Palopegteriparatide

FDA Drug Information • Also known as: Yorvipath

Brand Names: Yorvipath
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION 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

What Is Palopegteriparatide Used For?

1 INDICATIONS AND USAGE 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) ] .

Dosage and Administration

2 DOSAGE AND ADMINISTRATION 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 (5.1) ] . 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 (5.1) ] . 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...

Side Effects (Adverse Reactions)

6 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 [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. 6.1 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)

Drug Interactions

7 DRUG INTERACTIONS 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.

Contraindications

4 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 )

Pregnancy and Breastfeeding

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 1-844-442-7236. 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. Data Animal Data In an...

Overdosage

10 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 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.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.