Brand name: Yorvipath
Drug class: Parathyroid Agents

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Palopegteriparatide, a prodrug of teriparatide, is a parathyroid hormone analog (PTH(1-34)).

Uses for Palopegteriparatide

Palopegteriparatide has the following uses:

Palopegteriparatide is indicated for the treatment of hypoparathyroidism in adults.

Palopegteriparatide has not been studied for acute post-surgical hypoparathyroidism. The titration scheme of palopegteriparatide was only evaluated in adults who first achieved an albumin-corrected serum calcium of at least 7.8 mg/dL using calcium and active vitamin D treatment.

Palopegteriparatide Dosage and Administration

General

Palopegteriparatide is available in the following dosage form(s) and strength(s):

Injection: single-patient-use prefilled pens

• 168 mcg/0.56 mL pen for labeled doses of 6, 9, or 12 mcg

• 294 mcg/0.98 mL pen for labeled doses of 15, 18, or 21 mcg

• 420 mcg/1.4 mL pen for labeled doses of 24, 27, or 30 mcg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Use only one injection to achieve the once daily recommended dosage.

• Individualize dosage based on serum calcium.

• The recommended starting dosage is 18 mcg once daily and is titrated in 3 mcg increments or decrements with the goal of maintaining serum calcium within the normal range without the need for active vitamin D (e.g., calcitriol) or therapeutic calcium doses (elemental calcium >600 mg/day). The maximum recommended palopegteriparatide dosage is 30 mcg subcutaneously once daily. If an adequate response is not achieved with the maximum dose of 30 mcg, consider adding or restarting calcium and/or active vitamin D therapy and/or seek other treatment options.

• Refer to the Full Prescribing Information for complete dosage and administration information.

Cautions for Palopegteriparatide

Contraindications

Severe hypersensitivity to palopegteriparatide or any components of palopegteriparatide.

Warnings/Precautions

Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections

Use only one palopegteriparatide injection to achieve the recommended once daily dosage. Using two palopegteriparatide injections to achieve the recommended once daily dosage increases the variability of the total delivered dose, which can cause unintended changes in serum calcium levels, including hypercalcemia and hypocalcemia.

Serious Hypercalcemia

Serious events of hypercalcemia requiring hospitalization have been reported with palopegteriparatide. The risk is highest when starting or increasing the dose of palopegteriparatide, but may occur at any time. Measure serum calcium 7 to 10 days after any dose change or if there are signs or symptoms of hypercalcemia, and at a minimum of every 4 to 6 weeks once the maintenance dose is achieved. Treat hypercalcemia if needed. If albumin-corrected serum calcium is greater than 12 mg/dL, withhold palopegteriparatide for at least 2-3 days. For less serious hypercalcemia, adjust the dose of palopegteriparatide, active vitamin D, and/or calcium supplements.

Serious Hypocalcemia

Serious events of hypocalcemia have been observed with PTH products, including palopegteriparatide. The risk is highest when palopegteriparatide is abruptly discontinued, but may occur at any time, even in patients who have been on stable doses of palopegteriparatide. Measure serum calcium 7 to 10 days after any dose change or if there are signs or symptoms of hypocalcemia, and at a minimum of every 4 to 6 weeks once the maintenance dosage is achieved. Treat hypocalcemia if needed, and adjust the dose of palopegteriparatide, active vitamin D, and/or calcium supplements if hypocalcemia occurs.

Potential Risk of Osteosarcoma

Palopegteriparatide is a PTH analog. An increased incidence of osteosarcoma (a malignant bone tumor) has been reported in male and female rats treated with PTH analogs, including teriparatide. Osteosarcoma occurrence in rats is dependent on teriparatide or PTH dose and treatment duration. Osteosarcoma has been reported in patients treated with teriparatide in the postmarketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of teriparatide use.

Palopegteriparatide is not recommended in patients who are at increased risk of osteosarcoma, such as patients with the following:

• Open epiphyses. Palopegteriparatide is not approved in pediatric patients.

• Metabolic bone diseases other than hypoparathyroidism, including Paget's disease of bone.

• Unexplained elevations of alkaline phosphatase.

• Bone metastases or a history of skeletal malignancies.

• History of external beam or implant radiation therapy involving the skeleton.

• Hereditary disorders predisposing to osteosarcoma.

Instruct patients to promptly report clinical symptoms (e.g., persistent localized pain) and signs (e.g., soft tissue mass tender to palpation) that could be consistent with osteosarcoma.

Orthostatic Hypotension

Orthostatic hypotension has been reported with palopegteriparatide. Associated signs and symptoms may include decreased blood pressure, dizziness (including postural dizziness), palpitations, tachycardia, presyncope, or syncope. Such symptoms can be managed by dosing at bedtime, while reclining. Palopegteriparatide should be administered initially when the patient can sit or lie down due to the potential of orthostatic hypotension.

Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds

Palopegteriparatide increases serum calcium, and therefore, concomitant use with digoxin (which has a narrow therapeutic index) may predispose patients to digitalis toxicity if hypercalcemia develops. Digoxin efficacy may be reduced if hypocalcemia is present. When palopegteriparatide is used concomitantly with digoxin, measure serum calcium and digoxin levels routinely, and monitor for signs and symptoms of digoxin toxicity. Refer to the digoxin prescribing information for dose adjustments, if needed.

Specific Populations

Pregnancy

Available data from reports of pregnancies in the clinical trials from drug development are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are disease-associated risks to the mother and fetus related to hypocalcemia in pregnancy. In animal reproduction studies, administration of palopegteriparatide to pregnant rats and rabbits during the period of organogenesis resulted in no significant adverse effects up to doses 16- and 13-fold, respectively, the maximum recommended human dose (MRHD), based on PTH(1-34) and active metabolite PTH(1-33) exposure by AUC.

