XGEVA

Browse PDR's full list of drug information

XGEVA

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)

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.

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

Common Brand Names

Prolia, XGEVA

Dea Class

Rx

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

Dosage And 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.

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.

Drug Interactions

Albuterol; 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.
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.
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.

How Supplied

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

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.

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.

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.