Brand name: Yorvipath
Drug class: Parathyroid Agents

Introduction

Prodrug of teriparatide; parathyroid hormone analog (PTH[1-34]).

Uses for Palopegteriparatide

Hypoparathyroidism

Treatment of hypoparathyroidism in adults.

Has been shown in clinical studies to allow patients to achieve independence from the standard of care (no active vitamin D and ≤600 mg/day of calcium supplementation) while maintaining normal serum calcium concentrations; however, titration scheme only evaluated in adults who first achieved albumin-corrected serum calcium of ≥7.8 mg/dL using calcium and active vitamin D treatment.

Not studied for acute post-surgical hypoparathyroidism.

Designated an orphan drug by FDA for treatment of hypoparathyroidism.

Conventional treatment of hypoparathyroidism includes oral calcium supplementation and activated forms of vitamin D (1,25-dihydroxyvitamin D [e.g., calcitriol]); however, such therapy is often inadequate and can lead to serious long-term complications such as hypercalciuria, soft tissue calcification, and renal damage (e.g., nephrocalcinosis, nephrolithiasis). A recombinant human parathyroid hormone is available; however, use of parathyroid hormone generally recommended only when conventional therapy is unsatisfactory. Palopegteriparatide may provide another treatment option, but has not yet been incorporated into clinical practice guidelines.

Palopegteriparatide Dosage and Administration

General

Pretreatment Screening

• Confirm serum 25(OH) vitamin D is within normal range and albumin-corrected serum calcium is ≥7.8 mg/dL within 2 weeks before the first dose of palopegteriparatide.

Patient Monitoring

• Measure serum calcium 7–10 days after first palopegteriparatide dose and after any dose change in palopegteriparatide, active vitamin D, or calcium supplements, and monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia. Once palopegteriparatide maintenance dosage is established, measure serum calcium levels at minimum every 4–6 weeks or as indicated for symptoms of hypocalcemia or hypercalcemia.

Administration

Sub-Q Administration

Administer by sub-Q injection.

Supplied as prefilled injection pen in concentrations of 168 mcg/0.56 mL, 294 mcg/0.98 mL, and 420 mcg/1.4 mL.

Test pen flow prior to first use.

Administer sub-Q to abdomen or front of thigh. Rotate injection site daily.

Administer initially in environment in which patient can assume supine or sitting position if orthostatic hypotension should occur.

Use only 1 injection to achieve full once daily sub-Q dose. Using 2 injections increases dose variability and can cause unintended changes in calcium levels (hypercalcemia and hypocalcemia).

Dosage

Adults

Hypoparathyroidism

Sub-Q

Individualize dosage based on serum calcium. Recommended starting dosage is 18 mcg once daily; titrate dose in 3 mcg increments or decrements with goal of maintaining serum calcium concentrations within normal range without need for active vitamin D or therapeutic elemental calcium doses (>600 mg per day).

Do not increase dosage more often than every 7 days; do not decrease dosage more often than every 3 days.

Dosage range is 6 to 30 mcg (maximum) once daily. If adequate response not achieved with maximum dosage of 30 mcg once daily, consider adding or restarting calcium and/or active vitamin D therapy and/or seeking other treatment options.

Measure serum calcium 7–10 days after the first dose and after any dose change in palopegteriparatide, active vitamin D, or calcium supplements, and monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia. Adjust dosages of palopegteriparatide, active vitamin D, or calcium supplements based on measured albumin-corrected serum calcium concentration (see Titration Recommendations for Palopegteriparatide, Active Vitamin D, and Calcium Supplements under Dosage and Administration).

If a dose is missed by <12 hours, administer missed dose as soon as possible. If a dose is missed by >12 hours, skip missed dose and take next dose as scheduled. If dose is delayed or interrupted for ≥3 days, evaluate patients for signs and symptoms of hypocalcemia and consider measuring serum calcium.

Dosage Modification of Active Vitamin D and Calcium Supplements on Day of Palopegteriparatide Initiation or Up-titration

On the day of initiation or up-titration of palopegteriparatide, adjust dose of active vitamin D and calcium based on albumin-corrected serum calcium and current active vitamin D (see Table 1).

