Abaloparatide

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.

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.

Injection: 3120 mcg/1.56 mL (2000 mcg/mL) of abaloparatide in clear, colorless solution in a single-patient-use prefilled pen. The prefilled pen delivers 30 doses of TYMLOS, each containing 80 mcg of abaloparatide in 40 mcL. Injection: 3120 mcg/1.56 ml (2000 mcg/ml) of abaloparatide in clear, colorless solution in a single-patient-use prefilled pen. The prefilled pen delivers 30 daily doses of 80 mcg abaloparatide in 40 mcl. ( 3 )

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 )

5 WARNINGS AND PRECAUTIONS 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 )] .

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

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.

8.1 Pregnancy 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.

8.2 Lactation Risk Summary TYMLOS is not indicated for use in females of reproductive potential. There is no information on the presence of abaloparatide in human milk, the effects on the breastfed infant, or the effects on milk production.

8.4 Pediatric Use 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 )] .

8.5 Geriatric Use 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.

8.6 Renal Impairment No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. A study of a single dose of TYMLOS 80 mcg given subcutaneously was conducted in subjects with normal renal function or mild, moderate, or severe renal impairment. The maximal concentration (C max ) and area under the concentration-time curve (AUC) of abaloparatide increased 1.4- and 2.1-fold, respectively, in subjects with severe renal impairment, compared to subjects with normal renal function. Patients with severe renal impairment may have increased abaloparatide exposure that may increase the risk of adverse reactions; therefore, monitor for adverse reactions [see Clinical Pharmacology ( 12.3 )] .

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.

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.

Abaloparatide is a PTHrP(1-34) analog which acts as an agonist at the PTH1 receptor (PTH1R). This results in activation of the cAMP signaling pathway in target cells. Once-daily administration of abaloparatide stimulates new bone formation on trabecular and cortical bone surfaces by stimulation of osteoblastic activity. In rats and monkeys, abaloparatide had an anabolic effect on bone, demonstrated by increases in BMD and bone mineral content (BMC) that correlated with increases in bone strength at vertebral and/or nonvertebral sites [see Nonclinical Toxicology ( 13.2 )] .

Effects on Markers of Bone Turnover A dose-finding study of abaloparatide administered once daily for 24 weeks in postmenopausal women with osteoporosis demonstrated a dose-response relationship for BMD and bone formation markers. Daily administration of TYMLOS to postmenopausal women with osteoporosis for 18 months increased the bone formation marker serum procollagen type I N-propeptide (sPINP) and the bone resorption marker serum collagen type I cross-linked C-telopeptide (sCTX). The increase in geometric mean sPINP levels peaked at Month 1 at 93% above baseline in postmenopausal women then decreased slowly over time to 45% above baseline at Month 18. The increase in geometric mean sCTX levels in postmenopausal women peaked at Month 3 at 26% above baseline then decreased to baseline levels by Month 18. Daily administration of TYMLOS to men with osteoporosis for 12 months increased the bone formation marker sPINP and the bone resorption marker sCTX. The increase in geometric mean sPINP levels peaked at Month 1 at 133% above baseline in men then decreased slowly over time to 84% above baseline at Month 12. The increase in geometric mean sCTX levels in men peaked at Month 6 at 46% above baseline and was 35% above baseline by Month 12. Cardiac Electrophysiology A 4-way cross-over thorough QT/QTc study was conducted in 55 healthy subjects who received single doses of placebo, subcutaneous doses of abaloparatide at 80 mcg and 240 mcg (three times the recommended dose), and moxifloxacin 400 mg orally. Abaloparatide increased heart rate, with a mean peak increase of 15 beats per minute (bpm) and 20 bpm at the first time point (15 minutes) after dosing with 80 mcg and 240 mcg, respectively. There were no clinically meaningful effects of abaloparatide on QTcI (individually corrected QT intervals) or cardiac electrophysiology.

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.

, Mutagenesis, Impairment of Fertility 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).

17 PATIENT COUNSELING INFORMATION 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

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.