Romosozumab is a parenteral humanized IgG2 monoclonal antibody and sclerostin inhibitor. Romosozumab has a dual effect of increasing bone formation and, to a lesser extent, decreasing bone resorption. The drug is indicated for the treatment of osteoporosis in postmenopausal women at high risk for fracture or who have failed or are intolerant to other available osteoporosis therapy. Guidelines also generally limit the use of agents such as romosozumab for postmenopausal women with a previous history of fractures, a high risk of fractures, or intolerance to or failure of other osteoporosis therapy. In a randomized, double-blind, active-control trial of postmenopausal women (55 to 90 years), patients who received romosozumab for 12 months followed by alendronate had a significantly reduced risk of clinical fracture (composite endpoint of nonvertebral fracture and symptomatic vertebral fracture), compared to alendronate alone over a median follow-up duration of 33 months (9.7% romosozumab group vs. 13% alendronate alone). Romosozumab treatment followed by alendronate also resulted in a significantly reduced incidence of new vertebral fracture at 24 months (4.1% romosozumab group vs. 8% alendronate alone). A higher incidence of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, occurred in patients treated with romosozumab compared to those treated with alendronate during clinical trials. Romosozumab is not to be started in patients who have had a myocardial infarction or stroke within the preceding year. The anabolic effect of romosozumab decreases after 12 months of treatment; therefore, the treatment duration is limited to 12 doses. An anti-resorptive agent may be considered after completion of romosozumab therapy if osteoporosis treatment remains warranted.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Romosozumab is a clear to opalescent, colorless to light yellow solution.
-Romosozumab should be administered by a health care provider.
-Limit the duration of treatment to 12 doses. The anabolic effect of romosozumab decreases after 12 monthly doses. Consider therapy with an anti-resorptive agent if osteoporosis treatment remains warranted.
-Ensure adequate intake of calcium and vitamin D to reduce the risk of treatment-related hypocalcemia. Supplement with adequate calcium and vitamin D during treatment.
-Missed dose: If a dose is missed, administer it as soon as it can be rescheduled. Thereafter, schedule doses every month from the date of the last dose.
Subcutaneous Administration
-Allow the product to warm at room temperature for a minimum of 30 minutes before injecting. Do not warm in any other way.
-Prepare 2 injection sites. Recommended injection sites include the thigh, abdomen, or outer area of the upper arm. Rotate injection sites with each dose. If using the same injection site, ensure that it is not the same spot on the injection site used for a previous injection.
-Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.
-Use 2 separate syringes and 2 separate injections to administer the full romosozumab dose.
-Pull gray cap straight off needle.
-Inject subcutaneously.
-When done, gently lift syringe off skin.
-Repeat all steps with the second syringe to inject the full dose.
-Use caution during injection to avoid accidental needlestick injuries. The syringe needles do not have safety guards, and the needles are not removable.
Atypical low-energy or low trauma bone fractures of the femoral shaft have been reported in patients receiving romosozumab. Across 2 clinical trials including over 5,000 romosozumab-treated patients, one patient experienced an atypical femoral fracture. These fractures typically occur with minimal or no trauma to the affected area, and they may be bilateral. Fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Prodromal pain in the affected area, usually presenting as a dull, aching thigh pain, has been reported by patients weeks to months before a complete fracture occurs. Direct causality of these fractures has not been established, as these fractures also occur in osteoporotic patients who have not received romosozumab. Advise patients to report any new or unusual thigh, hip, or groin pain. Suspect an atypical fracture and perform an evaluation to rule out an incomplete femur fracture in any patient who presents with thigh or groin pain. Assess patients presenting with an atypical femur fracture for signs and symptoms of a fracture in the contralateral limb. Consider interruption of romosozumab therapy based on benefit-risk assessment.