The background risk of birth defects and miscarriages for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

If palopegteriparatide is administered during pregnancy, or if a patient becomes pregnant while receiving palopegteriparatide, healthcare providers should report palopegteriparatide exposure by calling 1-844-442-7236.

Maternal hypocalcemia can result in an increased rate of spontaneous abortion, premature and dysfunctional labor, and possibly preeclampsia. Infants born to mothers with hypocalcemia can have associated fetal and neonatal hyperparathyroidism, which may cause fetal and neonatal skeletal demineralization, subperiosteal bone resorption, osteitis fibrosa cystica, and neonatal seizures. Infants born to mothers with hypocalcemia should be monitored for signs of hypocalcemia or hypercalcemia, including neuromuscular irritability (e.g., myotonic jerks, seizures), apnea, cyanosis, and cardiac arrhythmias.

Lactation

There are no data available on the presence of palopegteriparatide or its metabolite in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. Infants breastfed by females treated with palopegteriparatide should be monitored for signs and symptoms of hypercalcemia or hypocalcemia. Monitoring of serum calcium in the infant should be considered.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for palopegteriparatide and any potential adverse effects on the breastfed child from the drug or from the underlying sub-optimally treated maternal condition.

Pediatric Use

The safety and effectiveness of palopegteriparatide have not been established in pediatric patients.

Geriatric Use

In Study 1, 8 of 61 (13%) palopegteriparatide-treated subjects were 65 years of age or older compared to 2 of 21 (10%) subjects in the placebo group. Clinical studies of palopegteriparatide did not include a sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

Renal Impairment

No dose adjustment is required in patients with mild, moderate, or severe renal impairment (estimated glomerular filtration rate ≥ 15 mL/min/1.73 m²).

In a dedicated renal impairment study, patients with severe renal impairment (estimated glomerular filtration rate 15 to 30 mL/min/1.73 m²) had no clinically significant difference in total PTH compared to subjects with normal renal function upon treatment with palopegteriparatide.

Common Adverse Effects

Adverse reactions occurring in ≥5% of patients: injection site reactions, vasodilatory signs and symptoms, headache, diarrhea, back pain, hypercalcemia, and oropharyngeal pain.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Drugs Affected by Serum Calcium: Palopegteriparatide increases serum calcium; therefore, concomitant use with digoxin (which has a narrow therapeutic index) may predispose patients to digitalis toxicity if hypercalcemia develops. Digoxin efficacy may be reduced if hypocalcemia is present. When palopegteriparatide is used concomitantly with digoxin, measure serum calcium and digoxin levels, and monitor for signs and symptoms of digoxin toxicity. Adjustment of the digoxin and/or palopegteriparatide dose may be needed.

Drugs Known to Affect Calcium: Drugs that affect serum calcium may alter the therapeutic response to palopegteriparatide. When these drugs are used concomitantly with palopegteriparatide, measure serum calcium levels more frequently.

Actions

Mechanism of Action

At physiological conditions, palopegteriparatide releases PTH(1-34) to maintain a continuous systemic exposure. Endogenous PTH maintains extracellular calcium and phosphate homeostasis by increasing serum calcium and decreasing serum phosphate. These effects are mediated by stimulating bone turnover to mobilize calcium and phosphate from bone, promoting renal calcium reabsorption and phosphate excretion, and facilitating active vitamin D synthesis, in turn increasing intestinal absorption of calcium and phosphate. Similar to endogenous PTH, PTH(1-34) released from palopegteriparatide exerts these effects through its main receptor, parathyroid hormone 1 receptor (PTH1R), which is highly expressed on osteoblasts, osteocytes, renal tubular cells, and in several other tissues.

Advice to Patients

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

• Advise patients that the healthcare provider may change the dose of palopegteriparatide, calcium, or active vitamin D supplements based on serum calcium levels.

• Advise patients to administer palopegteriparatide subcutaneously to the abdomen or front of the thigh. Advise patients to rotate the injection site daily.

• Advise patients that using two palopegteriparatide injections to achieve the recommended once daily dosage increases the variability of the total delivered dose, which can cause unintended changes in serum calcium levels, including hypercalcemia and hypocalcemia. Advise patients to use only one injection to achieve the recommended once daily dosage.

• Advise patients taking palopegteriparatide to contact their healthcare provider promptly if they develop symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness) or hypocalcemia, to report abrupt discontinuations in dosing, and to follow recommended serum calcium monitoring.

• Advise patients that administration of other PTH products causes an increase in the incidence of osteosarcoma in rats. No increased risk of osteosarcoma was observed with teriparatide compared to a general population. Advise patients to promptly report clinical symptoms (e.g., persistent localized pain) and signs (e.g., soft tissue mass tender to palpation) that could be consistent with osteosarcoma.

• When initiating palopegteriparatide treatment, advise patients to be prepared to immediately sit or lie down during or after administration 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.

• Advise patients to report use of a digoxin-containing medication and to follow recommended serum calcium and digoxin monitoring.

• Advise patients that serious hypersensitivity reactions (including anaphylaxis and angioedema) are possible with PTH products. Advise patients to discontinue palopegteriparatide and promptly seek medical attention if signs or symptoms of hypersensitivity reaction occur.

• Advise females who are exposed to palopegteriparatide during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage these patients to report their pregnancy to Ascendis Pharma (1-844-442-7236).

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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.

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