Abaloparatide is an analog of human parathyroid hormone related peptide, PTHrP (1-34). It is used for the treatment of postmenopausal women or men 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. Compared to placebo, lumber spine and total hip bone mineral density increased by 11.2% and 4.2%, respectively, with abaloparatide 80 mg after 18 months of treatment in postmenopausal women. Risks of vertebral and nonvertebral fracture were reduced by 86% and 43%, respectively. The fracture prevention benefits were maintained for 2 years after treatment when patients were switched to alendronate. In postmenopausal women, bone mineral density gains in the femoral neck, total hip, and one-third radius were greater with abaloparatide compared with teriparatide. The incidence of major osteoporosis-related fractures was significantly reduced with abaloparatide compared to teriparatide; however, overall fracture reduction was not significantly different between the 2 treatments. Compared to placebo, significant increases bone mineral density occurred with abaloparatide treatment for 12 months in men with osteoporosis, with treatment differences of 7.3% (95% CI 5.1 to 9.6) at the lumbar spine, 2.1% (95% CI 1 to 3.2) at the total hip, and 2.8% (95% CI 1.4 to 4.2) at the femoral neck. The cumulative use of abaloparatide for more than 2 years during a patient's lifetime is not recommended.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Subcutaneous Administration
General Information
-For subcutaneous use only. Do not administer intravenously or intramuscularly.
-Abaloparatide is available as a prefilled pen (TYMLOS pen) containing 30 doses of abaloparatide (each dose contains 80 mcg in 40 mcL).
-Needles are NOT included with the pen. The patient will need a separate prescription for the needles. The correct needles to use with the pen are 5 mm to 8 mm, 31-gauge. Compatible needles include Clickfine, BD Ultra-Fine, MedtFine, Easy Comfort, Clever Choice, Comfort EZ, and SureComfort.
-Abaloparatide pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting. Reserve the use of any pen for 1 patient only.
-Storage: Prior to the first use, store the pen in the refrigerator (do not freeze). After the first use, store the pen for up to 30 days at room temperature between 68 to 77 degrees F (20 to 25 degrees C); do not freeze the pen or expose it to heat. Keep the pen cap on the pen when not in use. Do not store the pen with a needle attached. Use the pen only for 30 days. Properly dispose of the pen 30 days after first opening it even if it still contains unused medicine.
Subcutaneous Administration (TYMLOS Pen)
-Patients and caregivers should receive proper training and instruction on the proper use of the abaloparatide pen.
-Pull off the pen cap from the pen. Keep the pen cap for storage between injections. Check the pen cartridge. The liquid should be clear, colorless, and free of particles; if not, do not use.
-Keep the needle straight and screw it onto the pen until fixed; a secure fit is ensured even if there is no noticeable stop. Do not over-tighten.
-Pull off the outer pen needle cap from the pen needle and keep it to re-cap the needle after the injection.
-Carefully pull off the inner pen needle cap and dispose of it.
-Each new pen must be primed prior to the first use only. This step removes air bubbles from the pen.-Turn the dose knob on the pen away from you (clockwise) until it stops. You will see "80" lined up in the dose display window.
-Hold the pen with the pen needle pointing up. Tap lightly with your finger on the cartridge holder to move any air bubbles in the cartridge to the top of the cartridge.
-Press the green injection button until it will not go any further. You will see "0" lined up in the dose display window. A drop of liquid should come out of the needle tip. If not, repeat the priming steps.
-Set the patient's dose on the pen by turning the dose knob on the pen away from you (clockwise) until the dose knob stops and "80" is lined up in the dose display window.
-Choose and clean an injection site in the periumbilical region of the abdomen. Avoid the 2-inch area around the navel. Do not inject into areas where the skin is tender, bruised, red, scaly, or hard. Avoid areas with scars or stretch marks.
-Insert the pen needle straight into the patient's skin.
-Press the green injection button on the pen until it cannot go any further and "0" is in the dose display window. Do not move the pen after inserting the needle.
-Continue to press the green injection button while counting to 10. Counting to 10 will allow the full dose to be given.
