Palopegteriparatide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh
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Overview
Palopegteriparatide is a parathyroid hormone analog (PTH(1-34)) that is FDA approved for the treatment of YORVIPATH is a parathyroid hormone analog (PTH(1-34)) that is FDA approved for the treatment of hypoparathyroidism in adults.
Limitations of Use:
- YORVIPATH was not studied for acute post-surgical hypoparathyroidism.
- YORVIPATH's titration scheme 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.. Common adverse reactions include injection site reactions, vasodilatory signs and symptoms, headache, diarrhea, back pain, hypercalcemia, and oropharyngeal pain.
- Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections:
- Serious Hypercalcemia.
- Serious Hypocalcemia.
- Potential Risk of Osteosarcoma.
- Orthostatic Hypotension.
- Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
YORVIPATH is indicated for the treatment of hypoparathyroidism in adults.
- Limitations of Use:
- YORVIPATH was not studied for acute post-surgical hypoparathyroidism.
- YORVIPATH's titration scheme 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.
Overview of Dosage and Monitoring:
- Use only one injection to achieve the once daily recommended dosage. Using two injections to achieve the recommended once daily dosage increases the risk of unintended changes in serum calcium levels, including hypocalcemia and hypercalcemia.
- The maximum recommended dosage is 30 mcg subcutaneously once daily. If an adequate response is not achieved with a maximum YORVIPATH dosage of 30 mcg, consider adding or restarting calcium and/or active vitamin D therapy and/or seek other treatment options.
- YORVIPATH's once daily subcutaneous dosage is individualized. 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). Calcium supplementation sufficient to meet daily dietary requirements may be continued.
- Advise patients to monitor daily for clinical signs and symptoms of hypocalcemia or hypercalcemia.
- Measure serum calcium 7 to 10 days after the first YORVIPATH dose and after any dose change in YORVIPATH, active vitamin D, or calcium supplements, and monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia. Once the YORVIPATH maintenance dosage is achieved, measure serum calcium levels at a minimum every 4 to 6 weeks or as indicated for symptoms of hypocalcemia or hypercalcemia.
- Adjust YORVIPATH, active vitamin D, and/or calcium supplements per Figure 1. Some patients may require an increase in the YORVIPATH dose over time to maintain the same therapeutic effect.
Laboratory Testing Prior to Initiation of YORVIPATH:
- Within two weeks before the first dose of YORVIPATH, confirm serum 25(OH) vitamin D is within the normal range and albumin-corrected serum calcium is ≥7.8 mg/dL.
- On the day of initiation or up-titration of YORVIPATH, adjust the dose of active vitamin D and calcium supplements based on albumin-corrected serum calcium and current active vitamin D intake.
- Dosage adjustments for active vitamin D (calcitriol) and calcium supplements upon the initiation or up-titration of YORVIPATH treatment depend on albumin-corrected serum calcium levels and current calcitriol intake. If serum calcium is ≥8.3 mg/dL and calcitriol intake exceeds 1 mcg/day, the dosage should be reduced by at least 50%, while calcium supplementation remains unchanged. If calcitriol intake is ≤1 mcg/day, it should be discontinued, but calcium dosage should still be maintained. For serum calcium levels between ≥7.8 and <8.3 mg/dL, regardless of the amount of calcitriol intake, the dosage should be reduced by at least 50%, with no changes to calcium intake. If serum calcium is ≥7.8 mg/dL and the patient is not currently on active vitamin D, calcium supplementation should be reduced by at least 1500 mg/day or discontinued entirely if the current intake is ≤1500 mg/day. It is important to note that if calcium supplements are necessary to meet dietary requirements, maintaining an elemental dosage of ≤600 mg/day may be considered rather than stopping calcium intake completely. These dosage adjustments help ensure proper management of calcium and vitamin D levels during YORVIPATH treatment.
Recommended Dosage, Titration Scheme, and Monitoring:
- The recommended starting dosage of YORVIPATH is 18 mcg once daily. Dosage adjustments should be made in 3 mcg increments or decrements. Do not increase the YORVIPATH dosage more often than every 7 days. Do not decrease the YORVIPATH dosage more often than every 3 days.
- The recommended dosage range of YORVIPATH is 6 to 30 mcg once daily.
- Measure serum calcium within 7 to 10 days after the first dose and any dose change in YORVIPATH, active vitamin D, or calcium supplements, and monitor for clinical symptoms of hypocalcemia or hypercalcemia. Adjust YORVIPATH, active vitamin D, and/or calcium supplements.
