PARSABIV 5mg injectible solution medication leaflet

Parsabiv 2.5 mg solution for injection

Parsabiv 5 mg solution for injection

Parsabiv 10 mg solution for injection

Parsabiv 2.5 mg solution for injection

Each vial contains 2.5 mg of etelcalcetide (as hydrochloride) in 0.5 mL of solution.

Each mL contains 5 mg etelcalcetide.

Parsabiv 5 mg solution for injection

Each vial contains 5 mg of etelcalcetide (as hydrochloride) in 1 mL of solution.

Each mL contains 5 mg etelcalcetide.

Parsabiv 10 mg solution for injection

Each vial contains 10 mg of etelcalcetide (as hydrochloride) in 2 mL of solution.

Each mL contains 5 mg etelcalcetide.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear colourless solution.

Parsabiv is indicated for the treatment of secondary hyperparathyroidism (SHPT) in adult patients withchronic kidney disease (CKD) on haemodialysis therapy.

The recommended initial dose of etelcalcetide is 5 mg administered by bolus injection 3 times perweek. Corrected serum calcium should be at or above the lower limit of the normal range prior toadministration of first dose of Parsabiv, a dose increase, or reinitiation after a dose stop (see also doseadjustments based on serum calcium levels). Parsabiv should not be administered more frequently than3 times per week.

Dose titration

Parsabiv should be titrated so that doses are individualised between 2.5 mg and 15 mg. The dose maybe increased in 2.5 mg or 5 mg increments no more frequently than every 4 weeks to a maximum doseof 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, andapproximately every 1-3 months during maintenance. Dose adjustment may be necessary at any timeduring treatment including the maintenance phase.

If PTH is below 100 pg/mL (10.6 pmol/L), the dose should be reduced or temporarily stopped. If PTHdoes not return to > 100 pg/mL following dose reduction, the dose should be stopped. For patients inwhom the dose is stopped, Parsabiv should be reinitiated at a lower dose once PTH returns to> 150 pg/mL (15.9 pmol/L) and pre-dialysis serum corrected calcium (cCa) ≥ 8.3 mg/dL(2.08 mmol/L). If the patient’s last administered dose was 2.5 mg, Parsabiv may be reinitiated at the2.5 mg dose level if PTH is > 300 pg/mL (31.8 pmol/L), and the most recent pre-dialysis serum cCa≥ 8.3 mg/dL (2.08 mmol/L).

Additional recommendations related to the management of low calcium are provided in the tablebelow.

Parsabiv may be used as part of a therapeutic regimen including phosphate binders and/or vitamin Dsterols, as appropriate (see section 5.1).

Dose adjustments based on serum calcium levels

Serum calcium should be measured within 1-week of initiation or dose adjustment of Parsabiv. Oncethe maintenance phase has been established for a patient, corrected serum calcium should be measuredapproximately every 4 weeks. In the studies total serum calcium was measured using Roche modularanalysers. The lower limit of the normal range for corrected serum calcium was 8.3 mg/dL(2.08 mmol/L). Other laboratory assays may have different cut-offs for the lower limit of the normalrange.

In the event that clinically meaningful decreases in corrected serum calcium levels below the lowerlimit of the normal range occur and/or symptoms of hypocalcaemia occur, the following managementis recommended:

Corrected serum calcium valueor clinical symptoms of Recommendationshypocalcaemia*:

- If clinically indicated:

- start or increase calcium supplements, calcium-< 8.3 mg/dL (2.08 mmol/L) and containing phosphate binders, and/or vitamin D≥ 7.5 mg/dL (1.88 mmol/L) sterols.

- increase dialysate calcium concentration.

- consider reducing Parsabiv dose.

- Stop Parsabiv until corrected serum calcium levels are≥ 8.3 mg/dL (2.08 mmol/L) and symptoms ofhypocalcaemia (if present) have resolved.

- If clinically indicated:

- start or increase calcium supplements, calcium-< 7.5 mg/dL (1.88 mmol/L) or containing phosphate binders, and/or vitamin Dsymptoms of hypocalcaemia sterols.

