Romosozumab

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# Black Box Warning

# Overview
Romosozumab is a sclerostin inhibitor that is FDA approved for the treatment of osteoporosis in postmenopausal women 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. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include arthralgia and headache.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
Indication
- Romosozumab is indicated for the treatment of osteoporosis in postmenopausal women 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.
Dosage
- Two separate syringes (and two separate subcutaneous injections) are needed to administer the total dose of 210 mg of romosozumab. Inject two 105 mg/1.17 mL prefilled syringes, one after the other.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding romosozumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness of romosozumab have not been established in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding romosozumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

### NonGuideline-Supported Use
There is limited information regarding romosozumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

# Contraindications
Romosozumab is contraindicated in patients with:
- Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with romosozumab.
- A history of systemic hypersensitivity to romosozumab or to any component of the product formulation. Reactions have included angioedema, erythema multiforme, and urticaria.

# Warnings
- In a randomized controlled trial in postmenopausal women, there was a higher rate of major adverse cardiac events (MACE), a composite endpoint of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, in patients treated with romosozumab compared to those treated with alendronate.
- Romosozumab should not be initiated in patients who have had a myocardial infarction or stroke within the preceding year. Consider whether the benefits 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 attention if symptoms occur. If a patient experiences a myocardial infarction or stroke during therapy, romosozumab should be discontinued.
- Hypersensitivity reactions, including angioedema, erythema multiforme, dermatitis, rash, and urticaria have occurred in romosozumab-treated patients. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of romosozumab.
- Hypocalcemia has occurred in patients receiving romosozumab. Correct hypocalcemia prior to initiating romosozumab.
- Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on romosozumab.
- Patients with severe renal impairment (estimated glomerular filtration rate  15 to 29 mL/min/1.73 m2) or receiving dialysis are at greater risk of developing hypocalcemia. Monitor serum calcium and adequately supplement patients who have severe renal impairment or are receiving dialysis with calcium and vitamin D. Instruct patients with severe renal impairment, including those receiving dialysis, about the symptoms of hypocalcemia and the importance of maintaining calcium levels with adequate calcium and vitamin D supplementation.
- 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. A routine oral examination should be performed by the prescriber prior to initiation of romosozumab treatment. Concomitant administration of drugs associated with ONJ (chemotherapy, bisphosphonates, denosumab, angiogenesis inhibitors, and corticosteroids) may increase the risk of developing ONJ. Other risk factors for ONJ include cancer, radiotherapy, poor oral hygiene, pre-existing 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 of each patient based on benefit-risk assessment. Patients who are suspected of having or who develop ONJ while on romosozumab should receive care by a dentist or an oral surgeon. In these patients, dental surgery to treat ONJ may exacerbate the condition. Discontinuation of romosozumab should be considered based on benefit-risk assessment.
- Atypical low-energy or low trauma fractures of the femoral shaft have been reported in patients receiving romosozumab. These 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. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated.
- Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs.
- During romosozumab 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 romosozumab therapy should be considered based on benefit-risk assessment.

# Adverse Reactions

## Clinical Trials Experience
- 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  in the placebo group and 5 subjects  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.
- The adverse reactions described below are from the 12-month treatment periods of Study 1 (placebo-controlled) and Study 2 (alendronate-controllmed).
Major Adverse Cardiac Events (MACE)
- During the 12-month double-blind treatment period of the placebo-controlled trial (Study 1), myocardial infarction occurred in 9 women (0.3%) in the romosozumab group and 8 (0.2%) women in the placebo group; stroke occurred in 8 women (0.2%) 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 women (0.5%) 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 ) 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 women (0.8%) in the romosozumab group and 5 (0.2%) women in the alendronate group; stroke occurred in 13 women (0.6%) 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 women (0.8%) 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 ) for romosozumab compared to alendronate.
Hypersensitivity Reactions
- 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 women  in the romosozumab group vs. 3  women in the control group), erythema multiforme (1 woman  in the romosozumab group vs. no woman in the control group), dermatitis (32 women  in the romosozumab group vs. 42 women  in the control group), rash (60 women  in the romosozumab group vs. 53 women  in the control group), and urticaria (23 women  in the romosozumab group vs. 27 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.
Hypocalcemia
- 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.
Injection Site Reactions
- 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  women in the romosozumab group; 70  in the control group) and erythema (80  women in the romosozumab group and 14  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.
Osteonecrosis of the Jaw
- Across both trials, osteonecrosis of the jaw occurred in one patient during treatment with romosozumab.
Atypical Subtrochanteric and Diaphysial Fractures
- Across both trials, atypical femoral fracture occurred in one patient during treatment with romosozumab.

