell tumor of bone: Monitor calcium concentrations throughout therapy, but particularly during first weeks following treatment initiation; monitor more frequently in those receiving concomitant therapy with other drugs that may also reduce serum calcium concentrations.2 Administer calcium, vitamin D, and magnesium supplementation as necessary.2

Risk of hypocalcemia is greater in patients receiving inadequate or no calcium supplementation and in those with increasing renal impairment, particularly those 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 2 (See Renal Impairment under Cautions.)

Osteonecrosis of the Jaw (ONJ)

ONJ reported in patients receiving denosumab.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, immunosuppressive therapy, angiogenesis inhibitors, corticosteroids), poor oral hygiene, and comorbidities (e.g., preexisting dental disease, anemia, coagulopathy, diabetes mellitus, infection, ill-fitting dentures).1 2 In patients with cancer, longer durations of denosumab use associated with higher incidence of ONJ.2 Concomitant use of other drugs known to cause ONJ also may increase risk.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 and receive appropriate preventive dentistry 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 Consider temporary discontinuance of denosumab therapy; however, the optimal duration of treatment interruption is unknown.2

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.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

Hypercalcemia Following Discontinuance of Therapy

Severe, symptomatic hypercalcemia requiring hospitalization and complicated by acute renal injury reported following discontinuance of denosumab therapy in patients with giant cell tumor of bone and in pediatric patients with growing skeletons.2 (See Pediatric Use under Cautions.) Hypercalcemia reported within the first year following treatment discontinuance.2

Following discontinuance of denosumab therapy, monitor patients for manifestations of hypercalcemia, periodically monitor serum calcium concentrations, reevaluate requirements for calcium and vitamin D supplementation, and manage patients as clinically appropriate.2

Multiple Vertebral Fractures Following Discontinuance of Therapy

Cases of multiple vertebral fractures reported following discontinuance of denosumab therapy.1 2 New vertebral fractures reported as early as 7 months (mean: 19 months) after the last dose.1

Risk factors include risk factors for or a history of osteoporosis and prior vertebral fractures.1 2

When denosumab is discontinued, the risk of fractures, including multiple vertebral fractures, increases.1 Following discontinuance, markers of bone resorption initially increase above pretreatment values and then return to pretreatment values 24 months after the last dose of the drug; BMD returns to pretreatment values within 18 months after the last dose.1

In patients with osteoporosis or bone loss associated with androgen deprivation or aromatase inhibitor therapy, assess benefits and risks for the patient prior to initiating denosumab therapy; if denosumab is discontinued, consider initiating therapy with an alternative bone resorption inhibitor.1

In patients with bone metastases from solid tumors, multiple myeloma, giant cell tumor of bone, or hypercalcemia of malignancy, evaluate the patient’s risk for vertebral fractures if denosumab is discontinued.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 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 in postmenopausal women with osteoporosis; most reactions were not specific to the injection site.1

Consider discontinuing denosumab if severe dermatologic symptoms develop.1

Musculoskeletal Pain

Severe and occasionally incapacitating bone, joint, and/or muscle pain reported in patients receiving denosumab.1 2 Symptoms reportedly recurred in some patients following rechallenge with the drug.2 Time to onset has ranged from 1 day to several months after treatment initiation.1

Consider discontinuing denosumab if severe musculoskeletal pain develops.1

Suppression of Bone Turnover

Significant suppression of bone remodeling reported in clinical trials of denosumab in patients 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 reported in <1% of patients receiving denosumab for periods of up to 5 years.1 2 Denosumab-neutralizing antibodies not reported to date, and antibody formation does not appear to affect denosumab pharmacokinetics, toxicity, or efficacy.1 2

Specific Populations

Pregnancy

Based on animal findings and mechanism of action, denosumab may cause fetal harm if administered to pregnant women.1 2 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Confirm pregnancy status prior to initiation of therapy in women with reproductive potential.1 2

Lactation

Not known whether denosumab distributes into human milk or affects breast-fed infants or milk production.1 2

