CLASSES
Agents Targeting Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)
Antineoplastic Monoclonal Antibodies Targeting Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL)
DESCRIPTION
Subcutaneously administered monoclonal antibody against human RANKL
Prolia is used for treatment of osteoporosis in men and postmenopausal women, and for osteoporosis prophylaxis in women with breast cancer and men with nonmetastatic prostate cancer
Xgeva is used for prevention of skeletal-related events due to bone metastases from solid tumors or multiple myeloma, for the treatment of refractory hypercalcemia of malignancy, and for adults and skeletally mature adolescents with giant cell tumor of bone
Severe hypocalcemia may occur in patients with severe renal impairment or with renal failure receiving dialysis
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, as well as for glucocorticoid-induced osteoporosis.
Subcutaneous dosage (Prolia)
Adults
60 mg subcutaneously once every 6 months. All patients should receive a minimum of 1,000 mg of calcium and at least 10 mcg (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. Patients at a high risk for fracture are those with a history of osteoporotic fracture, those with multiple risk factors for fracture, those who have failed or are intolerant to other available osteoporosis therapy, or those initiating or continuing systemic glucocorticoids (i.e., 7.5 mg/day or more of prednisone or equivalent) and expected to remain on glucocorticoids for at least 6 months. Denosumab is an alternative first-line treatment for postmenopausal women at high risk of fracture or who are unable to tolerate oral bisphosphonates. There is no limit to duration of treatment with denosumab. Do not stop or delay treatment with denosumab past 7 months without follow-up treatment to prevent bone loss and vertebral fractures. Subsequent treatment with a bisphosphonate is recommended to prevent bone loss. Switching from denosumab to an anabolic agent (i.e., teriparatide or abaloparatide) may result in loss of hip bone mineral density and is not recommended.
For the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.
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. 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.
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.
Subcutaneous dosage (Prolia)
Adults
60 mg subcutaneously once every 6 months. All patients should receive 1,000 mg of calcium and at least 10 mcg (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. CLINICAL STUDIES: Approval was 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 vs. placebo 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. In women with breast cancer, where the differences in BMD for denosumab vs. placebo 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 (Xgeva)
Adults
120 mg subcutaneously on days 1, 8, and 15 initially, then 120 mg subcutaneously 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
Denosumab is available as more than one indication-specific brand name product (e.g., Prolia, Xgeva). Avoid duplications. Prior to administration, ensure that the right product has been selected for the individual patient.
Denosumab should only be administered via the subcutaneous route. Do not administer intravenously, intramuscularly, 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.
For patients receiving Prolia regimens, ensure adequate intake of calcium and vitamin D to reduce the risk of treatment-related hypocalcemia.
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.
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. If a patient develops a clinically significant allergic reaction, discontinue denosumab and administer appropriate therapy to treat the reaction.
Dialysis, hypocalcemia, renal disease, 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. Correct pre-existing hypocalcemia before initiation of therapy. Patients with advanced renal disease, particularly those on dialysis, may be at an increased risk for developing severe hypocalcemia with serious outcomes, including hospitalization and death. Consider the benefit-risk profile when administering denosumab to patients with severe renal impairment or with renal failure receiving dialysis due to the potential for severe hypocalcemia. Frequent clinical monitoring of calcium concentrations is highly recommended in these patients. Monitor calcium and mineral concentrations (phosphorus and magnesium) within 14 days of Prolia injection in patients predisposed to hypocalcemia or disturbances of mineral metabolism (e.g., hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestines, severe renal impairment [CrCl less than 30 mL/minute], dialysis). 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 is highly recommended in patients with advanced renal disease receiving dialysis and may also 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 supplementation during denosumab treatment. In all patients, ensure adequate intake of calcium and vitamin D. Instruct patients to seek prompt medical care if signs or symptoms of hypocalcemia develop. Results from a long-term safety study has suggested an increased risk of hypocalcemia with denosumab use in patients with advanced renal disease and osteoporosis. An internal FDA study showed a substantial risk of severe and symptomatic hypocalcemia resulting in hospitalization and death in patients with advanced kidney disease on dialysis who were treated for osteoporosis with denosumab. Advise patients on dialysis to seek immediate medical care if they experience symptoms of hypocalcemia. To promote general bone health, guidelines for the prevention and treatment of osteoporosis recommend a target daily intake of 1,200 mg of elemental calcium for females older than 50 years and males older than 70 years. Target daily elemental calcium intake for males 70 years or younger is 1,000 mg. Daily vitamin D intake of 20 to 25 mcg (800 to 1,000 international units) is recommended for patients age 50 years and older.