Titration Recommendations for Palopegteriparatide, Active Vitamin D, and Calcium Supplements

Albumin-Corrected Serum Calcium <8.3 mg/dL

If albumin-corrected serum calcium is <8.3 mg/dL ≥7 days after palopegteriparatide was started or the dose was changed, continue the same calcium supplement and active vitamin D dosage and increase the palopegteriparatide dose by 3 mcg. If albumin-corrected serum calcium is <8.3 mg/dL at any other times, increase calcium supplements and/or active vitamin D toward prior doses based on the prescriber’s clinical judgement and continue the same palopegteriparatide dose.

Albumin-Corrected Serum Calcium 8.3 to 10.6 mg/dL

If albumin-corrected serum calcium is 8.3–10.6 mg/dL ≥7 days after palopegteriparatide was started or the dose was changed, the subsequent course of action is determined by whether the patient is still taking active vitamin D and calcium supplements as follows.

If the patient is not taking active vitamin D or calcium supplements, continue the same palopegteriparatide dose.

If the patient is still taking active vitamin D, decrease or discontinue the active vitamin D (see Table 1) and increase the palopegteriparatide dose by 3 mcg.

If the patient is not taking active vitamin D but is taking calcium supplements <1500 mg per day, discontinue the calcium supplement and increase the palopegteriparatide dose by 3 mcg.

If the patient is not taking active vitamin D but is taking calcium supplements ≥1500 mg per day, decrease the calcium supplement by ≥1500 mg and increase the palopegteriparatide dose by 3 mcg.

If the albumin-corrected serum calcium is 8.3 to 10.6 mg/dL at any other times, continue the same palopegteriparatide, calcium, and active vitamin D doses.

Albumin-Corrected Serum Calcium 10.7 to 11.9 mg/dL

If albumin-corrected serum calcium is 10.7–11.9 mg/dL, the subsequent course of action is determined by whether the patient is still taking active vitamin D and calcium supplements. If the patient is not taking active vitamin D or calcium supplements, decrease the palopegteriparatide dose by 3 mcg.

If the patient is still taking active vitamin D, decrease or discontinue the active vitamin D (see Table 1) and continue the same palopegteriparatide and calcium supplement doses.

If the patient is not taking active vitamin D but is taking calcium supplements <1500 mg per day, discontinue the calcium supplement and continue the same dose of palopegteriparatide.

If the patient is not taking active vitamin D but is taking calcium supplements ≥1500 mg per day, decrease the calcium supplement by ≥1500 mg and continue the same palopegteriparatide dose.

Albumin-Corrected Serum Calcium ≥12 mg/dL

If albumin-corrected calcium ≥12 mg/dL, withhold palopegteriparatide for 2–3 days and recheck serum calcium. If albumin-corrected serum calcium remains ≥12 mg/dL, withhold palopegteriparatide for a additional 2–3 days and recheck serum calcium. Once albumin-corrected calcium <12 mg/dL, resume titration of palopegteriparatide, active vitamin D, and calcium supplements per appropriate albumin-corrected serum calcium recommendations (see Table 1).

Special Populations

Hepatic Impairment

No specific dosage adjustment recommended at this time.

Renal Impairment

No dose adjustment required in patients with mild, moderate, or severe renal impairment.

Geriatric Patients

No specific dosage adjustment recommended at this time.

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 1 injection to achieve the once daily dosage. Using 2 injections increases dose variability and can cause unintended changes in calcium levels (hypercalcemia and hypocalcemia).

Serious Hypercalcemia

Serious events of hypercalcemia requiring hospitalization reported. Risk highest when increasing dose but may occur any time.

Measure serum calcium if signs or symptoms of hypercalcemia occur, 7–10 days after any dose change, and at minimum every 4–6 weeks once maintenance dose achieved. Treat hypercalcemia as needed and adjust dose of palopegteriparatide, active vitamin D, and/or calcium supplements. If albumin-corrected calcium is >12 mg/dL, withhold palopegteriparatide for 2–3 days.

Serious Hypocalcemia

Serious events of hypocalcemia reported. Risk highest when palopegteriparatide abruptly discontinued but may occur at any time.

Measure serum calcium if signs or symptoms of hypocalcemia occur, 7–10 days after any dose change, and at minimum every 4–6 weeks once maintenance dose achieved. Treat hypocalcemia as needed and adjust dose of palopegteriparatide, active vitamin D, and/or calcium supplements if needed.

Potential Risk of Osteosarcoma

Osteosarcoma observed in male and female rats treated with PTH analogs; occurrence in rats based on PTH analog dose and duration of therapy. Osteosarcoma reported with teriparatide during postmarketing experience; however, increased risk not observed in observational studies in humans.

