PARSABIV Solution for injection Ref.[9571] Active ingredients: Etelcalcetide

Hypocalcaemia

Etelcalcetide treatment should not be initiated in patients if the corrected serum calcium is less than the lower limit of the normal range (see section 4.3).

Potential manifestations of hypocalcaemia include paraesthesias, myalgias, muscle spasms and seizures.

Since etelcalcetide lowers serum calcium, patients should be advised to seek medical attention if they experience symptoms of hypocalcaemia and should be monitored for the occurrence of hypocalcaemia (see section 4.2). 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. If clinically meaningful decreases in corrected serum calcium levels occur, steps should be taken to increase serum calcium levels (see section 4.2).

Ventricular arrhythmia and QT prolongation secondary to hypocalcaemia

Decreases in serum calcium can prolong the QT interval, potentially resulting in ventricular arrhythmia (see section 4.8). 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.

Convulsions

Cases of seizures have been reported in patients treated with etelcalcetide (see section 4.8). 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. Serum calcium levels should be monitored in patients with a history of CHF while being treated with etelcalcetide (see section 4.2), which may be associated with reductions in serum calcium levels.

Co-administration with other medicinal products

Administer etelcalcetidewith caution in patients receiving any other medicinal products known to lower serum calcium. Closely monitor serum calcium (see section 4.5).

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 etelcalcetideshould be reduced or therapy discontinued. After discontinuation, therapy can be resumed at a lower dose to maintain PTH in the target range (see section 4.2).

Immunogenicity

In clinical studies, 7.1% of patients with SHPT treated with etelcalcetide for up to 6 months tested positive for binding antibodies, 80.3% 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’.

No interaction studies have been performed. There is no known risk of pharmacokinetic interaction with etelcalcetide.

In vitro, etelcalcetide did not inhibit or induce CYP450 enzymes and was itself not a substrate for metabolism by CYP450 enzymes. In vitro, etelcalcetide was not a substrate of efflux and uptake transporter proteins; and etelcalcetide was not an inhibitor of common transporter proteins.

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 (see section 4.4). Patients receiving etelcalcetide should not be given cinacalcet (see section 4.4).

Pregnancy

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 (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Parsabiv during pregnancy.

Breast-feeding

It is unknown whether etelcalcetide is present in human milk. Available data in rats have shown that etelcalcetide is excreted in milk (see section 5.3).

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or discontinue/abstain from Parsabiv 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 (see section 5.3).

Parsabiv 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 (see section 4.4 and 4.8).

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).
⁶ See section 4.4.

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. For further information regarding potential manifestations of hypocalcaemia and serum calcium monitoring, see sections 4.4 and 4.2 respectively.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products.