- The maintenance dosage is individualized and should be the YORVIPATH dose that achieves serum calcium within the normal range, without the need for active vitamin D or therapeutic doses of calcium. Calcium supplementation sufficient to meet daily dietary requirements may be continued. Once the maintenance dosage is achieved, monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia and measure serum calcium levels as indicated, and at a minimum every 4 to 6 weeks, as some patients may require further dose titration. If calcium levels remain low with the maximum recommended dosage of 30 mcg once daily, consider adding or restarting calcium and/or active vitamin D therapy and/or seek other treatment.
Titration Recommendations for Albumin-Corrected Serum Calcium Less Than 12 mg/dL:
- Ttitration recommendations for YORVIPATH, active vitamin D, and calcium in adults with specific albumin-corrected serum calcium ranges that are less than or equal to 12 mg/dL. The maximum recommended dosage of YORVIPATH is 30 mcg once daily.
- The titration of YORVIPATH, Active Vitamin D, and calcium supplements depends on albumin-corrected serum calcium levels. If the albumin-corrected serum calcium is less than 8.3 mg/dL, an increase in the dose of YORVIPATH, Active Vitamin D, or calcium supplements may be necessary to restore calcium levels to the normal range. When the albumin-corrected serum calcium falls between 8.3 and 10.6 mg/dL, no dose adjustment is typically required, as this range is considered optimal. However, regular monitoring should continue to ensure stability. If the albumin-corrected serum calcium rises to between 10.7 and 11.9 mg/dL, a dose reduction of YORVIPATH, Active Vitamin D, or calcium supplements should be considered to prevent hypercalcemia. Careful monitoring and appropriate dose adjustments are essential to maintain balanced calcium levels and avoid complications.
- The decision-making process for adjusting YORVIPATH, calcium supplements, and active vitamin D is based on a structured flowchart. If at least seven days have passed since starting or adjusting the YORVIPATH dose, further evaluation is needed. If the patient is still taking active vitamin D, the recommendation is to decrease or discontinue it (as per Table 1) while increasing the YORVIPATH dose by 3 mcg. If the patient is not taking active vitamin D but is still using calcium supplements, the next step is to determine the calcium supplement dosage. If the daily calcium supplement intake is 1500 mg or more, it should be reduced by at least 1500 mg, and the YORVIPATH dose should be increased by 3 mcg. If the calcium supplement intake is less than 1500 mg per day, calcium supplements should be discontinued entirely, and the YORVIPATH dose should be increased by 3 mcg. If the patient is not taking calcium supplements, the YORVIPATH dose remains unchanged. Similarly, if fewer than seven days have passed since starting or adjusting YORVIPATH, all doses should remain the same for YORVIPATH, calcium supplements, and active vitamin D.
Albumin-Corrected Serum Calcium 10.7 to 11.9 mg/dL:
- The process for adjusting YORVIPATH, calcium supplements, and active vitamin D. If a patient is still taking active vitamin D, the recommendation is to decrease or discontinue it ,while continuing the same YORVIPATH and calcium supplement doses. If the patient is not taking active vitamin D but is still using calcium supplements, further assessment is needed. If the calcium supplement intake is less than 1500 mg per day, the YORVIPATH dose should be decreased by 3 mcg. If the calcium supplement intake is 1500 mg or more per day, the next step is to adjust the calcium supplementation. If the calcium supplement intake is reduced by at least 1500 mg, the YORVIPATH dose remains the same. If calcium supplements are discontinued entirely, the YORVIPATH dose should also remain unchanged. Through this structured approach, calcium and YORVIPATH dosing are carefully managed to maintain optimal balance.
Titration Recommendations for Albumin-Corrected Serum Calcium 12 mg/dL or Greater:
- Withhold YORVIPATH for 2 to 3 days and then recheck serum calcium. If albumin-corrected serum calcium remains ≥12 mg/dL, withhold YORVIPATH for an additional 2 to 3 days and then recheck serum calcium. Once the albumin-corrected serum calcium is <12 mg/dL, resume titration of YORVIPATH, active vitamin D, and calcium supplements per the applicable section of Figure 1 using the most recent serum calcium value.
Dose Delay, Interruption, or Discontinuation of YORVIPATH:
- Take YORVIPATH as soon as possible if a dose is missed by less than 12 hours. Skip the missed dose if the dose has been missed by more than 12 hours. Take the next dose as scheduled.