Avoid use in patients with increased baseline risk of osteosarcoma (e.g., patients with open epiphyses, metabolic bone diseases other than hypoparathyroidism including Paget's disease of bone, unexplained elevations of alkaline phosphatase, bone metastases or history of skeletal malignancies, prior external beam or implant radiation therapy involving the skeleton, or hereditary disorders predisposing to osteosarcoma).

Orthostatic Hypotension

Orthostatic hypotension reported. Manage with bedtime dosing while reclining. Administer initially when patient can sit or lie down if symptoms of orthostatic hypotension occur.

Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds

Palopegteriparatide increases serum calcium concentrations, predisposing patients to digoxin toxicity. If used concomitantly with digoxin, measure serum calcium and digoxin levels routinely, and monitor for signs and symptoms of digoxin toxicity.

Immunogenicity

Low titer, non-neutralizing antibodies against PTH and low titer treatment-emergent antibodies against PEG reported in a few patients. Transient pharmacokinetic and pharmacodynamics effects of anti-PEG antibodies observed, but resolved with dose modification.

Specific Populations

Pregnancy

Insufficient data in pregnant women to determine whether there is drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No significant adverse effects observed in pregnant animals receiving palopegteriparatide doses of 16- and 13-fold maximum recommended doses.

Hypocalcemia in pregnancy poses risk to mother and fetus. If administered during pregnancy or if patient becomes pregnant while on palopegteriparatide, report palopegteriparatide exposure by calling 1-844-442-7236.

Lactation

Unknown whether palopegteriparatide is distributed into human milk, or if drug has any effects on breastfed infant or on milk production. Monitor for signs and symptoms of hypercalcemia or hypocalcemia in infants breastfed by females receiving palopegteriparatide; consider monitoring infant’s serum calcium.

Females and Males of Reproductive Potential

Fertility studies not conducted. No effects on fertility were observed in male and female rats.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Safety and efficacy not established.

Hepatic Impairment

Safety and efficacy not studied in patients with hepatic impairment; mild and moderate hepatic impairment not expected to have clinically significant impact on pharmacokinetics of palopegteriparatide.

Renal Impairment

No clinically significant differences in total PTH observed in patients with severe renal impairment compared to normal renal function while receiving palopegteriparatide.

Common Adverse Effects

Most common adverse reactions (≥5%): injection site reactions, vasodilatory signs and symptoms, headache, diarrhea, back pain, hypercalcemia, oropharyngeal pain.

Drug Interactions

Drugs that Affect Serum Calcium

Drugs that affect serum calcium may alter therapeutic response to palopegteriparatide. Measure serum calcium more frequently when palopegteriparatide is used concomitantly with drugs that affect calcium, particularly when these drugs are initiated, discontinued, or dose adjusted.

Digoxin

Potential pharmacodynamic interaction (increased serum calcium predisposing to digitalis toxicity); more frequent monitoring of serum calcium and digoxin levels advised.

Palopegteriparatide Pharmacokinetics

Absorption

Plasma Concentrations

Median time to reach maximum concentrations of PTH is 4 hours.

Elimination

Metabolism

PTH released includes PTH(1-34) and the active metabolite PTH(1-33).

PTH(1-34) and PTH(1-33) have comparable affinity to and activation of PTH1R.

Half-life

The apparent half life of PTH released is approximately 60 hours.

Stability

Storage

Parenteral

Prefilled Injection Pen

Before first use, store at 2–8°C in original container; do not freeze.

After first use, store at room temperature below 30°C for 14 days; discard 14 days after first use.

Actions

• Prodrug of teriparatide; parathyroid hormone analog (PTH[1-34]) bound to an inert methoxypolyethylene glycol carrier via a TransCon linker.

• When exposed to physiological temperature and pH, the linker is cleaved releasing palopegteriparatide in a sustained manner.

• Endogenous PTH maintains extracellular calcium and phosphate homeostasis by increasing serum calcium and decreasing serum phosphate.

• Similar to endogenous PTH, palopegteriparatide exerts effects through parathyroid hormone 1 receptor (PTH1R), which is highly expressed on osteoblasts, osteocytes, renal tubular cells, and in several other tissues.

Advice to Patients

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

• Advise patients that their healthcare provider may change the dose of palopegteriparatide, active vitamin D, or calcium 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 patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.

• 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).

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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.

Palopegteriparatide is obtained through a limited distribution network. Contact the manufacturer or consult the palopegteriparatide website ([Web]) for more information.

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