Arthralgia was among the most frequent adverse reactions reported with romosozumab during 2, 12-month controlled clinical trials. In a placebo-controlled trial in postmenopausal women with osteoporosis, 468 (13.1%) of 3,581 patients who received at least 1 dose of romosozumab experienced arthralgia, compared to 434 (12.1%) of 3,576 patients who received placebo. Arthralgia occurred in 166 (8.1%) of 2,040 postmenopausal women at high risk of fracture who received at least 1 dose of romosozumab compared to 194 (9.6%) of 2,014 women who received alendronate. Arthralgia was the most common adverse reaction leading to romosozumab discontinuation during the placebo-controlled trial (5 subjects (0.1%) in the romosozumab group compared to 6 subjects (0.2%) in the placebo group). During the 12-month treatment periods of each trial, muscle spasms occurred in 3.4% to 4.6% of romosozumab-treated patients compared to 3.9% of placebo-treated patients and 4% of alendronate-treated patients. Neck pain occurred in 1.7% to 2.2% of romosozumab-treated patients compared to 1.5% of placebo-treated patients and 2.1% of alendronate-treated patients.
Headache was among the most frequent adverse reactions reported with romosozumab during 2, 12-month controlled clinical trials. In a placebo-controlled trial in postmenopausal women with osteoporosis, 235 (6.6%) of 3,581 patients who received at least 1 dose of romosozumab experienced headache, compared to 208 (5.8%) of 3,576 patients who received placebo. Headache occurred in 106 (5.2%) of 2,040 postmenopausal women at high risk of fracture who received at least 1 dose of romosozumab compared to 110 (5.5%) of 2,014 women who received alendronate. During the 12-month treatment periods of each trial, insomnia occurred in 1.7% to 2% of romosozumab-treated patients compared to 1.9% of placebo-treated patients and 1.8% of alendronate-treated patients. Paresthesias occurred in 1.4% to 2% of romosozumab-treated patients compared to 1.7% of placebo-treated patients and 1.7% of alendronate-treated patients.
Peripheral edema was reported with romosozumab therapy during 2, 12-month controlled clinical trials. In a placebo-controlled trial in postmenopausal women with osteoporosis, 86 (2.4%) of 3,581 patients who received at least 1 dose of romosozumab experienced peripheral edema, compared to 67 (1.9%) of 3,576 patients who received placebo. Peripheral edema occurred in 34 (1.7%) of 2,040 postmenopausal women at high risk of fracture who received at least 1 dose of romosozumab compared to 38 (1.9%) of 2,014 patients who received alendronate. During the 12-month treatment periods of each trial, asthenia occurred in 2.3% to 2.5% of romosozumab-treated patients compared to 2.2% of placebo-treated patients and 2.6% of alendronate-treated patients.
A higher incidence of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, occurred in patients treated with romosozumab compared to those treated with alendronate during clinical trials. During an alendronate-controlled trial in postmenopausal women at high risk of fracture, 16 (0.8%) patients who received romosozumab experienced myocardial infarction (MI), compared to 5 (0.2%) patients who received alendronate. Stroke occurred in 13 (0.6%) romosozumab-treated patients vs. 7 (0.3%) alendronate-treated patients. Cardiovascular death occurred in 17 (0.8%) women who received romosozumab vs. 12 (0.6%) women who received alendronate. The number of women with positively adjudicated MACE was 41 (2%) in romosozumab-treated patients and 22 (1.1%) in alendronate-treated patients yielding a hazard ratio (HR) of 1.87 (95% CI, 1.11 to 3.14) for romosozumab compared to alendronate. In a placebo-controlled trial in postmenopausal women with osteoporosis, 9 (0.3%) patients who received romosozumab experienced MI, compared to 8 (0.2%) patients who received placebo. Stroke occurred in 8 (0.2%) of romosozumab-treated patients and 10 (0.3%) of placebo-treated patients. Cardiovascular death occurred in 17 (0.5%) women who received romosozumab vs. 15 (0.4%) women who received placebo. The number of women with positively adjudicated MACE was 30 (0.8%) in romosozumab-treated patients and 29 (0.8%) in placebo-treated patients yielding a HR of 1.03 (95% CI 0.62 to 1.72) for romosozumab compared to placebo. MACE occurred in patients with and without a history of MI or stroke. Do not begin treatment with romosozumab in patients who have had a MI or stroke within the preceding year. Consider the risk-benefit ratio in patients with other cardiovascular risk factors. Monitor for signs and symptoms of myocardial infarction and stroke, and instruct patients to seek prompt medical care if symptoms of MI or stroke occur. If a patient experiences a stroke or MI during treatment, discontinue romosozumab.