- If YORVIPATH treatment is delayed or interrupted for 3 days or more, evaluate patients for signs and symptoms of hypocalcemia and consider measuring serum calcium. If indicated, 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 after an interruption then measure serum calcium within 7 to 10 days and adjust doses of YORVIPATH, active vitamin D, and/or calcium supplements.
Preparation of Pen and Administration Instructions:
- Patients and caregivers who will administer YORVIPATH should receive appropriate training by a healthcare professional prior to first use.
- Follow the Instructions For Use to administer YORVIPATH using pen and needle:
- YORVIPATH must be refrigerated at 2°C to 8°C (36°F to 46°F) until first use.
- YORVIPATH should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. YORVIPATH is a clear, colorless solution. Do not use if solid particles appear or if the solution is cloudy or colored.
- When a pen is used for the first time, test pen flow.
- Click the needle straight onto the pen, then screw the needle onto the pen until secure.
- Administer YORVIPATH subcutaneously to the abdomen or front of the thigh. Rotate the injection site daily.
- YORVIPATH should be administered initially when the patient can sit or lie down because of the potential of orthostatic hypotension.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Palopegteriparatide in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Palopegteriparatide in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Palopegteriparatide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Palopegteriparatide in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Palopegteriparatide in pediatric patients.
Contraindications
YORVIPATH is contraindicated in patients with
- severe hypersensitivity to palopegteriparatide or to any of its excipients. *Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been observed with parathyroid hormone (PTH) analogs.
Warnings
Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections
Use only one YORVIPATH injection to achieve the recommended once daily dosage. Using two YORVIPATH 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 YORVIPATH. The risk is highest when starting or increasing the dose of YORVIPATH 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 YORVIPATH for at least 2-3 days. For less serious hypercalcemia, adjust the dose of YORVIPATH, active vitamin D, and/or calcium supplements.
Serious Hypocalcemia
Serious events of hypocalcemia have been observed with PTH products, including YORVIPATH. The risk is highest when YORVIPATH is abruptly discontinued, but may occur at any time, even in patients who have been on stable doses of YORVIPATH. 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 YORVIPATH, active vitamin D, and/or calcium supplements if hypocalcemia occurs.
Potential Risk of Osteosarcoma
- YORVIPATH 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.
- YORVIPATH is not recommended in patients who are at increased risk of osteosarcoma, such as patients with:
- Open epiphyses. YORVIPATH 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 YORVIPATH. 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. YORVIPATH 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
YORVIPATH 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 YORVIPATH 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.
Adverse Reactions
Clinical Trials Experience
The following clinically significant adverse reactions are described :
- Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections.
- Serious Hypercalcemia .
- Serious Hypocalcemia.
- Potential Risk of Osteosarcoma.
- Orthostatic Hypotension.
- Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds.
Clinical Trials Experience:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The phase 3 trial included 82 subjects with hypoparathyroidism with a median YORVIPATH treatment duration of 182 days.
- Adverse reactions associated with YORVIPATH in Study 1 during the 26-week blinded period (incidence ≥5% and occurring ≥2% more frequently than placebo).
- Adverse Reactions in ≥5% of Subjects with Hypoparathyroidism Treated with YORVIPATH and with ≥2% Higher Frequency Compared to Placebo .
- In a study evaluating adverse reactions in subjects with hypoparathyroidism treated with YORVIPATH, several side effects were observed at a frequency of at least 5% and at least 2% higher than in the placebo group. Among the 61 patients receiving YORVIPATH, the most frequently reported adverse reaction was injection site reactions, occurring in 24 patients (39%), compared to only 1 patient (5%) in the placebo group. Vasodilatory signs and symptoms, including dizziness, orthostatic hypotension, and palpitations, were reported in 17 patients (28%) in the YORVIPATH group, while no cases were observed in the placebo group. Headache was experienced by 13 patients (21%) treated with YORVIPATH, compared to 2 patients (10%) in the placebo group. Diarrhea was reported in 6 patients (10%) receiving YORVIPATH, while only 1 patient (5%) in the placebo group experienced this adverse reaction. Back pain, including flank and spinal pain, was observed in 5 patients (8%) treated with YORVIPATH, with no cases reported in the placebo group. Hypercalcemia occurred in 5 patients (8%) receiving YORVIPATH, whereas no cases were reported in the placebo group. Lastly, oropharyngeal pain was observed in 4 patients (7%) treated with YORVIPATH, with no occurrences in the placebo group. These findings suggest that YORVIPATH treatment is associated with a higher incidence of certain adverse reactions compared to placebo, particularly injection site reactions, vasodilatory symptoms, and headache.
