Abaloparatide

TYMLOS injection for subcutaneous administration contains abaloparatide, a synthetic 34 amino acid peptide. Abaloparatide is an analog of human parathyroid hormone related peptide, PTHrP(1-34). It has 41% homology to hPTH(1-34) (human parathyroid hormone 1-34) and 76% homology to hPTHrP(1-34) (human parathyroid hormone-related peptide 1-34). Abaloparatide has a molecular formula of C 174 H 300 N 56 O 49 and a molecular weight of 3961 daltons with the amino acid sequence shown below: Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH 2 TYMLOS injection is supplied as a sterile, colorless, clear solution in a glass cartridge which is pre-assembled into a disposable single-patient-use pen. The pen is intended to deliver 30 once daily abaloparatide doses of 80 mcg in 40 mcL. Each cartridge contains 1.56 mL of TYMLOS solution which contains 3.12 mg of abaloparatide, and the following inactive ingredients: 1.2 mg glacial acetic acid, 7.8 mg phenol, 7.92 mg sodium acetate trihydrate, and water for injection to a target pH range of 5.1 to 5.2.

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.

16.1 How Supplied TYMLOS (abaloparatide) injection is a clear and colorless solution, available as a pre-assembled single-patient-use disposable pen (NDC 70539-001-01) packaged in a cardboard carton (NDC 70539-001-02) with the Instructions for Use and Medication Guide. Each disposable pen embodies a glass cartridge that contains 3120 mcg of abaloparatide in 1.56 mL (2000 mcg/mL). Each pen provides a 30-day supply for once daily injection of 80 mcg abaloparatide in 40 mcL. Sterile needles are not included. 16.2 Storage and Handling Before first use, store TYMLOS under refrigeration between 2°C to 8°C (36°F to 46°F). After first use, store for up to 30 days at 20°C to 25°C (68°F to 77°F). Do not freeze or subject to heat.

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 , 5.3 ) 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 ( 5.3 ) 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.

TYMLOS is contraindicated in patients with a history of severe hypersensitivity to abaloparatide or any of the inactive ingredients of TYMLOS. Reactions have included anaphylaxis, angioedema, dyspnea, and urticaria [see Warnings and Precautions (5.1) , Adverse Reactions ( 6.2 )] . Severe hypersensitivity to abaloparatide or any of the inactive ingredients of TYMLOS. ( 4 )

Hypersensitivity Reactions: Anaphylaxis, angioedema, and urticaria have been reported in patients treated with parathyroid hormone analogs, including TYMLOS. If signs or symptoms of a hypersensitivity reaction occur, discontinue treatment with TYMLOS, initiate supportive care, and monitor until signs or symptoms resolve. Discontinue TYMLOS permanently in patients with a severe hypersensitivity reaction to TYMLOS. ( 5.1 ) Osteosarcoma: Avoid use in patients with increased risk of osteosarcoma including patients with open epiphyses, metabolic bone diseases including Paget's disease, bone metastases or history of skeletal malignancies, prior external beam or implant radiation therapy involving the skeleton, and hereditary disorders predisposing to osteosarcoma. ( 5.2 ) Orthostatic Hypotension: Instruct patients to sit or lie down if symptoms develop after dose administration. ( 5.3 ) Hypercalcemia: Avoid use in patients with pre-existing hypercalcemia and those known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism. ( 5.4 ) Hypercalciuria and Urolithiasis: Monitor urine calcium if pre-existing hypercalciuria or active urolithiasis are suspected. ( 5.5 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria have been reported in patients treated with parathyroid hormone (PTH) analogs, including TYMLOS [see Adverse Reactions (6.2) ] . If signs or symptoms of a hypersensitivity reaction occur, discontinue treatment with TYMLOS, initiate appropriate supportive care, and monitor until signs and symptoms resolve. Discontinue TYMLOS permanently in patients with a severe hypersensitivity reaction to TYMLOS . TYMLOS is contraindicated in patients with a history of severe hypersensitivity to abaloparatide or any of the inactive ingredients of TYMLOS [ see Contraindications (4) ]. 5.2 Risk of Osteosarcoma Abaloparatide caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats after subcutaneous administration at exposures 4 to 28 times the human exposure at the clinical dose of 80 mcg [see Nonclinical Toxicology ( 13.1 )] . It is unknown whether TYMLOS will cause osteosarcoma in humans. Osteosarcoma has been reported in patients treated with a PTH-analog in the post marketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of TYMLOS and/or use of a PTH-analog [see Dosage and Administration ( 2.3 ) and Nonclinical Toxicology ( 13.1 )] . Avoid TYMLOS use in patients with (these patients are at increased baseline risk of osteosarcoma): Open epiphyses (pediatric and young adult patients) (TYMLOS is not approved in pediatric patients) [see Use in Specific Populations ( 8.4 )] . Metabolic bone diseases other than osteoporosis, including Paget's disease of the bone. Bone metastases or a history of skeletal malignancies. Prior external beam or implant radiation therapy involving the skeleton. Hereditary disorders predisposing to osteosarcoma. 5.3 Orthostatic Hypotension Orthostatic hypotension may occur with TYMLOS, typically within 4 hours of injection. Associated symptoms may include dizziness, palpitations, tachycardia, or nausea, and may resolve by having the patient lie down. For the first several doses, TYMLOS should be administered where the patient can sit or lie down if necessary [see Adverse Reactions ( 6.1 )] . 5.4 Hypercalcemia TYMLOS may cause hypercalcemia. TYMLOS is not recommended in patients with pre-existing hypercalcemia or in patients who have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, because of the possibility of exacerbating hypercalcemia [see Adverse Reactions ( 6.1 )] . 5.5 Hypercalciuria and Urolithiasis TYMLOS may cause hypercalciuria. It is unknown whether TYMLOS may exacerbate urolithiasis in patients with active or a history of urolithiasis. If active urolithiasis or pre-existing hypercalciuria is suspected, measurement of urinary calcium excretion should be considered [see Adverse Reactions ( 6.1 )] .

