Palopegteriparatide

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) ] .

Injection: Clear, colorless solution in single-patient-use prefilled pens in three presentations Table 2 displays the YORVIPATH prefilled pen presentations, strengths, labeled doses, and deliverable dose ranges. Table 2: YORVIPATH Prefilled Pen Presentations, Strengths, Labeled Doses, and Deliverable Dose Ranges Pen Type and Strength Labeled Dose (mcg) Range of Deliverable Dose Deliverable dose range at each labeled dose setting based on prefilled pen performance. Use only labeled dose for titration (refer to Figure 1). (Minimum – Maximum) (mcg) Prefilled pen with blue push button (168 mcg/0.56 mL) 6 4.5 - 7.5 9 7.5 - 10.5 12 10.5 - 13.5 Prefilled pen with orange push button (294 mcg/0.98 mL) 15 13.1 - 16.5 18 16.1 - 19.5 21 19.1 - 22.5 Prefilled pen with burgundy push button (420 mcg/1.4 mL) 24 21.6 - 25.5 27 24.6 - 28.5 30 27.6 - 31.5 Injection: single-patient-use prefilled pen ( 3 ) 168 mcg/0.56 mL pen, labeled doses of 6, 9, or 12 mcg 294 mcg/0.98 mL pen, labeled doses of 15, 18, or 21 mcg 420 mcg/1.4 mL pen, labeled doses of 24, 27, or 30 mcg

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 )

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.

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.

Lactation : Monitor breastfed infants for symptoms of hypercalcemia or hypocalcemia. Consider monitoring serum calcium in the breastfed infant ( 8.2 ).

8.1 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 (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.

8.2 Lactation Risk Summary 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.

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

8.5 Geriatric 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.

8.6 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 m 2 ). In a dedicated renal impairment study, patients with severe renal impairment (estimated glomerular filtration rate 15 to 30 mL/min/1.73 m 2 ) had no clinically significant difference in total PTH compared to subjects with normal renal function upon treatment with YORVIPATH [see Clinical Pharmacology (12.3) ] .

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.

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

12.1 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.

12.2 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 is presented in Figure 3. Figure 3: Mean Steady-State Albumin-Corrected Serum Calcium Concentrations Following Subcutaneous Administration of YORVIPATH Mean dose (range): 22.3 (12-33) mcg/day, n = 7. in Subjects with Hypoparathyroidism The normal range for albumin-corrected serum calcium is 8.3 to 10.6 mg/dL. Figure 3 12.3 Pharmacokinetics YORVIPATH is a prodrug that releases PTH(1-34) via autocleavage of the TransCon linker. PTH C max 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. Figure 4: Mean Steady State PTH(1-34) Following Subcutaneous Administration of YORVIPATH Mean dose (range): 22.3 (12-33) mcg/day, n = 7. in Subjects with Hypoparathyroidism a PTH(1-34) concentrations includes PTH(1-34) and active metabolite PTH(1-33). Figure 4 Absorption The median (range) time to reach maximum concentrations (T max ) 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.

12.6 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of YORVIPATH or other teriparatide products. Mean duration of exposure to YORVIPATH in clinical studies was 850 days. Of patients with post-baseline assessments, 0.7% (1 of 139 YORVIPATH-treated patients) had low titer, non-neutralizing antibodies towards PTH and 5% (7 of 139 YORVIPATH-treated patients) had low titer treatment-emergent antibodies against PEG. Three of 139 YORVIPATH-treated patients (2.2%) had pre-existing PEG antibodies that had a transient impact on the pharmacokinetics of palopegteriparatide and serum calcium, however, therapeutic effectiveness was maintained by dose adjustment of YORVIPATH using the trial titration algorithm.

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.

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 is presented in Figure 3. Figure 3: Mean Steady-State Albumin-Corrected Serum Calcium Concentrations Following Subcutaneous Administration of YORVIPATH Mean dose (range): 22.3 (12-33) mcg/day, n = 7. in Subjects with Hypoparathyroidism The normal range for albumin-corrected serum calcium is 8.3 to 10.6 mg/dL. Figure 3

YORVIPATH is a prodrug that releases PTH(1-34) via autocleavage of the TransCon linker. PTH C max 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. Figure 4: Mean Steady State PTH(1-34) Following Subcutaneous Administration of YORVIPATH Mean dose (range): 22.3 (12-33) mcg/day, n = 7. in Subjects with Hypoparathyroidism a PTH(1-34) concentrations includes PTH(1-34) and active metabolite PTH(1-33). Figure 4 Absorption The median (range) time to reach maximum concentrations (T max ) 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.

, Mutagenesis, 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.

17 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 [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) ] .

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.