Palopegteriparatide

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 C 209 H 340 N 60 O 59 S 3 + 2 × (C 2 H 4 O) n , where n is between approximately 450 and 500. Figure 2: Structure of Palopegteriparatide YORVIPATH is a sterile, clear, and colorless solution in a glass cartridge which is pre-assembled in a single-patient-use prefilled pen for subcutaneous administration. The prefilled pen is co-packaged with disposable needles to administer 14 doses of YORVIPATH. YORVIPATH is available in three presentations containing 0.56 mL, 0.98 mL, or 1.4 mL of YORVIPATH solution, and each pen presentation can deliver one of three distinct doses for 14 days of therapy. Each mL of YORVIPATH solution contains 3456 mcg of palopegteriparatide, equivalent to 300 mcg of teriparatide (PTH(1-34)), and the following inactive ingredients: 41.7 mg mannitol, 2.5 mg metacresol, 0.13 mg sodium hydroxide, 1.18 mg succinic acid, and water for injection. YORVIPATH has a pH of 3.7 to 4.3. Each pen of 0.56 mL contains 168 mcg teriparatide equivalent to 1935 mcg palopegteriparatide. Each pen of 0.98 mL contains 294 mcg teriparatide equivalent to 3387 mcg palopegteriparatide. Each pen of 1.4 mL contains 420 mcg teriparatide equivalent to 4838 mcg palopegteriparatide. Figure 2

YORVIPATH is indicated for the treatment of hypoparathyroidism in adults. YORVIPATH is a parathyroid hormone analog (PTH(1-34)) indicated for the treatment of hypoparathyroidism in adults. ( 1 ) Limitations of Use : Not studied for acute post-surgical hypoparathyroidism. ( 1 ) Titration scheme 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. ( 1 ) 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 [see Dosage and Administration (2.3 , 2.4) and Clinical Studies (14) ] .

16.1 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). Table 6: YORVIPATH Prefilled Pen Presentations Prefilled Pen Presentation Labeled Doses Content of Pack NDC YORVIPATH (168 mcg/0.56 mL) identified by blue push button 6, 9, and 12 mcg 2 prefilled pens 30 needles 73362-100-01 YORVIPATH (294 mcg/0.98 mL) identified by orange push button 15, 18, and 21 mcg 2 prefilled pens 30 needles 73362-101-01 YORVIPATH (420 mcg/1.4 mL) identified by burgundy push button 24, 27, and 30 mcg 2 prefilled pens 30 needles 73362-102-01 16.2 Storage and Handling 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.

Use only one injection to achieve the once daily recommended dosage. ( 2.1 ) Maximum recommended YORVIPATH dosage is 30 mcg subcutaneously once daily. ( 2.1 ) Individualize YORVIPATH dosage based on serum calcium. ( 2.1 ) Refer to the Full Prescribing Information for complete dosage and administration information. ( 2 ) 2.1 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 [see Dosage and Administration (2.4 , 2.6) and Warnings and Precautions (5.2) ] . 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 [see Warnings and Precautions (5.2) ] . 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 [see Clinical Studies (14) ] . Refer to the Instructions for Use (IFU) for detailed instructions on the proper preparation and administration of YORVIPATH [see Dosage and Administration (2.6) ] . 2.2 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. 2.3 Modification of Active Vitamin D and Calcium Supplements on Day of YORVIPATH Initiation or Up-titration 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 (Table 1). Table 1: Dosage Adjustments to Active Vitamin D (calcitriol) and Calcium Supplements Upon Initiation or Up-titration of YORVIPATH Treatment Albumin-Corrected Serum Calcium Current Active Vitamin D (calcitriol) Intake Adjust Active Vitamin D (calcitriol) Intake Adjust Calcium Supplements ≥8.3 mg/dL >1 mcg/day Reduce calcitriol dosage by ≥50% Maintain current calcium dosage ≥8.3 mg/dL ≤1 mcg/day Discontinue calcitriol Maintain current calcium dosage ≥7.8 to <8.3 mg/dL Any amount Reduce calcitriol dosage by ≥50% Maintain current calcium dosage ≥7.8 mg/dL Not currently on active vitamin D Not applicable Reduce calcium daily dosage by at least 1500 mg or discontinue If calcium supplements are needed to meet dietary requirements, continuing dietary calcium supplements at elemental dosages ≤ 600 mg/day may be considered instead of discontinuing the calcium entirely. if current calcium daily dosage is ≤1500 mg/day 2.4 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 per Figure 1. 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 Figure 1 shows dosage titration 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 [see Dosage and Administration (2.1) ] . Figure 1: Titration of YORVIPATH, Active Vitamin D, and Calcium Supplements Albumin-Corrected Serum Calcium < 8.3 mg/dL: Albumin-Corrected Serum Calcium 8.3 to 10.6 mg/dL: Albumin-Corrected Serum Calcium 10.7 to 11.9 mg/dL: Figure 1 Figure 1 Figure 1 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. 2.5 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 per Figure 1 [see Dosage and Administration (2.4) ] . 2.6 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 [see Warnings and Precautions (5.6) ].

