YORVIPATH is prescribed for the treatment of hypoparathyroidism in adults.

Limitations of Use:

• YORVIPATH has not been studied for the treatment of acute post-surgical hypoparathyroidism.
• The dosing regimen of YORVIPATH was tested only in adults who had an albumin-corrected serum calcium level of at least 7.8 mg/dL after receiving calcium and active vitamin D treatments.

Dosage and Administration

• Administer YORVIPATH as a single injection to achieve the recommended once-daily dosage. Using multiple injections to achieve this dosage may lead to unintended fluctuations in serum calcium levels, including hypocalcemia and hypercalcemia.
• The maximum recommended dosage is 30 mcg subcutaneously once daily. If the desired response is not achieved with this dosage, consider adding or resuming calcium and/or active vitamin D therapy, or explore other treatment options.
• The YORVIPATH dosage is individualized. The recommended starting dosage is 18 mcg once daily, with adjustments in 3 mcg increments or decrements. The goal is to maintain serum calcium within the normal range without requiring active vitamin D or therapeutic calcium doses exceeding 600 mg/day.
• Patients should monitor themselves daily for signs and symptoms of hypocalcemia or hypercalcemia.
• Serum calcium should be measured 7 to 10 days after the first YORVIPATH dose and after any dose adjustments, including changes to active vitamin D or calcium supplements. Once the maintenance dosage is established, serum calcium levels should be checked at least every 4 to 6 weeks or as indicated by symptoms.

Laboratory Testing Prior to Initiation:

• Before starting YORVIPATH, ensure that the serum 25(OH) vitamin D level is within the normal range and that the albumin-corrected serum calcium level is at least 7.8 mg/dL.

Modification of Active Vitamin D and Calcium Supplements:

• Adjust the dose of active vitamin D and calcium supplements on the day YORVIPATH is initiated or when titrating the dose. This adjustment should be based on the albumin-corrected serum calcium level and the current intake of active vitamin D.

Recommended Dosage Titration and Monitoring:

• Start with a dosage of 18 mcg once daily, and adjust the dosage in 3 mcg increments or decrements. Dosage increases should not occur more frequently than every 7 days, and decreases should not occur more frequently than every 3 days.
• The dosage range for YORVIPATH is 6 to 30 mcg once daily.
• Measure serum calcium levels 7 to 10 days after the first dose and after any dosage adjustments, and monitor for clinical symptoms of hypocalcemia or hypercalcemia.

Dose Delay, Interruption, or Discontinuation:

• If a dose is missed by less than 12 hours, take it as soon as possible. If it has been more than 12 hours, skip the missed dose and take the next dose as scheduled.
• If YORVIPATH treatment is delayed or interrupted for 3 days or more, evaluate for signs and symptoms of hypocalcemia and consider measuring serum calcium. If necessary, resume treatment with or increase the dose of calcium supplements and active vitamin D. Resume YORVIPATH at the previously prescribed dose as soon as possible, then measure serum calcium within 7 to 10 days and adjust doses accordingly.

Preparation and Administration Instructions

• YORVIPATH should be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) until first use.
• Inspect YORVIPATH visually for any particulate matter or discoloration before administration. The solution should be clear and colorless.
• Use a pen to administer YORVIPATH subcutaneously to the abdomen or front of the thigh, rotating the injection site daily.
• Patients and caregivers should be trained by a healthcare professional before administering YORVIPATH for the first time.

Contraindications to YORVIPATH (palopegteriparatide) Injection

YORVIPATH is contraindicated in patients with severe hypersensitivity to palopegteriparatide or any of its components. Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been reported with parathyroid hormone (PTH) analogs.

Warnings and Precautions

Risk of Unintended Changes in Serum Calcium Levels

Use only one YORVIPATH injection per day as recommended. Using more than one injection daily can cause unpredictable changes in serum calcium levels, leading to either hypercalcemia or hypocalcemia.

Serious Hypercalcemia

Severe hypercalcemia, sometimes requiring hospitalization, has been reported. This risk is highest when starting or increasing the dose of YORVIPATH but can occur at any time. Monitor serum calcium levels 7 to 10 days after any dose adjustment or if symptoms of hypercalcemia appear. Hypercalcemia should be treated as necessary, and YORVIPATH should be withheld if serum calcium exceeds 12 mg/dL.

Serious Hypocalcemia

Severe hypocalcemia has been observed with YORVIPATH, especially when the treatment is abruptly discontinued. Monitor serum calcium levels 7 to 10 days after any dose adjustment or if symptoms of hypocalcemia appear. Treat hypocalcemia as needed and adjust the dose of YORVIPATH, active vitamin D, and/or calcium supplements accordingly.