Description of Selected Adverse Reactions
- Hypercalcemia
- The number of subjects who had at least one serum calcium measurement greater than the upper limit of the reference range at a post-baseline visit in Study 1. The incidence of hypercalcemia was greater in subjects treated with YORVIPATH.
Incidence of Elevated Albumin-Corrected Serum Calcium (>10.6 mg/dL or >12 mg/dL) Post-Baseline in Subjects with Hypoparathyroidism Treated with YORVIPATH or Placebo in Study 1 - Symptomatic hypercalcemia was reported in 8% of subjects treated with YORVIPATH, and all occurred within the first 3 months after initiation of YORVIPATH.
- In a study comparing YORVIPATH to a placebo, the incidence of elevated albumin-corrected serum calcium levels was notably higher in patients treated with YORVIPATH. Among the 61 patients receiving YORVIPATH, 33 patients (54.1%) experienced albumin-corrected serum calcium levels exceeding 10.6 mg/dL, whereas only 2 patients (9.5%) in the placebo group met this criterion. Additionally, serum calcium levels greater than 12 mg/dL were observed in 8 patients (13.1%) treated with YORVIPATH, while no cases were reported in the placebo group. These findings indicate that treatment with YORVIPATH is associated with a higher likelihood of elevated serum calcium levels compared to placebo, necessitating careful monitoring to prevent hypercalcemia.
- The number of subjects who had at least one serum calcium measurement greater than the upper limit of the reference range at a post-baseline visit in Study 1. The incidence of hypercalcemia was greater in subjects treated with YORVIPATH.
Postmarketing Experience
There is limited information regarding Palopegteriparatide Postmarketing Experience in the drug label.
Drug Interactions
Drugs Affected by Serum Calcium
- Digoxin
- YORVIPATH 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 YORVIPATH 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 YORVIPATH dose may be needed.
Drugs Known to Affect Serum Calcium
- Drugs that affect serum calcium may alter the therapeutic response to YORVIPATH. Measure serum calcium more frequently when YORVIPATH is used concomitantly with these drugs, particularly after these drugs are initiated, discontinued, or dose-adjusted.
Use in Specific Populations
Pregnancy
Risk Summary
- 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 area under the curve (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 YORVIPATH is administered during pregnancy, or if a patient becomes pregnant while receiving YORVIPATH, healthcare providers should report YORVIPATH exposure by calling 1-844-442-7236.
Clinical Considerations
- Disease-Associated Maternal and Embryo/Fetal Risk:
- 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.
Animal Data:
- In an embryo-fetal developmental toxicity study in rats, palopegteriparatide was administered subcutaneously during the period of organogenesis (gestation days (GD) 6 to 17) at doses of 2, 8, and 30 mcg/kg/day. In pregnant rats, there was no evidence of embryo-lethality, fetotoxicity, or fetal malformations up to the highest dose tested corresponding to 16-fold the MRHD, based on PTH(1-34) and active metabolite PTH(1-33) exposure by AUC.
- In an embryo-fetal developmental toxicity study in rabbits, palopegteriparatide was administered subcutaneously to pregnant female rabbits during the period of organogenesis (GD 7 to 19) at doses of 1, 3, and 6 mcg/kg/day. There was no evidence of any palopegteriparatide-related embryo-lethality, fetotoxicity, or fetal malformations at any dose level up to 13-fold the MRHD, based on PTH(1-34) exposure by AUC.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Palopegteriparatide in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Palopegteriparatide during labor and delivery.
Nursing Mothers
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 YORVIPATH 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 YORVIPATH and any potential adverse effects on the breastfed child from YORVIPATH or from the underlying sub-optimally treated maternal condition.
Pediatric Use
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 YORVIPATH 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 YORVIPATH and any potential adverse effects on the breastfed child from YORVIPATH or from the underlying sub-optimally treated maternal condition.
Geriatic Use
In Study 1, 8 of 61 (13%) YORVIPATH-treated subjects were 65 years of age or over compared to 2 of 21 (10%) subjects in the placebo group. Clinical studies of YORVIPATH did not include a sufficient number of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.
Gender
There is no FDA guidance on the use of Palopegteriparatide with respect to specific gender populations.
