4.1. Therapeutic indications

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

4.2. Posology and method of administration

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.

Dose titration

Parsabiv should be titrated so that doses are individualised between 2.5 mg and 15 mg. The dose may be increased in 2.5 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.

If PTH is below 100 pg/mL (10.6 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. For patients in whom 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 the 2.5 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 table below.

Parsabiv may be used as part of a therapeutic regimen including phosphate binders and/or vitamin D sterols, 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. 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. 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 normal range.

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

Corrected serum calcium value or clinical symptoms of hypocalcaemia*:

Recommendations

< 8.3 mg/dL (2.08 mmol/L) and ≥ 7.5 mg/dL (1.88 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.

< 7.5 mg/dL (1.88 mmol/L) or symptoms of hypocalcaemia

• Stop Parsabiv until corrected serum calcium levels are ≥ 8.3 mg/dL (2.08 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. If patient's last administered dose was 2.5 mg or 5 mg, reinitiate at 2.5 mg once corrected serum calcium levels are ≥ 8.3 mg/dL (2.08 mmol/L) and symptoms 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 the corrected serum calcium is at or above the lower limit of the normal range (see section 5.1).

Missed doses

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 are missed for more than 2 weeks, then Parsabiv should be administered at 5 mg, (or 2.5 mg if that was the patients last administered dose), and titrated to achieve the desired PTH.

Special population

Elderly

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

Paediatric population

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

Method of administration

Parsabiv is administered into the venous line of the dialysis circuit at the end of the haemodialysis treatment during rinse-back or intravenously after rinse-back. When given during rinse-back at least 150 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 mL sodium 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 colour prior to administration.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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 etelcalcetide with 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 etelcalcetide 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).

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'.

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

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)

Metabolism and nutrition disorders

Very common

Blood calcium decreased1, 4

Common

Hypocalcaemia1, 5

Hyperkalaemia2

Hypophosphataemia

Nervous system disorders

Common

Headache

Paraesthesia3

Uncommon

Convulsions6

Cardiac disorders

Common

Worsening heart failure1

QT prolongation1

Vascular disorders

Common

Hypotension

Gastrointestinal disorders

Very common

Nausea

Vomiting

Diarrhoea

Musculoskeletal and connective tissue disorders

Very common

Muscle spasms

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.

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

Overdose of etelcalcetide may lead to hypocalcaemia with or without clinical symptoms and may require treatment. In the event of overdose, serum calcium should be checked and patients should be monitored 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 a treatment for overdose. Single doses up to 60 mg and multiple doses up to 22.5 mg 3 times a week at the end of dialysis in patients receiving haemodialysis were safely administered in clinical studies.