Etelcalcetide

12.1 Mechanism of Action Etelcalcetide is a calcimimetic agent that allosterically modulates the calcium-sensing receptor (CaSR). Etelcalcetide binds to the CaSR and enhances activation of the receptor by extracellular calcium. Activation of the CaSR on parathyroid chief cells decreases PTH secretion.

1 INDICATIONS AND USAGE PARSABIV is indicated for the treatment of secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis. PARSABIV is a calcium-sensing receptor agonist indicated for: Secondary hyperparathyroidism (HPT) in adult patients with chronic kidney disease (CKD) on hemodialysis. ( 1 ) Limitations of Use: PARSABIV has not been studied in adult patients with parathyroid carcinoma, primary hyperparathyroidism, or with CKD who are not on hemodialysis and is not recommended for use in these populations. Limitations of Use: PARSABIV has not been studied in adult patients with parathyroid carcinoma, primary hyperparathyroidism, or with chronic kidney disease who are not on hemodialysis and is not recommended for use in these populations .

2 DOSAGE AND ADMINISTRATION Ensure corrected serum calcium is at or above the lower limit of normal prior to initiation, dose increase, or re-initiation. ( 2.1 ) The recommended starting dose is 5 mg administered by intravenous bolus injection three times per week at the end of hemodialysis treatment. ( 2.1 ) The maintenance dose is individualized and determined by titration based on parathyroid hormone (PTH) and corrected serum calcium response. The dose range is 2.5 to 15 mg three times per week. ( 2.1 ) The dose may be increased in 2.5 mg or 5 mg increments no more frequently than every 4 weeks. ( 2.2 ) Measure serum calcium within 1 week after initiation or dose adjustment and every 4 weeks for maintenance. ( 2.2 ) Measure PTH after 4 weeks from initiation or dose adjustment. ( 2.2 ) Decrease or temporarily discontinue PARSABIV in individuals with PTH levels below the target range. ( 2.2 ) Consider decreasing or temporarily discontinuing PARSABIV or use concomitant therapies to increase corrected serum calcium in patients with a corrected serum calcium below the lower limit of normal but at or above 7.5 mg/dL without symptoms of hypocalcemia. ( 2.2 ) Stop PARSABIV and treat hypocalcemia if the corrected serum calcium falls below 7.5 mg/dL or patients report symptoms of hypocalcemia. ( 2.2 ) Do not mix or dilute prior to administration. ( 2.3 ) Administer by intravenous bolus injection into the venous line of the dialysis circuit after hemodialysis, during rinse back or intravenously after rinse back. Administer a sufficient volume of saline, e.g. 150 mL of rinse back, after injection into the dialysis tubing. If administered after rinse back, administer PARSABIV intravenously followed by at least 10 mL of saline flush. ( 2.3 ) 2.1 Recommended Dosing Ensure corrected serum calcium is at or above the lower limit of normal prior to PARSABIV initiation, a PARSABIV dose increase, or re-initiation of PARSABIV therapy after a dosing interruption [see Dosage and Administration (2.2) and Warnings and Precautions (5.1) ] . The recommended starting dose of PARSABIV is 5 mg administered by intravenous (IV) bolus injection three times per week at the end of hemodialysis treatment [see Dosage and Administration (2.3) ] . The maintenance dose of PARSABIV is individualized and determined by titration based on parathyroid hormone (PTH) and corrected serum calcium response [see Dosage and Administration (2.2) ] . The maintenance dose is the dose that maintains PTH levels within the recommended target range and corrected serum calcium within the normal range. The lowest maintenance dose of PARSABIV is 2.5 mg three times per week, and the highest maintenance dose of PARSABIV is 15 mg three times per week . Administer PARSABIV only at the end of hemodialysis treatment. If a regularly scheduled hemodialysis treatment is missed, DO NOT administer any missed doses. Resume PARSABIV at the end of the next hemodialysis treatment at the prescribed dose. If doses of PARSABIV are missed for more than 2 weeks, re-initiate PARSABIV at the recommended starting dose of 5 mg (or 2.5 mg if that was the patient's last dose). 2.2 Monitoring and Dose Adjustment Monitor corrected serum calcium and PTH levels during dose initiation, dose adjustment, and dose maintenance according to the schedule in Table 1. Table 1: Recommended Schedule for Monitoring Corrected Serum Calcium and Parathyroid Hormone Levels during PARSABIV Treatment Dose Initiation or Dose Adjustment Maintenance Corrected Serum Calcium Levels 1 week after Every 4 weeks Parathyroid Hormone Levels 4 weeks after Per clinical practice Titrate PARSABIV dose based on PTH and corrected serum calcium response. At the maintenance dose, PTH levels should be within the recommended target range and corrected serum calcium within the normal range. Increase the dose of PARSABIV in 2.5 mg or 5 mg increments in individuals with corrected serum calcium within the normal range and PTH levels above the recommended target range based on the patient's PTH levels no more frequently than every 4 weeks up to a maximum dose of 15 mg three times per week. Decrease or temporarily discontinue PARSABIV dosing in individuals with PTH levels below the target range. In individuals with a corrected serum calcium below the lower limit of normal but at or above 7.5 mg/dL without symptoms of hypocalcemia, consider decreasing or temporarily discontinuing PARSABIV or use concomitant therapies to increase corrected serum calcium [see Warnings and Precautions (5.1) ] . If the dose is stopped, then re-initiate PARSABIV at a lower dose when the PTH is within the target range and hypocalcemia has been corrected. Stop PARSABIV and treat hypocalcemia if the corrected serum calcium falls below 7.5 mg/dL or patients report symptoms of hypocalcemia [see Warnings and Precautions (5.1) ] . When the corrected serum calcium is within normal limits, symptoms of hypocalcemia have resolved, and predisposing factors for hypocalcemia

