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Denosumab

Pronunciation

Pronunciation: den-OH-sue-mab
Class: Monoclonal antibody

Trade Names

Prolia
- Injection, solution 60 mg/mL

Xgeva
- Injection, solution 70 mg/mL

Pharmacology

Denosumab binds to receptor activator of nuclear factor kappa B ligand (RANKL), a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in cortical and trabecular bone.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

C max is 6.75 mcg/mL and T max is 10 days ( Prolia ). Bioavailability is 62% ( Xgeva ).

Elimination

The half-life is 25.4 ( Prolia ) to 28 days ( Xgeva ).

Special Populations

Renal Function Impairment

Renal impairment had no effect on the pharmacokinetics of denosumab.

Hepatic Function Impairment

Pharmacokinetics have not been studied.

Elderly

Pharmacokinetics are not affected by age.

Children

Pharmacokinetics have not been assessed.

Gender

Pharmacokinetics are not affected by gender.

Race

Pharmacokinetics are not affected by race.

Body weight

Cl and Vd were proportional to body weight.

Indications and Usage

Prolia

For the treatment of postmenopausal women with osteoporosis at high risk of fracture or patients who have failed or are intolerant to other available osteoporosis therapy; to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer; to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

Xgeva

Prevention of skeletal-related events in patients with bone metastases from solid tumors.

Contraindications

Preexisting hypocalcemia ( Prolia ).

Dosage and Administration

Bone Metastases from Solid Tumors ( Xgeva )
Adults

Subcutaneous 120 mg once every 4 wk.

Bone Loss in Men and Women/Postmenopausal Osteoporosis ( Prolia )
Adults

Subcutaneous 60 mg once every 6 mo.

General Advice

  • Administer via subcutaneous injection in the upper arm, upper thigh, or abdomen.
  • For bone loss in men and women and postmenopausal osteoporosis, all patients should receive calcium 1,000 mg daily and at least 400 units of vitamin D daily.
  • For skeletal-related events secondary to bone metastases from solid tumors, administer calcium, magnesium, and vitamin D as necessary.
  • Prior to administration, denosumab may be removed from the refrigerator and brought to room temperature (up to 77°F) by standing in the original container. This generally takes 15 to 30 min. Do not warm denosumab in any other way.
  • Avoid vigorous shaking of denosumab.
  • Persons sensitive to latex should not handle the gray needle cap on the single-use prefilled Prolia syringe, which contains dry natural rubber (a derivative of latex).
  • If a dose of Prolia is missed, administer as soon as the patient is available. Thereafter, schedule injections every 6 mo from the date of the last injection.

Storage/Stability

Refrigerate at 36° to 46°F in the original carton. Do not freeze. Prior to administration, denosumab may be allowed to reach up to 77°F in the original container. Once removed from the refrigerator, denosumab must not be exposed to temperatures above 77°F and must be used within 14 days. If not used within 14 days, denosumab should be discarded. Protect from direct light and heat.

Drug Interactions

None well documented.

Adverse Reactions

CNS

Fatigue/asthenia (45%); headache (13%); sciatica, vertigo (5%); insomnia (3%).

Cardiovascular

Angina pectoris (3%); atrial fibrillation (2%).

Dermatologic

Epidermal and dermal adverse reactions (eg, dermatitis, eczema, rash) (11%); pruritus (2%).

EENT

Cataracts (5%); pharyngitis (2%).

GI

Nausea (31%); diarrhea (20%); abdominal pain upper (3%); flatulence, gastroesophageal reflux disease (2%).

Genitourinary

Cystitis (6%).

Hematologic

Anemia (3%).

Metabolic-Nutritional

Hypophosphatemia (32%); hypocalcemia (18%); hypercholesterolemia (7%); peripheral edema (5%).

Musculoskeletal

Back pain (35%); arthralgia (14%); pain in extremity (12%); musculoskeletal pain (8%); bone pain (4%); myalgia (3%); osteonecrosis of the jaw, spinal osteoarthritis (2%).

Respiratory

Dyspnea (21%); cough (15%); upper respiratory tract infection (5%); pneumonia (4%).

Miscellaneous

New malignancy (5%); serious infection (4%); herpes zoster (2%); pancreatitis.

Precautions

Monitor

Monitor serum calcium, phosphorus, and magnesium levels, especially in patients predisposed to hypocalcemia (eg, excision of small intestine, history of hypoparathyroidism, malabsorption syndromes, parathyroid/thyroid surgery, severe renal impairment [CrCl less than 30 mL/min], receiving dialysis). Perform a routine oral exam prior to initiation of treatment and consider a dental examination with appropriate preventive dentistry prior to treatment in patients with risk factors for osteonecrosis of the jaw. Monitor patients for the development of infection. Monitor patients on long-term therapy for the development of osteonecrosis of the jaw, atypical fractures, and delayed fracture healing.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy have not been established. Use in children is not recommended.

Elderly

Greater sensitivity of some older individuals cannot be ruled out.

Renal Function

Patients with severe renal impairment (CrCl less than 30 mL/min) or receiving dialysis are at greater risk of developing hypocalcemia; consider the benefit-risk profile when administering denosumab to these patients. Adequate intake of calcium and vitamin D is important in patients with severe renal impairment or receiving dialysis.

Dermatologic adverse reactions

Epidermal and dermal adverse reactions, such as dermatitis, eczema, and rash, have occurred with Prolia .

Hypocalcemia and mineral metabolism

Hypocalcemia may be caused or exacerbated by the use of denosumab. Preexisting hypocalcemia must be corrected prior to initiating therapy.

Immunogenicity

As with all therapeutic proteins, immunogenicity may occur.

Long-term use

Treatment with Prolia resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The 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.

Osteonecrosis of the jaw

May occur and is generally associated with tooth extraction and/or local infection with delayed healing.

Serious infections

Have been reported with Prolia and included serious skin infections; infections of the abdomen, urinary tract, and ear; endocarditis; and opportunistic infections. Patients with impaired immune systems or taking concomitant immunosuppressant agents may be at increased risk for serious infections.

Overdosage

Symptoms

No cases reported.

Patient Information

  • Inform patients that they will be adequately supplemented with calcium, vitamin D, and magnesium as needed and instruct them on the importance of maintaining serum calcium levels while receiving denosumab.
  • Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcemia (paresthesia or muscle stiffness, twitching, spasms, or cramps), infections (including cellulitis), or dermatological reactions.
  • Advise patients to maintain good oral hygiene during treatment with denosumab and to inform their dentist prior to dental procedures that they are receiving denosumab. Advise patients to inform their health care provider or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery.
  • Advise patients to avoid invasive dental procedures during treatment with denosumab.
  • Advise patients to contact a health care provider if they become pregnant or are breast-feeding.
  • Inform patients that Prolia and Xgeva contain the same active ingredient and that they should not receive the two drugs together.

Copyright © 2009 Wolters Kluwer Health.

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