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.
• 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.
• Administer PARSABIV by intravenous bolus injection into the venous line of the dialysis circuit at the end of the hemodialysis treatment during rinse back or intravenously after rinse back.

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)].

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.

QT Interval Prolongation and Ventricular Arrhythmia

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). In these studies, the incidence of a maximum post-baseline predialysis QTcF > 500 msec in the placebo and PARSABIV groups was 1.9% and 4.8%, respectively [see Adverse Reactions (6.1)]. Patients with congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia may be at increased risk for QT interval prolongation and ventricular arrhythmias if they develop hypocalcemia due to PARSABIV. Closely monitor corrected serum calcium and QT interval in patients at risk receiving PARSABIV.

Seizures

Significant reductions in corrected serum calcium may lower the threshold for seizures. Patients with a history of seizure disorder may be at increased risk for seizures if they develop hypocalcemia due to PARSABIV. Monitor corrected serum calcium in patients with seizure disorders receiving PARSABIV.

Concurrent administration of PARSABIV with another oral calcium-sensing receptor agonist could result in severe, life-threatening hypocalcemia. Patients switching from cinacalcet to PARSABIV should discontinue cinacalcet for at least 7 days prior to initiating PARSABIV [see Dosage and Administration (2.4)]. Closely monitor corrected serum calcium in patients receiving PARSABIV and concomitant therapies known to lower serum calcium.

Measure corrected serum calcium prior to initiation of PARSABIV. Do not initiate in patients if the corrected serum calcium is less than the lower limit of normal. Monitor corrected serum calcium within 1 week after initiation or dose adjustment and every 4 weeks during treatment with PARSABIV [see Dosage and Administration (2.2)]. Educate patients on the symptoms of hypocalcemia, and advise them to contact a healthcare provider if they occur. 

If corrected serum calcium falls below the lower limit of normal or symptoms of hypocalcemia develop, start or increase calcium supplementation (including calcium, calcium-containing phosphate binders, and/or vitamin D sterols or increases in dialysate calcium concentration). PARSABIV dose reduction or discontinuation of PARSABIV may be necessary [see Dosage and Administration (2.2)].

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 eva luate 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)].