Abaloparatide

1 INDICATIONS AND USAGE TYMLOS is a human parathyroid hormone related peptide [PTHrP(1-34)] analog indicated for the: Treatment of postmenopausal women with osteoporosis at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy. ( 1.1 ) Treatment to increase bone density in men with osteoporosis at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy. ( 1.2 ) 1.1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture TYMLOS is indicated for the treatment of postmenopausal women with osteoporosis 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. In postmenopausal women with osteoporosis, TYMLOS reduces the risk of vertebral fractures and nonvertebral fractures. 1.2 Treatment to Increase Bone Density in Men with Osteoporosis at High Risk for Fracture TYMLOS is indicated to increase bone density in men with osteoporosis 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.

2 DOSAGE AND ADMINISTRATION Recommended dosage is 80 mcg subcutaneously once daily; patients should receive supplemental calcium and vitamin D if dietary intake is inadequate. ( 2.1 ) Administer as a subcutaneous injection into periumbilical region of abdomen. ( 2.2 ) Administer initially where the patient can sit or lie down in case symptoms of orthostatic hypotension occur. ( 2.2 , 5.2 ) 2.1 Recommended Dosage The recommended dosage of TYMLOS is 80 mcg administered subcutaneously once daily. Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate. 2.2 Administration Instructions Administer TYMLOS as a subcutaneous injection into the periumbilical region of the abdomen. Rotate the site of the injection every day and administer at approximately the same time every day. Do not administer intravenously or intramuscularly. Administer the first several doses where the patient can sit or lie down if necessary, in case symptoms of orthostatic hypotension occur [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . Visually inspect TYMLOS for particulate matter and discoloration prior to administration. TYMLOS is a clear and colorless solution. Do not use if solid particles appear or if the solution is cloudy or colored. Provide appropriate training and instruction to patients and caregivers on the proper use of the TYMLOS pen. 2.3 Treatment Duration The safety and efficacy of TYMLOS have not been evaluated beyond 2 years of treatment. Use of the drug for more than 2 years during a patient's lifetime is not recommended.

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: Orthostatic Hypotension [see Warnings and Precautions ( 5.2 )] Hypercalcemia [see Warnings and Precautions ( 5.3 )] Hypercalciuria and Urolithiasis [see Warnings and Precautions ( 5.4 )] Osteoporosis in postmenopausal women: The most common adverse reactions (incidence ≥2%) are hypercalciuria, dizziness, nausea, headache, palpitations, fatigue, upper abdominal pain, and vertigo. ( 6.1 ) Osteoporosis in men: The most common adverse reactions (incidence ≥2%) are injection site erythema, dizziness, arthralgia, injection site swelling, injection site pain, contusion, nausea, diarrhea, abdominal distension, abdominal pain, and bone pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Radius Health, Inc. at 1-855-672-3487 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions from Clinical Trial in Postmenopausal Women with Osteoporosis The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebo-controlled clinical trial in postmenopausal women with osteoporosis aged 49 to 86 years (mean age 69 years) who were randomized to receive 80 mcg of TYMLOS (N = 824) or placebo (N = 821), given subcutaneously once daily for 18 months [see Clinical Studies ( 14.1 )] . In this study, the incidence of all-cause mortality was 0.4% in the TYMLOS group and 0.6% in the placebo group. The incidence of serious adverse events was 10% in the TYMLOS group and 11% in the placebo group. The percentage of patients who discontinued study drug due to adverse events was 10% in the TYMLOS group and 6% in the placebo group. The most common adverse reactions leading to study drug discontinuation in the TYMLOS group were nausea (2%), dizziness (1%), headache (1%), and palpitations (1%). Table 1 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo, and occurred in at least 2% of the patients treated with TYMLOS. Table 1: Common Adverse Reactions Reported in Postmenopausal Women with Osteoporosis * * Adverse reactions reported in ≥2% of TYMLOS-treated patients. Preferred term TYMLOS (N=822) (%) Placebo (N=820) (%) Hypercalciuria 11 9 Dizziness 10 6 Nausea 8 3 Headache 8 6 Palpitations 5 0.4 Fatigue 3 2 Abdominal pain upper 3 2 Vertigo 2 2 Orthostatic Hypotension In the clinical trial of women with postmenopausal osteoporosis, the incidence of orthostatic blood pressure decline ≥20 mmHg systolic or ≥10 mmHg diastolic at 1 hour after the first injection was 4% in the TYMLOS group and 3% in the placebo group. At later time points the incidence was generally similar between the treatment groups. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0.5% of patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (10%) compared to placebo (6%) [see Warnings and Precautions ( 5.2 )] . Tachycardia In women with postmenopausal osteoporosis, adverse reactions of tachycardia, including sinus tachycardia, were reported in 2% of patients receiving TYMLOS and 1% of patients in the placebo group. In 5 of the 13 patients receiving TYMLOS who experienced tachycardia, symptoms occurred within 1 hour of administration. TYMLOS has been associated with a dose-dependent increase in heart rate which developed within 15 minutes after injection and resolved in about 6 hours [see Clinical Pharmacology ( 12.2 )] . Injection Site Reactions During the first month of the trial, injection site reactions were assessed daily one-hour after injection. TYMLOS had a higher incidence than placebo of injection site redness (58% vs. 28%), edema (11% vs. 3%), and pain (10% vs. 7%). Severe redness, severe edema, and severe pain were reported among 2.9%, 0.4%, and 0.4% of the TYMLOS-treated patients. Laboratory Abnormalities Hypercalcemia In the clinical trial of women with postmenopausal osteoporosis, TYMLOS caused increases in serum calcium concentrations [see Warnings and Precautions ( 5.3 )] . The incidence of hypercalcemia, defined as albumin-corrected serum calcium ≥10.7 mg/dL at 4 hours following injection at any visit, was 3% in TYMLOS-treated patients and 0.1% with placebo. Pre-dose serum calcium was similar to baseline in both groups. There were 2 (0.2%) TYMLOS-treated patients and no placebo-treated patients who discontinued from the study due to hypercalcemia. The incidence of hypercalcemia with TYMLOS was higher in patients with mild or moderate renal impairment (4%) compared to patients with normal renal function (1%). Increases in Serum Uric Acid TYMLOS increased serum uric acid concentrations. In the postmenopausal osteoporosis trial, among patients with normal baseline uric acid concentrations, 25% of patients in the TYMLOS group and 6% of patients in the placebo group had at least one post-baseline concentration above the normal range. The hyperuricemia observed in TYMLOS-treated patients was not associated with an increase in adverse reactions of gout or arthralgia over that observed with placebo. Hypercalciuria and Urolithiasis In the clinical trial of women with postmenopausal osteoporosis, the overall incidence of urine calcium:creatinine ratio >400 mg/g was higher with TYMLOS than with placebo (20% vs 15%, respectively). Urolithiases were reported in 2.1% of TYMLOS-treated patients and 1.7% of placebo-treated patients. Adverse Reactions from the Extension Study in Postmenopausal Women with Osteoporosis Following 18 months of treatment with TYMLOS or placebo, 1139 women transitioned to treatment with alendronate 70 mg administered orally once weekly. The incidence of adverse events occurring during alendronate treatment was similar in patients with prior placebo or TYMLOS therapy [see Clinical Studies ( 14.1 )] . Adverse Reactions from Clinical Trial in Men with Osteoporosis The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebo-controlled clinical trial in men with osteoporosis aged 42 to 85 years (mean age 68 years) who were randomized to receive 80 mcg of TYMLOS (N = 149) or placebo (N = 79), given subcutaneously once daily for 12 months [see Clinical Studies ( 14.2 )] . In this study, no patient from either treatment group had an adverse reaction with a fatal outcome during the trial. Serious adverse reactions were reported by 5.4% of subjects treated with TYMLOS and 5.1% of subjects in the placebo group. Adverse reactions leading to study drug discontinuation were reported for 6.7% of patients treated with TYMLOS and 5.1% of patients receiving placebo. The most common adverse reaction leading to study drug discontinuation in the TYMLOS group was dizziness (2%). Table 2 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo and occurred in at least 2% of the patients treated with TYMLOS. Table 2: Common Adverse Reactions Reported in Men with Osteoporosis Adverse reactions reported in ≥2% of TYMLOS-treated patients. Preferred Term TYMLOS (N=149) (%) Placebo (N=79) (%) Injection site erythema 13 5 Dizziness 9 1 Arthralgia 7 1 Injection site swelling 7 0 Injection site pain 6 0 Contusion 3 0 Abdominal distention 3 0 Diarrhea 3 0 Nausea 3 0 Abdominal Pain 2 0 Bone Pain 2 0 Orthostatic Hypotension In the clinical trial of men with osteoporosis, the incidence of orthostatic blood pressure declines of ≥20 mmHg systolic or ≥10 mmHg diastolic at 1 hour after the first injection was 6% in the TYMLOS group and 3% in the placebo group. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0 patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (9%) compared to placebo (1%) [see Warnings and Precautions ( 5.2 )] . Laboratory Abnormalities Hypercalcemia In the clinical trial of men with osteoporosis, TYMLOS caused increases in serum calcium concentrations [see Warnings and Precautions ( 5.3 )] . The incidence of hypercalcemia, defined as albumin-corrected serum calcium ≥10.8 mg/dL at 4 hours following injection at any visit, was 3% in TYMLOS-treated patients and 0% with placebo. Pre-dose serum calcium was similar to baseline in both groups. The incidence of hypercalcemia, defined as albumin-corrected serum calcium ≥10.8 mg/dL at 4 hours following injection, with TYMLOS was higher in patients with mild or moderate renal impairment (4%) compared to patients with normal renal function (0%). Increases in Serum Uric Acid TYMLOS increased serum uric acid concentrations. In the male osteoporosis trial, among patients with normal baseline uric acid concentrations, 7% of patients in the TYMLOS group and 6% of patients in the placebo group had at least one post-baseline concentration above the normal range. The hyperuricemia observed in TYMLOS-treated patients was not associated with an increase in adverse reactions of gout or arthralgia over that observed with placebo. Hypercalciuria and Urolithiasis In the clinical trial of men with osteoporosis, the overall incidence of urine calcium: creatinine ratio >400 mg/g was not greater with TYMLOS than with placebo. Urolithiases were reported in 2% of TYMLOS-treated patients and 1% of placebo-treated patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during the post-approval use of TYMLOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Abdominal distension, abdominal pain, abdominal discomfort Constipation, diarrhea, vomiting, decreased appetite Asthenia, lethargy, malaise, feeling abnormal, hot flush Insomnia Hypersensitivity and anaphylactic reactions, dyspnea (in the context of allergic reactions) Pruritus, rash Generalized pain and pain in bone, joint, back, and extremity Blood pressure increased Muscle spasms of the leg and back Injection site reactions including bruising, hemorrhage, pruritus, and rash

12.3 Pharmacokinetics Following seven days of subcutaneous administration of abaloparatide 80 mcg, the mean (SD) abaloparatide exposure was 812 (118) pg/mL for C max and 1622 (641) pg∙hr/mL for AUC 0–24 in postmenopausal women with osteoporosis. Absorption The median (range) time to peak concentration of abaloparatide 80 mcg was 0.51 hr (0.25 to 0.52 hr) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Distribution The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 50 L. Elimination Excretion The mean (SD) half-life of abaloparatide is approximately 1 h. The peptide fragments are primarily eliminated through renal excretion. Metabolism No specific metabolism or excretion studies have been performed with TYMLOS. The metabolism of abaloparatide is consistent with non-specific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance. Specific Populations Male and Female Subjects Mean serum abaloparatide concentration-time profiles observed in a study conducted in healthy men with a mean (±SD) age of 53.1 (±6.9) years were comparable to those observed in the healthy women with a mean (±SD) age of 53.7 (±7.1) years using the same dosing regimen. Geriatric Patients No age-related differences in abaloparatide pharmacokinetics were observed in men and postmenopausal women ranging from 18 to 85 years of age. Race No differences in abaloparatide pharmacokinetics based on race were observed in clinical trials. Patients with Renal Impairment A single 80 mcg subcutaneous dose of abaloparatide was administered to male and female patients with renal impairment: 8 patients with mild renal impairment (CLCr 60 to 89 mL/min), 7 patients with moderate renal impairment (CLCr 30 to 59 mL/min), 8 patients with severe renal impairment (CLCr 15 to 29 mL/min), and 8 healthy subjects with normal renal function (CLCr 90 or greater mL/min) matched by sex, age, and body mass index (BMI). Abaloparatide C max increased 1.0-, 1.3-, and 1.4-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Abaloparatide AUC increased 1.2-, 1.7-, and 2.1-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Patients undergoing dialysis were not included in the study. Drug Interactions In vitro studies showed that abaloparatide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes. Abaloparatide is not a substrate of the renal transporters OAT1, OAT3, OCT2, MATE1, or MATE2K.