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Tymlos

Generic Name: Abaloparatide
Class: Parathyroid Agents
Chemical Name: l-Alanyl-l-valyl-l-seryl-l-α-glutamyl-l-histidyl-l-glutaminyl-l-leucyl-l-leucyl-l-histidyl-l-α-aspartyl-l-lysylglycyl-l-lysyl-l-seryl-l-isoleucyl-l-glutaminyl-l-α-aspartyl-l-leucyl-l-arginyl-l-arginyl-l-arginyl-l-α-glutamyl-l-leucyl-l-leucyl-l-α-glutamyl-l-lysyl-l-leucyl-l-leucyl-2-methylalanyl-l-lysyl-l-leucyl-l-histidyl-l-threonyl-l-alaninamide
Molecular Formula: C174H300N56O49
CAS Number: 247062-33-5

Medically reviewed on Apr 2, 2018

Warning

  • Increased incidence of osteosarcoma in rats receiving abaloparatide; dose-dependent effect.1 Not known whether abaloparatide causes osteosarcoma in humans.1 (See Osteosarcoma under Cautions.)

  • Not recommended in patients at increased risk of osteosarcoma.1

  • Cumulative use of abaloparatide or other parathyroid hormone analogs (e.g., teriparatide) for >2 years during a patient's lifetime not recommended.1

Introduction

See also: Prolia

Synthetic human parathyroid hormone (parathormone, PTH)-related peptide analog; an osteoanabolic agent.1 2 5 6 7

Uses for Tymlos

Osteoporosis

Management of osteoporosis in postmenopausal women at high risk for fractures, including those with a history of osteoporotic fracture, those with multiple risk factors for fractures, or those intolerant of or failing to respond to other osteoporosis therapy.1 2 3 4

Cumulative use for >2 years during a patient's lifetime not recommended.1 (See Boxed Warning.)

Tymlos Dosage and Administration

General

  • Administer initial doses in a setting in which patient can assume a supine or sitting position if symptoms of orthostatic hypotension occur.1

  • Cumulative use of abaloparatide or other PTH analogs (e.g., teriparatide) for >2 years during a patient's lifetime not recommended.1 (See Osteosarcoma under Cautions.)

  • Supplemental calcium and vitamin D recommended if dietary intake is inadequate.1

Administration

Administer by sub-Q injection.1 Do not administer IV or IM.1

Sub-Q Administration

Administer sub-Q into the periumbilical region of the abdomen (avoid the 2-inch area around the navel) at the same time every day.1 Rotate injection site with each administration.1

Commercially available as a clear, colorless solution in a prefilled injection pen that delivers 80 mcg of abaloparatide per actuation.1

Use each injection pen for up to 30 days after the first injection and then dispose of properly, even if the pen contains unused solution.1

Dosage

Adults

Osteoporosis
Sub-Q

80 mcg once daily.1

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1

Renal Impairment

No dosage adjustment necessary in mild, moderate, or severe renal impairment.1

Cautions for Tymlos

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Osteosarcoma

Increased incidence of osteosarcoma in male and female rats; effect was dose dependent.1 Not known if drug causes osteosarcoma in humans.1

Not recommended in patients at increased baseline risk of osteosarcoma (e.g., those with Paget's disease of bone or unexplained increases in alkaline phosphatase concentrations, open epiphyses, bone metastases, skeletal malignancies, hereditary disorders predisposing to osteosarcoma, prior radiation therapy involving the skeleton).1

Cumulative use of abaloparatide or other PTH analogs (e.g., teriparatide) for >2 years during a patient's lifetime not recommended.1

Other Warnings and Precautions

Orthostatic Hypotension

Orthostatic hypotension may occur, generally within 4 hours of administration.1 Symptoms may include dizziness, palpitations, tachycardia, or nausea, and may resolve by having the patient recline.1 Administer the first several doses in a setting in which the patient can sit or recline if necessary.1

Hypercalcemia

Hypercalcemia reported; occurred at higher rate in patients with impaired renal function.1 Not recommended in patients with preexisting hypercalcemia or in those with underlying hypercalcemic disorder (e.g., primary hyperparathyroidism) because of possibility of exacerbating hypercalcemia.1

Hypercalciuria and Urolithiasis

May cause hypercalciuria.1 Not known whether drug may exacerbate urolithiasis in patients with active urolithiasis or a history of this condition.1

Consider measurement of urinary calcium excretion if active urolithiasis or preexisting hypercalciuria is suspected.1

Immunogenicity

Potential for immunogenicity with all therapeutic proteins, including abaloparatide.1 Development of antibodies (including neutralizing antibodies) to the drug reported; clinically important effects not observed.1

Specific Populations

Pregnancy

Do not use in females of reproductive potential.1 No data regarding use of drug in pregnant women to inform any drug-associated risks.1 Animal reproduction studies with abaloparatide not performed.1

Lactation

Not known whether abaloparatide is distributed into milk in humans, affects milk production, or affects the breast-fed infant.1

Pediatric Use

Safety and efficacy not established.1 Not recommended in pediatric patients with open epiphyses or hereditary disorders predisposing to osteosarcoma because of increased baseline risk of osteosarcoma.1 (See Osteosarcoma under Cautions.)