## Immunogenicity
- 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.

## Postmarketing Experience
There is limited information regarding Romosozumab Postmarketing Experience in the drug label.

# Drug Interactions
There is limited information regarding Romosozumab Drug Interactions in the drug label.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 
Risk Summary
- 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 32 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 1.5 to 56 times the expected exposure in humans.
Animal 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 32 times the clinical exposure observed in humans following a monthly subcutaneous dose of 210 mg, based on area under the concentration-time curve  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 1.5, 19, and 56 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 56 times expected clinical exposure). Femoral metaphysical bone mineral density was slightly decreased at 60 and 300 mg/kg (equivalent to 19 and 56 times expected clinical exposure).
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Romosozumab in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Romosozumab during labor and delivery.

### Nursing Mothers
- 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 1.5, 19 or 56 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.

### Pediatric Use
- Safety and effectiveness of romosozumab have not been established in pediatric patients.

### Geriatic Use
- Of the 6544 postmenopausal women with osteoporosis in the clinical studies of romosozumab, 5234 (80%) were age 65 years and over and 2390 (37%) were age 75 years and over. No overall differences in safety or efficacy were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

### Gender
- Romosozumab is indicated for postmenopausal women.

### Race
There is no FDA guidance on the use of Romosozumab with respect to specific racial populations.

### Renal Impairment
- No dose adjustment is required in patients with renal impairment.
- Patients with severe renal impairment (estimated glomerular filtration rate  15 to 29 mL/min/1.73 m2 by MDRD equation) or receiving dialysis are at greater risk of developing hypocalcemia. Monitor calcium concentrations and adequately supplement calcium and vitamin D in patients who have severe renal impairment or are receiving dialysis.

### Hepatic Impairment
There is no FDA guidance on the use of Romosozumab in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Romosozumab in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Romosozumab in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Two separate syringes (and two separate subcutaneous injections) are needed to administer the total dose of 210 mg of romosozumab. Inject two 105 mg/1.17 mL prefilled syringes, one after the other.
- Romosozumab should be administered by a healthcare provider.
- The recommended dose of romosozumab is 210 mg administered subcutaneously in the abdomen, thigh or upper arm. Administer romosozumab once every month.
- The treatment duration for romosozumab is 12 monthly doses.
- Patients should be adequately supplemented with calcium and vitamin D during treatment with romosozumab.
- If the romosozumab dose is missed, administer as soon as it can be rescheduled. Thereafter, romosozumab can be scheduled every month from the date of the last dose.
Step 1. Prior to Administration:
- Remove two syringes from the carton.
- Visually inspect romosozumab for particles and discoloration prior to administration. Romosozumab is a clear to opalescent, colorless to light yellow solution. Do not use if the solution is cloudy or discolored or contains particles.
- Do not use the syringe if:
any part appears cracked or broken
the gray needle cap is missing or not securely attached
the expiration date printed on the label has passed
- any part appears cracked or broken
- the gray needle cap is missing or not securely attached
- the expiration date printed on the label has passed
- Always hold the prefilled syringe by the syringe barrel to remove the syringe from the tray. See Figure A.
Do not grasp the plunger rod.
Do not grasp the gray needle cap.
Do not remove the gray needle cap until you are ready to inject.
- Do not grasp the plunger rod.
- Do not grasp the gray needle cap.
- Do not remove the gray needle cap until you are ready to inject.
- Allow romosozumab to sit at room temperature for at least 30 minutes before injecting. Do not warm in any other way.
Step 2: Select the Injection Site and Prepare the Syringe
- Prepare and clean two injection sites, one for each of the two injections. See Figure B.
- The recommended subcutaneous injection sites include:
The thigh
Abdomen, except for a two-inch area right around the navel
Outer area of upper arm
- The thigh
- Abdomen, except for a two-inch area right around the navel
- Outer area of upper arm
- Clean the injection sites with alcohol wipes. Let the skin dry.
Choose a different site each time you give an injection. If you want to use the same injection site, make sure it is not the same spot on the injection site you 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.
- Choose a different site each time you give an injection. If you want to use the same injection site, make sure it is not the same spot on the injection site you 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.
- Choose the first syringe. Pull the gray needle cap straight off and away from your body when you are ready to inject. See Figure C.
- Do not put the gray needle cap back onto the syringe.
Step 3: Inject romosozumab
- Insert needle and inject all the liquid subcutaneously. Do not administer into muscle or blood vessel. See Figure D.
- When done, gently lift the syringe off of the skin.
Step 4: Syringe and Needle Cap Disposal
- Immediately dispose of the syringe and needle cap in the nearest sharps container.
Important: Repeat all steps with the second syringe to inject the full dose.

