FDA

Yorvipath

Approved 9 Aug 2024SubcutaneousSolution

The FDA lists this product in 3 strengths and forms.

Indications

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) ] .

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. Severe hypersensitivity to palopegteriparatide or any components of YORVIPATH. ( 4 )

Warnings and precautions

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. ( 5.1 ) Serious Hypercalcemia and Hypocalcemia : Have occurred with YORVIPATH. Periodically measure serum calcium and monitor for signs and symptoms of hypercalcemia and hypocalcemia.

( 5.2 , 5.3 ) Potential Risk of Osteosarcoma : YORVIPATH is not recommended in patients at increased risk of osteosarcoma. ( 5.4 ) Orthostatic Hypotension : Has been reported with YORVIPATH. Monitor for signs and symptoms of orthostatic hypotension. ( 5.5 ) 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.

Indications

Contraindications

Warnings and precautions

Pregnancy and breastfeeding

8.1Pregnancy 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 calling1-877-229-2184.

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.

Adverse reactions

The following clinically significant adverse reactions are described elsewhere in the labeling: Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections and Total Delivered Dose [see Warnings and Precautions (5.1) ] Serious Hypercalcemia [see Warnings and Precautions (5.2) ] Serious Hypocalcemia [see Warnings and Precautions (5.3) ] Potential Risk of Osteosarcoma [see Warnings and Precautions (5.4) ] Orthostatic Hypotension [see Warnings and Precautions (5.5) ] Risk of Digoxin Toxicity with Concomitant Use of Digitalis Compounds [see Warnings and Precautions (5.6) ] 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.

6.1Clinical 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)

Yorvipath

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

Yorvipath

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

5.2Serious Hypercalcemia

5.3Serious Hypocalcemia

5.4Potential Risk of Osteosarcoma

5.5Orthostatic Hypotension

5.6Risk of Digoxin Toxicity With Concomitant Use of Digitalis Compounds

Interactions

7.1Drugs Affected by Serum Calcium Digoxin

7.2Drugs Known to Affect Serum Calcium

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

Composition

Strengths and forms

Official product information

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