denosumab (Prolia, Xgeva)

Dosing and uses of Prolia, Xgeva (denosumab)

• Adult
• Pediatric

 

Adult dosage forms and strengths

subcutaneous injection

• Prolia: 60mg/mL (1mL prefilled syringe or 1mL vial)
• Xgeva: 70mg/mL (120mg/1.7mL vial)

 

Osteoporosis

Treatment of men and postmenopausal women with osteoporosis who are at high risk for fracture; treatment to increase bone mass in men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer; treatment to increase bone mass in women at high risk for fracture who are receiving adjuvant aromatase inhibitor therapy for breast cancer

Prolia: 60 mg SC every 6 months

Supplement with calcium 1000 mg/day and vitamin D 400 IU/day

 

Aromatase Inhibitor Induced Bone Loss

Women with breast cancer: 60 mg (Prolia) SC every 6 months

 

Androgen Deprivation Induced Bone Loss

Men with prostate cancer: 60 mg (Prolia) SC every 6 months

 

Skeletal-Related Events

Prevention of skeletal-related events (SREs; eg, bone fractures and pain) in patients with bone metastases from solid tumors

Xgeva: 120 mg (1.7 mL) SC every 4 weeks

 

Giant Cell Tumor

Treatment of adults and skeletally mature adolescents with giant cell tumor of bone in whom surgical resection is impossible or is likely to result in severe morbidity

Xgeva: 120 mg SC every 4 weeks with additional 120 mg on days 8 and 15 during first month of therapy

 

Hypercalcemia of Malignancy

Indicated for treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy

Xgeva: 120 mg SC q4wk

Give 2 additional 120 mg doses during the first month of therapy on Days 8 and 15

 

Administration

Must be administered by healthcare professionaL

Administer SC in upper arm, upper thigh, or abdomen; do NOT administer intradermally, IM, or IV

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

Avoid vigorous shaking of vial/syringe

Storage

• Store refrigerated at 2-8°C (36-46°F)
• Once removed from refrigerator, preparation must be used within 14 days

 

Pediatric dosage forms and strengths

subcutaneous injection

• Xgeva: 70mg/mL (120mg/1.7mL vial)

 

Giant Cell Tumor

Treatment of skeletally mature adolescents with giant cell tumor of bone in whom surgical resection is impossible or is likely to result in severe morbidity

Xgeva: 120 mg SC every 4 weeks, with additional 120 mg on days 8 and 15 during first month of therapy

 

Administration

Must be administered by healthcare professionaL

Administer SC in upper arm, upper thigh, or abdomen; do NOT administer intradermally, IM, or IV

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

Avoid vigorous shaking of vial/syringe

Storage

• Store refrigerated at 2-8°C (36-46°F)
• Once removed from refrigerator, preparation must be used within 14 days

 

Prolia, Xgeva (denosumab) adverse (side) effects

>10%

Back pain (34.7%)

Extremity pain (11.7%)

 

1-10%

Musculoskeletal pain (7.6%)

Hypercholesterolemia (7.2%)

Cystitis (5.9%)

Upper respiratory tract infection (4.9%)

New malignancies (4.8%, compared with 4.3% in placebo group)

Sciatica (4.6%)

Nonfatal serious infection (4%)

Bone pain (3.7%)

Anemia (3.3%)

Upper abdominal pain (3.3%)

Rash (2.5%)

Flatulence (2.2%)

Osteonecrosis of jaw (2.2%)

Pruritus (2.2%)

Hypocalcemia (1.7%)

 

<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

Hypocalcemia

Marked elevation in PTH in patients with severe renal impairment or receiving dialysis

 

Warnings

Contraindications

History of systemic hypersensitivity, including anaphylaxis, facial swelling, and urticaria

Preexisting hypocalcemia

 

Cautions

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

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

Severe symptomatic hypocalcemia has been reported; hypocalcemia may worsen, especially in patients who have CrCl <30 mL/min or are on hemodialysis

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

Bone turnover suppression may increase risk for osteonecrosis of jaw; perform an oral examination prior to initiating therapy; osteonecrosis of the jaw, can occur spontaneously and is generally associated with tooth extraction and/or local infection with delayed healing; known risk factors include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders; risk of osteonecrosis of the jaw may increase with duration of therapy

Significant suppression demonstrated; monitor for consequences of bone oversuppression

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

Monitor patients for signs and symptoms of hypercalcemia and treat appropriately

Atypical femoral fracture has been reported; evaluate patients with thigh or groin pain to rule out a femoral fracture

Pancreatitis reported in clinical trials

Pediatric use is not recommended; drug may impair bone growth in children with open growth plates and may inhibit eruption of dentition

Latex allergy: If sensitive to latex, do not handle gray needle cap on single-use prefilled syringe, which contains dry natural rubber (a derivative of latex)

Pregnancy; females of reproductive potential should be advised to use highly effective contraception during therapy and for at least 5 months after last dose (Prolia)

Not indicated for the prevention of skeletal-related events in patients with multiple myeloma

Use caution in patients with renal impairment <30 mL/min) or patients on dialysis; risk of hypocalcemia increased; dose adjustment not necessary when administered at 60 mg every 6 months; once monthly dosing not evaluated in patients with renal impairment

Not for intravenous, intradermal, or intramuscular administration

 

Pregnancy and lactation

Pregnancy category: X; on basis of animal studies, may cause fetal harm when administered pregnant women; in utero, results in increased fetal loss, stillbirths, and postnatal mortality, including absent lymph nodes, abnormal bone growth, and decreased neonatal growth

Women with reproductive potential must use highly effective contraception during therapy and for ≥5 months after last dose

On basis of animal studies in pregnant mice lacking RANK/RANK ligand (RANKL) signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation post partum, maternal exposure during pregnancy may impair mammary gland development and lactation

Lactation: Unknown whether drug is distributed in breast milk; caution is advised

 

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.

 

Pharmacology of Prolia, Xgeva (denosumab)

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

Peak serum time: 10 days

Peak plasma concentration: 6.75 mcg/mL

AUC: 316 mcg•day/mL

 

Elimination

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

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