Romosozumab is not indicated for use in women of reproductive potential. In animal reproduction studies, weekly administration of romosozumab-aqqg to pregnant rats during the period of organogenesis at exposures greater than 31 times the clinical exposure produced skeletal abnormalities in the offspring. Administration of romosozumab-aqqg 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 1.4 to 54 times the expected exposure in humans [see Data].
Reproductive and developmental effects of romosozumab-aqqg were assessed in the rat in a preliminary and definitive embryo-fetal development study, a combined fertility and embryo-development study, and a pre- and postnatal development study.
Skeletal malformations including syndactyly and polydactyly occurred in 1 out of 75 litters across all rat reproductive toxicity studies, in the litter of a dam given weekly subcutaneous romosozumab-aqqg doses of 300 mg/kg (equivalent to at least 31 times the clinical exposure observed in humans following a monthly subcutaneous dose of 210 mg, based on area under the concentration-time curve [AUC] comparison).
In the offspring of female rats given weekly romosozumab-aqqg doses from 6 weeks before cohabitation through mating and lactation, femoral periosteal and endocortical circumferences were slightly decreased at 10, 60, and 300 mg/kg (equivalent to 1.4, 18, and 54 times the clinical exposure following a monthly subcutaneous dose of 210 mg, based on AUC comparison). Cortical thickness was increased at 300 mg/kg (equivalent to 54 times expected clinical exposure). Femoral metaphyseal bone mineral density was slightly decreased at 60 and 300 mg/kg (equivalent to 18 and 54 times expected clinical exposure).
Romosozumab is not indicated for use in women of reproductive potential. In animal studies where pregnant rats were given weekly doses of romosozumab-aqqg from 6 weeks before cohabitation through mating and lactation at 10, 60, or 300 mg/kg (equivalent to 1.4, 18 or 54 times the clinical exposure following a monthly subcutaneous dose of 210 mg, based on AUC comparison), romosozumab-aqqg was dose-dependently present in the serum of offspring on postnatal day 21 at 0.01 to 2.4 times maternal exposure due to gestational and/or lactational exposure.
In a rat carcinogenicity study, once-weekly romosozumab-aqqg doses of 3, 10 or 50 mg/kg were administered by subcutaneous injection to Sprague-Dawley rats from 8 weeks up to 98 weeks of age, resulting in systemic exposures that were up to 19 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison). Romosozumab-aqqg caused a dose-dependent increase in bone mass with trabecular and cortical bone thickening at all doses. There were no effects of romosozumab-aqqg on mortality and romosozumab-aqqg did not cause significant increases in tumor incidence in male or female rats.
Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.
No effects on fertility were observed in male and female rats given subcutaneous romosozumab-aqqg doses up to 300 mg/kg (up to 54 times the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab, based on AUC comparison). No effects were noted in reproductive organs in rats and cynomolgus monkeys dosed subcutaneously for 6 months with weekly doses up to 100 mg/kg (exposures up to 37 and 90 times, respectively, the systemic exposure observed in humans administered monthly subcutaneous doses of 210 mg based on AUC comparison).
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of romosozumab for the treatment of postmenopausal osteoporosis was evaluated in a multicenter, randomized, double-blind, placebo-controlled study (Study 1, NCT01575834) of 7180 postmenopausal women aged 55 to 90 years (mean age of 71 years). A total of 3581 and 3576 women received at least one dose of romosozumab and placebo, respectively, administered once every month during the 12-month double-blind study period. Women received at least 500 mg calcium and 600 international units of vitamin D supplementation daily and 77% received a loading dose of 50,000 to 60,000 international units of vitamin D within one week of randomization (if serum 25-hydroxyvitamin D concentrations were 40 ng/mL or less).
The safety of romosozumab for the treatment of postmenopausal osteoporosis in patients at high risk of fracture was evaluated in a multicenter, randomized, double-blind, alendronate-controlled study (Study 2, NCT01631214) of 4093 postmenopausal women aged 55 to 90 years (mean age of 74 years). A total of 2040 and 2014 women received at least one dose of romosozumab and alendronate, respectively, during the 12-month double-blind study period. Women received at least 500 mg calcium and 600 international units vitamin D supplementation daily and 74% received a loading dose of 50,000 to 60,000 international units of vitamin D within one week of randomization (if serum 25-hydroxyvitamin D concentrations were 40 ng/mL or less).
In Study 1, during the 12-month double-blind treatment period, the incidence of all-cause mortality was 0.7% (24/3576) in the placebo group and 0.8% (29/3581) in the romosozumab group. The incidence of nonfatal serious adverse events was 8.3% in the placebo group and 9.1% in the romosozumab group. The percentage of patients who withdrew from the study due to adverse events was 1.1% in the placebo group and 1.1% in the romosozumab group. The most common adverse reactions reported with romosozumab (greater than or equal to 5% and at a higher incidence than placebo) were arthralgia and headache. The most common adverse reaction leading to discontinuation of romosozumab was arthralgia (6 subjects [0.2%] in the placebo group and 5 subjects [0.1%] in the romosozumab group).
In Study 2, during the 12-month double-blind treatment period, the incidence of all-cause mortality was 1.1% (22/2014) in the alendronate group and 1.5% (30/2040) in the romosozumab group. The incidence of nonfatal serious adverse events was 13.3% in the alendronate group and 11.9% in the romosozumab group. The percentage of patients who withdrew from the study due to adverse events was 1.2% in the alendronate group and 1.2% in the romosozumab group. The most common adverse reactions reported with romosozumab (greater than or equal to 5%) were arthralgia and headache.
