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.

2.1 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.

• 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 have been addressed, re-initiate PARSABIV at a dose 5 mg lower than the last administered dose. If the last administered dose of PARSABIV was 2.5 mg or 5 mg, re-initiate at a dose of 2.5 mg.

2.3 Administration

• Do not mix or dilute PARSABIV prior to administration. The solution is clear and colorless. Inspect PARSABIV for particulate matter and discoloration prior to administration. Do not use PARSABIV vials if particulate matter or discoloration is observed.
• PARSABIV is removed by the dialyzer membrane and must be administered after blood is no longer circulating through the dialyzer.
• Administer PARSABIV 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 PARSABIV injection into the dialysis tubing.
  • If PARSABIV is administered after rinse back, administer PARSABIV intravenously followed by at least 10 mL of saline flush.

2.4 Switching from Cinacalcet to PARSABIV

• Discontinue cinacalcet for at least 7 days prior to starting PARSABIV, and initiate PARSABIV treatment at a starting dose of 5 mg. Ensure corrected serum calcium is at or above the lower limit of normal prior to PARSABIV initiation [see Warnings and Precautions (5.1)].

Hypersensitivity

PARSABIV is contraindicated in patients with known hypersensitivity to etelcalcetide or any of its excipients. Hypersensitivity reactions, including face edema and anaphylactic reaction, have occurred with PARSABIV [see Adverse Reactions (6)].

5.1 Hypocalcemia

PARSABIV lowers serum calcium [see Adverse Reactions (6.1)] and can lead to hypocalcemia, sometimes severe. Significant lowering of serum calcium can cause paresthesias, myalgias, muscle spasms, seizures, QT interval prolongation, and ventricular arrhythmia.

5.2 Worsening Heart Failure

In clinical studies with PARSABIV, cases of hypotension, congestive heart failure, and decreased myocardial performance have been reported. In clinical studies, heart failure requiring hospitalization occurred in 2% of PARSABIV-treated patients and 1% of placebo-treated patients. Reductions in corrected serum calcium may be associated with congestive heart failure, however, a causal relationship to PARSABIV could not be completely excluded. Closely monitor patients treated with PARSABIV for worsening signs and symptoms of heart failure.

5.3 Upper Gastrointestinal Bleeding

In clinical studies, two patients treated with PARSABIV in 1253 patient-years of exposure had upper gastrointestinal (GI) bleeding noted at the time of death while no patient in the control groups in 384 patient-years of exposure had upper GI bleeding noted at the time of death. The exact cause of GI bleeding in these patients is unknown, and there were too few cases to determine whether these cases were related to PARSABIV.

Patients with risk factors for upper GI bleeding (such as known gastritis, esophagitis, ulcers, or severe vomiting) may be at increased risk for GI bleeding while receiving PARSABIV treatment. Monitor patients for worsening of common GI adverse reactions of nausea and vomiting associated with PARSABIV [see Adverse Reactions (6.1)] and for signs and symptoms of GI bleeding and ulcerations during PARSABIV therapy. Promptly evaluate and treat any suspected GI bleeding.

5.4 Adynamic Bone

Adynamic bone may develop if PTH levels are chronically suppressed. If PTH levels decrease below the recommended target range, the dose of vitamin D sterols and/or PARSABIV should be reduced or therapy discontinued. After discontinuation, resume therapy at a lower dose to maintain PTH levels in the target range [see Dosage and Administration (2.1)].

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.

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.

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 to other products may be misleading.

In clinical studies, 7.1% (71 out of 995) of patients with secondary hyperparathyroidism treated with PARSABIV for up to 6 months tested positive for binding anti-etelcalcetide antibodies. Fifty-seven out of 71 had pre-existing anti-etelcalcetide antibodies. No evidence of altered pharmacokinetic profile, clinical response, or safety profile was associated with pre-existing or developing anti-etelcalcetide antibodies.

6.3 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of PARSABIV. Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Anaphylactic reaction
• Hypocalcemia in patients who were administered etelcalcetide concomitantly with other products known to lower serum calcium (e.g. cinacalcet, denosumab)
• Seizures secondary to hypocalcemia

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and efficacy of PARSABIV have not been established in pediatric patients.