Race
There is no FDA guidance on the use of Palopegteriparatide with respect to specific racial populations.
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 YORVIPATH.
Hepatic Impairment
There is no FDA guidance on the use of Palopegteriparatide in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Palopegteriparatide in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Palopegteriparatide in patients who are immunocompromised.
Administration and Monitoring
Administration
• Use only one injection to achieve the once daily recommended dosage. Using two injections to achieve the recommended once daily dosage increases the risk of unintended changes in serum calcium levels, including hypocalcemia and hypercalcemia.
• The maximum recommended dosage is 30 mcg subcutaneously once daily. If an adequate response is not achieved with a maximum YORVIPATH dosage of 30 mcg, consider adding or restarting calcium and/or active vitamin D therapy and/or seek other treatment options.
• YORVIPATH's once daily subcutaneous dosage is individualized. 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). Calcium supplementation sufficient to meet daily dietary requirements may be continued.
• Advise patients to monitor daily for clinical signs and symptoms of hypocalcemia or hypercalcemia.
• Measure serum calcium 7 to 10 days after the first YORVIPATH dose and after any dose change in YORVIPATH, active vitamin D, or calcium supplements, and monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia. Once the YORVIPATH maintenance dosage is achieved, measure serum calcium levels at a minimum every 4 to 6 weeks or as indicated for symptoms of hypocalcemia or hypercalcemia.
• Adjust YORVIPATH, active vitamin D, and/or calcium supplements per Figure 1. Some patients may require an increase in the YORVIPATH dose over time to maintain the same therapeutic effect.
• Refer to the Instructions for Use (IFU) for detailed instructions on the proper preparation and administration of YORVIPATH.
Monitoring
• Advise patients to monitor daily for clinical signs and symptoms of hypocalcemia or hypercalcemia.
• Measure serum calcium 7 to 10 days after the first YORVIPATH dose and after any dose change in YORVIPATH, active vitamin D, or calcium supplements, and monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia. Once the YORVIPATH maintenance dosage is achieved, measure serum calcium levels at a minimum every 4 to 6 weeks or as indicated for symptoms of hypocalcemia or hypercalcemia.
• Measure serum calcium within 7 to 10 days after the first dose and any dose change in YORVIPATH, active vitamin D, or calcium supplements, and monitor for clinical symptoms of hypocalcemia or hypercalcemia. Adjust YORVIPATH, active vitamin D, and/or calcium supplements.
• The maintenance dosage is individualized and should be the YORVIPATH dose that achieves serum calcium within the normal range, without the need for active vitamin D or therapeutic doses of calcium. Calcium supplementation sufficient to meet daily dietary requirements may be continued. Once the maintenance dosage is achieved, monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia and measure serum calcium levels as indicated, and at a minimum every 4 to 6 weeks, as some patients may require further dose titration. If calcium levels remain low with the maximum recommended dosage of 30 mcg once daily, consider adding or restarting calcium and/or active vitamin D therapy and/or seek other treatment.
IV Compatibility
There is limited information regarding the compatibility of Palopegteriparatide and IV administrations.
Overdosage
Accidental overdose of YORVIPATH may cause hypercalcemia that can be severe and require medical intervention. One subject in Study 1 accidentally received approximately 3-fold the prescribed dose of YORVIPATH for more than 7 consecutive days and developed albumin-corrected serum calcium as high as 16.1 mg/dL, requiring hospitalization.
Pharmacology
There is limited information regarding Palopegteriparatide Pharmacology in the drug label.
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.
Structure
YORVIPATH (palopegteriparatide injection) is a parathyroid hormone analog ( PTH ( 1-34 ) ). Palopegteriparatide is a prodrug of teriparatide ( PTH ( 1-34 ) ) consisting of PTH ( 1-34 ) transiently conjugated to an inert carrier via a proprietary TransCon Linker. PTH ( 1-34 ) is identical to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone. The carrier is a branched 40 kDa ( 2×20 kDa ) methoxypolyethylene glycol (mPEG) moiety. The average molecular weight of palopegteriparatide is approximately 47.4 kDa. The structure of palopegteriparatide drug substance is shown in Figure 2. The theoretical molecular formula is C209H340N60O59S3 + 2 × ( C2H4O ) n, where n is between approximately 450 and 500.