Distributes into milk in monkeys in concentrations up to 0.5% of serum concentrations at up to one month after the last dose.1 2

Studies in pregnant mice indicate denosumab exposure during pregnancy may impair maternal mammary gland development and lactation; however, no such impairment observed in monkeys.1 2

Manufacturer states that the developmental and health benefits of breast-feeding should be considered along with the mother’s need for Xgeva and any potential adverse effects on the breast-fed infant from the drug or the underlying maternal condition.2

Pediatric Use

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.1 2

Clinically important hypercalcemia reported following discontinuance of denosumab therapy in pediatric patients with growing skeletons who received the drug for treatment of giant cell tumor of bone or for other unlabeled (off-label) uses.2

May impair bone growth in children with open growth plates and may inhibit eruption of dentition.1 2

Manufacturer states that Prolia is not recommended in pediatric patients <4 years of age because of the high rates of skeletal growth in this age group and the potential for the drug to adversely affect long-bone growth and 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

Risk of hypocalcemia increases with increasing renal impairment; most common in patients with severe renal impairment (Clcr <30 mL/minute) or receiving dialysis and those receiving inadequate or no calcium supplementation.1 2 27 Marked elevations in serum parathyroid hormone (PTH) concentrations may occur in patients with severe renal impairment or receiving dialysis.1 Consider risks and benefits of denosumab in patients with severe renal impairment or receiving dialysis.1 Clinical monitoring of calcium, phosphorus, and magnesium highly recommended, and adequate calcium and vitamin D supplementation is important.1 2 (See Hypocalcemia and Mineral Metabolism under Cautions.)

Common Adverse Effects

Patients with 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

Patients with glucocorticoid-induced osteoporosis: Back pain,1 30 hypertension,1 30 bronchitis,1 headache.1

Patients with bone loss associated with androgen deprivation or aromatase inhibitor therapy: Arthralgia,1 back pain.1

Patients with bone metastases: Fatigue/asthenia,2 hypophosphatemia,2 nausea,2 dyspnea,2 diarrhea,2 hypocalcemia,2 cough,2 headache.2

Patients with multiple myeloma: Diarrhea,2 31 nausea,2 31 anemia,2 31 back pain,2 31 thrombocytopenia,2 31 peripheral edema,2 hypocalcemia,2 31 upper respiratory infection,2 rash,2 headache,2 severe hypophosphatemia.2

Patients with giant cell tumor of bone: Arthralgia,2 headache,2 nausea,2 back pain,2 fatigue,2 extremity pain,2 severe hypophosphatemia.2

Patients with bisphosphonate-refractory hypercalcemia of malignancy: Nausea,2 32 dyspnea,2 32 decreased appetite,2 32 headache,2 32 peripheral edema,2 32 vomiting,2 32 anemia,2 constipation,2 32 diarrhea,2 32 grade 3 hypophosphatemia.2

Interactions for Denosumab

Drugs Metabolized by Hepatic Microsomal 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

Etanercept

No effect on etanercept pharmacokinetics in postmenopausal women with rheumatoid arthritis and low BMD1

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

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

No accumulation observed at dosage of 60 mg every 6 months.1 At dosage of 120 mg every 4 weeks, accumulation is up to 2.8-fold and steady-state concentrations achieved by 6 months.2 At dosage of 120 mg every 4 weeks, with additional 120-mg dose on day 8 and day 15 during first month of therapy, steady state achieved in 3 months.2

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 human milk.1 2 Distributed into milk in monkeys (concentrations up to 0.5% of serum concentrations at up to 1 month after the last dose).1 2

Present in seminal fluid in low concentrations (maximum concentration of approximately 2% of serum concentrations) following administration of a single 60-mg dose; maximum amount of denosumab (administered as 60-mg dose) delivered to a female partner during vaginal intercourse would result in exposure levels approximately 11,000 times lower than those in a patient receiving a 60-mg dose of the drug and at least 38 times lower than the no observed effect level in monkeys.1

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

Age, race, and gender do not affect pharmacokinetics; pharmacokinetics not evaluated in pediatric patients.1 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 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 (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