Table 1 outlines the most common adverse reactions occurring in greater than or equal to 2% of romosozumab treated women in at least one study.
Table 1. Adverse Reactions Occurring in ≥2% of Romosozumab-Treated Women in at Least One Study (Studies 1 and 2):
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| Preferred Term | Placebo (N=3576) n (%) | Romosozumab (N=3581) n (%) | Alendronate (N=2014) n (%) | Romosozumab (N=2040) n (%) |
| Arthralgia | 434 (12.1) | 468 (13.1) | 194 (9.6) | 166 (8.1) |
| Headache | 208 (5.8) | 235 (6.6) | 110 (5.5) | 106 (5.2) |
| Muscle spasms | 140 (3.9) | 163 (4.6) | 81 (4.0) | 70 (3.4) |
| Edema peripheral | 67 (1.9) | 86 (2.4) | 38 (1.9) | 34 (1.7) |
| Asthenia | 79 (2.2) | 84 (2.3) | 53 (2.6) | 50 (2.5) |
| Neck pain | 54 (1.5) | 80 (2.2) | 42 (2.1) | 34 (1.7) |
| Insomnia | 68 (1.9) | 72 (2.0) | 36 (1.8) | 34 (1.7) |
| Paresthesia | 62 (1.7) | 72 (2.0) | 34 (1.7) | 29 (1.4) |
The adverse reactions described below are from the 12-month treatment periods of Study 1 (placebo-controlled) and Study 2 (alendronate-controlled).
During the 12-month double-blind treatment period of the placebo-controlled trial (Study 1), myocardial infarction occurred in 9 (0.3%) women in the romosozumab group and 8 (0.2%) women in the placebo group; stroke occurred in 8 (0.2%) women in the romosozumab group and 10 (0.3%) women in the placebo group. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 (0.5%) women in the romosozumab group and 15 (0.4%) women in the placebo group. The number of women with positively adjudicated MACE was 30 (0.8%) in the romosozumab group and 29 (0.8%) in the placebo group, yielding a hazard ratio of 1.03 (95% confidence interval [0.62, 1.72]) for romosozumab compared to placebo.
During the 12-month double-blind treatment period of the active-controlled trial (Study 2), myocardial infarction occurred in 16 (0.8%) women in the romosozumab group and 5 (0.2%) women in the alendronate group; stroke occurred in 13 (0.6%) women in the romosozumab group and 7 (0.3%) women in the alendronate group. These events occurred in patients with and without a history of myocardial infarction or stroke. Cardiovascular death occurred in 17 (0.8%) women in the romosozumab group and 12 (0.6%) women in the alendronate group. The number of women with positively adjudicated MACE was 41 (2.0%) in the romosozumab group and 22 (1.1%) in the alendronate group, yielding a hazard ratio of 1.87 (95% confidence interval [1.11, 3.14]) for romosozumab compared to alendronate.
Across both trials, hypersensitivity reactions were reported in 364 (6.5%) women in the romosozumab group and 365 (6.5%) women in the control group. Reported reactions included angioedema (3 [<0.1%] women in the romosozumab group vs. 3 [<0.1%] women in the control group), erythema multiforme (1 [<0.1%] woman in the romosozumab group vs. no woman in the control group), dermatitis (32 [0.6%] women in the romosozumab group vs. 42 [0.8%] women in the control group), rash (60 [1.1%] women in the romosozumab group vs. 53 [0.9%] women in the control group), and urticaria (23 [0.4%] women in the romosozumab group vs. 27 [0.5%] women in the control group). Although angioedema, dermatitis and urticaria were not reported at a higher incidence with romosozumab than control, there were cases of angioedema, dermatitis and urticaria that were determined to be related to romosozumab use.
Across both trials, adverse events of hypocalcemia occurred in 2 romosozumab-treated women and in 1 woman in the control group. 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 in the romosozumab group and 10 (0.2%) women in the control group. No patient receiving romosozumab developed serum calcium 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.
Across both trials, injection site reactions occurred in 278 (4.9%) women in the romosozumab group and 157 (2.8%) women in the control group. The most common injection site reactions were pain (94 [1.7%] women in the romosozumab group; 70 [1.3%] women in the control group) and erythema (80 [1.4%] women in the romosozumab group and 14 [0.3%] women in the control group). Injection site reactions resulted in discontinuation of treatment in 7 (0.1%) romosozumab-treated patients and 3 (<0.1%) patients in the control group.
Across both trials, osteonecrosis of the jaw occurred in one patient during treatment with romosozumab.
Across both trials, atypical femoral fracture occurred in one patient during treatment with romosozumab.
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other romosozumab products may be misleading.
The immunogenicity of romosozumab was evaluated using an immunoassay for the detection of anti-romosozumab-aqqg antibodies. An in vitro biological assay was performed to detect neutralizing antibodies for those subjects whose sera tested positive for anti-romosozumab-aqqg antibodies.
Among 5914 postmenopausal women treated with romosozumab 210 mg monthly, 18.1% of subjects developed antibodies to romosozumab-aqqg. Of the subjects who developed antibodies to romosozumab-aqqg, 4.7% had antibodies that were classified as neutralizing. Development of antibodies to romosozumab-aqqg was associated with lower serum romosozumab-aqqg concentrations. Antibodies to romosozumab-aqqg were generally not associated with changes in the efficacy or safety of romosozumab.
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