Across 2 clinical trials, hypersensitivity reactions occurred in 364 (6.5%) of women who received romosozumab and 365 (6.5%) of women in control groups (placebo or alendronate). Reactions included angioedema (3 women treated with romosozumab and 3 women treated with controls [less than 0.1% both groups]), erythema multiforme (1 [less than 0.1%] woman in romosozumab group vs. no woman in control groups), dermatitis (32 [0.6%] women in romosozumab group vs. 42 [0.8%] women in control groups), rash (60 [1.1%] women in romosozumab group vs. 53 [0.9%] women in control groups), and urticaria (23 [0.4%] women in romosozumab group vs. 27 [0.5%] women in control groups). Cases of angioedema, dermatitis, and urticaria were determined to be directly related to romosozumab, although they were not reported at a higher incidence than controls. If an anaphylactic or other clinically significant allergic reaction occurs, discontinue romosozumab and treat as clinically indicated.
Across 2 clinical trials, osteonecrosis of the jaw (ONJ) occurred in one woman who received romosozumab. ONJ is generally associated with tooth extraction and/or local infection with delayed healing; however, it may occur spontaneously. Perform a routine oral exam before starting romosozumab. For patients requiring invasive dental work, use clinical judgment to guide the management of each patient based on benefit-risk assessment. Refer patients who develop or are suspected of having ONJ to a dentist or oral surgeon for care. Dental surgery to treat ONJ may exacerbate the condition. Consider romosozumab discontinuation based on benefit-risk assessment.
Across 2 clinical trials, hypocalcemia occurred in 2 women who received romosozumab and 1 woman who received a control (placebo or alendronate). Decreases in albumin-adjusted serum calcium to below the lower limit of the reference range (8.3 mg/dL) were reported in 14 (0.2%) women treated with romosozumab and 10 (0.2%) women who received controls. No patient receiving romosozumab developed a serum calcium concentration less than 7.5 mg/dL. The nadir in albumin-adjusted serum calcium occurred by month 1 after romosozumab dosing in patients with normal renal function. Correct hypocalcemia before initiating romosozumab therapy. Monitor serum calcium concentrations in patients who have renal impairment or are receiving dialysis. Educate patients with severe renal impairment or renal failure about hypocalcemia symptoms and the importance of maintaining calcium concentrations with adequate calcium and vitamin D supplementation.
Across 2 clinical trials, an injection site reaction occurred in 278 (4.9%) women who received romosozumab and 157 (2.8%) women who received a control (placebo or alendronate). The most common injection site reactions were pain (94 [1.7%] romosozumab group; 70 [1.3%] control groups) and erythema (80 [1.4%] romosozumab group; 14 [0.3%] control groups). Injection site reactions resulted in discontinuation in 7 (0.1%) patients treated with romosozumab and 3 (less than 0.1%) patients in control groups.
As with all therapeutic proteins, there is the potential for immunogenicity and antibody formation with romosozumab treatment. Among 5,914 postmenopausal women treated with romosozumab 210 mg monthly, 18.1% developed antibodies to romosozumab. Neutralizing antibodies were identified in 4.7% of those who developed antibodies to romosozumab. Lower serum romosozumab concentrations occurred in patients with antibodies to romosozumab. Antibodies to romosozumab were generally not associated with changes in the safety and efficacy of romosozumab.