  • 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

  • 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

  • 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 the risk for multiple vertebral fractures may be increased after denosumab therapy is discontinued, particularly in those with a history of osteoporosis or vertebral fractures.1 2 Advise patients not to interrupt denosumab therapy without consulting their clinician.1 2

  • Advise patients of the potential for hypercalcemia following discontinuance of denosumab therapy in patients with giant cell tumor of bone and in pediatric patients with growing skeletons.2 Advise patients to report symptoms of hypercalcemia (e.g., nausea, vomiting, headache, decreased alertness) following denosumab discontinuance.2

  • Advise patients to inform their clinician if severe bone, joint, and/or muscle pain occurs.1

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

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

  • Inform patients receiving denosumab 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 female patients with reproductive potential that a pregnancy test is recommended prior to initiation of denosumab therapy and that they should use effective contraception during therapy and for at least 5 months after last dose of the drug.2 (See Fetal/Neonatal Morbidity and Mortality and also see Lactation 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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

AHFS DI Essentials™. © Copyright 2020, Selected Revisions August 26, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Amgen. Prolia (denosumab) injection for subcutaneous use prescribing information. Thousand Oaks, CA. 2018 Jun.

2. Amgen. Xgeva (denosumab) injection for subcutaneous use prescribing information. Thousand Oaks, CA. 2018 Jun.

3. Lewiecki EM. Denosumab--an emerging treatment for postmenopausal osteoporosis. Expert Opin Biol Ther. 2010; 10:467-76. http://www.ncbi.nlm.nih.gov/pubmed/20095877?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/19671655?dopt=AbstractPlus

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. http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM214383.pdf

10. Romas E. Clinical applications of RANK-ligand inhibition. Intern Med J. 2009; 39:110-6. http://www.ncbi.nlm.nih.gov/pubmed/19356186?dopt=AbstractPlus

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). http://www.aapsj.org/abstracts/NBC_2009/NBC09-000278.PDF

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. http://www.ncbi.nlm.nih.gov/pubmed/15176987?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15389672?dopt=AbstractPlus

15. Food and Drug Administration Center for Drug Evaluation and Research. Summary review (application number 125320). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/125320s000SumR.pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/19671656?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3038121&blobtype=pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/18725648?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/21060033?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/21343556?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/21353695?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3090685&blobtype=pdf

22. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA web site. Accessed 2018 Sep 20. http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

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. http://www.ncbi.nlm.nih.gov/pubmed/19308727?dopt=AbstractPlus

25. Baron R, Ferrari S, Russell RG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2011; 48:677-92. http://www.ncbi.nlm.nih.gov/pubmed/21145999?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/22723310?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/22461041?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3505375&blobtype=pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/20149736?dopt=AbstractPlus

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; :. http://www.ncbi.nlm.nih.gov/pubmed/23867211?dopt=AbstractPlus

30. Saag KG, Wagman RB, Geusens P et al. Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study. Lancet Diabetes Endocrinol. 2018; 6:445-54.

31. Raje N, Terpos E, Willenbacher W et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, phase 3 study. Lancet Oncol. 2018; 19:370-81.

32. Hu MI, Glezerman IG, Leboulleux S et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014; 99:3144-52.

33. Raje N, Vadhan-Raj S, Willenbacher W et al. Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial. Blood Cancer J. 2016; 6:e378.

105. Cosman F, de Beur SJ, LeBoff MS et al. Clinician's Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014; 25:2359-81. http://www.ncbi.nlm.nih.gov/pubmed/25182228?dopt=AbstractPlus

106. Watts NB, Bilezikian JP, Camacho PM et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010 Nov-Dec; 16 Suppl 3:1-37. http://www.ncbi.nlm.nih.gov/pubmed/21224201?dopt=AbstractPlus

622. Buckley L, Guyatt G, Fink HA et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2017; 69:1521-1537. http://www.ncbi.nlm.nih.gov/pubmed/28585373?dopt=AbstractPlus

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