Tymlos

• Generic Name: abaloparatide injection
• Brand Name: Tymlos

side effects drug center tymlos (abaloparatide injection) drug

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PROFESSIONAL

CONSUMER

SIDE EFFECTS

Contents

• Drug Description
• Indications & Dosage
• Side Effects & Drug Interactions
• Warnings & Precautions
• Overdosage & Contraindications
• Clinical Pharmacology
• Medication Guide

Drug Description

What is TYMLOS and how is it used?

TYMLOS is a prescription medicine used to:

• decrease the chance of having a fracture of the spine and other bones in postmenopausal women with thinning and weakening bones (osteoporosis).
• treat osteoporosis in postmenopausal women who are at high risk for bone fracture.

It is not known if TYMLOS is safe and effective for children 18 years and younger.

It is not recommended that people use TYMLOS for more than 2 years during their lifetime.

TYMLOS should not be used in children and young adults whose bones are still growing.

What are the possible side effects of TYMLOS?

TYMLOS can cause serious side effects including:

• See " What is the most important information I should know about TYMLOS?" at the end of this Medication Guide.
• Decrease in blood pressure when you change positions. Some people may feel dizzy, have a faster heartbeat, or feel lightheaded soon after the TYMLOS injection is given. These symptoms generally go away within a few hours. Take your injections of TYMLOS in a place where you can sit or lie down right away if you get these symptoms. If your symptoms get worse or do not go away, stop taking TYMLOS and call your healthcare provider.
• Increased blood calcium (hypercalcemia). TYMLOS can cause some people to have a higher blood calcium level than normal. Your healthcare provider may check your blood calcium before you start and during your treatment with TYMLOS. Tell your healthcare provider if you have nausea, vomiting, constipation, low energy, or muscle weakness. These may be signs there is too much calcium in your blood.
• Increased urine calcium (hypercalciuria). TYMLOS can cause some people to have higher levels of calcium in their urine than normal. Increased calcium may also cause you to develop kidney stones (urolithiasis) in your kidneys, bladder or urinary tract. Tell your healthcare provider right away if you get any symptoms of kidney stones which may include pain in your lower back or lower stomach area, pain when you urinate, or blood in your urine.

The most common side effects of TYMLOS include:

• dizziness
• nausea
• headache
• fast heartbeat
• feeling very tired (fatigue)
• upper stomach pain
• vertigo

These are not all the possible side effects of TYMLOS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

WARNING

RISK OF OSTEOSARCOMA

• Abaloparatide caused a dos e-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 dos e. It is unknown if TYMLOS will cause osteosarcomain humans [see WARNINGS AND PRECAUTIONS and Nonclinical Toxicology].
• 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].
• Cumulative us e 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].

 

DESCRIPTION

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 C₁₇₄H₃₀₀N₅₆O₄₉ 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-NH₂

TYMLOS injection is supplied as a sterile, colorless, clear solution in a glass cartridge which is preassembled 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. Each mL contains 2000 mcg abaloparatide and the following inactive ingredients: 5 mg phenol, 5.08 mg sodium acetate trihydrate, 6.38 mg acetic acid, and water for injection.

 

Indications & Dosage

INDICATIONS

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].

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].

 

DOSAGE AND ADMINISTRATION

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].
• Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate.

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 and ADVERSE REACTIONS].
• 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.

 

HOW SUPPLIED

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.

TYMLOS injection is supplied 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) of sterilized, clear, colorless fluid. Each pen provides a 30-day supply for once daily injection of 80 mcg abaloparatide in 40 mcL.

Sterile needles are not included.

Storage And Handling

• Before first use, store TYMLOS in a refrigerator 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.

Manufactured in Germany for: Radius Health, Inc., 950 Winter Street, Waltham, MA 02451. Revised: Oct 2020

 

Side Effects & Drug Interactions

SIDE EFFECTS

The following adverse reactions are described in greater detail in other sections:

• Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS]
• Hypercalcemia [see WARNINGS AND PRECAUTIONS]
• Hypercalciuria and Urolithiasis [see WARNINGS AND PRECAUTIONS]

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, placebocontrolled 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].

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*

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
* Adverse reactions reported in ≥2% of TYMLOS-treated patients.

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].

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 dosedependent increase in heart rate which developed within 15 minutes after injection and resolved in about 6 hours [see CLINICAL PHARMACOLOGY].

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]. 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].

