denosumab (Rx)

>10% (Prolia)

Back pain (34.7%)

Extremity pain (11.7%)

>10% (Xgeva)

Fatigue/asthenia (45%)

Hypophosphatemia (32%)

Nausea (31%)

Dyspnea (21%)

Diarrhea (20%)

Hypocalcemia (18%)

Cough (15%)

Headache (13%)

1-10% (Prolia)

Musculoskeletal pain (7.6%)

Cystitis (5.9%)

Vertigo (5%)

Upper respiratory tract infection (4.9%)

Peripheral edema (4.9%)

Sciatica (4.6%)

Pneumonia (3.9%)

Bone pain (3.7%)

Upper abdominal pain (3.3%)

Anemia (3.3%)

Insomnia (3.2%)

Myalgia (2.9%)

Angina pectoris (2.6%)

Rash (2.5%)

Pharyngitis (2.3%)

Asthenia (2.3%)

Flatulence (2.2%)

Pruritus (2.2%)

Spinal osteoarthritis (2.1%)

Gastroesophageal reflux disease (2.1%)

Atrial fibrillation (2%)

Herpes zoster (2%)

<1%

Serious infection of abdomen resulting in hospitalization (0.9%)

Serious infection of urinary tract resulting in hospitalization (0.7%)

Serious infection resulting in death (0.2%)

Pancreatitis (0.2%)

Serious infection of ear resulting in hospitalization (0.1%)

Postmarketing Reports

Prolia

• Drug-related hypersensitivity reactions: Anaphylaxis, rash, urticaria, facial swelling, and erythema
• Severe symptomatic hypocalcemia
• Musculoskeletal pain, including severe cases
• Parathyroid Hormone (PTH): Marked elevation in serum PTH in patients with severe renal impairment (CrCl <30 mL/min) or receiving dialysis
• Multiple vertebral fractures following discontinuation of Prolia
• Alopecia
• Vasculitis (eg, ANCA positive vasculitis, leukocytoclastic vasculitis)
• Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome

Xgeva

• Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases
• Hypercalcemia following treatment discontinuation in patients with giant cell tumor of bone and in patients with growing skeletons
• Hypersensitivity, including anaphylactic reactions
• Musculoskeletal pain, including severe musculoskeletal pain
• Positive rechallenge has been reported
• Lichenoid drug eruptions (e.g., lichen planus-like reactions)
• Atypical subtrochanteric and diaphyseal fracture

Contraindications

Hypersensitivity

Hypocalcemia

Pregnancy (Prolia only)

Cautions

Denosumab is available as 2 distinct brands (Prolia and Xgeva) that have different dosage strengths for their respective indications; do not use concurrently

Serious infections (including cellulitis) and dermatologic reactions (eg, dermatitis, rashes, eczema) have been reported; advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis; consider discontinuing therapy if severe symptoms develop

Hypersensitivity (including anaphylaxis) has been reported; symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported; discontinue use if severe symptoms develop

Atypical femoral fracture reported; risk increased with longer duration of treatment; events have occurred during and after treatment discontinued; evaluate patients with thigh or groin pain to rule out a femoral fracture

Following discontinuation of denosumab, fracture risk increases, including risk of multiple vertebral fractures

Thearpy results in significant suppression of bone turnover; cessation of therapy results in increased bone turnover above pretreatment values 9 months after last dose; bone turnover then returns to pretreatment values 24 months after last dose

Significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry; long-term consequences of the degree of suppression of bone remodeling observed may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing

Pediatric use

• Not approved for use in pediatric patients; hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products, including this drug; some cases required hospitalization
• Based on results from animal studies, this drug may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years

Osteonecrosis of the Jaw

• Bone turnover suppression may increase risk for osteonecrosis of jaw; perform an oral examination prior to initiating therapy; osteonecrosis of the jaw (ONJ), can occur spontaneously and is generally associated with tooth extraction and/or local infection with delayed healing; known risk factors include invasive dental procedures (eg, tooth extraction, dental implants, bone surgery), diagnosis of cancer, concomitant therapies (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and comorbid disorders; risk of ONJ may increase with duration of therapy
• Good oral hygiene practices should be maintained during treatment; concomitant administration of drugs associated with ONJ may increase risk of developing ONJ; risk of ONJ may increase with duration of exposure to treatment; for patients requiring invasive dental procedures, clinical judgment of treating physician and/or oral surgeon should guide management plan of each patient based on individual benefit-risk assessment
• Patients who are suspected of having or who develop ONJ while on therapy should receive care by a dentist or an oral surgeon; in these patients, extensive dental surgery to treat ONJ may exacerbate condition; consider discontinuing therapy based on individual benefit-risk assessment

Xgeva only

• Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury reported in patients with giant cell tumor of bone and patients with growing skeletons; hypercalcemia reported within first year after treatment discontinuation; after treatment is discontinued, monitor for signs and symptoms of hypercalcemia, assess serum calcium periodically, reevaluate patient’s calcium and vitamin D supplementation requirements and manage patients as clinically appropriate
• Based on data from animal studies and its mechanism of action, Xgeva can cause fetal harm when administered to a pregnant woman (see Pregnancy)

Prolia only

• Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections; consider benefit-risk profile in such patients before treating with Prolia; in patients who develop serious infections while on therapy, prescribers should assess need for continued therapy
• Atypical low energy or low trauma fractures of the shaft reported in patients receiving therapy; these fractures can occur anywhere in femoral shaft from just below lesser trochanter to above supracondylar flare and are transverse or short oblique in orientation without evidence of comminution; causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with antiresorptive agents
• In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported; time to onset of symptoms varied from one day to several months after starting Prolia; consider discontinuing use if severe symptoms develop
• In a large clinical trial which included women with postmenopausal osteoporosis, epidermal and dermal adverse events (eg, dermatitis, eczema, and rashes); most of these events were not specific to the injection

