Denosumab

Class: Bone Resorption Inhibitors
Chemical Name: Anti-(human osteoclast differentiation factor) (human monoclonal AMG162 heavy chain), disulfide with human monoclonal AMG162 light chain immunoglobulin G2 dimer.
Molecular Formula: C₆₄₀₄H₉₉₁₂N₁₇₂₄O₂₀₀₄S₅₀
CAS Number: 615258-40-7
Brands: Prolia

REMS:

FDA approved a REMS for denosumab to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of denosumab and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Bone resorption inhibitor; fully human monoclonal antibody specific for nuclear factor kappa-B ligand (RANKL); RANKL inhibitor.^{1 10}

Uses for Denosumab

Osteoporosis (Prolia)

Treatment of osteoporosis in postmenopausal women at high risk of fracture, defined as history of osteoporotic fracture or multiple risk factors for fracture.¹

Treatment of osteoporosis in postmenopausal women who have failed or are intolerant of other available osteoporosis therapies.¹

Denosumab Dosage and Administration

General

• 
  

  Correct preexisting hypocalcemia prior to initiating denosumab.¹

  
  


• 
  

  All postmenopausal women receiving denosumab (Prolia) for treatment of osteoporosis should receive 1 g of calcium and at least 400 units of vitamin D daily.¹

  
  

Administration

Sub-Q Administration

Administer by sub-Q injection into upper arm, upper thigh, or abdomen.¹ Should be administered by a health-care professional.¹

May warm to room temperature by allowing drug to stand in original packaging at room temperature (≤25°C) for approximately 15–30 minutes.¹ Do not use any other method to warm the drug.¹

Solution should appear clear, colorless to pale yellow; may contain trace amounts of translucent to white proteinaceous particles.¹ Do not use if solution is discolored, cloudy, or contains many particles or foreign matter.¹

Single-use prefilled syringe (Prolia): Remove gray needle cap and inject entire solution.¹ After injection is complete, activate needle guard by pointing needle away from body and gently sliding green safety guard toward needle until locked securely in place.¹ The needle cap contains dry natural rubber (latex) and should not be handled by individuals sensitive to latex.¹ (See Latex Sensitivity under Cautions.)

Single-use vial (Prolia): Use a 27-gauge needle to withdraw and inject the dose.¹ Do not re-enter vial; discard any remaining solution along with the vial.¹

Dosage

Adults

Osteoporosis (Prolia)

Treatment in Postmenopausal Women

Sub-Q

60 mg once every 6 months.¹

Administer a missed dose as soon as patient is available; give subsequent doses every 6 months from date of last dose.¹

Special Populations

Hepatic Impairment

Pharmacokinetics not evaluated in patients with hepatic impairment.¹

Renal Impairment

Dosage adjustment of Prolia not necessary in patients with renal impairment.¹ However, those with severe renal impairment (Cl_cr <30 mL/minute) or receiving dialysis are at greater risk of developing hypocalcemia.¹ (See Hypocalcemia and Mineral Metabolism under Cautions.)

Cautions for Denosumab

Contraindications

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  Hypocalcemia; preexisting hypocalcemia must be corrected prior to initiating denosumab treatment.¹

  
  

Warnings/Precautions

Risk Evaluation and Mitigation Strategy (REMS) for Prolia

FDA required and approved a REMS for Prolia: goals are to inform health-care providers and patients about the serious risks associated with use of denosumab, including serious infections, adverse dermatologic reactions, and suppression of bone turnover.⁸

The REMS requires that a medication guide be provided to the patient with each denosumab (Prolia) dose, outlines a communication plan requiring initial and continuing communications to certain targeted groups of prescribers, and requires that the manufacturer periodically submit REMS assessments to FDA.⁸

Prescribers are encouraged to register with the Prolia Postmarketing Active Safety Surveillance Program, a voluntary program designed to collect information on adverse events of interest.^{1 13} Available at or 800-772-6436.^{1 13}

Hypocalcemia and Mineral Metabolism

Decreased serum calcium concentrations can occur; denosumab may exacerbate preexisting hypocalcemia.¹

Preexisting hypocalcemia must be corrected prior to initiating denosumab treatment.¹

All patients should receive adequate calcium and vitamin D supplementation.¹ (See General under Dosage and Administration.)