- increase dialysate calcium concentration.

- Reinitiate Parsabiv at a dose 5 mg lower than the lastadministered dose. If patient’s last administered dose was2.5 mg or 5 mg, reinitiate at 2.5 mg once corrected serumcalcium levels are ≥ 8.3 mg/dL (2.08 mmol/L) andsymptoms of hypocalcaemia (if present) have resolved.

* Total calcium was measured using Roche modular analyser. For albumin levels < 4 g/dL cCa (mg/dL) = Total

Ca (mg/dL) + (4 - albumin[g/dL])*0.8.

Switch from cinacalcet to etelcalcetide

Etelcalcetide should not be initiated in patients until 7 days after the last dose of cinacalcet and thecorrected serum calcium is at or above the lower limit of the normal range (see section 5.1).

If a regularly scheduled haemodialysis treatment is missed, do not administer any missed doses.

Parsabiv should be administered at the next haemodialysis treatment at the same dose. If doses aremissed for more than 2 weeks, then Parsabiv should be administered at 5 mg, (or 2.5 mg if that wasthe patients last administered dose), and titrated to achieve the desired PTH.

Special population

Dosing recommendations for elderly patients are the same as for adult patients.

The safety and efficacy of etelcalcetide in children and adolescents less than 18 years have not yetbeen established. No data are available.

Parsabiv is administered into the venous line of the dialysis circuit at the end of the haemodialysistreatment during rinse-back or intravenously after rinse-back. When given during rinse-back at least150 mL of rinse-back volume should be administered after injection. If rinse-back is completed and

Parsabiv was not administered, then it may be administered intravenously followed by at least 10 mLsodium chloride 9 mg/mL (0.9%) solution for injection flush volume.

Parsabiv should not be diluted.

Parenteral medicinal products should be inspected visually for particulate matter and change in colourprior to administration.

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 normalrange (see sections 4.2 and 4.4).

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

Potential manifestations of hypocalcaemia include paraesthesias, myalgias, muscle spasms andseizures.

Since etelcalcetide lowers serum calcium, patients should be advised to seek medical attention if theyexperience 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-weekof initiation or dose adjustment of etelcalcetide and every 4 weeks during treatment. If clinicallymeaningful decreases in corrected serum calcium levels occur, steps should be taken to increase serumcalcium 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 ventriculararrhythmia (see section 4.8). Serum calcium levels should be closely monitored in patients withcongenital long QT syndrome, previous history of QT prolongation, family history of long QTsyndrome or sudden cardiac death and other conditions that predispose to QT prolongation andventricular arrhythmia while being treated with etelcalcetide.

Cases of seizures have been reported in patients treated with etelcalcetide (see section 4.8). Thethreshold for seizures may be lowered by significant reductions in serum calcium levels. Serumcalcium levels should be closely monitored in patients with a history of a convulsion disorder whilebeing treated with etelcalcetide.

Worsening heart failure

Decreased myocardial performance, hypotension, and congestive heart failure (CHF) may beassociated with significant reductions in serum calcium levels. Serum calcium levels should bemonitored 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 tolower serum calcium. Closely monitor serum calcium (see section 4.5).

Patients receiving etelcalcetide should not be given cinacalcet. Concurrent administration may resultin severe hypocalcaemia.

Adynamic bone

Adynamic bone may develop if PTH levels are chronically suppressed below 100 pg/mL. If PTHlevels decrease below the recommended target range, the dose of vitamin D sterols and/oretelcalcetideshould be reduced or therapy discontinued. After discontinuation, therapy can be resumedat 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 etelcalcetide for up to 6 months testedpositive for binding antibodies, 80.3% of these had pre-existing antibodies. No evidence of alteredpharmacokinetic profile, clinical response or safety profile was associated with pre-existing ordeveloping anti-etelcalcetide antibodies.

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 interactionwith etelcalcetide.

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

Concurrent administration of other medicinal products known to reduce serum calcium (e.g. cinacalcetand 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).