-After counting to 10, release the green injection button and slowly remove the pen from the injection site by pulling the pen needle straight out.
-Carefully place the outer needle cap back on the pen needle. Press on the outer needle cap until it snaps into place and is secure.
-Unscrew the used, capped needle from the pen. To unscrew the capped needle you may need to turn it 8 or more turns and then gently pull until the capped needle comes off. Properly dispose of the used needle.
-Firmly replace the pen cap onto the pen. Keep the pen cap on the pen for storage between injections.
-Rotate site of injection daily and administer at approximately the same time every day.
-The first several doses should be administered with the patient laying down in case symptoms of orthostatic hypotension occur.
Orthostatic hypotension has been reported with the use of abaloparatide. During clinical trials of women with postmenopausal osteoporosis, the incidence of orthostatic systolic blood pressure decline of 20 mmHg or more or diastolic decline of 10 mmHg or more at 1 hour after the first injection was 4% in the abaloparatide group compared to 3% in the placebo group. The incidence of orthostatic blood pressure decline was similar between groups at later time points. Orthostatic hypotension was reported as an adverse reaction in 1% of women receiving abaloparatide compared to 0.5% of placebo. In men with osteoporosis, orthostatic blood pressure declines of 20 mmHg or more systolic and 10 mmHg or more diastolic 1 hour after the first injection occurred in 6% of patients who received abaloparatide compared to 3% who received placebo. Orthostatic hypotension was reported as an adverse reaction in 1% of men receiving abaloparatide and no patients receiving placebo. Dizziness was reported by more than 10% of postmenopausal women in the abaloparatide group compared to 6% placebo and was one of the most common adverse reactions leading to study drug discontinuation (1%). Dizziness was reported in 9% of men with osteoporosis treated with abaloparatide (n = 149) compared to 1% of men treated with placebo (n = 79) during a randomized, double-blind trial, and dizziness was the most common adverse reaction that led to treatment discontinuation (2%).
During clinical trials of abaloparatide in women with postmenopausal osteoporosis, sinus tachycardia was reported in 2% of patients receiving abaloparatide compared to 1% of those in the placebo group. In 5 of the 13 women who experienced tachycardia with abaloparatide, symptoms occurred within 1 hour of administration. A dose-dependent increase in heart rate has been associated with abaloparatide beginning within 15 minutes after injection and resolving within 6 hours. Palpitations were reported in 5% of patients treated with abaloparatide in clinical trials compared to 0.4% of those receiving placebo and were one of the most common adverse reactions leading to study drug discontinuation (1%).
Hypersensitivity reactions, including anaphylaxis, anaphylactoid reactions, dyspnea, pruritus, and rash have been reported during postmarketing experience with abaloparatide.
Injection site reaction occurred during placebo-controlled clinical trials. Injection site redness (58%), edema (10%), and pain (9%) were reported at incidences greater than placebo in clinical trials with postmenopausal women. Redness, edema, and pain were reported as severe in 2.9%, 0.4%, and 0.4% of abaloparatide of patients, respectively. Reactions reported during abaloparatide treatment in men with osteoporosis include erythema (13%), swelling (7%), and pain (6%). Injection site reactions including bruising, hemorrhage, pruritus, and rash have been reported during postmarketing experience with abaloparatide.
Hypercalcemia can occur with the administration of abaloparatide. During clinical trials of women with postmenopausal osteoporosis, hypercalcemia (defined as albumin-corrected serum calcium 10.7 mg/dL or greater 4 hours after injection) occurred in 3% of patients receiving abaloparatide and at an incidence higher than placebo (0.1%). Baseline serum calcium was similar in both groups. The incidence of hypercalcemia was higher in women with mild or moderate renal impairment (4%) compared to those with normal renal function (1%). In men with osteoporosis, hypercalcemia (defined as albumin-corrected serum calcium 10.8 mg/dL or greater 4 hours after injection) occurred in 3% of patients receiving abaloparatide. No patients receiving placebo experienced hypercalcemia, and baseline serum calcium was similar in both groups. The incidence of hypercalcemia was higher in men with mild or moderate renal impairment (4%) compared to those with normal renal function (0%).