Risk of hypocalcemia is greater in patients with severe renal impairment (Cl_cr <30 mL/minute) or receiving dialysis.¹ Monitor such patients for symptoms of hypocalcemia and, like all patients, ensure adequate calcium and vitamin D supplementation.¹ (See Renal Impairment under Cautions.)

Clinical monitoring of calcium, phosphorus, and magnesium highly recommended in patients predisposed to hypocalcemia and disturbances of mineral metabolism (e.g., history of hypocalcemia, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, severe renal impairment, receiving dialysis).¹

Serious Infections

Denosumab may increase risk of infection.¹

Serious skin infections (e.g., cellulitis, erysipelas), endocarditis, and infections of the abdomen, urinary tract, and ear reported in a clinical trial evaluating denosumab in postmenopausal women with osteoporosis;¹ some infections required hospitalization.¹

Patients receiving concomitant immunosuppressive agents or with impaired immune systems may be at greater risk of serious infections.¹ Assess need for continued denosumab (Prolia) treatment in patients who develop serious infections.¹

Dermatologic Reactions

Adverse epidermal and dermal events (e.g., dermatitis, eczema, rash) were reported in a clinical trial evaluating denosumab in postmenopausal women with osteoporosis; most reactions were not specific to the injection site.¹

If severe dermatologic symptoms develop, consider discontinuing denosumab (Prolia).¹

Osteonecrosis of the Jaw (ONJ)

ONJ has been reported in patients receiving denosumab.¹ ONJ generally is associated with tooth extraction and/or local infection with delayed healing, but may occur spontaneously.¹

Risk factors for ONJ include invasive dental procedures (e.g., tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and comorbidities (e.g., preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures).¹

Perform routine oral examination prior to initiating denosumab.¹ Consider referring patients with risk factors for ONJ for dental examination and preventive dentistry prior to initiating denosumab.¹

If invasive dental procedures are required, clinical judgment of the prescriber and/or oral surgeon and assessment of risks and benefits should guide the management plan.¹

If ONJ develops or is suspected, refer patient to dentist or oral surgeon.¹ Extensive dental surgery to treat ONJ may exacerbate the condition.¹ Consider discontinuing denosumab (Prolia) based on patient-specific risk-benefit assessment.¹

Suppression of Bone Turnover

Significant suppression of bone remodeling was observed in clinical trials of denosumab (Prolia) in postmenopausal women with osteoporosis.^{1 4}

Denosumab treatment results in reduction in biochemical bone turnover markers⁴ and bone formation rates (as shown by tetracycline labeling).¹

Long-term effects of the degree of bone remodeling suppression seen with denosumab are unknown.¹ Because these effects may contribute to adverse outcomes, such as ONJ, atypical fractures, and delayed fracture healing, monitor patients for such events.¹

Immunogenicity and Antibody Formation

Denosumab-binding antibodies (preexisting, transient, and developing antibodies) reported rarely in postmenopausal women with osteoporosis receiving denosumab for up to 5 years.¹ Denosumab-neutralizing antibodies not reported to date, and antibody formation does not appear to affect denosumab pharmacokinetics, toxicity, or efficacy.¹

Sensitivity Reactions

Latex Sensitivity

Prolia: Some packaging components (i.e., needle cap) of prefilled syringes contain natural latex proteins in the form of dry natural rubber (latex),¹ and should not be handled by individuals sensitive to latex.^{1 5 6 7}

Some individuals may be hypersensitive to natural latex proteins;^{5 6 7} rarely, hypersensitivity reactions to natural latex proteins have been fatal.^{6 7}