Romosozumab is contraindicated in patients with a history of systemic hypersensitivity to romosozumab or any component of the formulation. If an anaphylactic or other clinically significant allergic reaction occurs, discontinue romosozumab and treat as clinically indicated. Angioedema, erythema multiforme, dermatitis, rash, and urticaria have been reported with romosozumab use.
Do not begin treatment with romosozumab in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits of romosozumab therapy outweigh the risks in patients with other cardiovascular risk factors. Monitor for signs and symptoms of myocardial infarction and stroke, and instruct patients to seek prompt medical care if symptoms occur. If a patient experiences a myocardial infarction or stroke during treatment, discontinue romosozumab. A higher incidence of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, occurred in patients treated with romosozumab vs. those treated with alendronate during clinical trials.
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving romosozumab. It is generally associated with tooth extraction and/or local infection with delayed healing; however, it may occur spontaneously. Perform a routine oral exam before starting romosozumab. Risk factors for ONJ include anemia, cancer, radiation therapy, coagulopathy, preexisting dental disease or infection, and poor oral hygiene. Concomitant use of other drugs associated with ONJ, including chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, and corticosteroid therapy, may increase the risk of developing ONJ. For patients requiring invasive dental work, use clinical judgment to guide the management of each patient based on benefit-risk assessment. Refer patients who develop or are suspected of having ONJ to a dentist or oral surgeon for care. Dental surgery to treat ONJ may exacerbate the condition. Consider romosozumab discontinuation based on benefit-risk assessment. For antiresorptive therapy, which may follow romosozumab treatment, preventive measures and continued regular follow-up with a dentist are recommended to minimize the risk of osteonecrosis.
Romosozumab is contraindicated in patients with preexisting hypocalcemia. Correct hypocalcemia before initiating romosozumab therapy. Monitor all patients for signs and symptoms of hypocalcemia. Patients with severe renal impairment (eGFR less than 30 mL/minute/1.73 m2) or renal failure requiring dialysis were at greater risk for hypocalcemia during clinical trials. Clinical monitoring of calcium and mineral levels (phosphorus and magnesium) is highly recommended in these patients. In all patients, ensure adequate intake of calcium and vitamin D. Instruct patients to seek medical care if symptoms of hypocalcemia develop.
Romosozumab is not indicated for use in women of reproductive potential, including during pregnancy. During animal studies in pregnant rats, skeletal malformations including syndactyly and polydactyly occurred in 1 of 75 litters of a dam who received weekly subcutaneous doses of romosozumab equivalent to at least 32 times the clinical exposure observed in humans after a monthly subcutaneous dose of 210 mg based on AUC comparison. Femoral periosteal and endocortical circumferences were slightly decreased in the offspring of rats given romosozumab at weekly doses equivalent to 1.4, 18, or 54 times the clinical exposure after a monthly subcutaneous dose of 210 mg based on AUC comparison from 6 weeks before cohabitation through mating and lactation. Cortical thickness was increased at a dose 56 times the expected clinical exposure, and femoral metaphyseal bone mineral density was slightly decreased at doses equivalent to 18 to 54 times the expected clinical exposure.
Romosozumab is not indicated for use in women of reproductive potential, including during breast-feeding. In pregnant rats given romosozumab at weekly doses equivalent to 1.4, 18, or 54 times the clinical exposure after a monthly subcutaneous dose of 210 mg based on AUC comparison from 6 weeks before cohabitation through mating and lactation, romosozumab was dose-dependently present in offspring serum on postnatal day 21 at 0.01 to 2.4 times maternal exposure due to maternal and/or lactational exposure.
Recommendations for calcium and vitamin D intake:
-To promote general bone health, guidelines for the prevention and treatment of osteoporosis recommend a target daily intake of 1,200 mg of elemental calcium for females older than 50 years. Daily vitamin D intake of 25 to 25 mcg (800 to 1,000 international units) is recommended for patients 50 years of age and older.