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TYMLOS in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Of the patients receiving TYMLOS for 18 months, 49% (300/610) developed anti-abaloparatide antibodies, of these, 68% (201/297) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, 2.3% (7/298) developed cross-reactivity to PTHrP, 43% (3/7) developed neutralizing antibodies to PTHrP, and 0% (0/298) developed cross-reactive antibodies to PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including bone mineral density (BMD) response, fracture reduction, immune-related hypersensitivity or allergic reactions, or other adverse events.

Most of the patients with anti-abaloparatide antibodies during treatment with TYMLOS, 85% (256/300), had follow-up antibody measurements six months after completion of TYMLOS therapy. Among these patients, 56% (143/256) remained antibody positive.

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

 

DRUG INTERACTIONS

No specific drug-drug interaction studies have been performed [see CLINICAL PHARMACOLOGY].

 

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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]. 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.

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].

Hypercalcemia

TYMLOS may cause hypercalcemia. TYMLOS is not recommended in patients with preexisting hypercalcemia or in patients who have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, because of the possibility of exacerbating hypercalcemia [see ADVERSE REACTIONS].

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].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

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].

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].

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].

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 and ADVERSE REACTIONS].

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]. 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].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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].

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.

Use In Specific Populations

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.

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.

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].

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. 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.

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].

 

Overdosage & Contraindications

OVERDOSE

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.

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.

 

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].

 

Clinical Pharmacology

CLINICAL PHARMACOLOGY

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. 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].

Pharmacodynamics

Effects On Markers Of Bone Turnover

A dose-finding study of abaloparatide administered once daily for 24 weeks demonstrated a dose-response relationship for BMD and bone formation markers.

Daily administration of TYMLOS to postmenopausal women with osteoporosis in clinical studies increased the bone formation marker serum procollagen type I N-propeptide (PINP). The increase in PINP levels peaked at Month 1 at 93% above baseline then decreased slowly over time. The increase in PINP was maintained above baseline throughout the treatment duration. At Month 18, PINP concentrations were approximately 45% above baseline. The increase in the bone resorption marker serum collagen type I cross-linked C-telopeptide (sCTX) peaked at Month 3 at 43% above baseline then decreased to 20% above baseline by Month 18.

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.

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.

Figure 1 below shows the mean (SD) abaloparatide pharmacokinetic profile in postmenopausal women (N = 8) on Day 7.

Figure 1: Mean Abaloparatide Pharmacokinetic Profile in Postmenopausal Women on Day 7

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

The mean (SD) half-life of abaloparatide is 1.7 (0.7) hrs. 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

Geriatric Patients

No age-related differences in abaloparatide pharmacokinetics were observed in postmenopausal women ranging from 49 to 86 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 Cmax 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.

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.

Clinical Studies

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, placebocontrolled 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 New Vertebral Fractures

The primary endpoint was the incidence of new vertebral fractures in patients treated with TYMLOS compared to placebo. TYMLOS resulted in a significant reduction in the incidence of new vertebral fractures compared to placebo at 18 months (0.6% TYMLOS compared to 4.2% placebo, p <0.0001). The absolute risk reduction in new vertebral fractures was 3.6% at 18 months and the relative risk reduction was 86% for TYMLOS compared to placebo (Table 2). The incidence of new vertebral fractures at 25 months was 0.6% in patients treated with TYMLOS then alendronate, compared to 4.4% in patients treated with placebo then alendronate  (p <0.0001). The relative risk reduction in new vertebral fractures at 25 months was 87% for patients treated with TYMLOS then alendronate, compared to patients treated with placebo then alendronate, and the absolute risk reduction was 3.9% (Table 2). After 24 months of open-label alendronate therapy, the vertebral fracture risk reduction achieved with TYMLOS therapy was maintained.

Table 2: Percentage of Postmenopausal Women with Osteoporosis with New Vertebral Fractures (modified Intent to Treat population)*†

	Percentage of Postmenopausal Women With Fractures		Absolute Risk Reduction (%) (95% CI‡)	Relative Risk Reduction (%) (95% CI‡)
	TYMLOS (N=690*) (%)	Placebo (N=711*) (%)
0-18 months	0.6	4.2	3.6 (2.1, 5.4)	86 (61, 95)
	TYMLOS/ Alendronate (N=544†) (%)	Placebo/ Alendronate (N=568†) (%)
0-25 months	0.6	4.4	3.9 (2.1, 5.9)	87 (59, 96)
* Includes patients who had both pre- and post-treatment spine radiographs in Study 003 † Includes patients who had both pre- and post-treatment spine radiographs in Study 005 ‡ Confidence Interval

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 2). 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  2 : Cumulative Incidence of Novertebral Fractures* Over 25 Months (Intent to Treat Population)†

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.