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.
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.
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, including the risk of multiple vertebral fractures, increases upon discontinuation of denosumab. Patients at higher risk for multiple vertebral fractures include those with risk factors or a history of osteoporosis or prior 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.
New primary malignancy
In clinical trials of osteoporotic patients, denosumab use was associated with a higher incidence of new onset neoplastic disease (new primary malignancy) 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.
Pregnancy
Denosumab is available as 2 products, Prolia and Xgeva. Prolia use is contraindicated during pregnancy. Xgeva use should be avoided during pregnancy. Denosumab can cause fetal harm when given during pregnancy based on findings in animals. The risk for adverse fetal effects may be greater during second and third trimesters. Monoclonal antibodies cross the placenta linearly, with the greatest amount transferred during the third trimester. If pregnancy occurs during therapy, discontinue treatment; inform the patient of the potential risk to the fetus. Animal studies conducted in cynomolgus monkeys and mice genetically engineered to lack RANKL demonstrated fetal harm. In cynomolgus monkeys dosed throughout gestation at a dose 25-fold higher than the recommended human dose, 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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to denosumab; information about the registry can be obtained at www.amgenpregnancy.com/en-us/patient/home.aspx or by calling 1-800-772-6436.
Contraception requirements, pregnancy testing, reproductive risk
Denosumab (Prolia) is contraindicated in patients who are pregnant. Treated females should avoid becoming pregnant while taking denosumab (Prolia or Xgeva) and should be informed of the potential reproductive risk should pregnancy occur. Contraception requirements are in the product label for Xgeva; it is advisable to consider the same recommendations for a person using Prolia who is able to become pregnant. Pregnancy testing should occur to verify the pregnancy status prior to initiating denosumab treatment. 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 their health care provider if pregnancy occurs or if the patient suspects pregnancy within 5 months of taking the last dose. 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. Male condom use is not necessary as it is unlikely the partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid.
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 the breastfed child, taking into account the importance of the drug to the treated patient. 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 lactation. The drug is a protein and would likely be digested in the gastrointestinal tract of the breastfed infant, 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, patients receiving treatment during pregnancy may have impaired lactation postpartum due to drug-induced interruption of 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.
Children, infants
Denosumab is available as 2 products, Prolia and Xgeva. The safety and efficacy of the Prolia product have not been established in adolescents, children, or infants. Xgeva should only be used in pediatric patients with selected conditions and with close clinical monitoring. Xgeva is recommended for use in the treatment of giant cell tumor of the bone (GCTB) only in skeletally mature adolescents; safety and efficacy in adolescents who are not skeletally mature, children, or infants have not been established. 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 requiring hospitalization and complicated with acute renal injury has been reported in denosumab-treated pediatric patients with GCTB with growing skeletons and in pediatric patients with osteogenesis imperfecta. Hypercalcemia has been reported within the first year after treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, assess serum calcium periodically, and reassess calcium and vitamin D supplementation requirements. 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 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.
