PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Monoclonal Antibody, Bone Resorption

    DEA CLASS

    Rx

    DESCRIPTION

    Monoclonal antibody against human RANKL
    For treatment of osteoporosis in men and postmenopausal women, osteoporosis prophylaxis in women with breast cancer and men with nonmetastatic prostate cancer, and prevention of skeletal-related events in patients with bone metastases from solid tumors
    Different brand names used for different indications; ensure the correct product is selected when prescribing

    COMMON BRAND NAMES

    Prolia, XGEVA

    HOW SUPPLIED

    Prolia/XGEVA Subcutaneous Inj Sol: 1mL, 60mg, 70mg

    DOSAGE & INDICATIONS

    For the treatment of osteoporosis in men and postmenopausal women at high risk for fracture.
    NOTE: Denosumab should be administered by a health care professional. Different products are indicated for different treatments; take care to select the right product for prescribing and avoid duplication.
    NOTE: Patients at a high risk for fracture are those with a history of osteoporotic fracture or with multiple risk factors for fracture. Denosumab is also appropriate for those patients who have failed or are intolerant to other available osteoporosis therapy.
    Subcutaneous dosage (Prolia)
    Adult postmenopausal females

    60 mg subcutaneous once every 6 months. All patients should receive 1000 mg of calcium and at least 400 international units of vitamin D daily. If a dose is missed, administer the dose as soon as possible and schedule future injections every 6 months from that date.

    Adults males

    60 mg subcutaneous once every 6 months. All patients should receive 1000 mg of calcium and at least 400 international units of vitamin D daily. If a dose is missed, administer the dose as soon as possible and schedule future injections every 6 months from that date.

    For the prevention of skeletal-related events in patients with bone metastases from solid tumors.
    NOTE: Denosumab is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.
    NOTE: In clinical trials, the definition of "skeletal-related events" was the occurrence of pathologic fracture, radiation therapy to the bone, surgery to the bone, or spinal cord compression.
    Subcutaneous dosage (Xgeva)
    Adults

    120 mg subcutaneously once every 4 weeks. To treat or prevent hypocalcemia, administer calcium and vitamin D as necessary. In a published clinical trial, study patients were encouraged to supplement with calcium greater than or equal to 500 mg and vitamin D greater than or equal to 400 units daily.

    For osteoporosis prophylaxis in men at high risk for bone fractures after receiving androgen deprivation therapy for nonmetastatic prostate cancer and in women at high risk for bone fractures after receiving adjuvant aromatase inhibitor therapy for breast cancer.
    NOTE: Denosumab should be administered by a health care professional. Different products are indicated for different treatments; take care to select the right product when prescribing and avoid duplication.
    Subcutaneous dosage (Prolia)
    Adults

    60 mg subcutaneous once every 6 months. All patients should receive 1000 mg of calcium and at least 400 international units of vitamin D daily. If a dose is missed, administer the dose as soon as possible and schedule future injections every 6 months from that date. Approval for osteoporosis prophylaxis is based on the results of 2 studies. The first was a clinical study of men with prostate cancer in which the differences in bone mineral density (BMD) between denosumab and placebo recipients at the 3 year treatment period were 7.9% (6.8% denosumab, -1.2% placebo) at the lumbar spine, 5.7% (3.2% denosumab, -2.6% placebo) at the total hip, and 4.9% (3% denosumab, -1.8% placebo) at the femoral neck. The other study involved women with breast cancer where the differences in BMD between denosumab and placebo recipients at the 2 year treatment period were 7.6% (6.2% denosumab, -1.4% placebo) at the lumbar spine, 4.7% (3.8% denosumab, -1% placebo) at the total hip, and 3.6% (2.8% denosumab, -0.8% placebo) at the femoral neck.

