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.

2.1 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.

5.1 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.

5.2 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)].

5.3 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)].

5.4 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)].

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.

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
• Muscle spasms of the leg and back
• Injection site reactions including bruising, hemorrhage, pruritus, and rash

8.1 Pregnancy

8.2 Lactation

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 (5.1)].

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 (Cmax) 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)].

Overdosage 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.

12.1 Mechanism of Action

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)].

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Following seven days of subcutaneous administration of abaloparatide 80 mcg, the mean (SD) abaloparatide exposure was 812 (118) pg/mL for Cmax and 1622 (641) pg∙hr/mL for AUC0–24 in postmenopausal women with osteoporosis.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of abaloparatide or of other abaloparatide products.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and Pharmacology

In toxicity studies in rats and monkeys of up to 26-week and 39-week duration, respectively, findings included vasodilation, increases in serum calcium, decreases in serum phosphorus, and soft tissue mineralization at doses ≥10 mcg/kg/day. The 10 mcg/kg/day dose resulted in systemic exposures to abaloparatide in rats and monkeys that were 2 and 3 times, respectively, the exposure in humans at daily subcutaneous doses of 80 mcg.

Pharmacologic effects of abaloparatide on the skeleton were assessed in 12- and 16-month studies in ovariectomized (OVX) rats and monkeys, at doses up to 11- and 1-times human exposure at the recommended subcutaneous dose of 80 mcg, respectively (based on AUC comparisons). In these animal models of postmenopausal osteoporosis, treatment with abaloparatide resulted in dose-dependent increases in bone mass at vertebral and/or nonvertebral sites, correlating with increases in bone strength. The anabolic effect of abaloparatide was due to the predominant increase in osteoblastic bone formation and was evidenced by increases in trabecular thickness and/or cortical thickness due to endosteal bone apposition. Abaloparatide maintained or improved bone quality at all skeletal sites evaluated and did not cause any mineralization defects.

In an 8-week study in androgen-deficient orchiectomized (ORX) male rats, a male osteoporosis model, the effects of 5 and 25 mcg/kg/day abaloparatide (≥47-fold clinical exposures by AUC) were examined on bone formation, bone mass, and bone strength. Abaloparatide induced bone formation and improved cortical and trabecular BMD, geometry, and architecture without increasing parameters of bone resorption.

14.1 Efficacy Study in Women with Postmenopausal Osteoporosis

The efficacy of TYMLOS for the treatment of postmenopausal osteoporosis was evaluated in Study 003 (NCT 01343004), an 18-month, randomized, multicenter, double-blind, placebo-controlled clinical trial in postmenopausal women aged 49 to 86 years (mean age of 69) who were randomized to receive TYMLOS 80 mcg (N = 824) or placebo (N = 821) given subcutaneously once daily. Approximately 80% of patients were Caucasian, 16% were Asian, and 3% were Black; 24% were Hispanic. At baseline, the mean T-scores were -2.9 at the lumbar spine, -2.1 at the femoral neck, and -1.9 at the total hip. At baseline, 24% of patients had at least one prevalent vertebral fracture and 48% had at least one prior nonvertebral fracture. Patients took daily supplemental calcium (500 to 1000 mg) and vitamin D (400 to 800 IU).

The efficacy study was extended as Study 005 (NCT 01657162), an open-label study where patients were no longer receiving TYMLOS or placebo but were maintained in their original randomized treatment group and received 70 mg alendronate weekly, with calcium and vitamin D supplements for 6 months. Study 005 enrolled 1139 patients, representing 92% of patients who completed Study 003. This included 558 patients who had previously received TYMLOS and 581 patients who had previously received placebo. The cumulative 25-month efficacy dataset included 18 months of exposure to TYMLOS or placebo in Study 003, 1 month of no treatment, followed by 6 months of alendronate therapy in Study 005. Study 005 was then continued to complete 18 months of additional alendronate exposure during which time patients were no longer blinded to their original Study 003 treatment group.

Effect on Nonvertebral Fractures

TYMLOS resulted in a significant reduction in the incidence of nonvertebral fractures at the end of the 18 months of treatment plus 1 month follow-up where no drug was administered (2.7% for TYMLOS-treated patients compared to 4.7% for placebo-treated patients). The relative risk reduction in nonvertebral fractures for TYMLOS compared to placebo was 43% (logrank test p = 0.049) and the absolute risk reduction was 2.0%.

Following 6 months of alendronate treatment in Study 005, the cumulative incidence of nonvertebral fractures at 25 months was 2.7% for women in the prior TYMLOS group compared to 5.6% for women in the prior placebo group (Figure 1). At 25 months, the relative risk reduction in nonvertebral fractures was 52% (logrank test p = 0.017) and the absolute risk reduction was 2.9%.

Figure 1: Cumulative Incidence of Nonvertebral Fractures1 over 25 Months (Intent to Treat Population)2

TYMLOS demonstrated consistent reductions in the risk of vertebral and nonvertebral fractures regardless of age, years since menopause, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline.

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1

Excludes fractures of the sternum, patella, toes, fingers, skull and face and those associated with high trauma.

2

Includes patients randomized in Study 003

14.2 Men with Osteoporosis

The efficacy of TYMLOS for the treatment of men with osteoporosis was evaluated in Study 019 (NCT 03512262), a 12-month, randomized, multicenter, double-blind, placebo-controlled clinical trial in men aged 42 to 85 years (mean age of 68) who were randomized to receive TYMLOS 80 mcg (N = 149) or placebo (N = 79) given subcutaneously once daily. Approximately 95% of patients were Caucasian, 4% were Asian, and <1% (0.4%) were Black; 16% were Hispanic. At baseline, the mean T-scores were -2.1 at the lumbar spine, -2.1 at the femoral neck, and -1.7 at the total hip. Patients took daily supplemental calcium (500 to 1000 mg) and vitamin D (400 to 800 IU).

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.

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 (5.1)].

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 (5.3)].

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)].

Hypersensitivity Reactions

Advise patients to seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction including anaphylaxis, dyspnea, or urticaria [see Contraindications (4) and Adverse Reactions (6.2)].

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 © 2023, Radius Health, Inc. All rights reserved.

Revised: December 2023
US-PI-000001-v10.0