4.1. Therapeutic indications

Secondary hyperparathyroidism

Adults

Treatment of secondary hyperparathyroidism (HPT) in adult patients with end-stage renal disease (ESRD) on maintenance dialysis therapy.

Paediatric population

Treatment of secondary hyperparathyroidism (HPT) in children aged 3 years and older with end-stage renal disease (ESRD) on maintenance dialysis therapy in whom secondary HPT is not adequately controlled with standard of care therapy (see section 4.4).

Mimpara may be used as part of a therapeutic regimen including phosphate binders and/or Vitamin D sterols, as appropriate (see section 5.1).

Parathyroid carcinoma and primary hyperparathyroidism in adults

Reduction of hypercalcaemia in adult patients with:

• parathyroid carcinoma.

• primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated.

4.2. Posology and method of administration

Posology

Secondary hyperparathyroidism

Adults and elderly (> 65 years)

The recommended starting dose for adults is 30 mg once per day. Mimpara should be titrated every 2 to 4 weeks to a maximum dose of 180 mg once daily to achieve a target parathyroid hormone (PTH) in dialysis patients of between 150-300 pg/mL (15.9-31.8 pmol/L) in the intact PTH (iPTH) assay. PTH levels should be assessed at least 12 hours after dosing with Mimpara. Reference should be made to current treatment guidelines.

PTH should be measured 1 to 4 weeks after initiation or dose adjustment of Mimpara. PTH should be monitored approximately every 1-3 months during maintenance. Either the intact PTH (iPTH) or bio-intact PTH (biPTH) may be used to measure PTH levels; treatment with Mimpara does not alter the relationship between iPTH and biPTH.

Dose adjustment based on serum calcium levels

Corrected serum calcium should be measured and monitored and should be at or above the lower limit of the normal range prior to administration of first dose of Mimpara (see section 4.4). The normal calcium range may differ depending on the methods used by your local laboratory.

During dose titration, serum calcium levels should be monitored frequently, and within 1 week of initiation or dose adjustment of Mimpara. Once the maintenance dose has been established, serum calcium should be measured approximately monthly. In the event that corrected serum calcium levels fall below 8.4 mg/dL (2.1 mmol/L) and/or symptoms of hypocalcaemia occur the following management is recommended:

Corrected Serum calcium value or clinical symptoms of hypocalcaemia

Recommendations

< 8.4 mg/dL (2.1 mmol/L) and > 7.5 mg/dL (1.9 mmol/L), or in the presence of clinical symptoms of hypocalcaemia

Calcium-containing phosphate binders, vitamin D sterols and/or adjustment of dialysis fluid calcium concentrations can be used to raise serum calcium according to clinical judgment.

< 8.4 mg/dL (2.1 mmol/L) and > 7.5 mg/dL (1.9 mmol/L) or persistent symptoms of hypocalcaemia despite attempts to increase serum calcium

Reduce or withhold dose of Mimpara.

≤ 7.5 mg/dL (1.9 mmol/L) or persistent symptoms of hypocalcaemia and Vitamin D cannot be increased

Withhold administration of Mimpara until serum calcium levels reach 8.0 mg/dL (2.0 mmol/L) and/or symptoms of hypocalcaemia have resolved.

Treatment should be reinitiated using the next lowest dose of Mimpara.

Paediatric population

Corrected serum calcium should be in the upper range of, or above, the age-specified reference interval prior to administration of first dose of Mimpara, and closely monitored (see section 4.4). The normal calcium range differs depending on the methods used by your local laboratory and the age of the child/patient.

The recommended starting dose for children aged ≥ 3 years to < 18 years is ≤ 0.20 mg/kg once daily based on the patient's dry weight (see table 1).

The dose can be increased to achieve a desired target iPTH range. The dose should be increased sequentially through available dose levels (see table 1) no more frequently than every 4 weeks. The dose can be increased up to a maximum dose of 2.5 mg/kg/day, not to exceed a total daily dose of 180 mg.

Table 1. Mimpara daily dose in paediatric patients

Patient dry weight (kg)

Starting dose (mg)

Available sequential dose levels (mg)

10 to < 12.5

1

1, 2.5, 5, 7.5, 10 and 15

≥ 12.5 to < 25

2.5

2.5, 5, 7.5, 10, 15, and 30

≥ 25 to < 36

5

5, 10, 15, 30, and 60

≥ 36 to < 50

5, 10, 15, 30, 60, and 90

≥ 50 to < 75

10

10, 15, 30, 60, 90, and 120

≥ 75

15

15, 30, 60, 90, 120, and 180

Dose adjustment based on PTH levels

PTH levels should be assessed at least 12 hours after dosing with Mimpara and iPTH should be measured 1 to 4 weeks after initiation or dose adjustment of Mimpara.