    For the treatment of giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.
    Subcutaneous dosage (Xgeva)
    Adults and Adolescents (who have reached skeletal maturity)

    120 mg subcutaneously once every 4 weeks; give 2 additional denosumab 120 mg doses on day 8 and 15 of the first month of therapy only. To treat or prevent hypocalcemia, give calcium and vitamin D as necessary. The objective response rate (ORR) was evaluated by an independent review committee (using a modified RECIST criteria) in 187 patients with giant cell tumor of the bone (GCTB) who received denosumab and had a baseline and at least 1 additional radiographic assessment in 2 open-label studies. In this analysis, the ORR was 25% (all partial responses) and the estimated median time to response was 3 months. At a median follow-up of 20 months (range, 2 to 44 months), 51% of responding patients (n = 24 of 47) had a response duration of 8 months. In an open-label study, a tumor response (defined as the elimination of at least 90% of giant cells or no radiological progression of the target lesion up to week 25) was achieved in 30 of 35 evaluable adult patients (86%) with recurrent or unresectable GCTB. All patients received supplementation with calcium 500 mg/day and vitamin D 400 international units/day. No concomitant treatment for GCTB was allowed during the study. In a second open-label study, denosumab treatment was evaluated in patients with GCTB who had surgically unsalvageable disease (e.g., sacral or spinal disease, pulmonary metastases) or surgically salvageable disease but planned surgery was likely to result in severe morbidity (e.g., joint resection, limb amputation, or hemipelvectomy). Ten patients in this study were skeletally mature adolescents (age range, 13 to 17 years) defined as having at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus) and a body weight of at least 45 kg. An ORR was achieved in 33% of skeletally mature adolescents.

    For the treatment of hypercalcemia of malignancy that is refractory to bisphosphonate therapy.
    Subcutaneous dosage
    Adults

    120 mg subcutaneous on days 1, 8, and 15 initially, then 120 mg subcutaneous every 4 weeks beginning on day 29. Patients with hypercalcemia of malignancy (with or without bone metastases) refractory to intravenous bisphosphonate therapy were treated with denosumab in an open-label, single-arm clinical trial (n = 33); refractory was defined as an albumin-corrected calcium of greater than 12.5 mg/dL within 7 to 30 days of receiving intravenous bisphosphonate therapy. Within 10 days of treatment with denosumab, 63.6% (95% CI, 45.1% to 79.6%) achieved a corrected serum calcium level less than or equal to 11.5 mg/dL and 36.4% (95% CI, 20.4% to 54.9%) achieved a corrected serum calcium level less than or equal to 10.8 mg/dL. By day 57, 69.7% (95% CI, 51.3% to 84.4%) and 63.7% (95% CI, 45.1% to 79.6%) had achieved responses, respectively.

    MAXIMUM DOSAGE

    Adults

    Treatment and prevention of osteoporosis (Prolia): 60 mg/dose subcutaneously.
    Prevention of skeletal-related events in patients with bone metastases from solid tumors (Xgeva): 120 mg/dose subcutaneously.
    Treatment of unresectable giant cell tumor of the bone (Xgeva): 120 mg/dose subcutaneously.

    Geriatric

    Treatment and prevention of osteoporosis (Prolia): 60 mg/dose subcutaneously.
    Prevention of skeletal-related events in patients with bone metastases from solid tumors (Xgeva): 120 mg/dose subcutaneously.
    Treatment of unresectable giant cell tumor of the bone (Xgeva): 120 mg/dose subcutaneously.

    Adolescents

    Treatment and prevention of osteoporosis (Prolia): safety and efficacy have not been established.
    Prevention of skeletal-related events in patients with bone metastases from solid tumors (Xgeva): safety and efficacy have not been established.
    Treatment of unresectable giant cell tumor of the bone (Xgeva): 120 mg/dose subcutaneously (in skeletally mature adolescents only).

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Patients with renal impairment may be at increased risk of severe hypocalcemia (see Precautions). No renal function-based dosage adjustments are recommended for patients receiving denosumab for the osteoporosis indication; however, no clinical data are available in patients with severe renal impairment (i.e., CrCl < 30 mL/min or requiring dialysis) receiving denosumab for the oncology indication.