Advise the patient to read the FDA-approved patient labeling ( Medication Guide and Instructions for Use ). Hypersensitivity Reactions Advise patients that serious hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, can occur with TYMLOS. Advise patients to discontinue TYMLOS and promptly seek immediate medical attention if signs or symptoms of hypersensitivity reactions occur [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . Risk of Osteosarcoma Advise patients that the active ingredient in TYMLOS, abaloparatide, caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats and that it is unknown whether TYMLOS will cause osteosarcoma in humans [see Warnings and Precautions ( 5.2 )] . Instruct patients to promptly report signs and symptoms of possible osteosarcoma such as persistent localized pain or occurrence of a new soft tissue mass that is tender to palpation. Hypercalcemia Advise patients that TYMLOS may cause hypercalcemia and discuss the symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness) [see Warnings and Precautions ( 5.4 )] . Instruct patients to promptly report signs and symptoms of hypercalcemia. Orthostatic Hypotension Advise patients to sit or lie down if they feel lightheaded or have palpitations after the injection until their symptoms resolve. If these symptoms persist or worsen, advise patients to consult their healthcare provider before continuing treatment [see Dosage and Administration ( 2.2 )] . Use of TYMLOS Pen Instruct patients and caregivers who administer TYMLOS on how to properly use the TYMLOS pen and to follow sharps disposal recommendations [see Dosage and Administration ( 2.2 )] . Advise patients not to share their TYMLOS pen or needles with other patients and not to transfer the contents of the pen to a syringe. Advise patients that each TYMLOS pen can be used for up to 30 days, and after the 30-day use period, to discard the TYMLOS pen, even if it still contains unused solution [see How Supplied/Storage and Handling ( 16.2 )] . Manufactured for: Radius Health, Inc. 22 Boston Wharf Road, 7th Floor Boston, MA 02210 TYMLOS is a registered trademark of Radius Health, Inc. Copyright © 2017, Radius Health, Inc. All rights reserved. US-PI-000001-v12.0

No specific drug-drug interaction studies have been performed [see Clinical Pharmacology ( 12.3 )] .

Carcinogenesis In a 2-year carcinogenicity study, abaloparatide was administered once daily to male and female Fischer rats by subcutaneous injection at doses of 10, 25, and 50 mcg/kg. These doses resulted in systemic exposures to abaloparatide that were 4, 16, and 28 times, respectively, the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons). Neoplastic changes related to treatment with abaloparatide consisted of marked dose-dependent increases in osteosarcoma and osteoblastoma incidence in all male and female dose groups. The incidence of osteosarcoma was 0-2% in untreated controls and reached 87% and 62% in male and female high-dose groups, respectively. The bone neoplasms were accompanied by marked increases in bone mass. The relevance of the rat findings to humans is uncertain. The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma [see Warnings and Precautions ( 5.2 )] . Mutagenesis Abaloparatide was not genotoxic or mutagenic in a standard battery of tests including the Ames test for bacterial mutagenesis, the chromosome aberration test using human peripheral lymphocytes, and the mouse micronucleus test. Impairment of Fertility Abaloparatide effects on female fertility have not been assessed nonclinically. No adverse effects of abaloparatide on male fertility were observed in male rats. In a male rat fertility study, abaloparatide was administered via subcutaneous injection 2 weeks prior to mating, through the mating period and for approximately 2 weeks after the mating period (for total of 6 weeks) at doses of 10, 25 and 70 µg/kg/day. Abaloparatide did not cause adverse effect on mating, fertility indices, conception rate, reproductive organ weights or sperm parameters up to 70 µg/kg/day (28-fold the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons).

Risk Summary TYMLOS is not indicated for use in females of reproductive potential. There are no human data with TYMLOS use in pregnant women to inform any drug associated risks. Animal reproduction studies with abaloparatide have not been conducted.

Safety and effectiveness of TYMLOS have not been established in pediatric patients. TYMLOS is not recommended for use in pediatric patients with open epiphyses or hereditary disorders predisposing to osteosarcoma because of an increased baseline risk of osteosarcoma [see Warnings and Precautions ( 5.2 )] .

Of the total number of patients in the postmenopausal osteoporosis clinical studies of TYMLOS, 82% were age 65 years and over, and 19% were age 75 years and over. In the male osteoporosis study, 74% were age 65 years and over and 23% were age 75 years or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

The following adverse reactions are described in greater detail in other sections: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Risk of Osteosarcoma [see Warnings and Precautions (5.2) ] Orthostatic Hypotension [see Warnings and Precautions ( 5.3 )] Hypercalcemia [see Warnings and Precautions ( 5.4 )] Hypercalciuria and Urolithiasis [see Warnings and Precautions ( 5.5 )] 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 ( 5.3 )] . 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 ( 5.4 )] . 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 ( 5.3 )] . Laboratory Abnormalities Hypercalcemia In the clinical trial of men with osteoporosis, TYMLOS caused increases in serum calcium concentrations [see Warnings and Precautions ( 5.4 )] . 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 Constipation, diarrhea, vomiting Asthenia, lethargy, malaise 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

In a clinical study, accidental overdose was reported in a patient who received 400 mcg in one day (5 times the recommended clinical dose); dosing was temporarily interrupted. The patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day the patient's serum calcium was within the normal range. The effects of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Overdos age Management There is no specific antidote for TYMLOS. Treatment of suspected overdose should include discontinuation of TYMLOS, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable.