Romosozumab

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Evenity: Romosozumab-aqqg 105 mg per 1.17 mL (1.17 mL)

Pharmacology

Mechanism of Action

Romosozumab inhibits sclerostin, a regulatory factor in bone metabolism that inhibits Wnt/Beta-catenin signaling pathway regulating bone growth (MacDonald 2009; McClung 2018); romosozumab increases bone formation and to a lesser extent, decreases bone resorption.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: ~3.92 L

Metabolism

Has not been characterized; expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG

Onset of Action

Peak increase in bone formation marker procollagen type 1 N-telopeptide (P1NP) and peak decrease in bone resorption marker type 1 collagen C-telopeptide (CTX) observed 2 weeks after initiation. Increased histomorphometric indices of bone formation observed 2 months after therapy initiation.

Time to Peak

Median: 5 days (range: 2 to 7 days)

Duration of Action

CTX decrease persists throughout 12 months of therapy; P1NP returns to baseline by 9 months and declines at 12 months; anabolic effect wanes after 12 months of treatment. After discontinuation of therapy, an increase in CTX above baseline value occurs within 3 months. CTX, P1NP, and bone mineral density (BMD) return to baseline within ~12 months of discontinuing therapy.

Half-Life Elimination

12.8 days after 3 doses over 12-week period (ie, 1 dose every 4 weeks)

Use in Specific Populations

Special Populations Note

Weight: The exposure of romosozumab decreases with increasing body weight.

Use: Labeled Indications

Osteoporosis: Treatment of osteoporosis in postmenopausal females at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture), or patients who have failed or are intolerant to other available osteoporosis therapy.

Limitations of use: The anabolic effect of romosozumab wanes after 12 monthly doses of therapy. Therefore, the duration of romosozumab use should be limited to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered.

Contraindications

Hypersensitivity (eg, angioedema, erythema multiforme, urticaria) to romosozumab or any component of the formulation; uncorrected hypocalcemia

Dosage and Administration

Dosing: Adult

Note: Correct hypocalcemia prior to initiation of therapy. Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.

Osteoporosis (postmenopausal females): SubQ: Two consecutive injections (105 mg each) for a total dose of 210 mg once monthly.

Discontinuation/interruption of therapy: Bone mineral density (BMD) returns to baseline within 12 months following discontinuation. Type 1-collagen C telopeptide (a bone resorption marker) temporarily increases above baseline levels within 3 months of discontinuation, then returns to baseline within ~12 months. If continued osteoporosis therapy is necessary following discontinuation of romosozumab, consider initiation of antiresorptive therapy (eg, bisphosphonate or denosumab) (Cosman 2016; Saag 2017; manufacturer’s labeling).

Duration of therapy: 12 months.

Missed dose: If a dose is missed, administer as soon as it can be rescheduled; subsequent doses should be scheduled every month from the date of last dose.

Dosing: Geriatric

Refer to adult dosing.

Administration

SubQ: Each monthly dose consists of 2 consecutive SubQ injections.

Remove 2 syringes from carton and allow to sit at room temperature for at least 30 minutes before administration. Administer into the abdomen, thigh, or outer area of upper arm; should only be administered by a health care professional. Rotate injection sites; if the same injection site is chosen, do not inject into the same spot used for the first injection. Avoid areas of skin that are tender, bruised, red, hard, scarred, or with stretch marks. Solution in syringe should appear clear to opalescent, colorless to light yellow; do not use if cloudy, discolored, or contains particulate matter.

Dietary Considerations

Osteoporosis prevention or treatment: Ensure adequate calcium and vitamin D intake; if dietary intake is inadequate, dietary supplementation is recommended. Females and males should consume:

Calcium: 1,000 mg/day (males: 50 to 70 years of age) or 1,200 mg/day (females ≥51 years of age and males ≥71 years of age) (IOM 2011; NOF [Cosman 2014]).

Vitamin D: 800 to 1,000 units daily (males and females ≥50 years of age) (NOF [Cosman 2014]). Recommended Dietary Allowance (RDA): 600 units daily (males and females ≤70 years of age) or 800 units daily (males and females ≥71 years of age) (IOM 2011).

Storage

Refrigerate at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. Upon removal from the refrigerator, may store at room temperature up to 25°C (77°F) in the original carton for up to 30 days. If not used within 30 days, discard. Do not expose to temperatures >25°C (77°F).

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>10%: Neuromuscular & skeletal: Arthralgia (8% to 13%)

1% to 10%:

Cardiovascular: Cardiac disorder (2%), peripheral edema (2%)

Central nervous system: Headache (5% to 7%), insomnia (2%), paresthesia (1%)

Dermatologic: Skin rash (1%)

Hypersensitivity: Hypersensitivity reaction (7%)

Local: Injection site reaction (5%), pain at injection site (2%), erythema at injection site (1%)

Neuromuscular & skeletal: Muscle spasm (3% to 5%), asthenia (3%), neck pain (2%)

<1%, postmarketing, and/or case reports: Acute myocardial infarction, angioedema, cerebrovascular accident, dermatitis, erythema multiforme, femur fracture, hypocalcemia, osteonecrosis of the jaw, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Bone fractures: Atypical femur fractures have been reported in patients receiving romosozumab. The fractures may occur anywhere along the femoral shaft (may be bilateral) and commonly occur with minimal to no trauma to the area. Some patients experience prodromal pain weeks or months before the fracture occurs. New or unusual thigh, hip, or groin pain should be reported to health care provider; any patient with thigh or groin pain should be suspected of having an atypical femur fracture and should be evaluated to rule out an incomplete femur fracture. If an atypical fracture is present, assess for signs/symptoms of fracture in contralateral limb. Consider interruption of therapy based on benefits/risks.
• Cardiovascular events: [US Boxed Warning]: Romosozumab may increase the risk of MI, stroke, and cardiovascular death and should not be initiated in patients who have had an MI or stroke within the previous year. Consider benefits/risks of therapy in patients with other cardiovascular risk factors. Discontinue use if MI or stroke occurs during therapy.
• Hypocalcemia: Hypocalcemia may occur. Correct hypocalcemia prior to initiation of therapy (contraindicated in patients with uncorrected hypocalcemia). Ensure adequate supplementation with calcium and vitamin D during therapy and monitor calcium levels closely, particularly in patients predisposed to hypocalcemia (eg, severe renal impairment and/or receiving dialysis).
• Hypersensitivity: Hypersensitivity reactions (eg, angioedema, erythema multiforme, urticaria, rash, dermatitis) have occurred; discontinue use for serious reactions (eg, anaphylaxis) and treat appropriately.
• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving romosozumab. Known risk factors for MRONJ include tooth extraction or other invasive dental procedures, cancer diagnosis, radiotherapy, concomitant therapy (eg, angiogenesis inhibitors, bisphosphonates, chemotherapy, corticosteroids, denosumab), poor oral hygiene, and comorbid disorders (anemia, coagulopathy, infection, preexisting dental or periodontal disease). Routine oral exam is recommended prior to initiation of therapy; patients should maintain good oral hygiene during treatment. Consider risk/benefits of therapy in patients requiring invasive dental procedures. Patients developing ONJ during therapy should receive care by an oral surgeon or dentist; consider discontinuation of therapy based on risk/benefit assessment.

Monitoring Parameters

Signs/symptoms of hypersensitivity; signs/symptoms of adverse cardiovascular events; serum calcium.

Bone mineral density (clinical trials assessed at baseline and then at 6 or 12 months [Cosman 2016; Saag 2017]); may consider monitoring biochemical markers of bone turnover (eg, fasting serum CTX, serum P1NP) at baseline, 3 months, and 6 months to assess treatment response (Cosman 2016; ES [Eastell 2019]; Saag 2017).

Pregnancy

Pregnancy Considerations

Romosozumab is a humanized monoclonal antibody (IgG₂). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Romosozumab is not indicated for use in females of reproductive potential.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience joint pain or headache. Have patient report immediately to prescriber signs of a heart attack (chest pain; pain in arms, back, neck, jaw, or abdomen; shortness of breath; cold sweats; severe dizziness; passing out; or severe nausea or vomiting); signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes); signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures); groin, hip, or thigh pain; jaw edema; or jaw pain (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.