8.5 Geriatric Use

Of the 503 patients in placebo-controlled studies who received PARSABIV, 177 patients (35.2%) were ≥ 65 years old and 72 patients (14%) were ≥ 75 years old. No clinically significant differences in safety or efficacy were observed between patients ≥ 65 years and younger patients (≥ 18 and < 65 years old). No differences in plasma concentrations of etelcalcetide were observed between patients ≥ 65 years and younger patients (≥ 18 and < 65 years old).

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.

12.2 Pharmacodynamics

Following a single intravenous bolus administration of etelcalcetide, PTH levels decreased within 30 minutes post-dose. In the single-dose study, the extent and duration of the reduction in PTH increased with increasing dose. Reduction in PTH levels correlated with plasma etelcalcetide concentrations in hemodialysis patients. The reduction in PTH resulted in reductions in calcium and attenuation of post-dialytic phosphate elevation. The effect of reducing PTH levels was maintained throughout the 6-month dosing period when etelcalcetide was administered by intravenous bolus three times a week.

12.3 Pharmacokinetics

The pharmacokinetics of etelcalcetide is linear and does not change over time following single (5 to 60 mg) and multiple intravenous doses (2.5 to 20 mg) in chronic kidney disease patients with secondary hyperparathyroidism requiring hemodialysis. Etelcalcetide exhibited tri-exponential decay following intravenous administration. Based on population pharmacokinetic analysis, following three times a week intravenous dosing at the end of each 3- to 6-hour hemodialysis session in chronic kidney disease patients, etelcalcetide plasma levels reached steady state in 7-8 weeks after dosing with a predicted accumulation ratio of 3- to 4-fold, and the effective half-life was 3 to 4 days.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No drug-related tumors were observed in Tg rasH2 transgenic mice when etelcalcetide was administered at doses of 0.3, 1, and 3 mg/kg in females and 0.375, 0.75, and 1.5 mg/kg in males once daily for 26 weeks by the subcutaneous route, representing up to 0.4-fold clinical exposure at the maximum human dose of 15 mg three times per week based on AUC. Etelcalcetide administration did not produce drug-related tumors when Sprague-Dawley rats were dosed at 0.2, 0.4, 0.8, and 1.6 mg/kg/day by the subcutaneous route for 89 weeks in females and 92 weeks in males, representing up to 0.4-fold clinical exposures achieved in patients receiving etelcalcetide at 15 mg three times per week, based on AUC.

Etelcalcetide was mutagenic in some strains of bacteria (Ames), but was not genotoxic in two in vitro and two in vivo mammalian genotoxicity assays.

There was no effect on male or female fertility when etelcalcetide was dosed at 0.75, 1.5, and 3 mg/kg/day by the intravenous route to rats at exposure levels up to 1.8-fold higher than exposures achieved in patients receiving etelcalcetide at 15 mg three times per week based on AUC.

Storage

Store in the original carton in refrigerator at 2°C to 8°C (36°F to 46°F) to protect from light. Once removed from the refrigerator:

• Do not expose to temperatures above 25°C (77°F).
• Use within 7 days if stored in the original carton.
• Use within 4 hours and do not expose to direct sunlight if removed from the original carton.

Hypocalcemia

Advise patients to report symptoms of hypocalcemia, including paresthesias, myalgias, muscle spasms, and seizures, to their healthcare provider [see Warnings and Precautions (5.1)].

Heart Failure

Advise patients with heart failure that use of PARSABIV may worsen their heart failure and additional monitoring may be required [see Warnings and Precautions (5.2)].

Upper Gastrointestinal Bleeding

Advise patients to report any symptoms of upper gastrointestinal bleeding to their healthcare provider [see Warnings and Precautions (5.3)].

Laboratory Monitoring

Inform patients of the importance of regular blood tests, in order to monitor the safety and efficacy of PARSABIV therapy.

Lactation

Advise women that use of PARSABIV is not recommended while breastfeeding [see Use in Specific Populations (8.2)].