For the treatment of osteoporosis in postmenopausal women at high risk for fracture:
Subcutaneous dosage:
Adult postmenopausal females: 210 mg subcutaneously once monthly for 12 months. Supplement calcium and vitamin D if dietary intake is inadequate. High fracture risk is defined as women with a history of osteoporotic fracture or multiple risk factors for fracture or those who have failed or are intolerant to other available osteoporosis therapy. Romosozumab may be considered for patients unable to use oral therapy and as initial therapy for those at very high fracture risk. Follow with a drug intended for long-term use, such as a bisphosphonate or denosumab, to prevent decline of bone density and loss of efficacy against fracture. Romosozumab is also a treatment option for patients previously treated with teriparatide or abaloparatide.
Maximum Dosage Limits:
-Adults
210 mg/month subcutaneously.
-Geriatric
210 mg/month subcutaneously.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Romosozumab products.
Romosozumab inhibits the action of sclerostin, a regulatory factor in bone metabolism, which leads to increased bone formation and, to a lesser extent, decreased bone resorption. Animal studies demonstrated that romosozumab increases trabecular and cortical bone mass and improves bone structure and strength through stimulation of new bone formation on trabecular and cortical bone surfaces by increasing osteoblastic activity.
Romosozumab is administered subcutaneously. Romosozumab exhibits nonlinear pharmacokinetics. The estimated volume of distribution at steady-state is approximately 3.92 L. Romosozumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. The clearance of romosozumab decreases as the dose increases. The estimated mean systemic clearance (CL/F) of romosozumab was 0.38 mL/hour/kg after a single subcutaneous dose of 3 mg/kg. The mean effective half-life was 12.8 days after 3 doses of 3 mg/kg every 4 weeks.
Affected cytochrome P450 isoenzymes and/or drug transporters: none
-Route-Specific Pharmacokinetics
Subcutaneous Route
After a single 210 mg dose in healthy volunteers, mean (standard deviation [SD]) romosozumab Cmax was 22.2 (5.8) mcg/mL and mean (SD) AUC was 389 (127) mcg x day/mL. Steady-state concentrations were achieved by month 3 after monthly administration of 210 mg to postmenopausal women. Mean trough romosozumab concentrations at months 3, 6, 9, and 12 ranged from 8 to 13 mcg/mL. Romosozumab exhibited nonlinear pharmacokinetics with exposure increasing greater than dose proportionally (e.g., 550-fold mean AUC increase for a 100-fold increase in the subcutaneous dose ranging from 0.1 to 10 mg/kg). Median Tmax is 5 days (range 2 to 7 days).
-Special Populations
Renal Impairment
No clinically significant differences in the pharmacokinetics of romosozumab were observed based on renal impairment, including end-stage renal disease requiring dialysis. The effect of end-stage renal disease not requiring dialysis on the pharmacokinetics of romosozumab is unknown.
Geriatric
No clinically significant differences in the pharmacokinetics of romosozumab were observed based on age.
Gender Differences
No clinically significant differences in the pharmacokinetics of romosozumab were observed based on gender.
Ethnic Differences
No clinically significant differences in the pharmacokinetics of romosozumab were observed based on race.
Obesity
Exposure of romosozumab decreases with increasing body weight.
Other
Alendronate Exposure
No clinically significant differences in the pharmacokinetics of romosozumab were observed based on prior exposure to alendronate.
Disease State
No clinically significant differences in the pharmacokinetics of romosozumab were observed based on low bone mass or osteoporosis.
Antibody Formation
Reduced serum romosozumab concentrations occurred in patients who developed anti-romosozumab antibodies. Mean romosozumab concentrations decreased up to 22% in the presence of anti-romosozumab antibodies. The presence of neutralizing antibodies led to decreased mean romosozumab concentrations of up to 63%.