Evenity Drug Information
Generic name: ROMOSOZUMAB-AQQG
Uses of Evenity
Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture EVENITY 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.
Limitations of Use
The anabolic effect of EVENITY wanes after 12 monthly doses of therapy. Therefore, the duration of EVENITY use should be limited to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered.
Dosage & Administration of Evenity
Important Dosage and Administration Instructions
Two separate syringes (and two separate subcutaneous injections) are needed to administer the total dose of 210 mg of EVENITY. Inject two 105 mg/1.17 mL prefilled syringes, one after the other. EVENITY should be administered by a healthcare provider.
Recommended Dosage
The recommended dose of EVENITY is 210 mg administered subcutaneously in the abdomen, thigh or upper arm. Administer EVENITY once every month. The treatment duration for EVENITY is 12 monthly doses.
Patients should be adequately supplemented with calcium and vitamin D during treatment with EVENITY. If the EVENITY dose is missed, administer as soon as it can be rescheduled. Thereafter, EVENITY can be scheduled every month from the date of the last dose.
Preparation and Administration Instructions
- Administration instructions: Prefilled syringe with automatic needle guard: Step 1: Prior to Administration: Remove two syringes from the carton. Visually inspect EVENITY for particles and discoloration prior to administration. EVENITY 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 the syringe has been dropped on a hard surface Always hold the syringe by the syringe body 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. Allow EVENITY to sit at room temperature for at least 30 minutes before injecting. Do not warm in any other way.
- Figure A 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.
- 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 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 the first syringe. Pull the gray needle cap straight off and away from your body when you are ready to inject. See Figure C. Figure C Do not put the gray needle cap back onto the syringe. Do not leave the cap off for more than 5 minutes as this can dry out the solution. The prefilled syringe may contain air bubbles. Do not try to push air bubbles out as it is normal to see air bubbles.
- Step 3: Inject EVENITY Pinch the skin around the injection site before injecting. Insert the needle into the pinched skin at or about a 45-degree angle. Slowly press the plunger head all the way down with your thumb until it is completely between the needle guard clips. Do not pull back on the plunger rod at any time. Do not remove the syringe until all the medicine has been injected. Do not administer into muscle or blood vessel. See Figure D. Figure D Slowly release pressure on the plunger head with your thumb and remove the syringe from the skin. Let go of the skin after the needle is removed. Releasing the plunger head covers the used needle. See Figure E.
- Figure E Step 4: Syringe and Gray 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. Figure A Figure B Figure C Figure D Figure E Administration instructions: Prefilled syringe: Step 1: Prior to Administration: Remove two syringes from the carton. See Figure F. See Figure G. Let the skin dry. Choose the first syringe. See Figure H. Insert needle and inject all the liquid subcutaneously. See Figure I. Figure I When done, gently lift the syringe off of the skin. Figure A Figure B Figure C Figure D
Side Effects of Evenity
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. A total of 3581 and 3576 women received at least one dose of EVENITY and placebo, respectively, administered once every month during the 12-month double-blind study period. The safety of EVENITY 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 EVENITY and alendronate, respectively, during the 12-month double-blind study period. The incidence of nonfatal serious adverse events was 8.3% in the placebo group and 9.1% in the EVENITY 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 EVENITY group.
The most common adverse reactions reported with EVENITY (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 EVENITY was arthralgia (6 subjects in the placebo group and 5 subjects in the EVENITY group). The incidence of nonfatal serious adverse events was 13.3% in the alendronate group and 11.9% in the EVENITY group.
Table 1 outlines the most common adverse reactions occurring in greater than or equal to 2% of EVENITY-treated women in at least one study. Table 1. Adverse Reactions Occurring in ≥ 2% of EVENITY-Treated Women in at Least One Study Studies The adverse reactions described below are from the 12-month treatment periods of Study 1 (placebo-controlled) and Study 2 (alendronate-controlled).
These events occurred in patients with and without a history of myocardial infarction or stroke. Although angioedema, dermatitis and urticaria were not reported at a higher incidence with EVENITY than control, there were cases of angioedema, dermatitis and urticaria that were determined to be related to EVENITY use. Hypocalcemia Across both trials, adverse events of hypocalcemia occurred in 2 EVENITY-treated women and in 1 woman in the control group.
No patient receiving EVENITY developed serum calcium less than 7.5 mg/dL. The nadir in albumin-adjusted serum calcium occurred by month 1 after EVENITY dosing in patients with normal renal function. The most common injection site reactions were pain (94 women in the EVENITY group; 70 women in the control group) and erythema (80 women in the EVENITY group and 14 women in the control group).
Osteonecrosis of the Jaw Across both trials, osteonecrosis of the jaw occurred in one patient during treatment with EVENITY. Atypical Subtrochanteric and Diaphyseal Fractures Across both trials, atypical femoral fracture occurred in one patient during treatment with EVENITY.
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| Preferred Term | Placebo (N = 3576) n (%) | EVENITY (N = 3581) n (%) | Alendronate (N = 2014) n (%) | EVENITY (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) |
Warnings & Cautions for Evenity
Major Adverse Cardiac Events (MACE) 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 EVENITY compared to those treated with alendronate. EVENITY 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, EVENITY should be discontinued.
Hypersensitivity Reactions
Hypersensitivity reactions, including angioedema, erythema multiforme, dermatitis, rash, and urticaria have occurred in EVENITY-treated patients. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of EVENITY.
Hypocalcemia Hypocalcemia has occurred in patients receiving EVENITY. Correct hypocalcemia prior to initiating EVENITY. Monitor patients for signs and symptoms of hypocalcemia.