There are no or limited amount of data from the use of etelcalcetide in pregnant women. Animalstudies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (seesection 5.3). As a precautionary measure, it is preferable to avoid the use of Parsabiv duringpregnancy.

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

A risk to breastfed newborns/infants cannot be excluded. A decision must be made whether todiscontinue breast-feeding or discontinue/abstain from Parsabiv therapy taking into account the benefitof 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 indicatedirect 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, certainpotential manifestations of hypocalcaemia may affect the ability to drive and use machines (seesection 4.4 and 4.8).

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 severityand transient in nature in the majority of patients. Discontinuation of therapy as a result of adversereactions 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

MedDRA system organ class Frequency category Adverse reactions(SOC)

Immune system disorders Not known Hypersensitivity reactions(including anaphylaxis)

Metabolism and nutrition disorders Very common Blood calcium decreased1, 4

Common Hypocalcaemia1, 5

Hyperkalaemia2

Hypophosphataemia

Nervous system disorders C ommon Headache

Paraesthesia3

Uncommon Convulsions6

C ardiac disorders Common Worsening heart failure1

QT prolongation1

Vascular disorders Common Hypotension

Gastrointestinal disorders Very common Nausea

Musculoskeletal and connective Very common Muscle spasmstissue disorders Common Myalgia1 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 asymptomaticreductions in serum cCa between 7.5 and < 8.3 mg/dL (1.88 and < 2.08 mmol/L) (that required medicalmanagement).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 ormoderate 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 thesestudies 1% of patients in the Parsabiv group and 0% of patients in the placebo group discontinuedtreatment due to the adverse event of low serum calcium. For further information regarding potentialmanifestations 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 groupcompared with the placebo group had a maximum increase from baseline of > 60 msec in the QTcFinterval (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 requiringhospitalisation 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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose of etelcalcetide may lead to hypocalcaemia with or without clinical symptoms and mayrequire treatment. In the event of overdose, serum calcium should be checked and patients should bemonitored for symptoms of hypocalcaemia (see section 4.4) and appropriate measures should be taken(see section 4.2). Although Parsabiv is cleared by dialysis, haemodialysis has not been studied as atreatment for overdose. Single doses up to 60 mg and multiple doses up to 22.5 mg 3 times a week atthe end of dialysis in patients receiving haemodialysis were safely administered in clinical studies.

Pharmacotherapeutic group: Calcium homeostasis, anti-parathyroid agents. ATC code: H05BX04

The calcium-sensing receptor on the surface of the chief cell of the parathyroid gland is the principalregulator of PTH secretion. Etelcalcetide is a synthetic peptide calcimimetic agent which reduces PTHsecretion through binding and activation of the calcium-sensing receptor. The reduction in PTH isassociated with a concomitant decrease in serum calcium and phosphate levels.

Following a single intravenous bolus administration of 5 mg etelcalcetide, PTH levels decreasedrapidly within 30 minutes post-dose and were maximally decreased for 1 hour, before returning tobaseline. The extent and duration of the reduction in PTH increased with increasing dose. Reduction in

PTH levels correlated with plasma etelcalcetide concentrations in haemodialysis patients. The effect ofreducing PTH levels was maintained throughout the 6-month dosing period when etelcalcetide wasadministered by intravenous bolus 3 times a week.

Placebo-controlled studies

Two 6-month, double-blind, placebo-controlled clinical studies were conducted in SHPT patients with

CKD receiving haemodialysis 3 times per week (n = 1,023). Patients were administered Parsabiv orplacebo at a starting dose of 5 mg 3 times per week at the end of haemodialysis and titrated every4 weeks through week 17 to a maximum dose of 15 mg 3 times per week to achieve target PTH level≤ 300 pg/mL. The median average weekly dose of Parsabiv during the efficacy assessment period(EAP) was 20.4 mg (6.8 mg per administration). Patients with lower screening PTH levels typicallyrequired lower doses (median average weekly doses of 15.0 mg, 21.4 mg, 27.1 mg, respectively, forpatients with screening PTH levels < 600 pg/mL, 600 to ≤ 1,000 pg/mL, and > 1,000 pg/mL). Patientswere maintained on dialysate calcium concentration ≥ 2.25 meq/L.