Pharmacodynamics
- Serum PTH(1-34) and serum calcium concentrations increased in a dose-related manner when YORVIPATH was administered to healthy volunteers. Exposure-response is not established in subjects with hypoparathyroidism.
Mean steady state concentration-time profile of albumin-corrected serum calcium concentrations over 24 hours following administration of YORVIPATH .
The mean steady-state albumin-corrected serum calcium concentrations were evaluated in subjects with hypoparathyroidism following subcutaneous administration of YORVIPATH. The normal reference range for albumin-corrected serum calcium is 8.3 to 10.6 mg/dL. In this study, patients received a mean YORVIPATH dose of 22.3 mcg/day, with individual doses ranging from 12 to 33 mcg/day. The analysis was conducted on a sample of seven subjects, highlighting the dose-dependent regulation of serum calcium levels in patients undergoing treatment.
Pharmacokinetics
- YORVIPATH is a prodrug that releases PTH(1-34) via autocleavage of the TransCon linker.
- PTH Cmax and AUC increased proportionally over a YORVIPATH dosage range of 12 to 24 mcg/day. PTH steady state is achieved after administration of YORVIPATH for 7 days.
- Mean steady state concentration-time profile of PTH(1-34) over 24 hours following administration of YORVIPATH is presented in Figure 4. At steady state, administration of YORVIPATH resulted. in continuous exposure to released PTH throughout the 24-hour dosing period.
- PTH(1-34) concentrations include both PTH(1-34) and its active metabolite, PTH(1-33), which contribute to the overall physiological effects of parathyroid hormone therapy. In a study evaluating these concentrations, subjects received a mean YORVIPATH dose of 22.3 mcg/day, with individual doses ranging from 12 to 33 mcg/day. The analysis was conducted on a sample of seven subjects, providing insight into the dose-dependent regulation of PTH levels in patients undergoing treatment.
Absorption
The median (range) time to reach maximum concentrations (Tmax) of PTH is 4 (4 to 8) hours.
Distribution
The estimated apparent volume of distribution (CV%) of palopegteriparatide is 4.8 (50) L. A similar distribution pattern as observed for endogenous PTH is expected for PTH released from palopegteriparatide.
Elimination
- The apparent half-life of PTH released from palopegteriparatide is approximately 60 hours. The estimated clearance (CV%) of palopegteriparatide at steady state is 0.58 (52) L/day.
- Metabolism
- Released PTH includes PTH(1-34) and the active metabolite PTH(1-33). PTH(1-33) and PTH(1-34) have comparable affinity to and activation of PTH1R.
Specific Populations
- There are no clinically significant differences in the pharmacokinetics of palopegteriparatide based on age, sex, or body weight. The data for race and ethnicity did not show any trends indicating differences, but the available data are too limited to make definitive conclusions.
- Patients with Renal Impairment
- A dedicated renal impairment study showed that mild, moderate, and severe renal impairment did not have a clinically significant impact on systemic exposure of total PTH following a single 50 mcg subcutaneous dose of palopegteriparatide. No studies were conducted in subjects with hypoparathyroidism who have severe renal impairment.
- Patients with Hepatic Impairment
- No dedicated hepatic impairment study was conducted. Mild and moderate hepatic impairment is not expected to have a clinically significant impact on the pharmacokinetics of palopegteriparatide.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Long-term animal studies to address the carcinogenic potential of palopegteriparatide have not been conducted. Palopegteriparatide was not genotoxic in an in vitro bacterial reverse-mutation assay (Ames test), an in vitro human lymphocyte chromosome-aberration assay, and an in vivo rat bone-marrow micronucleus assay. In fertility studies, palopegteriparatide was administered by subcutaneous injection at 2, 6, and 20 mcg/kg/day. Palopegteriparatide did not impair fertility in male and female rats up to the highest tested dose, which is 7-fold and 11-fold the MRHD, respectively, based on PTH ( 1-34 ) and active metabolite PTH ( 1-33 ) exposure by AUC.