Potential Risk of Osteosarcoma

YORVIPATH is a PTH analog, and an increased incidence of osteosarcoma has been reported in animal studies. Although there is no conclusive evidence of increased osteosarcoma risk in humans, YORVIPATH should not be used in patients at increased risk for this condition, such as those with open epiphyses, Paget’s disease, or a history of radiation therapy involving the skeleton.

Orthostatic Hypotension

Orthostatic hypotension, characterized by dizziness, palpitations, and fainting, has been reported with YORVIPATH. These symptoms can be managed by administering the dose at bedtime and ensuring the patient is sitting or lying down when the dose is given.

Risk of Digoxin Toxicity

YORVIPATH increases serum calcium levels, which can lead to digitalis toxicity when used with digoxin. Monitor serum calcium and digoxin levels closely and adjust the digoxin dose if necessary.

Adverse Reactions

Common adverse reactions in patients treated with YORVIPATH include:

• Injection site reactions (39%)
• Vasodilatory symptoms (28%)
• Headache (21%)
• Diarrhea (10%)
• Back pain (8%)
• Hypercalcemia (8%)
• Oropharyngeal pain (7%)

Drug Interactions

Drugs Affected by Serum Calcium

• Digoxin: Monitor serum calcium and digoxin levels closely when YORVIPATH is used concomitantly with digoxin due to the risk of digitalis toxicity if hypercalcemia develops.

Drugs Known to Affect Serum Calcium

• Measure serum calcium more frequently when YORVIPATH is used with other medications that affect serum calcium, particularly after initiating, discontinuing, or adjusting the dose of these medications.

Use in Specific Populations

• Renal Impairment: No dosage adjustment is required in patients with mild to severe renal impairment. However, no studies have been conducted in patients with severe renal impairment who also have hypoparathyroidism.
• Hepatic Impairment: No dedicated studies have been conducted, but mild to moderate hepatic impairment is not expected to significantly affect the pharmacokinetics of YORVIPATH.

Overdosage

Accidental overdose of YORVIPATH may lead to severe hypercalcemia, requiring medical intervention. In one case, a patient received approximately three times the prescribed dose for more than seven days, resulting in a serum calcium level of 16.1 mg/dL and necessitating hospitalization.

Mechanism of Action

YORVIPATH contains palopegteriparatide, which releases PTH(1-34) to provide continuous systemic exposure. Under normal physiological conditions, endogenous parathyroid hormone (PTH) plays a crucial role in maintaining the balance of calcium and phosphate in the body.

Role of PTH in Calcium and Phosphate Homeostasis:

• Increases Serum Calcium: PTH increases serum calcium levels by stimulating bone turnover, which releases calcium and phosphate into the bloodstream. It also enhances the reabsorption of calcium in the kidneys and promotes the synthesis of active vitamin D. This active vitamin D further increases the absorption of calcium from the intestines.
• Decreases Serum Phosphate: Simultaneously, PTH decreases serum phosphate levels by promoting its excretion through the kidneys.

PTH(1-34) and Its Receptor:

• Main Receptor: PTH(1-34) released from palopegteriparatide works by binding to the parathyroid hormone 1 receptor (PTH1R), which is highly expressed in osteoblasts, osteocytes, renal tubular cells, and various other tissues.

Pharmacodynamics

When YORVIPATH is administered, both serum PTH(1-34) and calcium concentrations increase in a dose-dependent manner. However, the exposure-response relationship for patients with hypoparathyroidism has not been fully established.

Pharmacokinetics

Absorption:

• The time to reach maximum serum concentration (Tmax) of PTH after YORVIPATH administration is approximately 4 to 8 hours.

Distribution:

• The apparent volume of distribution (CV%) of palopegteriparatide is estimated to be 4.8 (50) liters, suggesting a similar distribution pattern as endogenous PTH.

Elimination:

• The half-life of PTH released from palopegteriparatide is approximately 60 hours, with an estimated clearance (CV%) of 0.58 (52) liters per day at steady state.

Metabolism:

• PTH released from YORVIPATH includes both PTH(1-34) and its active metabolite, PTH(1-33). Both forms have comparable affinities for and activation of the PTH1R.

Considerations for Specific Populations

• Age, Sex, and Body Weight: There are no clinically significant differences in the pharmacokinetics of palopegteriparatide based on these factors.
• Race and Ethnicity: While available data do not indicate significant differences based on race or ethnicity, the data is too limited for definitive conclusions.
• Renal Impairment: Mild to severe renal impairment does not significantly affect the systemic exposure of PTH following a single dose of YORVIPATH. However, studies have not been conducted in patients with severe renal impairment who have hypoparathyroidism.
• Hepatic Impairment: No dedicated study has been conducted, but mild to moderate hepatic impairment is not expected to significantly impact the pharmacokinetics of YORVIPATH.

Reference: FDA Prescribing Information [PDF]