The dose should be adjusted based on iPTH as shown below:

• If iPTH is < 150 pg/mL (15.9 pmol/L) and ≥ 100 pg/mL (10.6 pmol/L), decrease the dose of Mimpara to the next lower dose.

• If iPTH < 100 pg/mL (10.6 pmol/L), stop Mimpara treatment, restart Mimpara at the next lower dose once the iPTH is > 150 pg/mL (15.9 pmol/L). If Mimpara treatment has been stopped for more than 14 days, restart at the recommended starting dose.

Dose adjustment based on serum calcium levels

Serum calcium should be measured within 1 week after initiation or dose adjustment of Mimpara.

Once the maintenance dose has been established, weekly measurement of serum calcium is recommended. Serum calcium levels in paediatric patients should be maintained within the normal range. If serum calcium levels decrease below the normal range or symptoms of hypocalcaemia occur, appropriate dose adjustment steps should be taken as shown in table 2 below:

Table 2. Dose adjustment in paediatric patients ≥ 3 to < 18 years of age

Corrected Serum calcium value or clinical symptoms of hypocalcaemia

Dosing recommendations

Corrected serum calcium at or below age-specified lower limit of normal

or if symptoms of hypocalcaemia occur, regardless of calcium level.

Stop treatment with Mimpara.*

Administer calcium supplements, calcium-containing phosphate binders and/or vitamin D sterols, as clinically indicated.

Corrected total serum calcium is above age-specified lower limit of normal, and

Symptoms of hypocalcaemia have resolved.

Restart at the next lower dose. If Mimpara treatment has been stopped for more than 14 days, restart at the recommended starting dose.

If patient was receiving the lowest dose (1 mg/day) prior to discontinuation, restart at the same dose (1 mg/day).

*If the dose has been stopped, corrected serum calcium should be measured within 5 to 7 days

The safety and efficacy of Mimpara in children aged less than 3 years for the treatment of secondary hyperparathyroidism have not been established. Insufficient data are available.

Switch from etelcalcetide to Mimpara

The switch from etelcalcetide to Mimpara and the appropriate wash out period has not been studied in patients. In patients who have discontinued etelcalcetide, Mimpara should not be initiated until at least three subsequent haemodialysis sessions have been completed, at which time serum calcium should be measured. Ensure serum calcium levels are within the normal range before Mimpara is initiated (see sections 4.4 and 4.8).

Parathyroid carcinoma and primary hyperparathyroidism

Adults and elderly (> 65 years)

The recommended starting dose of Mimpara for adults is 30 mg twice per day. The dose of Mimpara should be titrated every 2 to 4 weeks through sequential doses of 30 mg twice daily, 60 mg twice daily, 90 mg twice daily, and 90 mg three or four times daily as necessary to reduce serum calcium concentration to or below the upper limit of normal. The maximum dose used in clinical trials was 90 mg four times daily.

Serum calcium should be measured within 1 week after initiation or dose adjustment of Mimpara. Once maintenance dose levels have been established, serum calcium should be measured every 2 to 3 months. After titration to the maximum dose of Mimpara, serum calcium should be periodically monitored; if clinically relevant reductions in serum calcium are not maintained, discontinuation of Mimpara therapy should be considered (see section 5.1).

Paediatric population

The safety and efficacy of Mimpara in children for the treatment of parathyroid carcinoma and primary hyperparathyroidism have not been established. No data are available.

Hepatic impairment

No change in starting dose is necessary. Mimpara should be used with caution in patients with moderate to severe hepatic impairment and treatment should be closely monitored during dose titration and continued treatment (see sections 4.4 and 5.2).

Method of administration

Mimpara granules can be administered orally or through nasogastric or gastrostomy tubes.

The capsules should not be swallowed. The capsule must be opened and the entire contents of a capsule should be sprinkled in food or liquid and administered. In order to avoid dosing errors, capsules of different strengths (1, 2.5, or 5 mg) should not be mixed to achieve the desired dose.

It is recommended that Mimpara be taken with food or shortly after a meal, as studies have shown that bioavailability of cinacalcet is increased when taken with food (see section 5.2).