    ADMINISTRATION

    Injectable Administration

    NOTE: Denosumab is available as more than one indication-specific brand name product (e.g., Prolia, Xgeva). Avoid duplications. Be sure to take care in choosing the right product for the individual patient.
    Denosumab should only be administered via the subcutaneous (SC) route; do not administer intravenously (IV), intramuscularly (IM), or intradermally.
    Visually inspect the solution for particulate matter or discoloration before administration; the solution is clear and colorless to light yellow. A small amount of tiny, white or opalescent particles may be present and is acceptable. Do not use if discolored, cloudy, or if foreign particulate matter is present.

    Subcutaneous Administration

    Denosumab should be administered by a healthcare professional.
    Prior to administration, denosumab may be removed from the refrigerator and brought to room temperature; this generally takes 15 to 30 minutes. Do NOT warm this medication in any other manner. Once removed from the refrigerator, the drug must not be exposed to temperatures above 25 degrees C (77 degrees F) or direct light and must be used within 14 days.
    Do not vigorously shake denosumab.
     
    Administration using prefilled syringe with needle safety guard:
    Leave green needle safety guard in original position until after dosage administration; sliding guard prior to administration will prevent injection.
    Remove and discard needle cap immediately prior to dose administration.
    Administer full contents of denosumab prefilled syringe subcutaneously in the upper arm, the upper thigh, or the abdomen.
    Immediately following injection, point needle away from people and gently slide green safety guard over needle.
    Discard all used supplies as appropriate.
     
    Administration using single-use vials:
    Use a 27-gauge needle to withdraw and inject the denosumab dose.
    Administer subcutaneously in the upper arm, upper thigh, or abdomen.
    Do NOT re-insert needle into vial. Discard any unused medication and all used supplies as appropriate.

    STORAGE

    Prolia:
    - Avoid direct heat and sunlight
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Product must be used within 14 days after removal from refrigeration to room temperature (77 degrees F)
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in original container
    XGEVA:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard within 14 days after first use
    - Do not expose product to temperatures above 77 degrees F
    - Do not freeze
    - Product must be used within 14 days after removal from refrigeration to room temperature (77 degrees F)
    - Protect from direct sunlight
    - Protect from extreme heat
    - Protect from light
    - Store in original container
    - Store unopened containers in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: Denosumab is available in 2 different marketed products, Prolia and Xgeva, which are indicated for different therapeutic uses and are available in different strengths. Patients receiving Prolia should not receive Xgeva and vice versa.

    Dialysis, hypocalcemia, renal failure, renal impairment, vitamin D deficiency

    Denosumab has been associated with cases of severe, sometimes fatal, hypocalcemia; use is contraindicated with pre-existing hypocalcemia. Pre-existing hypocalcemia must be corrected before initiation of therapy. Monitor calcium concentrations throughout denosumab therapy, especially in the first weeks of initiating therapy, and supplement with vitamin D, calcium, and magnesium as necessary. More frequent monitoring may be necessary when administering denosumab with other drugs that can lower calcium concentrations. Patients with vitamin D deficiency may require a higher dose of vitamin D. For example, in clinical trials of osteoporotic females, patients with a baseline 25-hydroxyvitamin D serum level of > 20 ng/mL were supplemented with at least 400 international units of vitamin D daily, those with a baseline value of 12 to 20 ng/mL were supplemented with at least 800 international units of vitamin D daily, and those with a baseline value of < 12 ng/mL were excluded from study. Further, an increased risk of hypocalcemia has been seen in clinical trials involving patients with renal dysfunction, most commonly with severe renal impairment (CrCl < 30 mL/min) or renal failure (and/or on dialysis) and with no or inadequate calcium supplementation. Instruct patients to seek medical care if symptoms of hypocalcemia develop.