Effect On Bone Mineral Density (BMD)

Treatment with TYMLOS for 18 months in Study 003 resulted in significant increases in BMD compared to placebo at the lumbar spine, total hip and femoral neck, each with p<0.0001 (Table 3). Similar findings were seen following 6 months of alendronate treatment in Study 005 (Table 3).

Table 3: Mean Percent Changes in Bone Mineral Density (BMD) From Baseline to Endpoint in Postmenopausal Women with Osteoporosis (Intent to Treat Population)*† ‡

	TYMLOS (N=824*) (%)	Placebo (N=821*) (%)	Treatment Difference (%) (95% CI§)
18 Months
Lumbar Spine	9.2	0.5	8.8 (8.2, 9.3)
Total Hip	3.4	-0.1	3.5 (3.3, 3.8)
Femoral Neck	2.9	-0.4	3.3 (3.0, 3.7)
	TYMLOS/ Alendronate (N=558†) (%)	Placebo/ Alendronate (N=581†) (%)
25 Months
Lumbar Spine	12.8	3.5	9.3 (8.6, 10.1)
Total Hip	5.5	1.4	4.1 (3.7, 4.5)
Femoral Neck	4.5	0.5	4.1 (3.6, 4.6)
* Includes patients randomized in Study 003 † Includes patients enrolled in Study 005 ‡ Last-observation-carried-forward § Confidence Interval

TYMLOS demonstrated consistent increases in BMD regardless of age, years since menopause, race, ethnicity, geographic region, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline.

Effect On Bone Histology

Bone biopsy specimens were obtained from 71 patients with osteoporosis after 12 – 18 months of treatment (36 in the TYMLOS group and 35 in the placebo group). Of the biopsies obtained, 55 were adequate for quantitative histomorphometry assessment (27 in the TYMLOS group and 28 in the placebo group). Qualitative and quantitative histology assessment showed normal bone architecture and no evidence of woven bone, marrow fibrosis, or mineralization defects.

 

Medication Guide

PATIENT INFORMATION

TYMLOS®
(tim lows’)
(abaloparatide) injection, for subcutaneous use

What is the most important information I should know about TYMLOS?

TYMLOS may cause serious side effects including:

• Possible bone cancer (osteosarcoma). During animal drug testing, TYMLOS caused some rats to develop a bone cancer called osteosarcoma. It is not known if people who take TYMLOS will have a higher chance of getting osteosarcoma.
  • Tell your healthcare provider right away if you have pain in your bones, pain in any areas of your body that does not go away, or any new or unusual lumps or swelling under your skin that is tender to touch.

What is TYMLOS?

TYMLOS is a prescription medicine used to:

• decrease the chance of having a fracture of the spine and other bones in postmenopausal women with thinning and weakening bones (osteoporosis).
• treat osteoporosis in postmenopausal women who are at high risk for bone fracture.

It is not known if TYMLOS is safe and effective for children 18 years and younger.

It is not recommended that people use TYMLOS for more than 2 years during their lifetime.

TYMLOS should not be used in children and young adults whose bones are still growing.

Do not take TYMLOS:

• if you had an allergic reaction to abaloparatide, or any of the other ingredients in TYMLOS. See the end of this Medication Guide for a complete list of ingredients in TYMLOS.

Before you take TYMLOS, tell your healthcare provider about all of your medical conditions, including if you:

• have Paget’s disease of the bone or other bone disease.
• have or have had cancer in your bones.
• have or have had radiation therapy involving your bones.
• have or have had too much calcium in your blood.
• have or have had too much of an enzyme called alkaline phosphatase in your blood.
• have or have had an increase in your parathyroid hormone (hyperparathyroidism).
• will have trouble injecting yourself with the TYMLOS pen and do not have someone who can help you.
• are pregnant or plan to become pregnant. TYMLOS is not for pregnant women.
• are breastfeeding or plan to breastfeed. It is not known if TYMLOS passes into your breast milk. You and your healthcare provider should decide if you will take TYMLOS or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist each time you get a new medicine.

How should I use TYMLOS?