YORVIPATH is contraindicated in patients with a history of severe hypersensitivity to palopegteriparatide or any of the inactive ingredients of YORVIPATH. Reactions have included anaphylaxis, angioedema, and urticaria. Severe hypersensitivity to palopegteriparatide or any of the inactive ingredients of YORVIPATH. ( 4 )

Hypersensitivity Reactions : Anaphylaxis, angioedema, and urticaria have been reported in patients treated with parathyroid hormone analogs, including YORVIPATH. If signs or symptoms of a hypersensitivity reaction occur, discontinue treatment with YORVIPATH, initiate supportive care, and monitor until signs and symptoms resolve. Discontinue YORVIPATH permanently in patients with a severe hypersensitivity reaction to YORVIPATH. ( 5.1 ) Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections : Use only one daily YORVIPATH injection. Using two YORVIPATH injections to achieve the recommended once daily dosage increases the variability of the total delivered dose. ( 5.2 ) Serious Hypercalcemia and Hypocalcemia : Have occurred with YORVIPATH. Periodically measure serum calcium and monitor for signs and symptoms of hypercalcemia and hypocalcemia. ( 5.3 , 5.4 ) Potential Risk of Osteosarcoma : YORVIPATH is not recommended in patients at increased risk of osteosarcoma. ( 5.5 ) Orthostatic Hypotension : Has been reported with YORVIPATH. Monitor for signs and symptoms of orthostatic hypotension. ( 5.6 ) Digoxin Toxicity : Concomitant use with digoxin may predispose to digitalis toxicity if hypercalcemia develops. With concomitant use, frequently measure serum calcium and digoxin levels, and monitor for signs and symptoms of digoxin toxicity. ( 5.7 , 7.1 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria have been reported in patients treated with parathyroid hormone (PTH) analogs, including YORVIPATH [see Adverse Reactions (6.2) ] . If signs or symptoms of a hypersensitivity reaction occur, discontinue treatment with YORVIPATH, initiate appropriate supportive care, and monitor until signs and symptoms resolve. Discontinue YORVIPATH permanently in patients with a severe hypersensitivity reaction to YORVIPATH . YORVIPATH is contraindicated in patients with a history of severe hypersensitivity to palopegteriparatide or any of the inactive ingredients of YORVIPATH [see Contraindications (4) ] . 5.2 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 [see Dosage and Administration (2.1) and Warning and Precautions (5.3 , 5.4) ] . 5.3 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 [see Dosage and Administration (2.4) ]. For less serious hypercalcemia, adjust the dose of YORVIPATH, active vitamin D, and/or calcium supplements [see Dosage and Administration (2) and Adverse Reactions (6.1) ] . 5.4 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 [see Dosage and Administration (2.4) ] . 5.5 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 [see Use in Specific Populations (8.4) ] . 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. 5.6 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. 5.7 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 [see Drug Interactions (7.1) ] .