    Diabetes mellitus, immunosuppression, infection, surgery, tuberculosis

    Do not start denosumab in a patient who has an active infection including chronic, localized, or systemic infections such as sepsis or influenza. Because denosumab is a RANKL inhibitor and RANKL is expressed on activated B-lymphocytes, on activated T-lymphocytes, and in lymph nodes, there is a possibility that use of denosumab may impair immune function and increase the risk of infection. Serious infections resulting in hospitalization and/or death have been reported in clinical study of patients receiving denosumab. Among osteoporotic study patients, the incidence of fatalities resulting from serious infection was the same in both placebo and denosumab study treatment groups (0.2%), while the incidence of nonfatal serious infection was higher in the denosumab treatment group as compared to the placebo treatment group ; rates of reported infection and serious infection were similar in both denosumab and zoledronic acid treatment groups in a published phase 3 trial involving oncology patients (see Adverse Reactions). Consider the risks and benefits of continued denosumab treatment if a serious infection develops during therapy. Patients who have surgery while taking denosumab may be at greater risk for postoperative infections. Monitor all patients for infections during denosumab receipt. As with other monoclonal antibody therapies, carefully consider the benefits and risks of drug therapy in patients with a history of recurrent infections or with underlying conditions that may predispose them to infections (e.g., patients with advanced or uncontrolled diabetes mellitus or immunosuppression), and in those who have lived in tuberculosis or histoplasmosis endemic areas.

    Angioedema, latex hypersensitivity, urticaria

    Denosumab is contraindicated for use in patients with a history of hypersensitivity to any component of the product. Hypersensitivity reactions have occurred including anaphylaxis, facial swelling/angioedema, hypotension, pruritus, and urticaria. Additionally, the needle cover on the Prolia prefilled syringe contains dry, natural rubber; people with a latex hypersensitivity should not handle the grey needle cap on the single-use, prefilled syringe. If a patient develops a clinically significant allergic reaction, discontinue the drug and administer appropriate therapy to treat the reaction.

    Eczema

    In clinical trials of osteoporotic patients, denosumab use was associated with a statistically significant higher incidence of dermal and epidermal adverse events as compared to placebo use (10.8% vs 8.2%, respectively, p < 0.0001) ; no such adverse events were reported in the published phase 3 trial involving oncology patients. It may be prudent to use with caution in patients with pre-existing dermal conditions, including dermatitis, eczema, and/or recurrent rashes, as these disease may be exacerbated by denosumab therapy.

    Neoplastic disease

    In clinical trials of osteoporotic patients, denosumab use was associated with a higher incidence of new onset neoplastic disease as compared to placebo use (4.8% vs 4.3%, respectively) ; however, in a clinical trial involving oncology patients with pre-existing disease, the incidence of new onset primary malignancy was 0.5% in both denosumab treated patients and zoledronic acid treated patients. A causal relationship has not been established. Reports include higher incidence of malignancy of the breast, reproductive system, and gastrointestinal system among osteoporotic patients receiving denosumab. Denosumab is a monoclonal antibody that blocks the effects of endogenous RANKL (receptor activator of nuclear factor kappa-beta ligand). It is unknown if this activity may affect host defenses against neoplastic disease. Consider the risks and benefits of denosumab before treatment initiation in patients with a history of or current malignancy and before continuation in patients who develop a malignancy.

    Chemotherapy, corticosteroid therapy, dental disease, dental work

    Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab in clinical trials of both osteoporotic and oncology patients. ONJ is typically associated with dental procedures, such as tooth extraction, and local infection with delayed healing; however, cases have appeared spontaneously. If patients require invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan for each patient. A dental examination with appropriate preventive dentistry and correction of dental complications prior to initiating denosumab therapy is recommended for patients with risk factors for ONJ such as invasive dental procedures and dental work (e.g., tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant corticosteroid therapy, concomitant chemotherapy such as treatment with angiogenesis inhibitors, poor oral hygiene, and comorbid conditions such as periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, and ill-fitting dentures. Good oral hygiene practices should be maintained during treatment. Care by a dentist or oral surgeon is recommended if ONJ is suspected or occurs; it should be noted that dental surgery may exacerbate the condition. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ, and the risk of ONJ may increase with increased duration of treatment with denosumab. Discontinuation of therapy should be considered based on an individual risk-benefit basis assessment.