Oral administration

Capsules should be opened by gently squeezing and twisting the coloured top from the white body of the capsule, having first tapped the capsule gently so the contents settle in the bottom of the capsule (white part of the capsule). While opening it is recommended to hold the capsule upright over the small amount of soft food or liquid.

The entire granules should be sprinkled on to a small amount of soft food (e.g. apple sauce or yogurt) or liquid (e.g. apple juice or renal infant formula), and swallowed. If 1-3 capsules are used per day use at least 15 mL food; if 4-6 capsules are used per day use at least 30 mL food.

Patients should drink fluids after oral administration to make sure all of the mixture is swallowed.

Mixing granules in water for oral use is not recommended as it may lead to a bitter taste.

Granules mixed with soft food or liquid should be administered immediately.

Administration using nasogastric or gastrostomy tubes

• For patients who have nasogastric or gastrostomy tubes, the granules can be administered with a small amount (at least 5 mL) of water using PVC tubing. Flush with adequate volume for the used enteral tube. The granules are not compatible with tubes made of polyurethane and silicone.

Mimpara is also available as tablets. Children who require doses of 30 mg or more and who are able to swallow tablets may receive appropriate doses of Mimpara tablets.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypocalcaemia (see sections 4.2 and 4.4).

4.4. Special warnings and precautions for use

Serum calcium

Life threatening events and fatal outcomes associated with hypocalcaemia have been reported in adult and paediatric patients treated with Mimpara. Manifestations of hypocalcaemia may include paraesthesias, myalgias, cramping, tetany and convulsions. Decreases in serum calcium can also prolong the QT interval, potentially resulting in ventricular arrhythmia secondary to hypocalcaemia. Cases of QT prolongation and ventricular arrhythmia have been reported in patients treated with cinacalcet (see section 4.8). Caution is advised in patients with other risk factors for QT prolongation such as patients with known congenital long QT syndrome or patients receiving medicinal products known to cause QT prolongation.

Since cinacalcet lowers serum calcium, patients should be monitored carefully for the occurrence of hypocalcaemia (see section 4.2). Serum calcium should be measured within 1 week after initiation or dose adjustment of Mimpara.

Adults

Mimpara treatment should not be initiated in patients with a serum calcium (corrected for albumin) below the lower limit of the normal range.

In CKD patients receiving dialysis who were administered Mimpara, approximately 30% of patients had at least one serum calcium value less than 7.5 mg/dL (1.9 mmol/L).

Paediatric population

Mimpara should only be initiated for the treatment of secondary HPT in children ≥ 3 years old with ESRD on maintenance dialysis therapy, in whom secondary HPT is not adequately controlled with standard of care therapy, where serum calcium is in the upper range of, or above, the age-specified reference interval.

Closely monitor serum calcium levels (see section 4.2) and patient compliance during treatment with cinacalcet. Do not initiate cinacalcet or increase the dose if non-compliance is suspected.

Prior to initiating cinacalcet and during treatment, consider the risks and benefits of treatment and the ability of the patient to comply with the recommendations to monitor and manage the risk of hypocalcaemia.

Inform paediatric patients and/or their caregivers about the symptoms of hypocalcaemia and about the importance of adherence to instructions about serum calcium monitoring, and posology and method of administration.

CKD patients not on dialysis

Cinacalcet is not indicated for CKD patients not on dialysis. Investigational studies have shown that adult CKD patients not on dialysis treated with cinacalcet have an increased risk for hypocalcaemia (serum calcium levels < 8.4 mg/dL [2.1 mmol/L]) compared with cinacalcet-treated CKD patients on dialysis, which may be due to lower baseline calcium levels and/or the presence of residual kidney function.

Seizures

Cases of seizures have been reported in patients treated with Mimpara (see section 4.8). The threshold for seizures is lowered by significant reductions in serum calcium levels. Therefore, serum calcium levels should be closely monitored in patients receiving Mimpara, particularly in patients with a history of a seizure disorder.

Hypotension and/or worsening heart failure

Cases of hypotension and/or worsening heart failure have been reported in patients with impaired cardiac function, in which a causal relationship to cinacalcet could not be completely excluded and may be mediated by reductions in serum calcium levels (see section 4.8).

Co-administration with other medicinal products

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

Patients receiving Mimpara should not be given etelcalcetide. Concurrent administration may result in severe hypocalcaemia.