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hypocalcemia [see Warnings and Precautions (5.1) ] Worsening Heart Failure [see Warnings and Precautions (5.2) ] Upper Gastrointestinal Bleeding [see Warnings and Precautions (5.3) ] Adynamic Bone [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥ 5%) were blood calcium decreased, muscle spasms, diarrhea, nausea, vomiting, headache, hypocalcemia, and paresthesia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The data in Table 2 are derived from two placebo-controlled clinical studies in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis. The data reflect exposure of 503 patients to PARSABIV with a mean duration of exposure to PARSABIV of 23.6 weeks. The mean age of patients was approximately 58 years, and 60% of the patients were male. Of the total patients, 67% were Caucasian, 28% were Black or African American, 2.6% were Asian, 1.2% were Native Hawaiian or Other Pacific Islander, and 1.6% were categorized as Other. Table 2 shows common adverse reactions associated with the use of PARSABIV in the pool of placebo-controlled studies. These adverse reactions occurred more commonly on PARSABIV than on placebo and were reported in at least 5% of patients treated with PARSABIV. Table 2: Adverse Reactions Reported in ≥ 5% of PARSABIV-Treated Patients Adverse Reaction Included adverse reactions reported with at least 1% greater incidence in the PARSABIV group compared to the placebo group Placebo (N = 513) PARSABIV (N = 503) Blood calcium decreased Asymptomatic reductions in calcium below 7.5 mg/dL or clinically significant asymptomatic reductions in corrected serum calcium between 7.5 and < 8.3 mg/dL (that required medical management) 10% 64% Muscle spasms 7% 12% Diarrhea 9% 11% Nausea 6% 11% Vomiting 5% 9% Headache 6% 8% Hypocalcemia Symptomatic reductions in corrected serum calcium < 8.3 mg/dL 0.2% 7% Paresthesia Paresthesia includes preferred terms of paresthesia and hypoesthesia 1% 6% Other adverse reactions associated with the use of PARSABIV but reported in < 5% of patients in the PARSABIV group in the two placebo-controlled clinical studies were: Hyperkalemia: 3% and 4% for placebo and PARSABIV, respectively. Hospitalization for Heart Failure: 1% and 2% for placebo and PARSABIV, respectively. Myalgia: 0.2% and 2% for placebo and PARSABIV, respectively. Hypophosphatemia: 0.2% and 1% for placebo and PARSABIV, respectively. Description of Selected Adverse Reactions Hypocalcemia In the combined placebo-controlled studies, a higher proportion of patients on PARSABIV developed at least one corrected serum calcium value below 7.0 mg/dL (7.6% PARSABIV, 3.1% placebo), below 7.5 mg/dL (27% PARSABIV, 5.5% placebo), and below 8.3 mg/dL (79% PARSABIV, 19% placebo). In the combined placebo-controlled studies, 1% of patients in the PARSABIV group and 0% of patients in the placebo group discontinued treatment due to an adverse reaction attributed to a low corrected serum calcium. Hypophosphatemia In the combined placebo-controlled studies, 18% of patients treated with PARSABIV and 8.2% of patients treated with placebo had at least one measured phosphorus level below the lower normal limit (i.e., 2.2 mg/dL). QTc Interval Prolongation Secondary to Hypocalcemia In the combined placebo-controlled studies, more patients treated with PARSABIV experienced a maximum increase from baseline of greater than 60 msec in the QTcF interval (0% placebo versus 1.2% PARSABIV). The patient incidence of maximum post-baseline predialysis QTcF > 500 msec in the placebo and PARSABIV groups was 1.9% and 4.8%, respectively. Hypersensitivity In the combined placebo-controlled studies, the subject incidence of adverse reactions potentially related to hypersensitivity was 4.4% in the PARSABIV group and 3.7% in the placebo group. Hypersensitivity reactions in the PARSABIV group were pruritic rash, urticaria, and face edema. 6.2 Immunogenicity As with all peptide therapeutics, there is potential for immunogenicity. The detection of anti-drug binding antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to etelcalcetide with the incidence of antibodies