Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK, Breda, The Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Parsabiv should not be initiated if corrected serum calcium is less than the lower limit of the normal range (see sections 4.2 and 4.4).
Parsabiv 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 spasm 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 Parsabiv 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).
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 Parsabiv.
Cases of seizures have been reported in patients treated with Parsabiv (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 Parsabiv.
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 congestive heart failure while being treated with Parsabiv (see section 4.2), which may be associated with reductions in serum calcium levels.
Administer Parsabiv with caution in patients receiving any other medicinal products known to lower serum calcium. Closely monitor serum calcium (see section 4.5).
Patients receiving Parsabiv should not be given cinacalcet. Concurrent administration may result in severe hypocalcaemia.
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 Parsabiv should 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).
In clinical studies, 7.1% of patients with SHPT treated with Parsabiv 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. If formation of anti-etelcalcetide antibodies with a clinically significant effect is suspected, contact the Marketing Authorisation Holder to discuss antibody testing. Contact details are provided in section 6 of the package leaflet.
Parsabiv contains less than 1 mmol sodium 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 and Parsabiv may result in an increased risk of hypocalcaemia (see section 4.4). Patients receiving Parsabiv should not be given cinacalcet (see section 4.4).
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.
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.
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).
Very common side effects with Parsabiv are blood calcium decreased, muscle spasms, diarrhoea, nausea, and vomiting. They were mild to moderate in severity and transient in nature in the majority of patients. Discontinuation of therapy as a result of undesirable effects was mainly due to low blood calcium, nausea, and vomiting.
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:
Not known: Hypersensitivity reactions1 (including anaphylaxis)
Very common: Blood calcium decreased1,4
Common: Hypocalcaemia1,5, Hyperkalaemia2, Hypophosphataemia
Common: Headache, Paraesthesia3
Uncommon: Convulsions6
Common: Worsening heart failure1, QT prolongation1
Common: Hypotension
Very common: Nausea, Vomiting, Diarrhoea
Very common: Muscle spasms
Common: Myalgia
1 See section on 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.
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 please see sections 4.4 and 4.2 respectively.
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.
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 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.
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