General

Adynamic bone disease may develop if PTH levels are chronically suppressed below approximately 1.5 times the upper limit of normal with the iPTH assay. If PTH levels decrease below the recommended target range in patients treated with Mimpara, the dose of Mimpara and/or vitamin D sterols should be reduced or therapy discontinued.

Testosterone levels

Testosterone levels are often below the normal range in patients with end-stage renal disease. In a clinical study of adult ESRD patients on dialysis, free testosterone levels decreased by a median of 31.3% in the Mimpara-treated patients and by 16.3% in the placebo-treated patients after 6 months of treatment. An open-label extension of this study showed no further reductions in free and total testosterone concentrations over a period of 3 years in Mimpara-treated patients. The clinical significance of these reductions in serum testosterone is unknown.

Hepatic impairment

Due to the potential for 2 to 4 fold higher plasma levels of cinacalcet in patients with moderate to severe hepatic impairment (Child-Pugh classification), Mimpara should be used with caution in these patients and treatment should be closely monitored (see sections 4.2 and 5.2).

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

Medicinal products known to reduce serum calcium

Concurrent administration of other medicinal products known to reduce serum calcium and Mimpara may result in an increased risk of hypocalcaemia (see section 4.4). Patients receiving Mimpara should not be given etelcalcetide (see section 4.4).

Effect of other medicinal products on cinacalcet

Cinacalcet is metabolised in part by the enzyme CYP3A4. Co-administration of 200 mg bid ketoconazole, a strong inhibitor of CYP3A4, caused an approximate 2-fold increase in cinacalcet levels. Dose adjustment of Mimpara may be required if a patient receiving Mimpara initiates or discontinues therapy with a strong inhibitor (e.g. ketoconazole, itraconazole, telithromycin, voriconazole, ritonavir) or inducer (e.g. rifampicin) of this enzyme.

In vitro data indicate that cinacalcet is in part metabolised by CYP1A2. Smoking induces CYP1A2; the clearance of cinacalcet was observed to be 36-38% higher in smokers than non-smokers. The effect of CYP1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin) on cinacalcet plasma levels has not been studied. Dose adjustment may be necessary if a patient starts or stops smoking or when concomitant treatment with strong CYP1A2 inhibitors is initiated or discontinued.

Calcium carbonate

Co-administration of calcium carbonate (single 1,500 mg dose) did not alter the pharmacokinetics of cinacalcet.

Sevelamer

Co-administration of sevelamer (2,400 mg tid) did not affect the pharmacokinetics of cinacalcet.

Pantoprazole

Co-administration of pantoprazole (80 mg od) did not alter the pharmacokinetics of cinacalcet.

Effect of cinacalcet on other medicinal products

Medicinal products metabolised by the enzyme P450 2D6 (CYP2D6): Cinacalcet is a strong inhibitor of CYP2D6. Dose adjustments of concomitant medicinal products may be required when Mimpara is administered with individually titrated, narrow therapeutic index substances that are predominantly metabolised by CYP2D6 (e.g. flecainide, propafenone, metoprolol, desipramine, nortriptyline, clomipramine).

Desipramine: Concurrent administration of 90 mg cinacalcet once daily with 50 mg desipramine, a tricyclic antidepressant metabolised primarily by CYP2D6, significantly increased desipramine exposure 3.6-fold (90% CI 3.0, 4.4) in CYP2D6 extensive metabolisers.

Dextromethorphan: Multiple doses of 50 mg cinacalcet increased the AUC of 30 mg dextromethorphan (metabolised primarily by CYP2D6) by 11-fold in CYP2D6 extensive metabolisers.

Warfarin: Multiple oral doses of cinacalcet did not affect the pharmacokinetics or pharmacodynamics (as measured by prothrombin time and clotting factor VII) of warfarin.

The lack of effect of cinacalcet on the pharmacokinetics of R- and S-warfarin and the absence of auto-induction upon multiple dosing in patients indicates that cinacalcet is not an inducer of CYP3A4, CYP1A2 or CYP2C9 in humans.