Animal Pharmacology and Toxicology
In a 26-week rat study, daily subcutaneous administration of palopegteriparatide resulted in bone turnover imbalances in healthy euparathyroid rats. The bone effects tended towards a net catabolic effect (bone resorption) as evidenced by a decrease in proximal tibial trabecular bone volume and bone mineral content ( BMC ) in both sexes treated at the low dose of 5 mcg/kg/day ( 5-fold the MRHD, based on PTH ( 1-34 ) and active metabolite PTH ( 1-33 ) exposure by AUC ) and in females treated at 10 mcg/kg/day ( 9-fold the MRHD, based on PTH ( 1-34 ) and PTH ( 1-33 ) exposure by AUC ) . A net anabolic bone effect ( bone formation ) including histologic increases in bone at several skeletal sites accompanied by increased osteoblast cellularity and increases in proximal tibia trabecular bone volume and BMC were observed in males at 10 mcg/kg/day ( 10-fold the MRHD, based on PTH ( 1-34 ) and PTH ( 1-33 ) exposure by AUC ) and in both sexes treated at the high dose of 20 mcg/kg/day (19-fold the MRHD, based on PTH ( 1-34 ) and PTH ( 1-33 ) exposure by AUC ) . In a 4-week study in hypoparathyroid female rats, daily subcutaneous administration of palopegteriparatide at 5 and 10 mcg/kg/day (5- to 9-fold the MRHD, based on PTH ( 1-34 ) and PTH ( 1-33 ) exposure by AUC ) resulted in a net catabolic bone effect as bone resorption (e.g., high urinary C-telopeptide of type 1 collagen, decreased tibial trabecular bone volume, increase in osteoclast surface, and endocortical eroded surface) appeared to exceed bone formation.
Clinical Studies
Treatment of Adults with Hypoparathyroidism
The effectiveness and safety of YORVIPATH in adults with hypoparathyroidism were evaluated in a 26-week, randomized, double-blind, placebo-controlled, phase 3 study.
Study 1 was conducted in 82 subjects with hypoparathyroidism. Prior to randomization, all subjects underwent an approximate 4-week screening period in which calcium and active vitamin D supplements were adjusted to achieve an albumin-corrected serum calcium concentration between 7.8 and 10.6 mg/dL, a magnesium concentration ≥1.3 mg/dL and below the upper limit of the reference range, and a 25(OH) vitamin D concentration between 20 to 80 ng/mL. During the double-blind period, subjects were randomized to either YORVIPATH (N = 61) or placebo (N= 21), at a starting dose of 18 mcg/day, co-administered with conventional therapy (calcium and active vitamin D). Randomization was stratified by etiology of hypoparathyroidism (postsurgical vs. all other causes). Study drug and conventional therapy were subsequently titrated according to the albumin-corrected serum calcium levels.
The mean age at enrollment was 49 years (range: 19 to 78 years), 78% were female, and 93% were Caucasian. Eighty-five percent (85%) of subjects had hypoparathyroidism acquired from neck surgery. Of the subjects with other etiologies of hypoparathyroidism, 7 (8.5%) subjects had idiopathic disease, 2 had autoimmune polyglandular syndrome type 1 (APS-1), 1 had autosomal dominant hypocalcemia type 1 (ADH1, CaSR mutation), 1 had DiGeorge Syndrome, and 1 had hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome (GATA3 mutation). At baseline, the median duration of hypoparathyroidism was 8.5 years (range 1 to 56 years). Baseline mean albumin-corrected serum calcium was 8.8 mg/dL and 8.6 mg/dL and mean 24-hour urine calcium was 392 mg/day and 329 mg/day for YORVIPATH and placebo, respectively. The mean baseline dose of elemental calcium was 1839 mg/day, and the mean baseline doses of active vitamin D were 0.75 mcg/day in calcitriol-treated subjects (n=70), and 2.3 mcg/day in alfacalcidol-treated subjects (n=12).
Efficacy Assessment and Results:
- Efficacy was assessed based on the proportion of subjects who achieved all of the following at Week 26:
- Albumin-corrected serum calcium in the normal range (8.3 to 10.6 mg/dL),
- Independence from conventional therapy (defined as requiring no active vitamin D and ≤600 mg/day of calcium supplementation, including no use of pro re nata [PRN] doses) since Week 22,
- No increase in the study drug dose since Week 22,
- No missing active vitamin D and calcium data since Week 22, and
- Study drug dose of 30 mcg or less once daily during the 26-week treatment period
- In the YORVIPATH group, 68.9% (42/61) of subjects met the efficacy endpoint at Week 26 compared with 4.8% (1/21) of subjects in the placebo group. The treatment difference was 64.2% (95% confidence interval: 49.5%, 78.8%).