Hyperuricemia may occur during the administration of abaloparatide. During the postmenopausal clinical trials, among women with normal baseline uric acid concentrations, 25% of patients receiving abaloparatide had at least 1 concentration above normal vs. placebo (6%). Among men with osteoporosis with normal baseline uric acid concentrations, 7% treated with abaloparatide had at least 1 concentration above normal vs. 6% treated with placebo. There was no difference in the incidence of gout or arthralgia between treatment groups in postmenopausal women or men.
Hypercalciuria and nephrolithiasis (urolithiasis) have been reported with the use of abaloparatide. During clinical trials of women with postmenopausal osteoporosis, hypercalciuria was reported in 11% of those receiving abaloparatide. The incidence of a urine calcium:creatinine ratio greater than 400 mg/gram was higher in those receiving abaloparatide than placebo (20% vs. 15%). Urolithiasis was reported in 2.1% of patients receiving abaloparatide and in 1.7% of the placebo group. Urolithiasis was reported in 2% of men with osteoporosis treated with abaloparatide (n = 149) compared to 1% of men treated with placebo (n = 79) during a randomized, double-blind trial. The incidence of a urine calcium: creatinine ratio of more than 400 mg/gram was not greater with abaloparatide treatment than with placebo.
During abaloparatide postmenopausal osteoporosis clinical trials, nausea was reported in 8% of patients (vs. 3% placebo) and was the most common adverse reaction leading to study drug discontinuation (2%). Upper abdominal pain was reported in 3% of patients (vs. 2% placebo). Abdominal distension, diarrhea, and nausea (each 3% abaloparatide vs. 0% placebo) and abdominal pain (2% abaloparatide vs. 0% placebo) were reported during a clinical trial in men with osteoporosis. Abdominal distension, abdominal pain, constipation, diarrhea, and vomiting have been reported during postmarketing experience with abaloparatide.
During abaloparatide postmenopausal osteoporosis clinical trials, headache was reported in 8% of those receiving abaloparatide and was one of the most common adverse reactions leading to study drug discontinuation (1%). Fatigue was reported more often in the abaloparatide group (3%) than the placebo group, and vertigo was reported in 2% of both treatment groups. Insomnia, asthenia, lethargy, and malaise have been reported during postmarketing experience with abaloparatide.
Arthralgia was reported in 7% of men with osteoporosis treated with abaloparatide (n = 149) compared to 1% of men treated with placebo (n = 79) during a randomized, double-blind trial. Other reported adverse reactions in men with osteoporosis include bone pain (2% abaloparatide vs. 0% placebo) and contusion (3% abaloparatide vs. 0% placebo). Muscle cramps (spasms) of the leg and back, bone pain, back pain, extremity pain, arthralgia, and generalized pain have been reported during postmarketing experience with abaloparatide.
Abaloparatide may increase the risk of osteogenic sarcoma (osteosarcoma), a new primary malignancy. Osteosarcoma has been reported in patients with a PTH-analog in the postmarketing setting; however, increased risk has not been observed in observational human trials. There are limited data assessing risk beyond 2 years of therapy. Abaloparatide has been associated with an increased incidence of osteosarcoma in rat studies. The increased incidence was dependent on dose and duration of treatment; systemic exposure to abaloparatide in rats ranged from 4 to 28 times the exposure given to humans in an 80 mcg daily dose. The relevance of these animal osteosarcoma findings is uncertain relative to humans; however, the potential risk should be considered. Abaloparatide use has not been evaluated beyond 2 years; use beyond 2 years is not recommended.