    Pancreatitis

    Patients with a history of pancreatitis may be at an increased risk of recurrence during therapy. In clinical trials involving patients with osteoporosis, use of denosumab was associated with a higher incidence of pancreatitis as compared to patients receiving placebo (0.2% vs 0.1%, respectively); further, all eight of the cases in the denosumab treatment group were considered serious events including 1 death, while only 1 of the 4 cases in the placebo treated group was considered serious and none fatal. According to the manufacturer of denosumab, several patients who experienced pancreatitis during clinical trials had a prior history of the disorder. No cases of pancreatitis were reported in the published phase 3 clinical trial involving oncology patients.

    Bone fractures

    The risk of bone fractures increases upon discontinuation of denosumab in patients treated for osteoporosis, including the risk of multiple vertebral fractures. If denosumab is discontinued in these patients, consider transitioning to an alternative antiresportive therapy. Discontinuation of denosumab therapy may result in a greater short-term increase in bone loss. After discontinuation of therapy in clinical trials of osteoporotic patients, markers of bone resorption increased to levels 40 to 60% above pretreatment values, returning to baseline levels within 12 months. Measurements of bone mineral density decreased to baseline values within 12 months of therapy discontinuation. Bone fractures developing along the femoral shaft (below the lesser trochanter to above the supracondylar flare) have also been reported by denosumab recipients, some of whom were receiving concurrent glucocorticoid therapy. These fractures were transverse or short oblique, not comminuted, some were bilateral, and occurred with minimal to no trauma. A definitive causal relationship with denosumab has not been established as fractures of this type are also present in untreated osteoporotic patients. Many patients experience a dull, aching thigh pain weeks to months before the complete fracture occurs, thus, health care providers are advised to rule out an incomplete femur fracture in any patient presenting with thigh or groin pain. Consider treatment interruptions based on the risk-to-benefit assessment of the individual patient.

    Children, infants

    Denosumab is a monoclonal antibody that inhibits RANKL and thus affects osteoclast activity and bone remodeling; use in pediatric patients may impair bone growth and inhibit tooth eruption. Denosumab is available as 2 products, Prolia and Xgeva. The safety and efficacy of Prolia have not been established in adolescents, children or infants and its use is not recommended in these patients. The safety and efficacy of Xgeva have not been established in children or infants; however, Xgeva is recommended for use in the treatment of giant cell tumor of the bone (GCTB) in skeletally mature adolescents. In an analysis that looked at the efficacy of Xgeva in 10 adolescent patients with GCTB, skeletal maturity was defined as having at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus) and a body weight of at least 45 kg. Clinically significant hypercalcemia has been reported weeks to months after discontinuation of Xgeva in patients with growing skeletons; monitor these patients for signs and symptoms of hypercalcemia and treat appropriately. Denosumab administered to adolescent primates at doses of up to 50 times the human equivalent dose resulted in the development of abnormal growth plates consistent with denosumab-activity.