The primary endpoint in each study was the proportion of patients with > 30% reduction from baselinein PTH during the EAP (EAP, defined as weeks 20 to 27 inclusive). The secondary endpoints were theproportion of patients with a mean PTH ≤ 300 pg/mL during the EAP, and percent change frombaseline during the EAP for PTH, serum cCa, phosphate and calcium phosphate product (Ca × P).

Demographic and baseline characteristics between the two groups in each study were similar. Themean age of patients across the 2 studies was 58.2 (range 21 to 93) years. Mean (SE) baseline PTHconcentrations across the 2 studies were 846.9 (21.8) pg/mL, and 835.9 (21.0) pg/mL for the Parsabivand placebo groups, respectively with approximately 21% of subjects enrolling across both studieshaving baseline PTH > 1,000 pg/mL. The average duration of haemodialysis prior to study entry was5.4 years and 68% of patients were receiving vitamin D sterols at study entry, with 83% receivingphosphate binders.

Both studies demonstrated that Parsabiv reduced PTH, while lowering calcium, phosphate and Ca × P.

Results of all primary and secondary endpoints were statistically significant and the results wereconsistent across both studies as shown in table 2.

Table 2. Effects of Parsabiv on PTH, corrected serum calcium, phosphate and Ca × P in6-month placebo-controlled studies

Study 1 Study 2

Parsabiv Placebo Parsabiv Placebo(N = 254) (N = 254) (N = 255) (N = 260)

PTH

Patients with > 30% reduction in188 (74.0)a 21 (8.3) 192 (75.3)a 25 (9.6)

PTH during the EAP, n (%)

Patients with ≤ 300 pg/mL in PTH126 (49.6)a 13 (5.1) 136 (53.3)a 12 (4.6)during the EAP, n (%)

Mean percent change during the

- 55.11 (1.94)a 13.00 (2.81) -57.39 (1.91)a 13.72 (2.50)

EAP, % (SE)

Corrected serum calcium

Mean percent change during the

- 7.29 (0.53)a 1.18 (0.29) -6.69 (0.55)a 0.58 (0.29)

EAP, % (SE)

Phosphate

Mean percent change during the

- 7.71 (2.16)b -1.31 (1.42) -9.63 (1.61)a -1.60 (1.42)

EAP, % (SE)

Ca × P

Mean percent change during the

- 14.34 (2.06)a -0.19 (1.44) -15.84 (1.57)a -1.06 (1.42)

EAP, % (SE)a p < 0.001 versus placebob p = 0.003 versus placebo

Parsabiv decreased PTH regardless of baseline PTH, duration of dialysis, and whether or not patientswere receiving vitamin D sterols. Patients with lower screening PTH levels were more likely to reach

PTH ≤ 300 pg/mL during EAP.

Parsabiv was associated with reductions in bone metabolism markers (bone specific alkalinephosphatase and type I collagen c-telopeptide) and fibroblast growth factor 23 (exploratory endpoints)at the end of the study (week 27), compared with placebo.

Active-controlled study

A 6-month, double-blind, active-controlled study compared the efficacy and safety of Parsabiv withcinacalcet in 683 SHPT patients with CKD on haemodialysis. The dosing regimen for Parsabiv wassimilar to that in the placebo-controlled studies (starting dose of 5 mg titrated every 4 weeks with2.5 mg to 5 mg increments to a maximum of 15 mg 3 times a week). The starting dose of cinacalcetwas 30 mg daily, titrated every 4 weeks in 30 mg increments or 60 mg for the last uptitration to amaximum dose of 180 mg daily following the cinacalcet prescribing information. The median averageweekly dose of Parsabiv during the EAP was 15.0 mg (5.0 mg per administration) and of cinacalcetwas 360.0 mg (51.4 mg per administration). The primary endpoint was non-inferiority for theproportion of patients who achieved > 30% reduction from baseline in mean PTH during the EAP(weeks 20 to 27). Key secondary endpoints were the proportion of patients who achieved > 50% and> 30% reductions from baseline in mean PTH during the EAP and the mean number of days ofvomiting or nausea per week in the first 8 weeks, sequentially tested for superiority. Mean (SE)baseline PTH concentrations were 1,092.12 (33.8) and 1,138.71 (38.2) pg/mL for the Parsabiv andcinacalcet groups respectively. Demographics and other baseline characteristics were similar to theplacebo-controlled studies.

