romosozumab (Rx)

>10%

Arthralgia (8.1-13.1%)

1-10%

Headache (5.2-6.6%)

Hypersensitivity (6.5%)

Injection site reactions (4.9%)

Muscle spasms (3.4-4.6%)

Asthenia (2.3-2.5%)

Peripheral edema (1.7-2.4%)

Neck pain (1.7-2.2%)

Insomnia (1.7-2%)

Paresthesia (1.4-2%)

<1%

Hypocalcemia (0.2%)

Major adverse cardiac event (MACE)

• Study 1

  • Myocardial infarction (MI): 0.3% (0.2% placebo)
  • Stroke: 0.2% (0.3% placebo)
  • Cardiovascular (CV) death 0.5% (0.4% placebo)

• Study 2

  • MI: 0.8% (0.2% alendronate)
  • Stroke: 0.6% (0.3% alendronate)
  • CV death 0.8% (0.6% alendronate)
  • Positively adjudicated MACE: 2% (1.1% alendronate); hazard ratio 1.87

Frequency Not Defined

Osteonecrosis of the jaw (ONJ)

Atypical femoral fracture

Contraindications

Hypocalcemia; preexisting hypocalcemia must be corrected before initiating

Systemic hypersensitivity (eg, angioedema, erythema multiforme, urticaria)

Cautions

A higher rate of MACE, a composite endpoint of CV death, nonfatal MI, and nonfatal stroke was observed in a randomized controlled trial in postmenopausal women treated with romosozumab compared with alendronate; monitor for signs and symptoms of myocardial infarction and stroke and instruct patients to seek prompt medical attention if symptoms occur

Hypersensitivity reactions reported, including angioedema, erythema multiforme, dermatitis, rash, and urticaria; discontinue drug and initiate appropriate treatment if anaphylaxis or other clinically significant allergic reaction occurs

Hypocalcemia reported; correct hypocalcemia before initiating; monitor for signs and symptoms of hypocalcemia; ensure adequate supplementation with calcium and vitamin D during therapy

Atypical subtrochanteric and diaphyseal femoral fractures

• Atypical low-energy or low-trauma femoral shaft fractures reported; many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs
• Femoral fractures: During treatment, patients should be advised to report new or unusual thigh, hip, or groin pain; any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture
• Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb; interruption of therapy should be considered based on benefit-risk assessment

Osteonecrosis of the jaw

• ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing and has been reported in patients receiving romosozumab
• Perform routine oral examination before initiating treatment; concomitant administration of drugs associated with ONJ (chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, and corticosteroids) may increase ONJ risk
• Other risk factors include cancer, radiotherapy, poor oral hygiene, preexisting dental disease or infection, anemia, and coagulopathy
• For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan
• Discontinuation should be considered based on benefit-risk assessment

Pregnancy

Not indicated for use in women of reproductive potential

In animal reproduction studies, weekly administration to pregnant rats during the period of organogenesis at exposures >32 times the clinical exposure produced skeletal abnormalities in the offspring

Administration to rats prior to mating and through to the end of lactation produced minimal-to-slight decreases in femoral bone mineral density and/or cortical circumferences in the offspring at 1.5-56 times the expected exposure in humans

Lactation

Not indicated for use in women of reproductive potential

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 (IgG2) that binds sclerostin, a regulatory factor in bone metabolism

Sclerostin inhibition increases bone formation and, to a lesser extent, decreases bone resorption

Animal studies showed that romosozumab stimulates new bone formation on trabecular and cortical bone surfaces by stimulating osteoblastic activity, resulting in increases in trabecular and cortical bone mass and improvements in bone structure and strength

Absorption

Peak plasma time: 5 days

Peak plasma concentration: 22.2 mcg/mL

AUC: 389 mcg·day/mL

Steady-state achieved by 3 months following monthly injections

Development of antibodies to romosozumab led to decreased mean concentrations up to 22%

Distribution

Vd: ~3.92 L

Metabolism

Not characterized; IgG2 expected to be degraded into small peptides and amino acids via catabolic pathways similar to endogenous IgG

Elimination

Half-life: 12.8 days

Clearance: 0.38 mL/hr/kg

SC Preparation

Remove 2 syringes from carton and visually inspect for particles and discoloration; solution should appear clear to opalescent, colorless to light yellow

Do not use if solution is cloudy, discolored, or contains particles

Do not use if syringe is cracked or broken, gray needle cap is missing or not securely attached, or passed the expiration date

Always hold syringe by the barrel to remove from the tray; do not grasp by plunger rod or gray needle cap

Do not remove gray needle cap until ready to inject

Allow to sit at room temperature for at least 30 minutes before injecting; do not warm in any other way

Clean injection site with alcohol wipes; let skin dry

Choose different injection site for each injection; if same injection location, do not inject near previous injection site

Do not inject in areas where skin is tender, bruised, red, or hard; avoid scars or stretch marks

SC Administration

Administered SC once monthly by healthcare professional

Total dose of 210 mg SC requires 2 separate 105-mg prefilled syringes (and 2 separate SC injections)

Inject two 105-mg prefilled syringes, one after the other, in abdomen (except for 2-inch area around navel), thigh, or outer area of upper arm

Missed dose: Administer as soon as possible; thereafter, schedule doses once monthly from the date of the last dose

Storage

Refrigerate at 2-8°C (36-46°F) in the original carton to protect from light

Do not freeze

Do not shake

If removed from refrigerator, can be kept at room temperature up to 25°C (77°F) in original carton and must be used within 30 days; if not used within 30 days, discard

Do not expose to temperatures >25°C (77°F)