    Contraception requirements, male-mediated teratogenicity, pregnancy

    Denosumab is available as 2 products, Prolia and Xgeva. Prolia use is contraindicated in women who are pregnant. Xgeva use should be avoided during pregnancy. Denosumab can cause fetal harm when given during pregnancy based on findings in animals. Adverse fetal effects may be greater during second and third trimesters. Monoclonal antibodies cross the placenta in a linear fashion, with the greatest amount transferred during the third trimester. If pregnancy occurs during therapy, treatment should be discontinued, the patient should consult their healthcare provider, and the patient should be informed of the potential risk to the fetus. Women who become pregnant during treatment with denosumab should enroll in Amgen’s Pregnancy Surveillance Program at 1-800-77-AMGEN (1-800-772-6436). Animal studies conducted in cynomolgus monkeys and mice genetically engineered to lack RANKL demonstrated fetal harm. In cynomolgus monkeys dosed with denosumab 50 mg/kg subcutaneously throughout gestation, stillbirths, fetal loss, and postnatal mortality occurred. Other effects included the absence of peripheral (axillary, inguinal, mandibular, and mesenteric) lymph nodes, reduced bone strength, abnormal bone growth, decreased neonatal growth, decreased hematopoiesis, tooth malalignment, and dental dysplasia. Measurable blood levels of denosumab, at 22 to 621% of maternal levels, were detected at birth through 1 month of age. The effects of denosumab on bone quality and strength returned to normal during observation through 6 months of age. Tooth eruption was normal; however, dental dysplasia was still present. Small mandibular and mesenteric lymph nodes were present with axillary and inguinal nodes still missing. Mineralization in multiple tissues also occurred in 1 recovery animal. No maternal harm occurred prior to labor and adverse effects during labor were infrequent. In mice, fetal lymph node development was also lacking and postnatal impairment of bone and tooth development occurred. Women should avoid becoming pregnant while taking denosumab. Contraception requirements are in the product label for Xgeva; it would be advisable to consider the same recommendations for a woman of reproductive potential using Prolia. Females of reproductive potential who receive Xgeva should be instructed to use highly effective contraception during therapy, for at least 5 months after the last dose, and to contact her healthcare professional if she becomes pregnant or suspects pregnancy within 5 months of taking the last dose. The risk to a female partner or fetus of exposure to denosumab through seminal fluid is unlikely; in a study of 12 healthy male volunteers, denosumab (Prolia) was present in seminal fluid at a concentration approximately 2% of serum exposure. After vaginal intercourse, the amount of drug delivered to a female partner would result in exposures approximately 11,000 times lower than that seen after the recommended dose. However, it is not known whether denosumab (Xgeva) is present in seminal fluid. Male-mediated teratogenicity may be possible. Advise males who take denosumab of the potential risk to a fetus if he engages in unprotected sexual intercourse with a pregnant partner.

    Breast-feeding

    Denosumab is not recommended for use during breast-feeding. Either the drug or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants, taking into account the importance of the drug to the mother. It is not known if denosumab is excreted into human milk. Maternal antibodies are known to be present in human milk; however, data are limited regarding use of denosumab during breast-feeding. The drug is a protein and would likely be digested in the infants gastrointestinal tract, but exposure and effects on the nursing infant are not known. Exposure of pediatric patients to denosumab is not recommended as it may impair bone growth and inhibit tooth eruption. Additionally, females receiving treatment during pregnancy may have impaired lactation postpartum due to drug-induced interruption of maternal mammary gland development; animal studies have demonstrated conflicting results regarding altered maturation of mammary glands. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternal drug exposure, health care providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    hypophosphatemia / Delayed / 0-15.4
    osteonecrosis / Delayed / 0.7-7.1
    hypocalcemia / Delayed / 0-3.1
    hypomagnesemia / Delayed / 0-3.0
    fatigue / Early / 0-3.0
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known

    Moderate

    dyspnea / Early / 21.0-27.0
    peripheral edema / Delayed / 0-24.0
    anemia / Delayed / 4.0-21.0
    bone pain / Delayed / 4.0-19.0
    neutropenia / Delayed / 9.0
    oral ulceration / Delayed / Incidence not known
    erythema / Early / Incidence not known
    atopic dermatitis / Delayed / Incidence not known
    tetany / Early / Incidence not known
    neuropathic pain / Delayed / Incidence not known
    constipation / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    asthenia / Delayed / 2.3-45.0
    back pain / Delayed / 10.0-34.7
    nausea / Early / 10.0-31.0
    headache / Early / 10.0-24.0
    diarrhea / Early / 20.0-20.0
    abdominal pain / Early / 3.3-3.3
    rash (unspecified) / Early / 2.5-2.5
    pruritus / Rapid / 2.2-2.2
    flatulence / Early / 2.2-2.2
    gastroesophageal reflux / Delayed / 2.1-2.1
    chills / Rapid / 11.0
    myalgia / Early / 3.0
    fever / Early / 11.0
    musculoskeletal pain / Early / 8.0
    arthralgia / Delayed / 10.0
    cough / Delayed / 15.0
    dental pain / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    paresthesias / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    flushing / Rapid / Incidence not known