### Monitoring
- Monitor for signs and symptoms of myocardial infarction and stroke and instruct patients to seek prompt medical attention if symptoms occur.
- Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on romosozumab.
- Monitor calcium concentrations and adequately supplement calcium and vitamin D in patients who have severe renal impairment or are receiving dialysis.

# IV Compatibility
There is limited information regarding the compatibility of Romosozumab and IV administrations.

# Overdosage
There is limited information regarding Romosozumab overdosage.  If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

# Pharmacology

## Mechanism of Action
- Romosozumab inhibits the action of sclerostin, a regulatory factor in bone metabolism. Romosozumab increases bone formation and, to a lesser extent, decreases bone resorption. Animal studies showed that romosozumab-aqqg 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.

## Structure
There is limited information regarding Romosozumab Structure in the drug label.

## Pharmacodynamics
- In postmenopausal women with osteoporosis, romosozumab increased the bone formation marker procollagen type 1 N-telopeptide (P1NP) with a peak increase from baseline of approximately 145% compared to placebo 2 weeks after initiating treatment, followed by a return to concentrations seen with placebo at month 9 and a decline from baseline to approximately 15% below the concentration change seen with placebo at month 12.
- Romosozumab decreased the bone resorption marker type 1 collagen C-telopeptide (CTX) with a maximal reduction from baseline of approximately 55% compared to placebo 2 weeks after initiating treatment. CTX remained below concentrations seen with placebo and was approximately 25% below the concentration change seen with placebo at month 12.
- After discontinuation of romosozumab, P1NP levels returned to baseline within 12 months; CTX increased above baseline levels within 3 months and returned toward baseline levels by month 12.

## Pharmacokinetics
- Administration of a single dose of 210 mg romosozumab in healthy volunteers resulted in a mean (standard deviation ) maximum romosozumab-aqqg serum concentration (Cmax) of 22.2 (5.8) mcg/mL and a mean (SD) AUC of 389 (127) mcg*day/mL. Steady-state concentrations were achieved by month 3 following the monthly administration of 210 mg to postmenopausal women. The mean trough serum romosozumab-aqqg concentrations at months 3, 6, 9, and 12 ranged from 8 to 13 mcg/mL.
- Romosozumab-aqqg exhibited nonlinear pharmacokinetics with exposure increasing greater than dose proportionally (e.g., 550-fold increase in mean AUCinf for the 100-fold increase in subcutaneous doses ranging from 0.1 to 10 mg/kg [0.03 to 3.3 times the approved recommended dosage for a 70 kg woman).
Absorption
- The median time to maximum romosozumab-aqqg concentration (Tmax) is 5 days (range: 2 to 7 days).
Distribution
- The estimated volume of distribution at steady-state is approximately 3.92 L.
Elimination
- Romosozumab-aqqg exhibited nonlinear pharmacokinetics with the clearance of romosozumab-aqqg decreasing as the dose increased. The estimated mean systemic clearance (CL/F) of romosozumab-aqqg was 0.38 mL/hr/kg, following a single subcutaneous administration of 3 mg/kg (the approved recommended dosage for a 70 kg woman). The mean effective t1/2 was 12.8 days after 3 doses of 3 mg/kg (the approved recommended dosage for a 70 kg woman) every 4 weeks.
Metabolism
- The metabolic pathway of romosozumab-aqqg has not been characterized. As a humanized IgG2 monoclonal antibody, romosozumab-aqqg is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
Anti-Product Antibody Formation Affecting Pharmacokinetics
- Development of anti-romosozumab-aqqg antibodies was associated with reduced serum romosozumab-aqqg concentrations. The presence of anti-romosozumab-aqqg antibodies led to decreased mean romosozumab-aqqg concentrations up to 22%. The presence of neutralizing antibodies led to decreased mean romosozumab-aqqg concentrations up to 63%.
Specific Populations
- No clinically significant differences in the pharmacokinetics of romosozumab-aqqg were observed based on age (20-89 years), sex, race, disease state (low bone mass or osteoporosis), prior exposure to alendronate, or renal impairment including end-stage renal disease (ESRD) requiring dialysis. The effect of ESRD not requiring dialysis on the pharmacokinetics of romosozumab-aqqg is unknown.
Body Weight
- The exposure of romosozumab-aqqg decreases with increasing body weight.