Parsabiv was non-inferior to cinacalcet for the primary endpoint, and was superior to cinacalcet for thesecondary endpoints of proportion of patients achieving > 30% reduction from baseline in mean PTHduring the EAP (68.2% Parsabiv versus 57.7% cinacalcet; p = 0.004); and proportion of patientsachieving > 50% reduction from baseline in mean PTH during the EAP (52.4% Parsabiv versus 40.2%cinacalcet; p = 0.001). No statistically significant difference between the two groups was observed forthe secondary endpoint evaluating the mean number of days of vomiting or nausea per week in thefirst 8 weeks.

“Switch study”

Results from a study which evaluated changes in corrected serum calcium levels when switchingpatients from cinacalcet to Parsabiv showed that treatment with Parsabiv, at a starting dose of 5 mg,could be safely initiated after a 7-day discontinuation of cinacalcet, provided that the corrected serumcalcium was ≥ 8.3 mg/dL (2.08 mmol/L).

A 52-week, single arm extension study to the placebo-controlled and “switch” studies described abovewas conducted to characterise the long term safety and efficacy of Parsabiv in 891 SHPT patients with

CKD on haemodialysis. All subjects received Parsabiv at a starting dose of 5 mg 3 times a week. Thedose of Parsabiv could be titrated at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg toachieve target PTH levels ≤ 300 pg/mL while maintaining serum cCa concentrations.

At the end of 52 weeks, Parsabiv was not associated with any new safety findings and demonstratedmaintenance of treatment effect as evidenced by a decrease in pre-dialysis PTH by > 30% frombaseline in 2/3rd of patients. In addition, Parsabiv decreased pre-dialysis PTH to ≤ 300 pg/mL in morethan 50% of patients and decreased mean PTH, cCa, cCa × P, and phosphate from baseline.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Parsabiv in one or more subsets of the paediatric population in the treatment of hyperparathyroidism(see section 4.2 for information on paediatric use).

In the population pharmacokinetics model, volume of distribution at steady-state was approximately796 L. Etelcalcetide is predominately bound to plasma albumin by reversible covalent binding.

Non-covalent binding of etelcalcetide to plasma proteins is low with a fraction unbound ratio of 0.53.

The ratio of blood-to-plasma [14C]-etelcalcetide concentrations is approximately 0.6.

Etelcalcetide is not metabolised by CYP450 enzymes. Etelcalcetide is biotransformed in blood byreversible disulphide exchange with endogenous thiols to predominantly form conjugate with serumalbumin. The plasma exposure of biotransformation products was approximately 5-fold higher thanthat of etelcalcetide and their concentration-time course parallels that of etelcalcetide. Thepredominant biotransformation product (albumin bound) was minimally active in vitro.

Intravenous administration 3 times per week at the end of a haemodialysis session resulted in aneffective half-life of 3 to 5 days. Etelcalcetide is rapidly cleared in subjects with normal renal function,whilst in CKD patients requiring haemodialysis, etelcalcetide was predominantly eliminated byhaemodialysis. Etelcalcetide was efficiently removed with a haemodialysis clearance value of7.66 L/hour. Following a single radiolabelled dose of etelcalcetide in CKD patients with secondary

HPT receiving haemodialysis, approximately 60% of dosed [14C]-etelcalcetide was recovered indialysate and approximately 7% recovered in urine and faeces combined over 175 days of collectionperiod. The inter-subject variability of the system clearance in the patient population is approximately70%.