Patients should be adequately supplemented with calcium and vitamin D while on EVENITY. Patients with severe renal impairment (estimated glomerular filtration rate 15 to 29 mL/min/1.73 m 2 ) 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 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 EVENITY. A routine oral examination should be performed by the prescriber prior to initiation of EVENITY 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 EVENITY should receive care by a dentist or an oral surgeon.
In these patients, dental surgery to treat ONJ may exacerbate the condition. Discontinuation of EVENITY should be considered based on benefit-risk assessment.
Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical low-energy or low trauma fractures of the femoral shaft have been reported in patients receiving EVENITY. 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 EVENITY 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.
Pregnancy Safety for Evenity
Pregnancy Risk Summary EVENITY 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.
Data 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 31 times the clinical exposure observed in humans following a monthly subcutaneous dose of 210 mg, based on area under the concentration-time curve comparison). Cortical thickness was increased at 300 mg/kg (equivalent to 54 times expected clinical exposure).
Pediatric Use of Evenity
Pediatric Use Safety and effectiveness of EVENITY have not been established in pediatric patients.
Contraindications for Evenity
EVENITY is contraindicated in patients with: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with EVENITY. A history of systemic hypersensitivity to romosozumab-aqqg or to any component of the product formulation.
Reactions have included angioedema, erythema multiforme, and urticaria. Hypocalcemia Known hypersensitivity to EVENITY
Clinical Studies of Evenity
Women were randomized to receive subcutaneous injections of either EVENITY (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.
The coprimary efficacy endpoints were new vertebral fracture at month 12 and month 24. Effect on Fractures EVENITY 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 EVENITY during the first year and transitioned to denosumab compared to those who transitioned from placebo to denosumab (see Table 2 ).
Table 2. Effect of EVENITY on the Incidence and Risk of Fractures in Study 1 EVENITY 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 EVENITY-treated women to placebo-treated women at month 12 or month 24.
Effect on Bone Mineral Density (BMD) EVENITY 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 EVENITY 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 EVENITY and placebo patients were overall maintained at month 24, when comparing patients who transitioned from EVENITY 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 EVENITY discontinuation, BMD returns to approximately baseline levels within 12 months in the absence of follow-on anti-resorptive therapy. 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 EVENITY showed normal bone architecture and quality at all time points.
There was no evidence of woven bone, mineralization defects, or marrow fibrosis. At month 2 in women treated with EVENITY, 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 EVENITY, 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. 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 two primary 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. Effect on Fractures EVENITY significantly reduced the incidence of new vertebral fracture at 24 months (see Table 3 ).
Table 3. Effect of EVENITY on the Incidence of New Vertebral Fractures in Study 2 EVENITY 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. Table 4.
Effect of EVENITY on the Risk of Clinical Fractures in Study 2 EVENITY 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 p = 0.04 compared to alendronate alone. Twelve months of treatment with EVENITY followed by 12 months of treatment with alendronate significantly increased BMD compared with alendronate alone. The BMD increase with EVENITY over alendronate observed at month 12 was maintained at month 24.
| Proportion of Women with Fractures | Absolute Risk Reduction (%) (95% CI) Absolute and relative risk reduction are based on the Mantel-Haenszel method adjusting for age and prevalent vertebral fracture strata. | Relative Risk Reduction (%) (95% CI) | p-value P-value is based on logistic regression model adjusting for age and prevalent vertebral fracture strata. | ||
|---|---|---|---|---|---|
| At Month 12 | Placebo (N = 3591) | EVENITY (N = 3589) | |||
| N = Number of subjects randomized | |||||
| New vertebral fracture | 1.8% | 0.5% | 1.3 (0.8, 1.8) | 73 (53, 84) | < 0.001 |
| At Month 24 | Placebo Followed by Denosumab (N = 3591) | EVENITY Followed by Denosumab (N = 3589) | |||
| New vertebral fracture | 2.5% | 0.6% | 1.9 (1.3, 2.5) | 75 (60, 84) | < 0.001 |
| Proportion of Women with Fracture (%) | Risk Reduction | p-value P-value is based on logistic regression model for new vertebral fracture) adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | |||
|---|---|---|---|---|---|
| Alendronate Alone (N = 2047) | EVENITY Followed by Alendronate (N = 2046) | Absolute Risk Reduction (%) (95% CI) Absolute and relative risk reductions are based on the Mantel-Haenszel method adjusting for age strata, baseline total hip BMD T-score (≤ -2.5, > -2.5), and presence of severe vertebral fracture at baseline. | Relative Risk Reduction (%) (95% CI) | ||
| N = Number of subjects randomized | |||||
| New vertebral fracture through Month 24 | 8.0% | 4.1% | 4.0 (2.5, 5.6) | 50 (34, 62) | < 0.001 |
| Proportion of Women with Fracture (%) % = number of subjects who had a clinical fracture through the primary analysis period/N*100%; the duration of follow-up varied across subjects. | Hazard Ratio (95% CI) Hazard ratio and P-value are based on Cox proportional hazards model adjusting for age strata, baseline total hip BMD T-score, and presence of severe vertebral fracture at baseline. | p-value | ||
|---|---|---|---|---|
| Alendronate Alone (N = 2047) | EVENITY Followed by Alendronate (N = 2046) | |||
| N = Number of subjects randomized | ||||
| Clinical fracture through primary analysis period Primary analysis period ended when clinical fracture events were confirmed for at least 330 subjects and all subjects completed the month 24 study visit. The median duration of follow-up for the primary analysis period was 33 months. | 13.0% | 9.7% | 0.73 (0.61, 0.88) | < 0.001 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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