• Read the detailed Instructions for Use provided with your medicine.
• Use TYMLOS exactly as your healthcare provider tells you to use it.
• Do not try to inject TYMLOS yourself until you or your caregiver receive training from a healthcare provider on the right way to use the TYMLOS pen.
• You should receive your first several injections of TYMLOS where you can sit or lie down if necessary, until you know how it affects you.
• Inject TYMLOS 1 time each day into your lower stomach area (abdomen) just under your skin (subcutaneous). Avoid giving your injection within the 2-inch area around your belly button (navel).
• Talk to your healthcare provider about how to change (rotate) your injection site for each injection. Do not give TYMLOS in your veins (intravenously) or deep into your muscles (intramuscularly).
• You can take TYMLOS with or without food or drink.
• Take TYMLOS at about the same time each day.
• If you forget or cannot take TYMLOS at your usual time, take it as soon as you can on that day.
• The TYMLOS pen has enough medicine for 30 days. It is set to give 1 dose of medicine with each injection. Do not take more than 1 injection in the same day.
• Do not transfer the medicine from the TYMLOS pen to a syringe. This can cause you to use the wrong dose of TYMLOS. If you do not have pen needles to use with your TYMLOS pen, talk with your healthcare provider.
• Do not share your TYMLOS pen or pen needles with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.
• TYMLOS should look clear and colorless. Do not use TYMLOS if it has particles in it, or if it is cloudy or colored.
• Your healthcare provider may do blood and urine tests during your treatment with TYMLOS.
• Your healthcare provider may ask you to have a bone mineral density test after your treatment with TYMLOS.
• If you take more TYMLOS than prescribed you may have symptoms such as muscle weakness, low energy, headache, nausea, dizziness (especially when getting up after sitting for a while) and a faster heartbeat. Stop taking TYMLOS and call your healthcare provider right away.
• If your healthcare provider recommends calcium and vitamin D supplements, you can take them while using TYMLOS.

What are the possible side effects of TYMLOS?

TYMLOS may cause serious side effects including:

• See “What is the most important information I should know about TYMLOS?”
• Decrease in blood pressure when you change positions. Some people may feel dizzy, have a faster heartbeat, or feel lightheaded soon after the TYMLOS injection is given. These symptoms generally go away within a few hours. Take your injections of TYMLOS in a place where you can sit or lie down right away if you get these symptoms. If your symptoms get worse or do not go away, stop taking TYMLOS and call your healthcare provider.
• Increased blood calcium (hypercalcemia). TYMLOS can cause some people to have a higher blood calcium level than normal. Your healthcare provider may check your blood calcium before you start and during your treatment with TYMLOS. Tell your healthcare provider if you have nausea, vomiting, constipation, low energy, or muscle weakness. These may be signs there is too much calcium in your blood.
• Increased urine calcium (hypercalciuria). TYMLOS can cause some people to have higher levels of calcium in their urine than normal. Increased calcium may also cause you to develop kidney stones (urolithiasis) in your kidneys, bladder or urinary tract. Tell your healthcare provider right away if you get any symptoms of kidney stones which may include pain in your lower back or lower stomach area, pain when you urinate, or blood in your urine.

The most common side effects of TYMLOS include:

• dizziness
• fast heartbeat
• upper stomach pain
• nausea
• feeling tired (fatigue)
• spinning feeling (vertigo)
• headache

These are not all the possible side effects of TYMLOS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store TYMLOS?

• Before first use, store TYMLOS pens in the refrigerator between 36°F to 46°F (2°C to 8°C).
• After first use, store your TYMLOS pen for up to 30 days at room temperature between 68°F to 77°F (20°C to 25°C).
• Do not freeze the TYMLOS pen or expose it to heat.
• Do not use TYMLOS after the expiration date printed on the pen and packaging.
• Throw away the TYMLOS pen after 30 days even if some medicine is left in the pen (see “Instructions for Use”). Keep TYMLOS and all medicines out of the reach of children.

General information about the safe and effective use of TYMLOS.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TYMLOS for a condition for which it was not prescribed. Do not give TYMLOS to other people, even if they have the same condition you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about TYMLOS that is written for health professionals.

What are the ingredients in TYMLOS?

Active ingredient: abaloparatide

Inactive ingredients: phenol, sodium acetate trihydrate, acetic acid, and water for injection.

This Medication Guide has been approved by the U.S. Food and Drug Administration.