Of the postmenopausal women receiving abaloparatide for 18 months, 41% (318/773) developed anti-abaloparatide antibodies, and 26% (204/773) had neutralizing antibody formation to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, 2.4% (7/297) developed cross-reactivity to PTHrP and 43% (3/7) developed neutralizing antibodies to PTHrP. Only 0.3% (1/297) developed cross-reactive antibodies to PTH that were not neutralizing 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, or other adverse reactions. Most (86%) of the patients with anti-abaloparatide antibodies during treatment had follow-up antibody measurements every 6 months after completion of therapy until seroconverting to antibody negative or being lost to follow-up. Among these patients, 127 remained antibody positive at 1 year after treatment discontinuation, 55 remained antibody positive at 2 years, and 6 remained antibody positive at 3 years. After 12 moths of treatment with abaloparatide, 25% (36/142) of male patients developed anti-abaloparatide antibodies and 1.4% (2/142) had neutralizing antibody formation to abalolparatide. Among patients with with anti-abaloparatide antibodies who were tested for cross-reactivity, no patients developed cross-reactivity to PTHrP or PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including bone mineral density (BMD) response or adverse reactions.
Abaloparatide is contraindicated in patients with abaloparatide hypersensitivity. Anaphylaxis, dyspnea, and urticaria have occurred during treatment.
Use abaloparatide cautiously in patients with pre-existing orthostatic hypotension. Orthostatic hypotension may occur with the administration of abaloparatide, usually within 4 hours of injection. Symptoms include dizziness, palpitations, tachycardia or nausea. These symptoms may resolve if the patient lies down. Therefore, the first several daily doses should be administered at a location where the patient can sit or lie down if needed.
Abaloparatide may cause hypercalcemia and is not recommended in patients with pre-existing hypercalcemia or in patients who have an underlying hypercalcemic disorder (e.g., primary hyperparathyroidism) due to the possibility of exacerbating the condition. Measure serum calcium at least 16 hours after drug administration if indicated.
Avoid the use of abaloparatide in patients at increased risk of osteogenic sarcoma (osteosarcoma), including those with open epiphyses (e.g., pediatric patients), metabolic bone diseases other than osteoporosis (e.g., Paget's disease of the bone), bone metastases or a history of skeletal malignancies, prior external beam or implant radiation therapy involving the skeleton, and hereditary disorders predisposing to osteosarcoma. Osteosarcoma, as a new primary malignancy, has been reported in patients with a PTH-analog in the postmarketing setting; however, increased risk has not been observed in observational human trials. There are limited data assessing risk beyond 2 years of therapy. Abaloparatide has been associated with an increased incidence of osteosarcoma in rat studies. This increased incidence was dependent on e.g., dose and duration of treatment; systemic exposure to abaloparatide in the rats ranged from 4 to 28 times the exposure given to humans in an 80-mcg daily dose. The relevance of these animal osteosarcoma findings is uncertain relative to humans; however, the potential risk should be considered. Abaloparatide use has not been evaluated beyond 2 years; use beyond 2 years is not recommended.
Use abaloparatide cautiously in patients with active urolithiasis (nephrolithiasis) or pre-existing hypercalciuria. Abaloparatide may cause hypercalciuria. It is unknown if abaloparatide may exacerbate urolithiasis in patients with active urolithiasis or a history or nephrolithiasis. Consider measuring urinary calcium excretion if active urolithiasis or pre-existing hypercalciuria is suspected.
Patients with severe renal impairment and renal failure may have increased abaloparatide exposure. Monitor these patients for adverse reactions during abaloparatide therapy.
Abaloparatide is not indicated for women of reproductive potential. There are no human or animal data on the use of abaloparatide during pregnancy to inform any drug associated risks.
Abaloparatide is not indicated for women of reproductive potential; there is no experience with use of the drug during breast-feeding. There are no data on the presence of abaloparatide in human milk, the effects on the breast-fed infant, or the effects on milk production.
Safety and efficacy of abaloparatide has not been established in infants, children, or adolescents. Pediatric patients are more likely to have open epiphyses or hereditary disorders predisposing them to an increased risk for osteosarcoma.
Recommendations for calcium and vitamin D intake:
-To promote general bone health, guidelines for the prevention and treatment of osteoporosis recommend a target daily intake of 1,200 mg of elemental calcium for females older than 50 years. Daily vitamin D intake of 25 to 25 mcg (800 to 1,000 international units) is recommended for patients 50 years of age and older.