Specific Populations

Pregnancy

Category C.¹

Prolia: Indicated only in postmenopausal women.¹

Women who become pregnant during denosumab treatment are encouraged to enroll in the manufacturer's Pregnancy Surveillance Program at 800-772-6436.¹

Lactation

Not known whether denosumab is distributed into milk.¹ Discontinue nursing or drug.¹

Pediatric Use

Safety and efficacy not established.¹

Denosumab potentially may impair bone growth in children with open growth plates and may inhibit eruption of dentition.¹

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

No pharmacokinetic studies performed in patients with hepatic impairment.¹

Renal Impairment

Pharmacokinetics not affected by renal impairment;¹ dosage adjustment not necessary.¹

Patients with severe renal impairment (Cl_cr <30 mL/minute) or receiving dialysis are at greater risk of hypocalcemia.¹ Consider risks and benefits of denosumab (Prolia) in such patients.¹ (See Hypocalcemia and Mineral Metabolism under Cautions.)

Common Adverse Effects

Prolia: Back pain,¹ extremity pain,¹ musculoskeletal pain,¹ hypercholesterolemia,¹ cystitis.¹

Interactions for Denosumab

No formal drug interaction studies to date.¹

Immunosuppressive Agents

Concomitant use with immunosuppressive agents may increase the risk of serious infections.¹ Assess risks and benefits to guide use of denosumab in patients receiving immunosuppressive agents.¹ (See Serious Infections under Cautions.)

Denosumab Pharmacokinetics

Absorption

Bioavailability

Approximately 61% following sub-Q administration.¹¹

Prolonged absorption phase;¹² maximum serum concentrations are attained approximately 10 days after a 60-mg sub-Q dose.¹

Characterization of other monoclonal antibodies indicates that absorption is probably mediated by the lymphatic system.^{3 14}

Onset

Studies in postmenopausal women with osteoporosis indicate reduction in bone resorption biomarkers observed within 3 days after a 60-mg dose; maximal reductions observed by 1 month.¹

Duration

Studies in postmenopausal women with osteoporosis indicate effect on bone resorption markers partially attenuated at the end of each 6-month dosing interval.¹ Bone mineral density and levels of bone resorption markers return to baseline within 12 months after discontinuing denosumab.¹

Distribution

Extent

Not known whether denosumab is distributed into milk.¹¹

Elimination

Elimination Route

Clearance may occur via the reticuloendothelial system; renal excretion is not expected.^{3 14}

Half-life

Approximately 25 days.¹

Special Populations

Pharmacokinetics not evaluated in patients with hepatic impairment;¹ pharmacokinetics not affected by renal impairment.¹

Stability

Storage

Parenteral

Injection for Sub-Q Use

2–8ºC; do not freeze.¹ Protect from direct light and heat.¹

Use within 14 days after removal from refrigerator.¹ Do not expose to temperatures >25ºC.¹

Do not shake vigorously.¹

Actions

• 
  

  Denosumab, a fully human monoclonal IgG₂ antibody, is a bone resorption inhibitor.^{1 10}

  
  


• 
  

  Denosumab is specific for and binds to nuclear factor kappa-B ligand (RANKL), and acts as a RANKL inhibitor preventing interaction with its receptor (RANK).^{1 10} The interaction between RANK and RANKL is integral to the normal bone resorption process.¹⁰ As a result, denosumab inhibits osteoclast formation, function, and survival and, ultimately, bone resorption.^{1 10}

  
  


• 
  

  In postmenopausal women with osteoporosis, denosumab increases bone mineral density (BMD) and reduces the incidence of vertebral, nonvertebral, and hip fractures.^{1 4}

  
  


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  The effects of denosumab are considered reversible since bone turnover markers and BMD return to baseline within 12 months after the drug is discontinued.^{1 10 12}

  
  

