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.

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 )

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 )] .

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. […]

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

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 )] .

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 )] .