0.98 ML teriparatide 0.3 MG/ML Pen Injector

INDICATIONS AND USAGE Teriparatide injection is indicated: For the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined herein as having a history of osteoporotic fracture or multiple risk factors for fracture) or who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Teriparatide injection reduces the risk of vertebral and nonvertebral fractures. To increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture or who have failed or are intolerant to other available osteoporosis therapy. For the treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture or who have failed or are intolerant to other available osteoporosis therapy. Teriparatide injection is a synthetic parathyroid hormone analog, (PTH 1-34), indicated for: Treatment of postmenopausal women with osteoporosis at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy ( 1 ) Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy ( 1 ) Treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy ( 1 )

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 Treatment Albumin-Corrected Serum Calcium Current Active Vitamin D (calcitriol) Intake Adjust Active Vitamin D (calcitriol) Intake Adjust Calcium Supplements ≥8.3 mg/dL >1 mcg/day Reduce calcitriol dosage by ≥50% Maintain current calcium dosage ≥8.3 mg/dL ≤1 mcg/day Discontinue calcitriol Maintain current calcium dosage ≥7.8 to <8.3 mg/dL Any amount Reduce calcitriol dosage by ≥50% Maintain current calcium dosage ≥7.8 mg/dL Not currently on active vitamin D Not applicable Reduce calcium daily dosage by at least 1500 mg or discontinue If calcium supplements are needed to meet dietary requirements, continuing dietary calcium supplements at elemental dosages ≤600 mg/day may be considered instead of discontinuing the calcium entirely. if current calcium daily dosage is ≤1500 mg/day 2.4 Recommended Dosage, Titration Scheme, and Monitoring The recommended starting dosage of YORVIPATH is 18 mcg once daily. 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. Measure serum calcium within 7 to 10 days after the first dose and any dose change in YORVIPATH, active vitamin D, or calcium supplements, and monitor for clinical symptoms of hypocalcemia or hypercalcemia. Adjust YORVIPATH, active vitamin D, and/or calcium supplements per Figure 1. 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. Calcium supplementation sufficient to meet daily dietary requirements may be continued. Once the maintenance dosage is achieved, monitor for clinical signs and symptoms of hypocalcemia or hypercalcemia and measure serum calcium levels as indicated, and at a minimum every 4 to 6 weeks, as some patients may require further dose titration. 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. The maximum recommended dosage of YORVIPATH is 30 mcg once daily [see Dosage and Administration (2.1) ] . Figure 1: Titration of YORVIPATH, Active Vitamin D, and Calcium Supplements Albumin-Corrected Serum Calcium <8.3 mg/dL: Albumin-Corrected Serum Calcium 8.3 to 10.6 mg/dL: Albumin-Corrected Serum Calcium 10.7 to 11.9 mg/dL: Figure 1 Figure 1 Figure 1 Titration Recommendations for Albumin-Corrected Serum Calcium 12 mg/dL or Greater Withhold YORVIPATH for 2 to 3 days and then recheck serum calcium. 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. 2.5 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. Resume YORVIPATH at the previously prescribed dose as soon as possible after an interruption then measure serum calcium within 7 to 10 days and adjust doses of YORVIPATH, active vitamin D, and/or calcium supplements per Figure 1 [see Dosage and Administration (2.4) ] . 2.6 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 w

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. ( 5.6 , 7.1 ) 5.1 Risk of Unintended Changes in Serum Calcium Levels Related to Number of Daily Injections and Total Delivered Dose 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 (5.2 , 5.3) ] . 5.2 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) , Adverse Reactions (6.1) ] . 5.3 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) ] . 5.4 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. 5.5 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. 5.6 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) ] .

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 )

Mechanism of Action Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues. The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular micro-architecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation.