Yorvipath Drug Information

YORVIPATH is indicated for the treatment of hypoparathyroidism in adults. Limitations of Use: Not studied for acute post-surgical hypoparathyroidism. 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.

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. 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. 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.

Refer to the Instructions for Use (IFU) for detailed instructions on the proper preparation and administration of YORVIPATH.

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.

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

Recommended Dosage, Titration Scheme, and Monitoring

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. 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. 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. 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.

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.

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.

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. Table 3: Adverse Reactions in ≥ 5% of Subjects with Hypoparathyroidism Treated with YORVIPATH and with ≥ 2% Higher Frequency Compared to Placebo in Study 1 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. 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

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.

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.

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 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. 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. 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.

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

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.

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.