Etelcalcetide

Concurrent administration of other medicinal products known to reduce serum calcium (e.g. cinacalcet and denosumab) and etelcalcetide may result in an increased risk of hypocalcaemia. Patients receiving etelcalcetide should not be given cinacalcet.

Serum calcium levels should be monitored in patients with a history of congestive heart failure while being treated with etelcalcetide, which may be associated with reductions in serum calcium levels.

Decreases in serum calcium can prolong the QT interval, potentially resulting in ventricular arrhythmia. 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.

There are no or limited amount of data from the use of etelcalcetide in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of etelcalcetide during pregnancy.

It is unknown whether etelcalcetide is present in human milk. Available data in rats have shown that etelcalcetide is excreted in milk.

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or discontinue/abstain from etelcalcetide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No data are available on the effect of etelcalcetide on human fertility. Animal studies do not indicate direct or indirect harmful effects with respect to fertility.

Etelcalcetide has no or negligible influence on the ability to drive and use machines. However, certain potential manifestations of hypocalcaemia may affect the ability to drive and use machines.

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:

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.
⁴ Asymptomatic reductions in calcium below 7.5 mg/dL (1.88 mmol/L) or clinically significant asymptomatic reductions in serum cCa between 7.5 and <8.3 mg/dL (1.88 and <2.08 mmol/L) (that required medical management).
⁵ Symptomatic reductions in serum cCa <8.3 mg/dL (2.08 mmol/L).

Description of selected adverse reactions

Hypocalcaemia

Most events of asymptomatic blood calcium decreased and symptomatic hypocalcaemia were mild or moderate in severity. In the combined placebo-controlled studies, a higher proportion of patients in the Parsabiv group compared with patients in the placebo group developed at least one serum cCa value <7.0 mg/dL (1.75 mmol/L) (7.6% Parsabiv; 3.1% placebo), <7.5 mg/dL (1.88 mmol/L) (27.1% Parsabiv; 5.5% placebo), and <8.3 mg/dL (2.08 mmol/L) (78.6% Parsabiv; 19.4% 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.

QTc prolongation secondary to hypocalcaemia

In the combined placebo-controlled studies, a higher percentage of patients in the Parsabiv group compared with the placebo group had a maximum increase from baseline of >60 msec in the QTcF interval (1.2% Parsabiv; 0% placebo). The patient incidence of maximum post-baseline pre-dialysis QTcF >500 msec in the Parsabiv and placebo groups was 4.8% and 1.9%, respectively.

Worsening heart failure

In the combined placebo-controlled studies, the subject incidence of adjudicated CHF events requiring hospitalisation was 2.2% in the Parsabiv treatment group compared to 1.2% in the placebo group.