ROMOSOZUMAB: 434 Adverse Event Reports & Safety Profile

Romosozumab-aqqg is a humanized monoclonal antibody (IgG2) produced in a mammalian cell line (Chinese Hamster Ovary) by recombinant DNA technology that binds to and inhibits sclerostin. Romosozumab-aqqg has an approximate molecular weight of 149 kDa. EVENITY (romosozumab-aqqg) injection is supplied as a sterile, preservative-free, clear to opalescent, colorless to light yellow solution for subcutaneous injection in a single-use prefilled syringe.

Two

105 mg/1.17 mL single-use prefilled syringes are required to administer the recommended 210 mg dose of EVENITY [see Dosage and Administration (2.1) ]. Each single-use prefilled syringe delivers 1.17 mL of solution containing 105 mg of romosozumab-aqqg, acetate (3.8 mg), calcium (0.61 mg), polysorbate 20 (0.07 mg) and sucrose (70 mg) in Water for Injection, USP, and sodium hydroxide to a pH of 5.2.

AND USAGE EVENITY is a sclerostin inhibitor 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. ( 1 ) Limitations of Use: Limit duration of use to 12 monthly doses. If osteoporosis therapy remains warranted, continued therapy with an anti-resorptive agent should be considered. ( 1.2 )

1.1 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.

1.2 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) and Clinical Studies (14.1) ]</span> .

AND ADMINISTRATION Two separate subcutaneous injections are needed to administer the total dose of 210 mg. Inject two syringes, one after the other. ( 2.1 ) Should be administered by a healthcare provider. ( 2.1 )

Administer

210 mg subcutaneously once every month for 12 doses in the abdomen, thigh, or upper arm. ( 2.2 ) Adequately supplement calcium and vitamin D during treatment. ( 2.2 )

2.1 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.

2.2 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) and Clinical Studies (14.1) ]</span> . 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.

2.3 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 [see How Supplied/Storage and Handling (16) ] . 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. 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 prefilled syringe by the syringe barrel to remove the syringe from the tray.

See

Figure F . 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 [see How Supplied/Storage and Handling (16) ] . Figure F 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 G . Figure G 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 H . Figure H 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. Insert needle and inject all the liquid subcutaneously. Do not administer into muscle or blood vessel.

See

Figure I . Figure I 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. Figure A Figure B Figure C Figure D

EVENITY is contraindicated in patients with: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with EVENITY [see Warnings and Precautions (5.3) , Adverse Reactions (6.1) and Use in Specific Populations (8.7) ]. A history of systemic hypersensitivity to romosozumab-aqqg or to any component of the product formulation. Reactions have included angioedema, erythema multiforme, and urticaria [see Warnings and Precautions (5.2) and Adverse Reactions (6.1) ] . Hypocalcemia ( 4 ) Known hypersensitivity to EVENITY ( 4 )

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) ].

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 <span class="opacity-50 text-xs">[see Boxed Warning and Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Contraindications (4) and Adverse Reactions (6.1) ]</span>.

5.3 Hypocalcemia Hypocalcemia has occurred in patients receiving EVENITY. Correct hypocalcemia prior to initiating EVENITY <span class="opacity-50 text-xs">[see Contraindications (4) , Adverse Reactions (6.1) and Use in Specific Populations (8.7) ]</span> . Monitor patients for signs and symptoms of hypocalcemia. Patients should be adequately supplemented with calcium and vitamin D while on EVENITY <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) and Clinical Studies (14.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span>.