Hypocalcemia

• Hypocalcemia may occur; monitor calcium levels during therapy, especially in the first weeks of initiating therapy, and adequately supplement all patients with calcium and vitamin D
• Hypocalcemia may be exacerbated by therapy with Prolia; correct pre-existing hypocalcemia prior to initiating therapy; in patients predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment [CrCl <30 mL/min] or receiving dialysis), clinical monitor calcium and mineral levels (phosphorus and magnesium) within 14 days of injection; in some postmarketing cases, hypocalcemia persisted for weeks or months and required frequent monitoring and IV and/or oral calcium replacement, with or without vitamin D
• Hypocalcemia is a significant risk in patients with severe renal impairment [CrCl <30 mL/min] or receiving dialysis; dose adjustment not necessary when administered at 60 mg every 6 months; once monthly dosing not evaluated in patients with renal impairment; these patients may also develop marked elevations of serum parathyroid hormone (PTH)
• Concomitant use of calcimimetic drugs may worsen hypocalcemia risk and serum calcium should be closely monitored; Instruct all patients with severe renal impairment, including those receiving dialysis, about symptoms of hypocalcemia and importance of maintaining calcium levels with adequate calcium and vitamin D supplementation

Severe hypocalcemia in patients on dialysis

• On November 22, 2022: FDA is investigating the risk of severe hypocalcemia with serious outcomes, including hospitalization and death, in patients with advanced kidney disease on dialysis treated with Prolia
• Interim results from an ongoing safety study suggests an increased risk of hypocalcemia in patients with advanced kidney disease
• Preliminary results from a separate internal FDA study further investigating hypocalcemia in dialysis patients treated with Prolia show a substantial risk with serious outcomes, including hospitalization and death
• Consider the risks of hypocalcemia with use in patients on dialysis
• If used in these patients, supplement with adequate calcium and vitamin D and consider more frequent blood calcium monitoring
• Advise patients on dialysis to immediately seek help if they experience symptoms of hypocalcemia (eg, unusual tingling or numbness in the hands, arms, legs, or feet; painful muscle spasms or cramps; voice box or lung spasms causing difficulty breathing; vomiting; seizures; or irregular heart rhythm)

Pregnancy

Prolia: Contraindicated

Xgeva

• Based on findings in animals and its mechanism of action, denosumab can cause fetal harm when administered to a pregnant woman
• In utero exposure in cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth
• Present at low concentrations (~2% of serum exposure) in seminal fluid of male subjects receiving therapy; following vaginal intercourse, maximum amount of denosumab delivered to a female partner would result in exposures ~11,000 times lower than the prescribed 60 mg subcutaneous dose; male condom use not necessary as it is unlikely that a female partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid

Pregnancy testing

• Prolia and Xgeva
• Verify pregnancy status of females of reproductive potential prior to initiating treatment

Contraception

• Prolia and Xgeva
• Females: Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of denosumab
• Males: Denosumab was present at low concentrations (~2% of serum exposure) in the seminal fluid of male subjects; condom use would not be necessary as it is unlikely that a female partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab via seminal fluid

Lactation

There is no information regarding presence of denosumab in human milk, effects on breastfed infant, or effects on milk production;

Detected in maternal milk of cynomolgus monkeys up to 1 month after last dose (≤0.5% milk: serum ratio) and maternal mammary gland development was normal, with no impaired lactation; however, pregnant RANKL knockout mice showed altered maturation of maternal mammary gland, leading to impaired lactation

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Monoclonal antibody that specifically targets RANKL; binds to RANKL and inhibits its binding to RANK receptor, thereby preventing osteoclast formation; this results in decreased bone resorption and increases bone mass in osteoporosis; in solid tumors with bony metastases, RANKL inhibition decreases tumor-induced bone destruction and SREs

Absorption

Prolia

• Peak serum time: 10 days
• Peak plasma concentration: 6.75 mcg/mL
• AUC: 316 mcg•day/mL

Xgeva

• Bioavailability: 62%
• Steady was achieved by 6 months with multiple SC doses of 120 mg q4Weeks

Elimination

Duration: Markers of bone resorption return to baseline within 12 months of discontinuing therapy

Half-life: 25.4 days (Prolia); 28 days (Xgeva)

SC Preparation

Visually inspect for particulate matter and discoloration prior to administration

Solution should appear clear, colorless-to-pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles

Do not use if discolored or cloudy, or if the solution contains many particles or foreign particulate matter

Prior to administration, remove from refrigerator bring to room temperature (up to 25°C/77°F); generally takes 15-30 minutes; do not warm in any other way

Latex allergy

• Prolia only
• People sensitive to latex should not handle the grey needle cap on the single-use prefilled syringe, which contains dry natural rubber (a derivative of latex)

SC Administration

SC administration only

Must be administered by healthcare professional

Use a 27-gauge needle to withdraw and inject the entire contents of the vial; do not reenter the vial

Do not administer intradermally, IM, or IV

Administer SC in upper arm, upper thigh, or abdomen

Administer calcium and vitamin D as needed to treat or prevent hypocalcemia

Avoid vigorous shaking of vial/syringe

Discard vial after single-dose or entry

Storage

Xgeva and Prolia

• Refrigerate at 2-8°C (36-46°F); do not freeze
• Once removed from refrigerator, preparation must be used within 14 days and not exposed to temperatures above 25°C (77°F)
• Protect from direct light and heat