The pharmacokinetics of etelcalcetide is linear and does not change over time following single (5 to60 mg) and multiple intravenous doses (2.5 to 20 mg) in CKD patients with secondary HPT receivinghaemodialysis. Following 3 times a week intravenous dosing at the end of each 3 to 4 hourhaemodialysis session in CKD patients, etelcalcetide plasma levels reached near steady-state 4 weeksafter dosing with an observed accumulation ratio of 2- to 3-fold.

No specific pharmacokinetic studies of etelcalcetide have been conducted in patients with mild tosevere kidney impairment. The pharmacokinetics of etelcalcetide was characterised in CKD patientsreceiving haemodialysis. Etelcalcetide is intended for CKD patients receiving haemodialysis.

No specific study in patients with hepatic impairment was performed.

Body weight, gender, age, race

No body weight, gender, age, or race-related pharmacokinetic differences have been observed in adultpatients studied.

The expected pharmacological effect of decreased PTH and calcium in blood were observed in animalstudies at clinical exposure levels. Reductions in serum calcium associated with tremoring,convulsions and stress-related findings were observed at clinical exposure levels. All effects werereversible upon cessation of treatment.

Etelcalcetide was mutagenic in some strains of bacteria (Ames), however was not genotoxic in in vitroand in vivo mammalian genotoxicity assays and therefore is considered non-genotoxic in humans. Inmouse and rat carcinogenicity studies, there were no etelcalcetide-related tumours up to exposure of0.4-fold clinical exposure levels.

There was no effect on male or female fertility when etelcalcetide was administered to rats at exposurelevels up to 1.8-fold higher than clinical exposures levels achieved in patients receiving etelcalcetideat 15 mg three times per week.

There were no effects on embryo-foetal development in rats and rabbits when exposed to up to 1.8 to4.3 times clinical exposure levels during organogenesis. In a pre- and post-natal development study inrats there was a minimal increase in perinatal pup mortality, delay in parturition and transientreductions in post-natal growth associated with maternal toxicities of hypocalcaemia, tremoring, andreductions in body weight and food consumption at 1.8 times clinical exposure levels.

Studies in rats showed [14C]-etelcalcetide was excreted in the milk at concentrations similar to plasma.

Sodium chloride

Succinic acid

Water for injections

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

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

4 years.

Once removed from the refrigerator:

- Parsabiv is stable for a maximum of 7 cumulative days if stored in the original carton. Nospecial temperature storage requirements are needed.

- If removed from the original carton Parsabiv is stable for a maximum of 4 hours if protectedfrom direct sunlight.

Store in a refrigerator (2°C - 8°C).

Keep the vial in the outer carton in order to protect from light.

Parsabiv 2.5 mg solution for injection

Single use vial (type I glass) with stopper (fluoropolymer laminated elastomeric) and an aluminiumseal with flip-off dust cover. Each vial contains 0.5 mL solution for injection.

Parsabiv 5 mg solution for injection

Single use vial (type I glass) with stopper (fluoropolymer laminated elastomeric) and an aluminiumseal with flip-off dust cover. Each vial contains 1 mL solution for injection.

Parsabiv 10 mg solution for injection

Single use vial (type I glass) with stopper (fluoropolymer laminated elastomeric) and an aluminiumseal with flip-off dust cover. Each vial contains 2 mL solution for injection.

Pack sizes of 1, 6, 12 and 42 vials.

Not all pack sizes may be marketed.

For single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

Parsabiv 2.5 mg solution for injection

EU/1/16/1142/001 - 1 vial

EU/1/16/1142/002 - 6 vials

EU/1/16/1142/003 - 12 vials

EU/1/16/1142/004 - 42 vials

Parsabiv 5 mg solution for injection

EU/1/16/1142/005 - 1 vial

EU/1/16/1142/006 - 6 vials

EU/1/16/1142/007 - 12 vials

EU/1/16/1142/008 - 42 vials

Parsabiv 10 mg solution for injection

EU/1/16/1142/009 - 1 vial

EU/1/16/1142/010 - 6 vials

EU/1/16/1142/011 - 12 vials

EU/1/16/1142/012 - 42 vials

Date of first authorisation: 11 November 2016

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.