## Nonclinical Toxicology
Carcinogenicity
- 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.
Mutagenicity
- Mutagenesis has not been evaluated, as monoclonal antibodies are not expected to alter DNA or chromosomes.
Impairment of Fertility
- No effects on fertility were observed in male and female rats given subcutaneous romosozumab-aqqg doses up to 300 mg/kg (up to 56 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 38 and 93 times, respectively, the systemic exposure observed in humans administered monthly subcutaneous doses of 210 mg based on AUC comparison).
- No adverse effects were noted in rats and monkeys after 26 once-weekly subcutaneous romosozumab-aqqg doses up to 100 mg/kg, equivalent to systemic exposures of 38 and 93 times, respectively, the systemic exposure observed in humans following a monthly subcutaneous dose of 210 mg romosozumab (based on AUC comparison).
- Bone safety studies of up to 12-month duration were conducted in ovariectomized rats and monkeys with once-weekly romosozumab-aqqg doses yielding exposures ranging from 1 to 22 times the systemic exposure in humans given monthly doses of 210 mg, based on AUC comparison. Romosozumab-aqqg increased bone mass and improved cancellous bone microarchitecture and cortical bone geometry by increasing bone formation on periosteal, endocortical, and trabecular surfaces, and decreasing bone resorption on trabecular and endocortical surfaces. The increases in bone mass were significantly correlated with increases in bone strength. In rats and monkeys, bone quality was maintained at all skeletal sites at doses ranging from 1 to 22 times human exposure, and slightly improved in vertebrae at 19 to 22 times human exposure. There was no evidence of mineralization defects, osteoid accumulation, or woven bone formation.

# Clinical Studies
Study 1 (NCT01575834) was a randomized, double-blind, placebo-controlled study of postmenopausal women aged 55 to 90 years (mean age of 71 years) with bone mineral density (BMD) T-score less than or equal to 2.5 at the total hip or femoral neck. Women were randomized to receive subcutaneous injections of either romosozumab (N = 3589) or placebo (N = 3591) for 12 months. At baseline, 18% of women had a vertebral fracture. After the 12-month treatment period, women in both arms transitioned to open-label anti-resorptive therapy (denosumab) for 12 months while remaining blinded to their initial treatment. Women received 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. The coprimary efficacy endpoints were new vertebral fracture at month 12 and month 24.
Effect on Fractures
- Romosozumab significantly reduced the incidence of new vertebral fractures through month 12 compared to placebo. In addition, the significant reduction in fracture risk persisted through the second year in women who received romosozumab during the first year and transitioned to denosumab compared to those who transitioned from placebo to denosumab (see Table 2).
- Romosozumab significantly reduced the incidence of clinical fracture (a composite endpoint of symptomatic vertebral fracture and nonvertebral fracture) at 12 months. However, 88% of these clinical fractures were nonvertebral fractures and the incidence of nonvertebral fractures was not statistically significantly different when comparing romosozumab-treated women to placebo-treated women at month 12 or month 24.
Effect on BMD
- Romosozumab significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with placebo at month 12. The treatment differences in BMD were 12.7% at the lumbar spine, 5.8% at the total hip, and 5.2% at the femoral neck.
- Following the transition from romosozumab to denosumab at month 12, BMD continued to increase through month 24. In patients who transitioned from placebo to denosumab, BMD also increased with denosumab use. The differences in BMD achieved at month 12 between romosozumab and placebo patients were overall maintained at month 24, when comparing patients who transitioned from romosozumab to denosumab to those who transitioned from placebo to denosumab. There was no evidence of differences in effects on BMD at the lumbar spine or total hip across subgroups defined by baseline age, baseline BMD, or geographic region.
- After romosozumab discontinuation, BMD returns to approximately baseline levels within 12 months in the absence of follow-on antiresorptive therapy.
Bone Histology and Histomorphometry
- A total of 154 transiliac crest bone biopsy specimens were obtained from 139 postmenopausal women with osteoporosis at month 2, month 12, and/or month 24. All of these biopsies were adequate for qualitative histology and 138 (90%) were adequate for full quantitative histomorphometry assessment. Qualitative histology assessments from women treated with romosozumab showed normal bone architecture and quality at all time points. There was no evidence of woven bone, mineralization defects, or marrow fibrosis.
- Histomorphometry assessments on biopsies at months 2 and 12 compared the effect of romosozumab with placebo (15 specimens at month 2 and 39 specimens at month 12 in the romosozumab group, 14 specimens at month 2 and 31 specimens at month 12 in the placebo group). At month 2 in women treated with romosozumab, histomorphometric indices of bone formation at trabecular and endocortical surfaces were increased. These effects on bone formation were accompanied by a decrease in indices of bone resorption. At month 12, both bone formation and resorption indices were decreased with romosozumab, while bone volume, and trabecular and cortical thickness were increased.
Study 2 (NCT01631214) was a randomized, double-blind, alendronate-controlled study of postmenopausal women aged 55 to 90 years (mean age of 74 years) with BMD T-score less than or equal to 2.5 at the total hip or femoral neck and either one moderate or severe vertebral fracture or two mild vertebral fractures, or BMD T-score less than or equal to -2.0 at the total hip or femoral neck and either two moderate or severe vertebral fractures or a history of a proximal femur fracture. Women were randomized (1:1) to receive either monthly subcutaneous injections of romosozumab (N = 2046) or oral alendronate 70 mg weekly (N = 2047) for 12 months, with 500 to 1000 mg calcium and 600 to 800 international units vitamin D supplementation daily. After the 12-month treatment period, women in both arms transitioned to open-label alendronate 70 mg weekly while remaining blinded to their initial treatment.
- This was an event driven trial. The coprimary efficacy endpoints were the incidence of morphometric vertebral fracture at 24 months and time to the first clinical fracture through the primary analysis period, which ended when at least 330 subjects had a clinical fracture and all subjects had completed the 24-month visit.  Clinical fracture was a composite endpoint of nonvertebral fracture and symptomatic vertebral fracture.
Effect on Fractures
- Romosozumab significantly reduced the incidence of new vertebral fracture at 24 months (see Table 3).
- Romosozumab significantly reduced the risk of clinical fracture through the end of the primary analysis period (see Table 4). This was an event-driven trial and the duration of follow-up varied across subjects. The median duration of subject follow-up for the primary analysis period was 33 months. Subjects with nonvertebral fracture comprised 83% of the subjects with clinical fracture during the primary analysis period.
- Romosozumab followed by alendronate also significantly reduced the risk of nonvertebral fracture through the primary analysis period (with a median follow-up of 33 months), with a hazard ratio of 0.81 (95% CI: 0.66, 0.99; p = 0.04) compared to alendronate alone.
Effect on Bone Mineral Density (BMD)
- Romosozumab significantly increased BMD at the lumbar spine, total hip, and femoral neck compared with alendronate at month 12. The treatment differences in BMD were 8.7% at the lumbar spine, 3.3% at the total hip, and 3.2% at the femoral neck.
- Twelve months of treatment with romosozumab followed by 12 months of treatment with alendronate significantly increased BMD compared with alendronate alone. The BMD increase with romosozumab over alendronate observed at month 12 was maintained at month 24. The treatment differences in BMD at month 24 were 8.1% at the lumbar spine, 3.8% at the total hip, and 3.8% at the femoral neck.
- There was no evidence of differences in effects on BMD at the lumbar spine or total hip across subgroups defined by baseline age, baseline BMD, or geographic region.