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 [see Dosage and Administration (2.1) and Warnings and Precautions (5.2) ] . 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 [see Dosage and Administration (2.6) ]. Adverse Reactions Hypersensitivity Reactions Advise patients that serious hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, can occur with YORVIPATH. Advise patients to discontinue YORVIPATH and promptly seek medical attention if signs or symptoms of hypersensitivity reactions occur [see Contraindications (4) and Warnings and Precautions (5.1) ] . 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 [see Warnings and Precautions (5.2) ]. 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 [see Warnings and Precautions (5.3 , 5.4) ] . 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 [see Warnings and Precautions (5.5) ] . 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 [see Warnings and Precautions (5.6) ] . Digoxin Toxicity Advise patients to report use of a digoxin-containing medication and to follow recommended serum calcium and digoxin monitoring [see Warnings and Precautions (5.7) ] . 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 (1-877-229-2184) [see Use in Specific Populations (8.1) ] .

Drugs Known to Affect Calcium : When used concomitantly with YORVIPATH, measure serum calcium levels more frequently. ( 7.2 ) 7.1 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. 7.2 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.

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.

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 (see Clinical Considerations ). 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) (see Data ). 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 1-877-229-2184. 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. Data 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.

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

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.

The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections [see Warnings and Precautions (5.2) ] Serious Hypercalcemia [see Warnings and Precautions (5.3) ] Serious Hypocalcemia [see Warnings and Precautions (5.4) ] Potential Risk of Osteosarcoma [see Warnings and Precautions (5.5) ] Orthostatic Hypotension [see Warnings and Precautions (5.6) ] Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds [see Warnings and Precautions (5.7) ] Adverse reactions occurring in ≥ 5% of patients: injection site reactions, vasodilatory signs and symptoms, headache, diarrhea, back pain, hypercalcemia, and oropharyngeal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascendis Pharma at 1-844-442-7236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 (Study 1) [see Clinical Studies (14) ] . Adverse reactions associated with YORVIPATH in Study 1 during the 26-week blinded period (incidence ≥ 5% and occurring ≥ 2% more frequently than placebo) are shown in Table 3. Table 3: Adverse Reactions in ≥ 5% of Subjects with Hypoparathyroidism Treated with YORVIPATH and with ≥ 2% Higher Frequency Compared to Placebo in Study 1 Adverse Reaction YORVIPATH N=61 n (%) Placebo N=21 n (%) Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects with the adverse reaction; %, percent of subjects with the adverse reaction. Injection site reactions Injection site reactions includes the preferred terms injection site bruising, injection site erythema, injection site rash, and injection site reaction. 24 (39) 1 (5) Vasodilatory signs and symptoms Vasodilatory signs and symptoms includes the preferred terms blood pressure orthostatic decreased, dizziness, dizziness postural, orthostatic hypotension, palpitations, postural orthostatic tachycardia syndrome, presyncope, syncope, and vertigo. 17 (28) 0 Headache 13 (21) 2 (10) Diarrhea 6 (10) 1 (5) Back pain Back pain includes the preferred terms back pain, flank pain, and spinal pain. 5 (8) 0 Hypercalcemia 5 (8) 0 Oropharyngeal pain 4 (7) 0 Description of Selected Adverse Reactions Hypercalcemia Table 4 summarizes 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. Symptomatic hypercalcemia was reported in 8% of subjects treated with YORVIPATH, and all occurred within the first 3 months after initiation of YORVIPATH. Table 4: 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 YORVIPATH N=61 Placebo N=21 Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects meeting criteria. Albumin-Corrected Serum Calcium >10.6 mg/dL, n (%) Subjects meeting albumin-corrected serum calcium > 10.6 mg/dL criterion includes subjects meeting albumin-corrected serum calcium > 12 mg/dL criterion. 33 (54.1) 2 (9.5) Albumin-Corrected Serum Calcium >12 mg/dL, n (%) 8 (13.1) 0 (0) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of YORVIPATH. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic reactions: Anaphylaxis, angioedema, drug hypersensitivity, urticaria

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.