Geriatric Use

No overall differences in safety or efficacy observed between geriatric patients and younger adults, but increased sensitivity of some older patients cannot be ruled out.1

Hepatic Impairment

Information lacking regarding exposure of abaloparatide in patients with hepatic impairment; no specific dosage recommendations available for this patient population.1

Renal Impairment

Possible increased exposure of abaloparatide in patients with severe renal impairment; no dosage adjustment required, but monitor such patients for potential adverse effects.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Hypercalciuria,1 4 dizziness,1 4 nausea,1 4 headache,1 4 palpitations,1 4 fatigue,1 upper abdominal pain,1 3 vertigo.1

Interactions for Tymlos

No formal drug interaction studies to date.1

Does not inhibit or induce CYP isoenzymes at therapeutic concentrations based on in vitro studies.1

Tymlos Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is 36% following sub-Q administration.1

Median time to peak plasma concentrations: 0.51 hours.1

Exhibits a dose-response relationship for bone mineral density (BMD) and bone formation markers when administered once daily for 24 weeks.1

Special Populations

In patients with mild, moderate, or severe renal impairment, AUC increased by 1.2-, 1.7-, or 2.1-fold, respectively.1 Peak plasma concentrations increased by 1.3- or 1.4-fold in those with moderate or severe renal impairment; not increased in those with mild renal impairment.1 9

In postmenopausal women, age and race do not appear to affect pharmacokinetics.1

Distribution

Plasma Protein Binding

Approximately 70% in vitro.1

Not known if abaloparatide is distributed into human milk.1

Elimination

Metabolism

Metabolism thought to be mediated by proteolytic enzymes.1

Elimination Route

Principally excreted in urine as peptide fragments.1

Half-life

1.7 hours.1

Stability

Storage

Parenteral

Solution for Injection

2–8°C prior to first use; 20–25°C after first use for up to 30 days, then discard.1

Do not freeze; do not expose to heat.1

Actions

  • Synthetic human PTH-related peptide analog containing 34 amino acids.1 5 6 7 8

  • Exhibits agonist activity at the PTH receptor type 1 resulting in activation of cyclic adenosine-3′,5′-monophosphate (cAMP) signaling pathway target cells.1 7

  • Exhibits anabolic effect on bone (demonstrated by elevations in BMD and bone mineral content) correlating with increases in bone strength at vertebral and/or nonvertebral sites in animals.1 6

Advice to Patients

  • Importance of patients obtaining and reading a copy of the manufacturer's patient information (medication guide and instructions for use) prior to initiation of therapy and each time the prescription is refilled.1

  • Importance of informing patients about the increased incidence of osteosarcoma in rats receiving abaloparatide; clinical relevance of this effect in humans unknown.1 (See Boxed Warning.) Advise patients to immediately report signs and symptoms of potential osteosarcoma (e.g., persistent localized pain, new soft tissue mass tender to palpation).1

  • Importance of informing patients that abaloparatide may cause hypercalcemia and instructing patients to immediately report symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness).1

  • Importance of advising patients to sit or recline until symptoms resolve if lightheadedness or palpitations occur following administration of abaloparatide and to contact a clinician prior to continuing therapy if such symptoms persist or worsen.1

  • Importance of instructing patients and caregivers on the proper use and disposal of the injection pen.1 Importance of advising patients to not share the injection pen with others and to not transfer contents of the pen to a syringe.1 Importance of informing patients that each injection pen may be used for up to 30 days and then the pen should be discarded, even if it contains unused solution.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Abaloparatide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for subcutaneous use

2 mg/mL

Tymlos (available as prefilled cartridge pen)

Radius Health

AHFS DI Essentials. © Copyright 2018, Selected Revisions April 2, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Radius Health, Inc. Tymlos (abaloparatide) subcutaneous injection prescribing information. Waltham, MA; 2017 Apr.

2. Moreira CA, Fitzpatrick LA, Wang Y et al. Effects of abaloparatide-SC (BA058) on bone histology and histomorphometry: The ACTIVE phase 3 trial. Bone. 2017; 97:314-319. http://www.ncbi.nlm.nih.gov/pubmed/27826127?dopt=AbstractPlus

3. Cosman F, Miller PD, Williams GC et al. Eighteen Months of Treatment With Subcutaneous Abaloparatide Followed by 6 Months of Treatment With Alendronate in Postmenopausal Women With Osteoporosis: Results of the ACTIVExtend Trial. Mayo Clin Proc. 2017; 92:200-210. http://www.ncbi.nlm.nih.gov/pubmed/28160873?dopt=AbstractPlus

4. Miller PD, Hattersley G, Riis BJ et al. Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial. JAMA. 2016; 316:722-33. http://www.ncbi.nlm.nih.gov/pubmed/27533157?dopt=AbstractPlus

5. McCloskey EV, Johansson H, Oden A et al. The Effect of Abaloparatide-SC on Fracture Risk Is Independent of Baseline FRAX Fracture Probability: A Post Hoc Analysis of the ACTIVE Study. J Bone Miner Res. 2017; http://www.ncbi.nlm.nih.gov/pubmed/28474780?dopt=AbstractPlus

6. Leder BZ, O'Dea LS, Zanchetta JR et al. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2015; 100:697-706. http://www.ncbi.nlm.nih.gov/pubmed/25393645?dopt=AbstractPlus

7. Cosman F, Hattersley G, Hu MY et al. Effects of Abaloparatide-SC on Fractures and Bone Mineral Density in Subgroups of Postmenopausal Women With Osteoporosis and Varying Baseline Risk Factors. J Bone Miner Res. 2017; 32:17-23. http://www.ncbi.nlm.nih.gov/pubmed/27612281?dopt=AbstractPlus

8. Hattersley G, Dean T, Corbin BA et al. Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology. 2016; 157:141-9. http://www.ncbi.nlm.nih.gov/pubmed/26562265?dopt=AbstractPlus

9. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 208743Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208743Orig1s000ClinPharmR.pdf

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