- At Week 26 of the study evaluating the efficacy of YORVIPATH in adults with hypoparathyroidism, a significantly higher response rate was observed in the YORVIPATH group compared to the placebo group. Overall, 42 out of 61 patients (68.9%) treated with YORVIPATH met the response criteria, whereas only 1 out of 21 patients (4.8%) in the placebo group achieved a response, resulting in a response rate difference of 64.2% (95% CI: 49.5%, 78.8%).
When evaluating individual response components, 49 patients (80.3%) in the YORVIPATH group achieved normal albumin-corrected serum calcium levels (8.3 to 10.6 mg/dL), compared to 10 patients (47.6%) in the placebo group, with a response rate difference of 32.7% (95% CI: 9.2%, 56.3%). Independence from active vitamin D was achieved by 58 patients (95.1%) in the YORVIPATH group, compared to only 5 patients (23.8%) in the placebo group, with a response rate difference of 71.3% (95% CI: 52.5%, 90.2%). Similarly, 53 patients (86.9%) receiving YORVIPATH were able to maintain independence from a therapeutic dose of calcium (≤600 mg elemental calcium daily), compared to just 1 patient (4.8%) in the placebo group, with a response rate difference of 82.2% (95% CI: 70.0%, 94.4%). Additionally, 57 patients (93.4%) in the YORVIPATH group maintained a stable study drug dose without increases since Week 22, compared to 12 patients (57.1%) in the placebo group, with a response rate difference of 36.4% (95% CI: 14.2%, 58.5%). Furthermore, 56 patients (91.8%) in the YORVIPATH group received a study drug dose of ≤30 mcg/day throughout the 26-week period, but this outcome was not applicable to the placebo group. These findings demonstrate the superior efficacy of YORVIPATH over placebo in achieving biochemical control and reducing dependence on conventional therapies in adults with hypoparathyroidism.
- The proportion of subjects randomized to YORVIPATH who met the efficacy endpoint decreased over time as follows: 68.9% (42/61) at Week 26 and 39.3% (24/61) at both Week 52 and Week 78 during the open-label extension period. Allowing for dose up-titration, the proportion of subjects who were able to maintain normocalcemia and independence from active vitamin D and therapeutic dose of calcium was 64% (39/61) at Week 52 and 66% (40/61) at Week 78.
How Supplied
YORVIPATH is available in a prefilled, disposable, 14-dose pen-injector (Table 6). Each pen contains a clear and colorless solution of 3456 mcg/mL of palopegteriparatide equivalent to 300 mcg/mL of teriparatide. Each pack contains 2 prefilled pens and 28 needles for 28 injections (plus two spare needles).
Storage
Do not freeze. Store away from heat. Keep YORVIPATH in the packaging to protect from light.
Until first use, store YORVIPATH in the refrigerator between 2°C to 8°C (36°F to 46°F).
After first use, store YORVIPATH for 14 days at room temperature below 30°C (86°F). After each use, remove the needle and put the pen cap on to protect from light. Discard the prefilled pen 14 days after first use.
Images
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Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Dosage and Administration:
- Advise patients to use only one injection to achieve the once daily recommended dosage.
- Advise patients that the healthcare provider may change the dose of YORVIPATH, calcium, or active vitamin D supplements based on serum calcium levels.
- Advise patients to administer YORVIPATH subcutaneously to the abdomen or front of the thigh. Advise patients to rotate the injection site daily.
Adverse Reactions:
- Risk of YORVIPATH Adverse Reactions with Use of Two Injections to Achieve the Recommended Once Daily Dosage:
- Advise patients that using two YORVIPATH 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 YORVIPATH injection to achieve the recommended once daily dosage.
- Serious Hypercalcemia and Serious Hypocalcemia:
- Advise patients taking YORVIPATH 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 YORVIPATH dosing, and to follow recommended serum calcium monitoring.
- Potential Risk of Osteosarcoma:
- 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.
- Orthostatic Hypotension:
- When initiating YORVIPATH 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.
- Digoxin Toxicity:
- Advise patients to report use of a digoxin-containing medication and to follow recommended serum calcium and digoxin monitoring.
- Hypersensitivity:
- Advise patients that serious hypersensitivity reactions (including anaphylaxis and angioedema) are possible with PTH products. Advise patients to discontinue YORVIPATH and promptly seek medical attention if signs or symptoms of hypersensitivity reaction occur.
- Pregnancy:
- Advise females who are exposed to YORVIPATH 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).
Precautions with Alcohol
Alcohol-Palopegteriparatide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
Yorvipath
Look-Alike Drug Names
There is limited information regarding Palopegteriparatide Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.