For the treatment of osteoporosis:
-for the treatment of postmenopausal women with osteoporosis at high risk for fracture:
Subcutaneous dosage:
Adult postmenopausal females: 80 mcg subcutaneously once daily. Reserve use for postmenopausal women at high risk for fracture, including a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Supplement calcium and vitamin D if dietary intake is inadequate. Cumulative use of abaloparatide for more than 2 years during a patient's lifetime is not recommended. Follow abaloparatide treatment with a bisphosphonate or denosumab to prevent decline of bone density and loss of efficacy against fracture. The North American Menopause Society (NAMS) recommends that use of parathyroid analogs in postmenopausal women be reserved for those patients with a high risk of fracture who do not have hypercalcemia, bone metastases, any bone tumor-predisposing disorder, or a history of skeletal irradiation.
-for the treatment of men with osteoporosis at high risk for fracture:
Subcutaneous dosage:
Adults: 80 mcg subcutaneously once daily. Reserve use for men at high risk for fracture, including a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. Supplement calcium and vitamin D if dietary intake is inadequate. Cumulative use of abaloparatide for more than 2 years during a patient's lifetime is not recommended.
Maximum Dosage Limits:
-Adults
80 mcg/day subcutaneously.
-Geriatric
80 mcg/day subcutaneously.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Abaloparatide products.
Abaloparatide is a synthetic peptide analog of the parathyroid hormone-related protein (PTHrP 1-34), which acts as an agonist at the PTH1 receptor (PTH1R) with greater selectivity than teriparatide. Binding to the PTH1R results in activation of the cAMP signaling pathway in target cells. New bone formation on trabecular and cortical bone surfaces occurs through stimulation of osteoblastic activity with once-daily administration of abaloparatide. In animal studies, abaloparatide had an anabolic effect on bone, resulting in increased bone mineral density (BMD) and bone mineral content that correlated with increases in bone strength at vertebral and/or nonvertebral sites. When administered once daily for 24 weeks, a dose-response relationship was observed for BMD and bone formation markers in postmenopausal women with osteoporosis.
Abaloparatide is administered subcutaneously. Plasma protein binding is approximately 70%, and the volume of distribution is 50 L. The half-life of abaloparatide is approximately 1 hour. No specific metabolism studies have been performed with abaloparatide. Metabolism is consistent with non-specific proteolytic degradation into smaller peptide fragments. Peptide fragments are primarily eliminated through renal excretion.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None
No metabolism-related drug interactions are expected. Abaloparatide does not inhibit or induce CYP450 enzymes, and it is not a substrate of OAT1, OAT3, OCT2, MATE1, OR MATE2K.
-Route-Specific Pharmacokinetics
Subcutaneous Route
After 7 days of subcutaneous administration of abaloparatide 80 mcg/day, the mean maximal concentration Cmax (SD) was 812 (118) pg/mL and the mean (SD) exposure was 1,622 (641) pg x hour/mL for AUC in postmenopausal women with osteoporosis. The mean time to peak concentration (Tmax) was 0.51 hour (0.25 to 0.52 hour) after subcutaneous administration. The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%.
-Special Populations
Renal Impairment
In a small pharmacokinetic study, abaloparatide was administered to male and female patients with mild renal impairment (CrCl 60 to 89 mL/minute), moderate renal impairment (CrCl 30 to 59 mL/minute), and severe renal impairment (CrCl 15 to 29 mL/minute). The abaloparatide Cmax increased 1-, 1.3-, and 1.4-fold in patients with mild, moderate, and severe renal impairment, respectively, and AUC increased 1.2-, 1.7-, and 2.1-fold, respectively. Patients undergoing dialysis were not included in the study.
Geriatric
No differences in abaloparatide pharmacokinetics were observed in postmenopausal women and men ranging from 18 to 85 years of age.
Gender Differences
The mean serum concentration-time profiles of abaloparatide were comparable between healthy men with a mean age of 53.1 (+/- 6.9) years and healthy women with a mean age of 53.7 (+/- 7.1) years with the same dosing regimen.
Ethnic Differences
No differences in abaloparatide pharmacokinetics based on race were observed based in clinical trials.