WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION, STROKE AND CARDIOVASCULAR DEATH EVENITY may increase the risk of myocardial infarction, stroke, and cardiovascular death [see Warnings and Precautions (5.1) ] . 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. If a patient experiences a myocardial infarction or stroke during therapy, EVENITY should be discontinued. WARNING: POTENTIAL RISK OF MYOCARDIAL INFARCTION, STROKE AND CARDIOVASCULAR DEATH See full prescribing information for complete boxed warning. EVENITY may increase the risk of myocardial infarction, stroke and cardiovascular death. ( 5.1 ) 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. ( 5.1 ) If a patient experiences a myocardial infarction or stroke during therapy, EVENITY should be discontinued. ( 5.1 )
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Major Adverse Cardiac Events (MACE): Monitor for symptoms of MI and stroke and seek prompt medical attention if symptoms occur. ( 5.1 ) Hypersensitivity: Hypersensitivity reactions, including angioedema, erythema multiforme, dermatitis, rash, and urticaria. Discontinue EVENITY if a clinically significant allergic reaction occurs. ( 5.2 ) Hypocalcemia: Adequately supplement calcium and vitamin D during treatment with EVENITY. ( 5.3 ) Osteonecrosis of the Jaw: Monitor for symptoms. Consider discontinuation of therapy based on benefit-risk assessment. ( 5.4 ) Atypical Femoral Fracture: Evaluate new or unusual thigh, hip, or groin pain to rule out an incomplete femur fracture. ( 5.5 ) 5.1 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 [see Boxed Warning and Adverse Reactions (6.1) ] . 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. 5.2 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 [see Contraindications (4) and Adverse Reactions (6.1) ]. 5.3 Hypocalcemia Hypocalcemia has occurred in patients receiving EVENITY. Correct hypocalcemia prior to initiating EVENITY [see Contraindications (4) , Adverse Reactions (6.1) and Use in Specific Populations (8.7) ] . Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on EVENITY [see Dosage and Administration (2.2) and Clinical Studies (14.1) ] . Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 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. 5.4 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 [see Adverse Reactions (6.1) ] . 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. 5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical low-energy or low trauma fractures of the femoral shaft have been reported in patients receiving EVENITY [see Adverse Reactions (6.1) ] . 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. Interruption of EVENITY therapy should be considered based on benefit-risk assessment [see Clinical Studies (14) ].
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Major adverse cardiac events [see Boxed Warning and Warnings and Precautions (5.1) ] Hypersensitivity [see Contraindications (4) and Warnings and Precautions (5.2) ] Hypocalcemia [see Contraindications (4) and Warnings and Precautions (5.3) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.4) ] Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see Warnings and Precautions (5.5) ] The most common adverse reactions (≥ 5%) reported with EVENITY in clinical trials were arthralgia and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 EVENITY 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 EVENITY 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 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. 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 EVENITY group. 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 [0.2%] in the placebo group and 5 subjects [0.1%] in the EVENITY 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 EVENITY group. The incidence of nonfatal serious adverse events was 13.3% in the alendronate group and 11.9% in the EVENITY 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 EVENITY group. The most common adverse reactions reported with EVENITY (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 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 1 and 2) 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) The adverse reactions described below are from the 12-month treatment periods of Study 1 (placebo-controlled) and Study 2 (alendronate-controlled). 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 (0.3%) women in the EVENITY group and 8 (0.2%) women in the placebo group; stroke occurred in 8 (0.2%) women in the EVENITY 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 EVENITY group and 15 (0.4%) women in the placebo group. The number of women with positively adjudicated MACE was 30 (0.8%) in the EVENITY group and 29 (0.8%) in the placebo group, yielding a hazard ratio of 1.03 (95% confidence interval [0.62, 1.72]) for EVENITY 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 EVENITY group and 5 (0.2%) women in the alendronate group; stroke occurred in 13 (0.6%) women in the EVENITY 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 EVENITY group and 12 (0.6%) women in the alendronate group. The number of women with positively adjudicated MACE was 41 (2.0%) in the EVENITY group and 22 (1.1%) in the alendronate group, yielding a hazard ratio of 1.87 (95% confidence interval [1.11, 3.14]) for EVENITY compared to alendronate [see Boxed Warning and Warnings and Precautions (5.1) ]. Hypersensitivity Reactions Across both trials, hypersensitivity reactions were reported in 364 (6.5%) women in the EVENITY group and 365 (6.5%) women in the control group. Reported reactions included angioedema (3 [< 0.1%] women in the EVENITY group vs. 3 [< 0.1%] women in the control group), erythema multiforme (1 [< 0.1%] woman in the EVENITY group vs. no woman in the control group), dermatitis (32 [0.6%] women in the EVENITY group vs. 42 [0.8%] women in the control group), rash (60 [1.1%] women in the EVENITY group vs. 53 [0.9%] women in the control group), and urticaria (23 [0.4%] women in the EVENITY group vs. 27 [0.5%] women in the control group). 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 [see Contraindications (4) and Warnings and Precautions (5.2) ] . Hypocalcemia Across both trials, adverse events of hypocalcemia occurred in 2 EVENITY-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 EVENITY group and 10 (0.2%) women 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 [see Contraindications (4) and Warnings and Precautions (5.3) ] . Injection Site Reactions Across both trials, injection site reactions occurred in 278 (4.9%) women in the EVENITY group and 157 (2.8%) women in the control group. The most common injection site reactions were pain (94 [1.7%] women in the EVENITY group; 70 [1.3%] women in the control group) and erythema (80 [1.4%] women in the EVENITY group and 14 [0.3%] women in the control group). Injection site reactions resulted in discontinuation of treatment in 7 (0.1%) EVENITY-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 EVENITY [see Warnings and Precautions (5.4) ]. Atypical Subtrochanteric and Diaphyseal Fractures Across both trials, atypical femoral fracture occurred in one patient during treatment with EVENITY [see Warnings and Precautions (5.5) ].