ADVERSE REACTIONS
Severe
hypophosphatemia / Delayed / 0-20.0
osteonecrosis / Delayed / 0.7-7.1
hypocalcemia / Delayed / 0-5.0
new primary malignancy / Delayed / 0-4.8
hypomagnesemia / Delayed / 0-3.0
fatigue / Early / 0-3.0
atrial fibrillation / Early / 0-1.0
pancreatitis / Delayed / 0.2-0.2
infection / Delayed / 4.0
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
angioedema / Rapid / Incidence not known
vasculitis / Delayed / 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 / 1.1-21.0
bone pain / Delayed / 3.7-19.0
neutropenia / Delayed / 8.5-8.5
cystitis / Delayed / 5.9-5.9
neuropathic pain / Delayed / 4.6-4.6
antibody formation / Delayed / 0-1.0
constipation / Delayed / 10.0
angina / Early / 3.0
oral ulceration / Delayed / Incidence not known
tetany / Early / Incidence not known
hypercalcemia / Delayed / Incidence not known
wheezing / Rapid / Incidence not known
erythema / Early / Incidence not known
eosinophilia / Delayed / Incidence not known
atopic dermatitis / Delayed / Incidence not known
hypotension / Rapid / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
Mild
asthenia / Delayed / 2.3-45.0
flushing / Rapid / 10.4-10.4
myalgia / Early / 2.9-10.4
fever / Early / 10.4-10.4
chills / Rapid / 10.4-10.4
vertigo / Early / 0-5.0
abdominal pain / Early / 3.3-3.3
rash / Early / 2.5-2.5
pruritus / Rapid / 2.2-2.2
flatulence / Early / 2.2-2.2
gastroesophageal reflux / Delayed / 2.1-2.1
pharyngitis / Delayed / 2.3
dental pain / Delayed / 10.0
back pain / Delayed / 10.0
arthralgia / Delayed / 2.1
headache / Early / 10.0
musculoskeletal pain / Early / 7.6
anorexia / Delayed / 10.0
diarrhea / Early / 10.0
nausea / Early / 10.0
vomiting / Early / 10.0
cough / Delayed / 10.0
muscle cramps / Delayed / Incidence not known
paresthesias / Delayed / Incidence not known
urticaria / Rapid / Incidence not known
lichen planus-like eruption / Delayed / Incidence not known
alopecia / Delayed / 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.
Budesonide; Glycopyrrolate; 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.
Calcitonin: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as calcitonin. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
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.
Cinacalcet: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as cinacalcet. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
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.
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.
Etelcalcetide: (Moderate) Monitor serum calcium, phosphorus, and magnesium concentrations within 14 days of denosumab injection during concurrent treatment with calcimimetics such as etelcalcetide. The risk for hypocalcemia and other disturbances of mineral metabolism may increase during coadministration. Monitor serum calcium concentrations closely in patients with severe renal impairment (CrCl less than 30 mL/minute) or renal failure (and/or on dialysis) receiving calcimimetics. An increased risk of hypocalcemia was seen in clinical trials involving patients with renal dysfunction. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
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.
Olopatadine; 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.
Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
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.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
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.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
PREGNANCY AND LACTATION
Pregnancy
Denosumab is available as 2 products, Prolia and Xgeva. Prolia use is contraindicated during pregnancy. Xgeva use should be avoided during pregnancy. Denosumab can cause fetal harm when given during pregnancy based on findings in animals. The risk for adverse fetal effects may be greater during second and third trimesters. Monoclonal antibodies cross the placenta linearly, with the greatest amount transferred during the third trimester. If pregnancy occurs during therapy, discontinue treatment; inform the patient of the potential risk to the fetus. Animal studies conducted in cynomolgus monkeys and mice genetically engineered to lack RANKL demonstrated fetal harm. In cynomolgus monkeys dosed throughout gestation at a dose 25-fold higher than the recommended human dose, 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. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to denosumab; information about the registry can be obtained at www.amgenpregnancy.com/en-us/patient/home.aspx or by calling 1-800-772-6436.
Denosumab (Prolia) is contraindicated in patients who are pregnant. Treated females should avoid becoming pregnant while taking denosumab (Prolia or Xgeva) and should be informed of the potential reproductive risk should pregnancy occur. Contraception requirements are in the product label for Xgeva; it is advisable to consider the same recommendations for a person using Prolia who is able to become pregnant. Pregnancy testing should occur to verify the pregnancy status prior to initiating denosumab treatment. 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 their health care provider if pregnancy occurs or if the patient suspects pregnancy within 5 months of taking the last dose. 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. Male condom use is not necessary as it is unlikely the partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid.
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.