    DRUG INTERACTIONS

    Azelastine; Fluticasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Beclomethasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Betamethasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Budesonide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Budesonide; Formoterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Ciclesonide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Corticosteroids: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Corticotropin, ACTH: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Cortisone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Deflazacort: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Dexamethasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Fludrocortisone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Flunisolide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Fluticasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Fluticasone; Salmeterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Fluticasone; Vilanterol: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Formoterol; Mometasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Hydrocortisone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Lenalidomide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
    Methylprednisolone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Mometasone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Nintedanib: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
    Pomalidomide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
    Prednisolone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Prednisone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.
    Thalidomide: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection and/or osteonecrosis of the jaw, a rare condition that has been reported during denosumab therapy.
    Triamcinolone: (Moderate) The safety and efficacy of denosumab use in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with denosumab may be at a greater risk of developing an infection.

    PREGNANCY AND LACTATION

    Pregnancy

    Denosumab is not recommended for use during breast-feeding. Either the drug or breast-feeding should be discontinued because of the potential for serious adverse reactions in nursing infants, taking into account the importance of the drug to the mother. It is not known if denosumab is excreted into human milk. Maternal antibodies are known to be present in human milk; however, data are limited regarding use of denosumab during breast-feeding. The drug is a protein and would likely be digested in the infants gastrointestinal tract, but exposure and effects on the nursing infant are not known. Exposure of pediatric patients to denosumab is not recommended as it may impair bone growth and inhibit tooth eruption. Additionally, females receiving treatment during pregnancy may have impaired lactation postpartum due to drug-induced interruption of maternal mammary gland development; animal studies have demonstrated conflicting results regarding altered maturation of mammary glands. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternal drug exposure, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Denosumab neutralizes the biologic activity of receptor activator of nuclear factor kappa-B ligand (RANKL) by binding to it and blocking its interaction with cell surface receptors known as receptor activator of nuclear factor-kappa-beta (RANK). Endogenous RANKL, a transmembrane or soluble protein, is expressed on the surface of both precursor and mature osteoclasts and is essential for their formation, function, and survival. RANKL inhibition by denosumab (Prolia) decreases RANKL activation of RANK receptors on the surface of osteoclasts resulting in a down regulation of osteoclast activity and thus a reduction of bone resorption; an increase in bone mass and strength in both cortical and trabecular bone is seen. By blocking RANKL from activating RANK, denosumab (Xgeva) inhibits the increased osteoclast activity that leads to bone pathology in solid tumor with osseous metastases. Additionally, denosumab prevents osteolysis and tumor growth in giant cell tumors of the bone containing stromal cells that express RANKL and osteoclast-like giant cells that express the RANK receptor.

    PHARMACOKINETICS

    Denosumab is given by subcutaneous injection. After reaching Cmax, serum concentrations of denosumab decrease over a period of 4 to 5 months. The mean terminal half-life is approximately 25.4 days (+/- 8.5 days) after a single-dose administration of 60 mg and approximately 28 days with repeat dosing of 120 mg every 4 weeks.

    Subcutaneous Route

    The bioavailability after subcutaneous administration was 62% in one pharmacokinetic trial. After a single 60-mg subcutaneous dose to fasted, healthy adults (n = 73, age range: 18 to 64 years), a maximum serum concentration of 6.75 (+/- 1.89) mcg/mL was achieved at a median time of 10 days (range: 3 to 21 days). Multiple subcutaneous doses of 60 mg given every 6 months did not result in denosumab accumulation or otherwise affect denosumab pharmacokinetics. Doses above 60 mg displayed approximately dose-proportional increases in drug exposure. Up to a 2.8-fold accumulation in serum denosumab has been noted with doses of 120 mg of denosumab administered subcutaneously every 4 weeks to adult cancer patients with bone metastases; steady-state was achieved by 6 months. Following the administration of denosumab 120 mg subcutaneously every 4 weeks with 2 additional 120 mg doses given on day 8 and 15 of the first month of therapy, steady-state levels were achieved in 3 months.