Yorvipath

5 WARNINGS AND PRECAUTIONS 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) ] .

6 ADVERSE REACTIONS 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

<table width="85%"><caption>Table 3: Adverse Reactions in &#x2265; 5% of Subjects with Hypoparathyroidism Treated with YORVIPATH and with &#x2265; 2% Higher Frequency Compared to Placebo in Study 1</caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction</th><th styleCode="Rrule">YORVIPATH N=61 n (%)</th><th styleCode="Rrule">Placebo N=21 n (%)</th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top">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.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Injection site reactions<footnote>Injection site reactions includes the preferred terms injection site bruising, injection site erythema, injection site rash, and injection site reaction.</footnote></td><td styleCode="Rrule">24 (39)</td><td styleCode="Rrule">1 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vasodilatory signs and symptoms<footnote>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.</footnote></td><td styleCode="Rrule">17 (28)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">13 (21)</td><td styleCode="Rrule">2 (10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">6 (10)</td><td styleCode="Rrule">1 (5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain<footnote>Back pain includes the preferred terms back pain, flank pain, and spinal pain. </footnote></td><td styleCode="Rrule">5 (8)</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypercalcemia</td><td styleCode="Rrule">5 (8)</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Oropharyngeal pain</td><td styleCode="Rrule">4 (7)</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="85%"><caption>Table 4: Incidence of Elevated Albumin-Corrected Serum Calcium (&gt; 10.6 mg/dL or &gt; 12 mg/dL) Post-Baseline in Subjects with Hypoparathyroidism Treated with YORVIPATH or Placebo in Study 1 </caption><col width="50%" align="left" valign="middle"/><col width="25%" align="center" valign="middle"/><col width="25%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">YORVIPATH N=61</th><th styleCode="Rrule">Placebo N=21</th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top">Abbreviations: N, total number of subjects in the treatment arm; n, number of subjects meeting criteria.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Albumin-Corrected Serum Calcium &gt;10.6 mg/dL, n (%)<footnote>Subjects meeting albumin-corrected serum calcium &gt; 10.6 mg/dL criterion includes subjects meeting albumin-corrected serum calcium &gt; 12 mg/dL criterion.</footnote></td><td styleCode="Rrule">33 (54.1)</td><td styleCode="Rrule">2 (9.5)</td></tr><tr><td styleCode="Lrule Rrule">Albumin-Corrected Serum Calcium &gt;12 mg/dL, n (%)</td><td styleCode="Rrule">8 (13.1)</td><td styleCode="Rrule">0 (0)</td></tr></tbody></table>