# How Supplied
- Romosozumab (romosozumab-aqqg) injection is a clear to opalescent, colorless to light yellow solution for subcutaneous injection supplied in a single-use prefilled syringe.
- Each single-use prefilled syringe contains 105 mg of romosozumab in a deliverable volume of 1.17 mL. To deliver a full dose, inject two 105 mg/1.17 mL romosozumab prefilled syringes, one after the other for a total dose of 210 mg.

## Storage
- Refrigerate romosozumab at 2C to 8C (36F to 46F) in the original carton to protect from light. Do not freeze. Do not shake.
- If removed from the refrigerator, romosozumab can be kept at room temperature up to 25C (77F) in the original carton and must be used within 30 days. If not used within 30 days, discard romosozumab.
- Do not expose romosozumab to temperatures above 25C (77F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (MEDICATION GUIDE).
Major Adverse Cardiac Events
- Advise patients to seek immediate medical attention if they experience signs or symptoms of a myocardial infarction or stroke.
Hypersensitivity Reactions
- Advise patients to seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction including angioedema, erythema multiforme, dermatitis, rash, and urticaria.
Calcium and Vitamin D Supplements to Prevent Hypocalcemia
- Advise patients to take calcium and vitamin D supplements daily to reduce the risk of hypocalcemia. Advise patients to seek immediate medical attention for symptoms of hypocalcemia.
Osteonecrosis of the Jaw
- Advise patients to practice good oral hygiene during treatment with romosozumab and tell their dentist that they are receiving romosozumab before having dental work.
Atypical Femoral Fracture
- Advise patients to report signs and symptoms that could be consistent with impending atypical femoral fracture including new or unusual thigh, hip, or groin pain.

## Medication Guide

# Precautions with Alcohol
Alcohol-Romosozumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

# Brand Names
Evenity

# Look-Alike Drug Names
There is limited information regarding Romosozumab Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price