PARSABIV

Posology The recommended initial dose of etelcalcetide is 5 mg administered by bolus injection 3 times per week. Corrected serum calcium should be at or above the lower limit of the normal range prior to administration of first dose of Parsabiv, a dose increase, or reinitiation after a dose stop (see also dose adjustments based on serum calcium levels).

Parsabiv should not be administered more frequently than 3 times per week. 5 mg and 15 mg. 5 mg or 5 mg increments no more frequently than every 4 weeks to a maximum dose of 15 mg 3 times per week to achieve the desired parathyroid hormone (PTH) target.

Dose adjustments based on PTH levels PTH should be measured after 4 weeks from initiation or dose adjustment of Parsabiv, and approximately every 1-3 months during maintenance. Dose adjustment may be necessary at any time during treatment including the maintenance phase.

6 pmol/L), the dose should be reduced or temporarily stopped. If PTH does not return to > 100 pg/mL following dose reduction, the dose should be stopped. 08 mmol/L). 08 mmol/L). Additional recommendations related to the management of low calcium are provided in the table below.

1). Dose adjustments based on serum calcium levels Serum calcium should be measured within 1-week of initiation or dose adjustment of Parsabiv. Once the maintenance phase has been established for a patient, corrected serum calcium should be measured approximately every 4 weeks.

In the studies total serum calcium was measured using Roche modular analysers. 08 mmol/L). Other laboratory assays may have different cut-offs for the lower limit of the normal range. 88 mmol/L) • If clinically indicated: - start or increase calcium supplements, calcium-containing phosphate binders, and/or vitamin D sterols.

- increase dialysate calcium concentration. - consider reducing Parsabiv dose. 08 mmol/L) and symptoms of hypocalcaemia (if present) have resolved. • If clinically indicated: - start or increase calcium supplements, calcium-containing phosphate binders, and/or vitamin D sterols.

- increase dialysate calcium concentration. • Reinitiate Parsabiv at a dose 5 mg lower than the last administered dose. 08 mmol/L) and symptoms of hypocalcaemia (if present) have resolved. * Total calcium was measured using Roche modular analyser.

Summary of the safety profile Very common adverse reactions with Parsabiv are blood calcium decreased (64%), vomiting (13%), muscle spasms (12%), diarrhoea (11%), and nausea (11%), . They were mild to moderate in severity and transient in nature in the majority of patients.

Discontinuation of therapy as a result of adverse reactions was mainly due to low blood calcium, nausea, and vomiting. Tabulated list of adverse reactions Adverse reactions are listed below using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Table 1. Adverse reactions from controlled clinical studies and post-marketing experience MedDRA system organ class (SOC) Frequency category Adverse reactions Immune system disorders Not known Hypersensitivity reactions(including anaphylaxis) Very common Blood calcium decreased1, 4 Metabolism and nutrition disorders Common Hypocalcaemia1, 5 Hyperkalaemia2 Hypophosphataemia Common Headache Paraesthesia3 Nervous system disorders Uncommon Convulsions6 Cardiac disorders Common Worsening heart failure1 QT prolongation1 Vascular disorders Common Hypotension Gastrointestinal disorders Very common Nausea Vomiting Diarrhoea Very common Muscle spasmsMusculoskeletal and connective tissue disorders Common Myalgia 1 See section Description of selected adverse reactions.

2 Hyperkalaemia includes preferred terms of hyperkalaemia and blood potassium increased. 3 Paraesthesia includes preferred terms of paraesthesia and hypoaesthesia. 08 mmol/L) (that required medical management). 08 mmol/L). 4. Description of selected adverse reactions Hypocalcaemia Most events of asymptomatic blood calcium decreased and symptomatic hypocalcaemia were mild or moderate in severity.

4% placebo). In these studies 1% of patients in the Parsabiv group and 0% of patients in the placebo group discontinued treatment due to the adverse event of low serum calcium. 2 respectively. 2% Parsabiv; 0% placebo). 9%, respectively.

3). Potential manifestations of hypocalcaemia include paraesthesias, myalgias, muscle spasms and seizures. 2). Serum calcium levels should be measured prior to initiating treatment, within 1-week of initiation or dose adjustment of etelcalcetide and every 4 weeks during treatment.

2). 8). Serum calcium levels should be closely monitored in patients with congenital long QT syndrome, previous history of QT prolongation, family history of long QT syndrome or sudden cardiac death and other conditions that predispose to QT prolongation and ventricular arrhythmia while being treated with etelcalcetide.

8). The threshold for seizures may be lowered by significant reductions in serum calcium levels. Serum calcium levels should be closely monitored in patients with a history of a convulsion disorder while being treated with etelcalcetide.

Worsening heart failure Decreased myocardial performance, hypotension, and congestive heart failure (CHF) may be associated with significant reductions in serum calcium levels. 2), which may be associated with reductions in serum calcium levels.

Co-administration with other medicinal products Administer etelcalcetide with caution in patients receiving any other medicinal products known to lower serum calcium. 5). Patients receiving etelcalcetide should not be given cinacalcet.

Concurrent administration may result in severe hypocalcaemia. Adynamic bone Adynamic bone may develop if PTH levels are chronically suppressed below 100 pg/mL. If PTH levels decrease below the recommended target range, the dose of vitamin D sterols and/or etelcalcetide should be reduced or therapy discontinued.

2). 3% of these had pre-existing antibodies. No evidence of altered pharmacokinetic profile, clinical response or safety profile was associated with pre-existing or developing anti-etelcalcetide antibodies. Excipient with known effect This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

1. 4).