Advice to Patients

• 
  

  Denosumab (Prolia) medication guide must be provided to the patient each time the drug is administered; importance of reading the medication guide prior to initiating therapy and prior to each subsequent dose.^{1 2 8}

  
  


• 
  

  Importance of receiving adequate calcium and vitamin D supplementation during denosumab therapy, and importance of seeking medical attention if signs or symptoms of hypocalcemia develop (e.g., spasms, twitches, muscle cramps, numbness or tingling in fingers, toes, or near mouth).^{1 2}

  
  


• 
  

  Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis (e.g., fever, chills, severe abdominal pain, frequent or urgent need to urinate or burning feeling when urinating, skin that is red, swollen, hot, or tender to touch).^{1 2}

  
  


• 
  

  Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatologic reactions (e.g., redness, itching, rash, dry skin, blisters that ooze or crust, peeling skin).^{1 2}

  
  


• 
  

  Importance of maintaining good oral hygiene during denosumab treatment; importance of informing dentist about denosumab treatment prior to dental procedures.¹ Advise patients to inform clinician or dentist if persistent pain and/or slow healing of mouth or jaw occurs after dental surgery.¹

  
  


• 
  

  Importance of informing clinician about latex allergy.¹ (See Latex Sensitivity under Cautions.)

  
  


• 
  

  Inform postmenopausal women receiving denosumab (Prolia) for the treatment of osteoporosis that if a dose is missed, the dose should be given as soon as convenient and subsequent dose should be scheduled for 6 months from date of last dose.¹

  
  


• 
  

  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Prolia is indicated only in postmenopausal women.¹ (See Pregnancy under Cautions.)

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

  
  


• 
  

  Importance of informing patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Denosumab

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for subcutaneous use	60 mg/mL	Prolia	Amgen

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Xgeva 120MG/1.7ML Solution (AMGEN): 2/$1,900.01 or 5/$5,499.85

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Amgen. Prolia (denosumab) injection prescribing information. Thousand Oaks, CA. 2010 Jun.

2. Amgen. Prolia (denosumab) injection medication guide. Thousand Oaks, CA. 2010 Jun.

3. Lewiecki EM. Denosumab--an emerging treatment for postmenopausal osteoporosis. Expert Opin Biol Ther. 2010; 10:467-76. [PubMed 20095877]

4. Cummings SR, San Martin J, McClung MR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009; 361:756-65. [PubMed 19671655]

5. Food and Drug Administration. Amended economic impact analysis of final rule requiring use of labeling on natural rubber containing devices. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1998; 63:50660-704.

6. Food and Drug Administration. Latex-containing devices; user labeling. 21 CFR Part 801. Proposed rule. (Docket No. 96N-0119) Fed Regist. 1996; 61:32617-21.

7. Food and Drug Administration. Natural rubber-containing medical devices; user labeling. 21 CFR Part 801. Final rule. (Docket No. 96N-0119) Fed Regist. 1997; 62:51021-30.

8. Prolia™ (densoumab) injection risk evaluation and mitigation stratetgy (REMS). From FDA website. Accessed Nov 12, 2010.

10. Romas E. Clinical applications of RANK-ligand inhibition. Intern Med J. 2009; 39:110-6. [PubMed 19356186]

11. Rodriquez, RD, Sutjandra L, Peterson MC, et al. Population pharmacokinetic meta-analysis of denosumab in healthy and cancer subjects and postmenopausal women with osteopenia or osteoporosis. The AAPS Journal.2009;11(S1).

12. Bekker PJ, Holloway DL, Rasmussen AS et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004; 19:1059-66. [PubMed 15176987]

13. Amgen. Prolia Postmarketing Active Safety Surveillance Program. Available at . Accessed August 26, 2010.

14. Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004; 93:2645-68. [PubMed 15389672]

15. Food and Drug Administration Center for Drug Evaluation and Research. Summary review (application number 125320). From FDA website.

More Denosumab resources

• Denosumab Side Effects (in more detail)
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