Tymlos

TYMLOS — abaloparatide injection, solution
Radius Health, Inc.

WARNING: RISK OF OSTEOSARCOMA

  • Abaloparatide caused a dose-dependent increase in the incidence of osteosarcoma (a malignant bone tumor) in male and female rats. The effect was observed at systemic exposures to abaloparatide ranging from 4 to 28 times the exposure in humans receiving the 80 mcg dose. It is unknown if TYMLOS will cause osteosarcoma in humans [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
  • The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, bone metastases or skeletal malignancies, hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton [see Warnings and Precautions (5.1)].
  • Cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

TYMLOS is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture defined as a history of osteoporotic fracture, 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 [ see Clinical Studies (14)].

Limitations of Use

Because of the unknown relevance of the rodent osteosarcoma findings to humans, cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended [see Warnings and Precautions (5.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

  • The recommended dosage of TYMLOS is 80 mcg subcutaneously once daily.
  • Cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended [see Warnings and Precautions (5.1)].
  • 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)].
  • TYMLOS is a clear and colorless solution. Visually inspect TYMLOS for particulate matter and discoloration prior to administration. 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.

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

TYMLOS is contraindicated in patients with a history of systemic hypersensitivity to abaloparatide or to any component of the product formulation. Reactions have included anaphylaxis, dyspnea and urticaria [see Adverse Reactions (6.3)].

5 WARNINGS AND PRECAUTIONS

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.

The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, bone metastases or skeletal malignancies, hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton.

Cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended.

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 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)]

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.

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)].

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 (10% vs. 3%) and pain (9% 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)].

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