Midazolam: Co-administration of cinacalcet (90 mg) with orally administered midazolam (2 mg), a CYP3A4 and CYP3A5 substrate, did not alter the pharmacokinetics of midazolam. These data suggest that cinacalcet would not affect the pharmacokinetics of those classes of medicines that are metabolised by CYP3A4 and CYP3A5, such as certain immunosuppressants, including cyclosporine and tacrolimus.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no clinical data from the use of cinacalcet in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, parturition or postnatal development. No embryonal/foetal toxicities were seen in studies in pregnant rats and rabbits with the exception of decreased foetal body weights in rats at doses associated with maternal toxicities (see section 5.3). Mimpara should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is not known whether cinacalcet is excreted in human milk. Cinacalcet is excreted in the milk of lactating rats with a high milk to plasma ratio. Following careful benefit/risk assessment, a decision should be made to discontinue either breast-feeding or treatment with Mimpara.

Fertility

There are no clinical data relating to the effect of cinacalcet on fertility. There were no effects on fertility in animal studies.

4.7. Effects on ability to drive and use machines

Mimpara may have major influence on the ability to drive and use machines, since dizziness and seizures have been reported by patients taking this medicinal product (see section 4.4).

4.8. Undesirable effects

Summary of the safety profile

Secondary hyperparathyroidism, parathyroid carcinoma and primary hyperparathyroidism

Based on available data from patients receiving cinacalcet in placebo-controlled studies and single-arm studies the most commonly reported adverse reactions were nausea and vomiting. Nausea and vomiting 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 nausea and vomiting.

Tabulated list of adverse reactions

Adverse reactions, considered at least possibly attributable to cinacalcet treatment in the placebo-controlled studies and single-arm studies based on best-evidence assessment of causality 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).

Incidence of adverse reactions from controlled clinical studies and post-marketing experience are:

MedDRA system organ class

Frequency

Adverse reaction

Immune system disorders

Common*

Hypersensitivity reactions

Metabolism and nutrition disorders

Common

Anorexia

Decreased appetite

Nervous system disorders

Common

Seizures†

Dizziness

Paraesthesia

Headache

Cardiac disorders

Not known*

Worsening heart failure†

QT prolongation and ventricular arrhythmia secondary to hypocalcaemia†

Vascular disorders

Common

Hypotension

Respiratory, thoracic and mediastinal disorders

Common

Upper respiratory infection

Dyspnoea

Cough

Gastrointestinal disorders

Very common

Nausea

Vomiting

Common

Dyspepsia

Diarrhoea

Abdominal pain

Abdominal pain – upper

Constipation

Skin and subcutaneous tissue disorders

Common

Rash

Musculoskeletal and connective tissue disorders

Common

Myalgia

Muscle spasms

Back pain

General disorders and administration site conditions

Common

Asthenia

Investigations

Common

Hypocalcaemia†

Hyperkalaemia

Reduced testosterone levels†

† see section 4.4

*see section “Description of selected adverse reactions”

Description of selected adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions including angioedema and urticaria have been identified during post-marketing use of Mimpara. The frequencies of the individual preferred terms including angioedema and urticaria cannot be estimated from available data.

Hypotension and/or worsening heart failure

There have been reports of idiosyncratic cases of hypotension and/or worsening heart failure in cinacalcet-treated patients with impaired cardiac function in post-marketing safety surveillance, the frequencies of which cannot be estimated from available data.

QT prolongation and ventricular arrhythmia secondary to hypocalcaemia

QT prolongation and ventricular arrhythmia secondary to hypocalcaemia have been identified during post-marketing use of Mimpara, the frequencies of which cannot be estimated from available data (see section 4.4).

Paediatric population

The safety of Mimpara for the treatment of secondary HPT in paediatric patients with ESRD receiving dialysis was evaluated in two randomised controlled studies and one single-arm study (see section 5.1). Among all paediatric subjects exposed to cinacalcet in clinical studies a total of 19 subjects (24.1%; 64.5 per 100 subject years) had at least one adverse event of hypocalcaemia. A fatal outcome was reported in a paediatric clinical trial patient with severe hypocalcaemia (see section 4.4).

Mimpara should be used in paediatric patients only if the potential benefit justifies the potential risk.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Doses titrated up to 300 mg once daily have been administered to adult patients receiving dialysis without adverse outcome. A daily dose of 3.9 mg/kg was prescribed to a paediatric patient receiving dialysis in a clinical study with subsequent mild stomach ache, nausea and vomiting.

Overdose of Mimpara may lead to hypocalcaemia. In the event of overdose, patients should be monitored for signs and symptoms of hypocalcaemia, and treatment should be symptomatic and supportive. Since cinacalcet is highly protein-bound, haemodialysis is not an effective treatment for overdose.